NOVEL INHIBITORS OF PIKFYVE AND METHODS USING SAME

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is an international PCT application which claims priority to, and the benefit of, U.S. Provisional Application Ser. No. 63/253,407, filed on October 7, 2021, the contents of which are hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to novel inhibitors of the PIKFYVE, a phosphoinositide kinase, useful for the treatment of diseases or disorders characterized by dysregulation of phosphoinositide-mediated signal transduction pathways, including hyperproliferative diseases (such as MET or RAS dependent cancers, including prostate cancer), autoimmune diseases, Crohn’s disease, psoriasis, neurological diseases, diabetes, corneal fleck dystrophy, and viral infection (including HIV, Ebola, and coronavirus infections). The invention further relates to pharmaceutical compositions comprising PIKFYVE inhibitors and methods of treatment of such diseases and disorders.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins which play a variety of crucial roles in the regulation of a wide range of cellular processes. Such kinases include lipid kinases, serine-threonine protein kinases, tyrosine protein kinases, and other kinases. Inhibition of various protein kinases, especially selective inhibition, has become an important strategy in treating many diseases and disorders.

PIKFYVE (or PIKfyve) is a phosphoinositide kinase whose primary function is the phosphorylation of phosphoinositide-3 -phosphate (PtdIns3P or PI3P) to form phosphoinositide-3, 5 -diphosphate (PtdIns(3,5)P2 or PI(3,5P)2). PIKFYVE also phosphorylates phosphoinositide to form phosphoinositide-5-phosphate (PtdIns5P or PI5P). PIKFYVE includes an FYVE-finger domain, a zinc-finger domain, which is responsible for binding of the protein to PI3P. PI3P is a membrane bound lipid, and binding of PIKFYVE to PI3P can result in insertion of the kinase into cellular membranes, such as endosomes, vacuoles and other intracellular vesicles.

PI(3,5)P2 is one of seven phosphoinositides found in eukaryotic cell membranes, along with the more abundant PI3P, PI4P (phosphoinositide-4-phosphate), PI5P, PI(4,5)P2 (phosphoinositide-4, 5-diphosphate), and PIP3 (phosphoinositide-3, 4, 5 -triphosphate). Phosphoinositides are membrane-bound regulatory lipids, and they participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation, and many other cellular functions. Like other phosphoinositides, PI(3,5)P2 acts as a signaling molecule in various cellular signaling pathways, as well as being a precursor for the synthesis of PI5P.

PI(3,5)P2 is present at the lowest concentration of the phosphoinositides and after formation is it is rapidly dephosphorylated back to PI3P by the phosphatase Sac3. PIKFYVE is the only kinase which forms PI(3,5)P2 and unusually, PIKFYVE exists in a large multi-protein complex, the PAS complex, also comprising Sac3. The presence of a kinase and a phosphatase with opposite activities in the same complex suggests the critical importance of the concentration of PI(3,5)P2 to normal cell functioning. In addition to PIKFYVE and Sacl, the PAS complex also contains ArPIKFYVE, a regulatory protein which scaffolds the complex. Studies show that in most eukaryotic organisms, silencing or knockout of PIKFYVE function (or its equivalent) is lethal during embryonic development, further suggesting the critical importance of this protein and its product PI(3,5)P2.

PI(3,5)P2 helps regulate endosomal operations, such as membrane fission and fusion, that maintain endosomal homeostasis and support trafficking pathways throughout cells. Inhibition of PIKFYVE function in in-vitro cell studies shows the formation of numerous cytosolic vacuoles which grow larger over time, but such defects are shown to be reversible upon resupply of PI(3,5)P2 or functioning PIKFYVE. While homozygous knockout models of PIKFYVE are lethal, heterozygous knockout it not. This as well as other studies suggest that PIKFYVE activity, and consequently PI(3,5)P2 cellular concentration, is normally in excess of that required for normal cell functioning. Under the sustained activation of glutamate receptors, PIKFYVE has also been shown to facilitate the lysosomal degradation of type 1.2 voltage-dependent calcium channels in neurons. This helps protect neurons from excitotoxicity, and suggests a role in treating or preventing central nervous system dysfunction. In neuroendocrine cells, PIKFYVE also negatively regulates calcium-dependent exocytosis. In addition, PIKFYVE has also been shown to phosphorylate Transcription Factor EB (TFEB), which may be related to the activity of PIKFYVE inhibitors in treating multiple myeloma.

PIKFYVE and PI(3,5)P2 have been linked to the pathogenesis of several diseases and disorders. PIKFYVE mutations are found in 8 out of 10 families with Francois-Neetens corneal fleck dystrophy. Interference with PIKFYVE function is associated with impaired glucose uptake. Studies in mice show that selective PIKFYVE disruption in skeletal muscle cells results in systemic insulin resistance, glucose intolerance, hyperinsulinemia and increased adiposity, all of which are signs of prediabetes in humans. This is further supported by studies showing that acute insulin treatment results in increases in PI(3,5)P2 concentration in adipocytes, and this promotes increased GLUT4 translocation and surface expression, increasing glucose transport into cells. In various other cell and animal models, PI(3,5)P2 has been shown to be elevated by hyperosmotic shock in adipocytes, mitogenic signals (such as IL-2 and UV light in lymphocytes), protein kinase C activation in platelets, and epidermal growth factor stimulation of COS cells.

Several small molecule inhibitors of PIKFYVE have recently been reported, including Apilimod. Apilimod, studied as an autoimmune disease treatment (Crohn’s disease, rheumatoid arthritis) was originally identified as an inhibitor of IL- 12 and IL-23 synthesis, but was later found to also have potent PIKFYVE inhibitory activity. It is suspected that Apilimod’ s activity may have been due to PIKFYVE inhibition rather than interreference with IL- 12 and IL-23. PIKFYVE inhibitors have also shown promise as cancer therapies, in particular, for the treatment of non-Hodgkin lymphoma, multiple myeloma, melanoma, liver cancer, and glioblastoma. PIKFYVE inhibition has also shown promise as a therapy for amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD), in particular ALS and FTD marked by repeat expansions of the C9ORF72 gene (C9FTD/ALS). PIKFYVE inhibition has also been suggested to be useful in the downstream inhibition of RANK signaling (receptor activator of nuclear factor kappa N), which plays an important role in bone remodeling and may be useful in treating bone resorption in multiple myeloma, prostate cancer and breast cancer patients.

Because of the critical role of intracellular vesicle trafficking in the life cycle of some eukaryotic viruses, PIKFYVE inhibitors also have been found effective in inhibiting viral infection. Enveloped viruses have a life cycle that begins with binding of a viral surface protein to a specific extracellular membrane protein on the target cell. For some viruses, such as HIV, receptor binding triggers fusion of the viral envelope with the cell membrane, resulting in deposition of the viral nucleoprotein complex into the cytoplasm. However, for other viruses, including Ebola, influenza A, vesicular stomatitis virus, Lassa fever virus, lymphocytic choriomeningitis virus, and coronaviruses (including MERS-CoV, SARS-CoV and SARS-CoV-2), receptor binding triggers endocytosis of the entire viral particle. The resulting endosome is transported within the cell until something triggers fusion of the viral envelope with the endosome membrane, resulting in deposition of the viral nucleoprotein complex into the cytoplasm. The triggering event can be acidification of the endosome or proteolysis of viral surface proteins.

Apilimod and other PIKFYVE inhibitors have been found to prevent infection by some of these enveloped viruses, either by interfering with endosome formation or by blocking endosome trafficking or otherwise preventing the triggering of endosome-viral envelope fusion.

There continues to be a need for new, selective inhibitors of PIKFYVE. The present disclosure provides novel, highly effective small-molecule inhibitors of PIKFYVE. SUMMARY OF THE INVENTION

Therefore, first aspect, the invention provides a compound of Formula I: in free or pharmaceutically acceptable salt form, wherein

(i) X is selected from -CH-, -CR3-, -S-, -O-, -N-, -NH-, and -NR3-;

(ii) Y is selected from -C- and -N-;

(iii) Z is selected from -CH-, -CR3-, -S-, -O-, -N-, -NH-, and -NR3-;

(iv) W is -CH-, -CR4-, or -N-;

(v) A is an optionally substituted heteroaryl (e.g., 5-membered heteroaryl) or heterocycloalkyl (e.g., 3- to 6-membered heterocycloalkyl);

(vi) B is halo, an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-6cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3 -to 6-membered heterocycloalkenyl, optionally substituted Ci-ealkyl, optionally substituted C2-6alkenyl (e.g., vinyl), - N(Ra)-R2, -0-R2, -(CO)-R2, -(CO)-O-R2, -(CO)-N(Ra)-R2, -O-(CO)-R2, -N(Ra)- (CO)-R2, -(CO)-N(Ra)-(CO)-R ₂ , N(Ra)-(CO)-N(Ra)-R2, optionally substituted - (Ci-ealkyl)-(3- to 6-membered heterocycloalkyl), optionally substituted -(Ci- 6alkyl)-(C3-6cycloalkyl), optionally substituted -(Ci-6alkyl)-N(Ra)-R2, optionally substituted -(Ci-6alkyl)-O-R2, optionally substituted -(Ci-6alkyl)-(CO)-N(Ra)-R2, optionally substituted -CH2-(3- to 6-membered heterocycloalkyl), optionally substituted -CH2-(C3-6cycloalkyl), -CH2-N(Ra)-R2, -CH2-O-R2, or -CH2-(CO)- N(Ra)-R2; optionally substituted -(CO)-(3- to 6-membered heterocycloalkyl), optionally substituted -(CO)-(C3-6cycloalkyl); optionally substituted -CH2-(6- to 12-membered bicyclic heterocycloalkyl), or optionally substituted -(CO)-(6- to 12-membered bicyclic heterocycloalkyl); (vii) Ri is an optionally substituted Ci-ealkyl, optionally substituted C3-6cycloalkyl, optionally substituted Ci-ealkoxy, optionally substituted 3- to 7-membered heterocycloalkyl, -C(O)-R2, -C(O)O-R ₂ , -OC(O)-R2, -C(O)N(Ra)-R2, -N(Ra)C(O)- R ₂ , -N(Ra)-R ₂ , or -O-R^

(viii) Ra is H, optionally substituted Ci-ealkyl, or optionally substituted Cs-ecycloalkyl; and

(ix) R ₂ is optionally substituted Ci-ealkyl, optionally substituted C3-6cycloalkyl, optionally substituted Ci-ealkoxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 3- to 7-membered heterocycloalkyl;

(x) R3 is H, optionally substituted Ci-ealkyl (e.g., methyl), optionally substituted Cs- ecycloalkyl, optionally substituted haloCi-ealkyl (e.g., CF3), or optionally substituted 3- to 6-membered heterocycloalkyl; and

(xi) R4 is halogen (e.g., fluoro), -OH, -NH ₂ , Ci-ealkyl (e.g., methyl), Cs-ecycloalkyl (e.g., isopropyl), haloCi-ealkyl (e.g., CF3), Ci-ealkoxy (e.g., methoxy), -NH(Ci- ealkyl) (e.g., methylamino), or -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino); provided that:

(a) when A is an optionally substituted pyrazole, said pyrazole is substituted by at least one optionally substituted aryl (e.g., phenyl) ring;

(b) when A is optionally substituted pyrazol-l-yl, X is not O when Y is - CH- and Z is -CH-;

(c) when B is pyrid-4-yl, Ri is morpholin-4-yl, X is -CH-, Y is -CH-, and Z is -S-, A is not 3-(3-methylphenyl)-5-hydroxy-pyrazol-l-yl, 3-(3- methoxyphenyl)-5-hydroxy-pyrazol-l-yl, or 3-(3-isopropoxyphenyl)- 5-hydroxy-pyrazol-l-yl; and

(d) when B is phenyl, Ri is N-cyclohexylamino, X is -O-, Y is -CH-, and Z is -CH-, A is not 3,5-diphenyl-pyrazol-l-yl, 3-methyl-5-phenyl- pyrazol-l-yl, 3-trifluoromethyl-5-phenyl-pyrazol-l-yl, or 3,5- dimethy 1-4-phenyl-pyrazol- 1 -yl. In a second aspect, the invention provides a pharmaceutical composition comprising the compound of Formula I, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

In a third aspect, the invention provides a method for the treatment or prophylaxis of a disease or disorder characterized by dysregulation of phosphoinositide-mediated signal transduction pathways or which may be ameliorated by modulating (e.g., inhibiting) PIKFYVE-dependent signaling pathways or by modulating (e.g., inhibiting) endosome formation or trafficking, comprising administering to a patient in need thereof an effective amount of the compound of Formula I, in free or pharmaceutically acceptable salt form.

DETAILED DESCRIPTION

In a first aspect, the invention provides a compound of Formula I: in free or pharmaceutically acceptable salt form, wherein

(i) X is selected from -CH-, -CR3-, -S-, -O-, -N-, -NH-, and -NR3-;

(ii) Y is selected from -C- and -N-;

(iii) Z is selected from -CH-, -CR3-, -S-, -O-, -N-, -NH-, and -NR3-;

(iv) W is -CH-, -CR4-, or -N-;

(v) A is an optionally substituted heteroaryl (e.g., 5-membered heteroaryl) or heterocycloalkyl (e.g., 3- to 6-membered heterocycloalkyl);

(vi) B is halo, an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-6cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3 -to 6-membered heterocycloalkenyl, optionally substituted Ci-ealkyl, optionally substituted C2-6alkenyl (e.g., vinyl), - N(Ra)-R2, or -0-R2, -(CO)-R2, -(CO)-O-R2, -(CO)-N(Ra)-R2, -O-(CO)-R2, -N(Ra)- (CO)-R2, -(CO)-N(Ra)-(CO)-R ₂ , N(Ra)-(CO)-N(Ra)-R2, optionally substituted - (Ci-ealkyl)-(3- to 6-membered heterocycloalkyl), optionally substituted -(Ci- 6alkyl)-(C3-6cycloalkyl), optionally substituted -(Ci-6alkyl)-N(Ra)-R2, optionally substituted -(Ci-6alkyl)-O-R2, optionally substituted -(Ci-6alkyl)-(CO)-N(Ra)-R2, optionally substituted -CH ₂ -(3- to 6-membered heterocycloalkyl), optionally substituted -CH ₂ -(C ₃ -6cycloalkyl), -CH ₂ -N(Ra)-R2, -CH2-O-R2, -CH ₂ -(CO)-N(Ra)- R2; optionally substituted -(CO)-(3- to 6-membered heterocycloalkyl), optionally substituted -(CO)-(C ₃ -6cycloalkyl); optionally substituted -CH2-(6- to 12- membered bicyclic heterocycloalkyl), or optionally substituted -(CO)-(6- to 12- membered bicyclic heterocycloalkyl);

(vii) Ri is an optionally substituted Ci-ealkyl, optionally substituted C ₃ -6cycloalkyl, optionally substituted Ci-ealkoxy, optionally substituted 3- to 7-membered heterocycloalkyl, -C(O)-R2, -C(O)O-R ₂ , -OC(O)-R2, -C(O)N(Ra)-R2, -N(Ra)C(O)- R2, -N(Ra)-R2, or -O-R2;

(viii) Ra is H, optionally substituted Ci-ealkyl, or optionally substituted C ₃ -6cycloalkyl; and

(ix) R2 is optionally substituted Ci-ealkyl, optionally substituted C ₃ -6cycloalkyl, optionally substituted Ci-ealkoxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 3- to 7-membered heterocycloalkyl;

(x) R ₃ is H, optionally substituted Ci-ealkyl (e.g., methyl), optionally substituted C ₃ - ecycloalkyl, optionally substituted haloCi-ealkyl (e.g., CF ₃ ), or optionally substituted 3- to 6-membered heterocycloalkyl; and

(xi) R4 is halogen (e.g., fluoro), -OH, -NH2, Ci-ealkyl (e.g., methyl), C ₃ -6cycloalkyl (e.g., isopropyl), haloCi-ealkyl (e.g., CF ₃ ), Ci-ealkoxy (e.g., methoxy), -NH(Ci- ealkyl) (e.g., methylamino), or -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino); provided that:

(a) when A is an optionally substituted pyrazole, said pyrazole is substituted by at least one optionally substituted aryl (e.g., phenyl) ring; (b) when A is optionally substituted pyrazol-l-yl, X is not O when Y is - CH- and Z is -CH-;

(c) when B is pyrid-4-yl, Ri is morpholin-4-yl, X is -CH-, Y is -CH-, and Z is -S-, A is not 3-(3-methylphenyl)-5-hydroxy-pyrazol-l-yl, 3-(3- methoxyphenyl)-5-hydroxy-pyrazol-l-yl, or 3-(3-isopropoxyphenyl)- 5-hydroxy-pyrazol-l-yl; and

(d) when B is phenyl, Ri is N-cyclohexylamino, X is -O-, Y is -CH-, and Z is -CH-, A is not 3,5-diphenyl-pyrazol-l-yl, 3-methyl-5-phenyl- pyrazol-l-yl, 3-trifluoromethyl-5-phenyl-pyrazol-l-yl, or 3,5- dimethy 1-4-phenyl-pyrazol- 1 -yl.

In particular embodiments, the invention provides a compound according to the following Formulas:

1.1 The compound of Formula I, wherein X is -S-, Z is -CH- or -CR3-, and Y is -C-;

1.2 The compound of Formula I, wherein X is -CH- or -CR3-, Z is -S-, and Y is -C-;

1.3 The compound of Formula I, wherein X is -O-, Z is -CH- or -CR3-, and Y is -C-;

1.4 The compound of Formula I, wherein X is -CH- or -CR3-, Z is -O-, and Y is -C-;

1.5 The compound of Formula I, wherein X is -NH-, Z is -CH- or -CR3-, and

Y is -C-;

1.6 The compound of Formula I, wherein X is -CH- or -CR3-, Z is -NH-, and

Y is -C-;

1.7 The compound of Formula I, wherein X is -NR3-, Z is -CH- or -CR3-, and

Y is -C-;

1.8 The compound of Formula I, wherein X is -CH- or -CR3-, Z is -NR3-, and

Y is -C-;

1.9 The compound of Formula I, wherein X and Z are -CH- or -CR3-, and Y is -N-; 1.10 The compound of Formula I, wherein X is -S-, Z is -N-, and Y is -C-;

1.11 The compound of Formula I, wherein X is -N-, Z is -S-, and Y is -C-;

1.12 The compound of Formula I, wherein X is -O-, Z is -N-, and Y is -C-;

1.13 The compound of Formula I, wherein X is -N-, Z is -O-, and Y is -C-;

1.14 The compound of Formula I, wherein X is -NH-, Z is -N-, and Y is -C-;

1.15 The compound of Formula I, wherein X is -N-, Z is -NH-, and Y is -C-;

1.16 The compound of Formula I, wherein X is -NR3-, Z is -N-, and Y is -C-;

1.17 The compound of Formula I, wherein X is -N-, Z is -NR3-, and Y is -C-;

1.18 The compound of Formula I, wherein X is -N-, Z is -CH- or -CR3-, and Y is -N-;

1.19 The compound of Formula I, wherein X is -CH- or -CR3-, Z is -N-, and Y is -N-;

1.20 The compound of Formula I, wherein X and Z are -N-, and Y is -N-;

1.21 The compound of Formula I or any of 1.1-1.20, wherein X or Z is -CH-;

1.22 The compound of F ormula I, or any of 1.1 - 1.21 , wherein R3 is H;

1.23 The compound of Formula I, or any of 1.1-1.21, wherein R3 is Ci-ealkyl (e.g., methyl);

1.24 The compound of Formula I or any of 1.1-1.23, wherein W is -CH- or - CR4-, optionally wherein Ri is fluoro, -OH, -NH2, methyl, CF3, methoxy, methylamino, or dimethylamino;

1.25 The compound of Formula I or any of 1.1-1.23, wherein W is -N-;

1.26 The compound of Formula I, wherein the compound of Formula I has a core structure selected from any of the following:

wherein A, B and Ri are as defined for the Compound of Formula I above; The compound of Formula I, wherein the compound of Formula I has a core structure selected from any of the following:

wherein A, B and Ri are as defined for the Compound of Formula I above; The compound of Formula I, wherein the compound of Formula I has a core structure selected from any of the following:

wherein A, B and Ri are as defined for the Compound of Formula I above; The compound of Formula I, or any of 1.1-1.28, wherein A is an optionally substituted heteroaryl; The compound of Formula 1.29, wherein A is a heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, triazine, indole, benzimidazole, benzoxazole, benzothiazole, indazole, benzisoxazole, and benzisothiazole; The compound of Formula 1.29, wherein A is a 5-membered heteroaryl, e.g., selected from thiophene, furan, pyrrole, oxazole, imidazole, thiazole, pyrazole, isoxazole, isothiazole, triazole (e.g., 1,2, 3 -triazole, or 1,2,4- triazole), oxadiazole (e.g., 1,2,3-oxadiazole, or 1,2,4-oxadiazole), thiadiazole (e.g., 1,2, 3 -thiadiazole, or 1,2,4-thiadiazole), and tetrazole (e.g., 1,2,3,4-tetrazole); The compound of Formula 1.31, wherein said heteroaryl is selected from oxazole, imidazole, thiazole, pyrazole, isoxazole and isothiazole; The compound of Formula 1.32, wherein said heteroaryl is pyrazole (e.g., 3 -substituted-pyrazol- 1 -yl, 1 -substituted-pyrazol-3 -y 1, 2-substituted- pyrazol-4-yl, 4-substituted-pyrazol-l-yl, or 5-substituted-pyrazol-3-yl); The compound of Formula 1.33, wherein said heteroaryl is 3 - substituted- pyrazol- 1-yl; The compound of Formula 1.32, wherein said heteroaryl is thiazole (e.g., 2-substituted-thiazol-4-yl, 2-substituted-thiazol-5-yl, 4-substituted-thiazol- 2-yl, or 5-substituted-thiazol-2-yl); The compound of Formula 1.32, wherein said heteroaryl is oxazole (e.g., 2-substituted-oxazol-4-yl, 2-substituted-oxazol-5-yl, 4-substituted-oxazol- 2-yl, or 5-substituted-oxazol-2-yl); The compound of Formula 1.32, wherein said heteroaryl is imidazole (e.g., 2-substituted-imidazol-4-yl, 4-substituted-imidazol-2-yl, 2- substituted-imidazol-5-yl, 5-substituted-imidazol-2-yl, 4-substituted- imidazol-l-yl, or l-substituted-imidazol-4-yl); Any of Compounds 1.23-1.37, wherein said heteroaryl is substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), carboxy (COOH), aryl, heteroaryl, C3-6cycloalkyl, and 3- to 10-membered heterocycloalkyl or heterocycloalkenyl (e.g., 3- to 6- membered heterocycloalkyl or heterocycloalkenyl, such as 1 -piperidinyl, 3- piperidinyl, 1,2,3,6-tetrahydropyridin-l-yl or l,2,3,6-tetrahydropyridin-3- yl), wherein said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl, is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy, ethoxy), haloCi-ealkyl (e.g., CF3), haloCi-ealkoxy (e.g., OCF3), carboxy (COOH), C3-6cycloalkyl, and 5- or 6-membered heterocycloalkyl, and wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), haloCi-ealkoxy (e.g., OCF3), and C3-6cycloalkyl;

1.39 The compound of Formula 1.38, wherein said heteroaryl is substituted with a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl, e.g., selected from piperidinyl (e.g., piperidin-l-yl, or piperidin-3-yl) and 1,2,3,6-tetrahydropyridine (e.g., 1,2,3,6-tetrahydropyridin-l-yl or 1, 2,3,6- tetrahydropyridin-3-yl);

1.40 The compound of Formula 1.38, wherein said heteroaryl is substituted with aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl or pyrimidinyl), wherein said aryl or heteroaryl is optionally substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy or ethoxy), haloCi -ealkoxy (e.g., OCF3), and haloCi-ealkyl (e.g., CF3);

1.41 The compound of Formula 1.38, wherein said heteroaryl is substituted with an optionally substituted heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl (e.g., indol-l-yl, or indol-3- yl), indazolyl (e.g., indazol- 1 -yl, or indazol-3-yl), benzimidazolyl (e.g., benzimidazol-l-yl, or benzimidazol-2-yl), benzisoxazolyl (e.g., benzisoxazol-3-yl), benzisothiazolyl (e.g., benzisothiazol-3-yl), benzoxazolyl (e.g., benzoxazol-2-yl), benzothiazolyl (e.g., benzothiazol-2- yi);

1.42 The compound of Formula 1.38, wherein said heteroaryl is substituted with unsubstituted phenyl or Ci-ealkyl (e.g., methyl or t-butyl);

1.43 The compound of Formula 1.38, wherein said heteroaryl is substituted with phenyl substituted with one, two or three groups independently selected from OH, CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy or ethoxy), haloCi-ealkoxy (e.g., OCF3), haloCi-ealkyl (e.g., CF3), C3-6cycloalkyl, and 5- or 6-membered heterocycloalkyl, and wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), haloCi- ealkoxy (e.g., OCF3), and C3-6cycloalkyl;

1.44 The compound Formula 1.43, wherein said heteroaryl is 3-substituted- pyrazol-l-yl, and said substituent is phenyl substituted with one, two or three groups independently selected from CN, Ci-ealkyl (e.g., methyl or t- butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy or ethoxy), haloCi-ealkoxy (e.g., OCF3), haloCi-ealkyl (e.g., CF3), C3-6cycloalkyl, and 5- or 6-membered heterocycloalkyl, and wherein said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), haloCi-ealkoxy (e.g., OCF3), and C3-6cycloalkyl;

1.45 The compound Formula 1.43, wherein said heteroaryl is 3-substituted- pyrazol-l-yl, and said substituent is phenyl substituted with one group selected from CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy or ethoxy), haloCi-ealkoxy (e.g., OCF3), and haloCi-ealkyl (e.g., CF3), wherein said alkyl or alkoxy is optionally substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), and Ci-ealkoxy (e.g., methoxy);

1.46 The compound of Formula 1.45, wherein said phenyl is meta-substituted;

1.47 The compound of Formula 1.45 or 1.46, wherein said phenyl is substituted with one group selected from methyl, bromo, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, hydroxymethyl, methoxymethyl, 1- hydroxy ethyl, and 1 -methoxy ethyl;

1.48 The compound Formula 1.43, wherein said heteroaryl is 2-substituted- thiazol-4-yl, 2-substituted imidazole-4-yl, 2-substituted oxazol-4-yl, or 4- substituted imidazole-2-yl, and said substituent is phenyl substituted with one group selected from CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy or ethoxy), haloCi -ealkoxy (e.g., OCF3), and haloCi-ealkyl (e.g., CF3), wherein said alkyl or alkoxy is optionally substituted with one or more groups selected from OH, CN, Ci- ealkyl (e.g., methyl), and Ci-ealkoxy (e.g., methoxy);

1.49 The compound of Formula 1.48, wherein said phenyl is meta-substituted;

1.50 The compound of Formula 1.48 or 1.49, wherein said phenyl is substituted with one group selected from methyl, bromo, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, hydroxymethyl, methoxymethyl, 1- hydroxy ethyl, and 1 -methoxy ethyl;

1.51 The compound of Formula 1.50, wherein said phenyl is substituted with methyl;

1.52 The compound of any of Formulas 1.37-1.47, wherein said heteroaryl is an imidazolyl, and in addition to being substituted with said heterocycloalkyl, heterocycloalkenyl, aryl (e.g., phenyl) or heteroaryl, said imidazolyl is also N-substituted with a Ci-ealkyl (e.g., methyl);

1.53 The compound of Formula 1.29, wherein substituent A is 3-(3- methoxyphenyl)-pyrazol-l-yl, 3-(3-tolyl)-pyrazol-l-yl, 3-(3- bromophenyl)-pyrazol- 1 -y 1, 3 -(3 -ethoxyphenyl)-pyrazol- 1 -y 1 3 -(3 - trifluoromethylphenyl)-pyrazol-l-yl, or 3-(3-trifluoromethoxyphenyl)- pyrazol-l-yl;

1.54 The compound of Formula 1.29, wherein substituent A is 3-(3- hydroxymethy lphenyl)-pyrazol- 1 -y 1, 3 -(3 -( 1 -hydroxy ethyl)-pheny 1)- pyrazol-l-yl, or 3-(3-methoxymethylphenyl)-pyrazol-l-yl;

1.55 The compound of Formula 1.29, wherein substituent A is 2-(3-tolyl)- thiazol-4-yl, 2-(3-tolyl)-imidazol-4-yl, 2-(3-tolyl)-oxazol-4-yl, 4-(3-tolyl)- imidazol-2-yl, or 4-(3 -tolyl)- l-methyl-imidazol-2-yl;

1.56 The compound of Formula I or any of 1.1-1.55, wherein A is an optionally substituted heterocycloalkyl;

1.57 The compound of Formula 1.56, wherein said heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydropyran, morpholine, piperidine, and piperazine; The compound of Formula 1.56, wherein said heterocycloalkyl is pyrrolidine; Any of Compounds 1.56-1.59, wherein said heterocycloalkyl is substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), carboxy (COOH), aryl, heteroaryl, C3-6cycloalkyl, and 3- to 6- membered heterocycloalkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), carboxy (COOH), C3-6cycloalkyl, and 5- or 6- membered heterocycloalkyl; The compound of Formula 1.59, wherein said heterocycloalkyl is substituted with aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl or pyrimidinyl), wherein said aryl or heteroaryl is optionally substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl or t- butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), and haloCi- ealkyl (e.g., CF3); The compound of Formula 1.60, wherein said heterocycloalkyl is substituted with unsubstituted phenyl; The compound of Formula 1.60, wherein said heterocycloalkyl is substituted with phenyl substituted with one, two or three groups independently selected from CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), and haloCi-ealkyl (e.g., CF3) The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted aryl or optionally substituted heteroaryl; The compound of Formula 1.63, wherein B is selected from halo (e.g., bromo), phenyl, pyridine, pyrimidine, pyridazine, pyrazine, triazine, tetrazine, thiophene, furan, pyrrole, oxazole, imidazole, thiazole, pyrazole, isoxazole, isothiazole, indole, indazole, benzimidazole, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole, each optionally an N- oxide thereof (e.g., pyridyl-N-oxide), and each optionally substituted;

1.65 The compound of Formula 1.63, wherein B is selected from phenyl, pyridine, pyrimidine, pyridazine, and pyrazine, each optionally substituted;

1.66 The compound of Formula 1.63, wherein B is selected from pyridine and pyrimidine, each optionally substituted;

1.67 The compound of Formula 1.63, wherein B is optionally substituted pyrazole (e.g., 1 -substituted 4-pyrazolyl);

1.68 The compound of Formula 1.66, wherein B is pyridine, e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, or 4-pyridinyl-N-oxide, each optionally substituted;

1.69 The compound of Formula 1.63, wherein B is pyrazole substituted with Ci-ealkyl, e.g., l-methyl-4-pyrazolyl;

1.70 The compound of Formula I, or any of 1.1-1.62, wherein B is optionally substituted heterocycloalkyl or heterocycloalkenyl;

1.71 The compound of Formula 1.63, wherein B is selected from morpholine, piperidine, 1,2,3,6-tetrahydropyridinyl, piperazine, tetrahydropyran, pyrrolidine, tetrahydrofuran, oxetane, azetidine, oxirane, and aziridine, e.g., each optionally substituted with Ci-ealkyl (e.g., N- substituted, e.g., N- methyl), Ci-ealkoxy (e.g., methoxy), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), or -SCh-Ci-ealkyl (e.g., methylsulfonyl);

1.72 The compound of Formula 1.71, wherein B is selected from 3-methoxy-3- oxetanyl, 4-(dimethylamino)-l-piperidinyl, 3 -(dimethylamino)- 1- pyrrolidinyl, 4-methyl-l-piperazinyl, and 4-(methylsulfonyl)-l- piperazinyl;

1.73 The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted -CH2-(3- to 6-membered heterocycloalkyl);

1.74 The compound of Formula 1.73, wherein B is -CH2-(3- to 6-membered heterocycloalkyl) and said heterocycloalkyl is selected from morpholine, piperidine, piperazine, tetrahydropyran, pyrrolidine, tetrahydrofuran, oxetane, azetidine, oxirane, and aziridine, each optionally substituted, for example, by halo (e.g., F), Ci-ealkyl (e.g., methyl, isopropyl), C3- ecycloalkyl (e.g., cyclopropyl, cyclobutyl), -NH(Ci-ealkyl) (e.g., N- methylamino, N-methylcyclopropylamino), -NH(C3-6cycloalkyl), (e.g., N- cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO2- Ci-ealkyl (e.g., methylsulfonyl), hydroxy(Ci-ealkyl) (e.g., 2-hydroxy-2- propyl), -N(Ci-6alkyl)(SO2-Ci-6alkyl) (e.g., N-methyl-N- (methylsulfonyl)amino), -N(Ci-6alkyl)(CO-Ci-6alkyl) (e.g., N-methyl-N- (acetyl)amino), or heterocycloalkyl (e.g., 4-morpholinyl, 1 -pyrrolidinyl, 1- azetidinyl, l,3-dioxolan-2-yl, 4-tetrahydropyranyl), or a combination thereof;

1.75 The compound of Formula 1.74, wherein B is selected from -CH2- (morpholine), -CH2-(piperidine), -CH2-(piperazine), and -CH2- (pyrrolidine), each optionally substituted, for example, by halo (e.g., F), Ci-ealkyl (e.g., methyl, isopropyl), C3-6cycloalkyl (e.g., cyclopropyl, cyclobutyl), -NH(Ci -ealkyl) (e.g., N-methylamino, N- methylcyclopropylamino), -NH(C3-ecycloalkyl), (e.g., N- cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO2- Ci-ealkyl (e.g., methylsulfonyl), hydroxy(Ci-ealkyl) (e.g., 2-hydroxy-2- propyl), -N(Ci-6alkyl)(SO2-Ci-ealkyl) (e.g., N-methyl-N- (methylsulfonyl)amino), -N(Ci-6alkyl)(CO-Ci-ealkyl) (e.g., N-methyl-N-( acetyl)amino), or heterocycloalkyl (e.g., 4-morpholinyl, 1 -pyrrolidinyl, 1- azetidinyl, l,3-dioxolan-2-yl, 4-tetrahydropyranyl), or a combination thereof;

1.76 The compound of Formula 1.74 or 1.75, wherein the -CH2- of the CH2-(3- to 6-membered heterocycloalkyl) is substituted by a methyl group, i.e., it is a -CH(CH3)-(3- to 6-membered heterocycloalkyl) (e.g., CH(CH3)- (piperidine), CH(CH3)-(piperazine), or CH(CH3)-(pyrrolidine), each optionally further substituted as set forth above;

1.77 The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted -(CO)-(3- to 6-membered heterocycloalkyl); The compound of Formula 1.77, wherein B is -(CO)-(3- to 6-membered heterocycloalkyl) and said heterocycloalkyl is selected from morpholine, piperidine, piperazine, tetrahydropyran, pyrrolidine, tetrahydrofuran, oxetane, azetidine, oxirane, and aziridine, each optionally substituted, for example, by halo (e.g., F), Ci-ealkyl (e.g., methyl, isopropyl), C3- ecycloalkyl (e.g., cyclopropyl, cyclobutyl), -NH(Ci-ealkyl) (e.g., N- methylamino, N-methylcyclopropylamino), -NH(C3-6cycloalkyl), (e.g., N- cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO2- Ci-ealkyl (e.g., methylsulfonyl), hydroxy(Ci-ealkyl) (e.g., 2-hydroxy-2- propyl), -N(Ci-6alkyl)(SO2-Ci-6alkyl) (e.g., N-methyl-N- (methylsulfonyl)amino), -N(Ci-6alkyl)(CO-Ci-6alkyl) (e.g., N-methyl-N-( acetyl)amino), or heterocycloalkyl (e.g., 4-morpholinyl, 1 -pyrrolidinyl, 1- azetidinyl, l,3-dioxolan-2-yl, 4-tetrahydropyranyl), or a combination thereof; The compound of Formula 1.78, wherein B is selected from -(CO)- (morpholine), -(CO)-(piperidine), -(CO)-(piperazine), and -(CO)- (pyrrolidine), each optionally substituted, for example, by halo (e.g., F), Ci-ealkyl (e.g., methyl, isopropyl), C3-6cycloalkyl (e.g., cyclopropyl, cyclobutyl), -NH(Ci -ealkyl) (e.g., N-methylamino, N- methylcyclopropylamino), -NH(C3-ecycloalkyl), (e.g., N- cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO2- Ci-ealkyl (e.g., methylsulfonyl), hydroxy(Ci-ealkyl) (e.g., 2-hydroxy-2- propyl), -N(Ci-6alkyl)(SO2-Ci-ealkyl) (e.g., N-methyl-N- (methylsulfonyl)amino), -N(Ci-6alkyl)(CO-Ci-ealkyl) (e.g., N-methyl-N-( acetyl)amino), or heterocycloalkyl (e.g., 4-morpholinyl, 1 -pyrrolidinyl, 1- azetidinyl, l,3-dioxolan-2-yl, 4-tetrahydropyranyl), or a combination thereof; The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted Ci-ealkyl (e.g., wherein B is methyl, ethyl, propyl, isopropyl n- butyl, s-butyl, or t-butyl, optionally further substituted by methyl, ethyl, etc.), for example, substituted by OH, or Ci-ealkoxy (e.g., methoxy); The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted C3-6cycloalkyl (e.g., wherein B is cyclopropyl, or cyclobutyl), for example, substituted by OH, or Ci-ealkoxy (e.g., methoxy); The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted -CH2-(6- to 12-membered bicyclic heterocycloalkyl); The compound of F ormula I, or any of 1.1 - 1.62, wherein B is optionally substituted -(CO)-(6- to 12-membered bicyclic heterocycloalkyl); The compound of Formula 1.82 or 1.83, wherein said bicyclic heterocycloalkyl is a bridged heterocycloalkyl, for example, selected from: The compound of Formula 1.82 or 1.83, wherein said bicyclic heterocycloalkyl is a spiro heterocycloalkyl, for example, selected from: The compound of Formula 1.82 or 1.83, wherein said bicyclic heterocycloalkyl is a fused heterocycloalkyl, for example, selected from:

1.87 The compound of Formula 1.84, 1.85, or 1.86, wherein the ring -NH- is substituted by a Ci-ealkyl (e.g., methyl) and/or wherein a ring carbon is substituted by a -N(Ci-6alkyl)(Ci-ealkyl) (e.g., -NMe2);

1.88 The compound of F ormula I, or any of Compounds 1.1-1.87, wherein substituent B is substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl, isopropyl, 2-hydroxy-2-propyl), halogen (e.g., F), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), carboxy (COOH), -NH(Ci -ealkyl) (e.g., N-methylamino, N-methylcyclopropylamino), - NH(C3-6cycloalkyl) (e.g., N-cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO-Ci-ealkyl(e.g., methylsulfonyl), -SO2-Ci-ealkyl, -NH-SO2-(Ci-ealkyl), -N(Ci-6alkyl)-SO2-(Ci-ealkyl) (e.g., N-methyl-N- (methylsulfonyl)amino), -NH-C(O)-(Ci-ealkyl) (e.g., N-acetylamino), - N(Ci-ealkyl)-C(O)-(Ci-ealkyl) (e.g., N-methyl-N-(acetyl)amino), aryl, heteroaryl, C3-ecycloalkyl (e.g., cyclopropyl, cyclobutyl), and 3- to 6- membered heterocycloalkyl (e.g., 4-morpholinyl, 1 -pyrrolidinyl, 1- azetidinyl, l,3-dioxolan-2-yl, 4-tetrahydropyranyl), or a combination thereof, wherein said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is each optionally independently substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl or t-butyl), halogen (e.g., F or Br), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), carboxy (COOH), C3-6cycloalkyl, and 5- or 6-membered heterocycloalkyl; The compound of Formula 1.88, wherein substituent B is substituted with one or two groups selected from halogen (e.g., F), Ci-ealkyl (e.g., methyl, isopropyl, 2-hydroxy-2-propyl), C3-6cycloalkyl (e.g., cyclopropyl, cyclobutyl), -NH(Ci -ealkyl) (e.g., N-methylamino, N- methylcyclopropylamino), -NH(C3-ecycloalkyl) (e.g., N- cyclopropylamino), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., dimethylamino), -SO- Ci-ealkyl (e.g., methylsulfonyl), -SCh-Ci-ealkyl, -NH-SO2-(Ci-ealkyl), - N(Ci-ealkyl)-SO2-(Ci-ealkyl) (e.g., N-methyl-N-(methylsulfonyl)amino), - NH-C(O)-(Ci-ealkyl), -N(Ci-6alkyl)-C(O)-(Ci- ₆ alkyl) (e.g., N-methyl-N- acetylamino), and 3- to 6-membered heterocycloalkyl (e.g., 4- morpholinyl, 1 -pyrrolidinyl, 1 -azetidinyl, l,3-dioxolan-2-yl, 4- tetrahydropyranyl), wherein said alkyl is optionally independently substituted with one or more groups selected from OH and halogen; The compound of Formula 1.89, wherein each of said Ci-ealkyl is methyl or ethyl; The compound of F ormula I, or any one of F ormulas 1.1-1.90, wherein group B is -CH2-(piperidine), -CH2-(piperazine), -CH2-(pyrrolidine), - CH2-(azetidine), -(CO)-(piperidine), -(CO)-(piperazine), or -(CO)- (pyrrolidine), substituted by one or two groups selected from the group consisting of fluoro, Ci-ealkyl (e.g., methyl), -N(Ci-6alkyl)(Ci-ealkyl) (e.g., -NMe2), -SO2-Ci-ealkyl (e.g., -SCh-Me), -N(Ci-6alkyl)-SO2-(Ci-6alkyl) (e.g., -N(Me)-SO ₂ -Me), -N(Ci-6alkyl)-C(O)-(Ci- ₆ alkyl) (e.g., -N(Me)- C(O)-Me), azetidinyl (e.g.,l-azetidinyl), pyrrolidinyl (e.g., 1 -pyrrolidinyl), and Ci-ealkyl substituted by OH (e.g., -C(Me)2OH), or wherein group B is unsubstituted -CH2-(morpholine); The compound of Formula 1.91, wherein said group B is substituted by a single one of said groups; The compound of Formula 1.91, said group B is substituted by one fluoro and one group selected from -N(Ci-6alkyl)(Ci-6alkyl) (e.g., -NMe2), azetidinyl (e.g.,l-azetidinyl), and pyrrolidinyl (e.g., 1-pyrrolidinyl); The compound of any of Formulas 1.91-1.93, wherein the -CH2- of the CH2-(3- to 6-membered heterocycloalkyl) is substituted by a methyl group, i.e., it is a -CH(CH3)-(piperidine), CH(CH3)-(piperazine), or CH(CH3)-(pyrrolidine), each optionally further substituted as set forth above; The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of: The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of:

The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of: The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of: The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of:

The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of: The compound of F ormula I, or any of 1.1 - 1.94, wherein group B is selected from the group consisting of: The compound of F ormula I, or any of Compounds 1.1-1.101, wherein substituent B is unsubstituted; The compound of F ormula I, or any of Compounds 1.1 - 1.102, wherein Ri is Ci-ealkyl, C3-6cycloalkyl, or Ci-ealkoxy, each substituted with an optionally substituted 3- to 7-membered heterocycloalkyl; The compound of F ormula I, or any of Compounds 1.1 - 1.102, wherein Ri is -C(O)-R ₂ , -C(O)O-R2, -OC(O)-R2, -C(O)N(Ra)-R2, -N(Ra)C(O)-R2, - N(Ra)-R2, or -O-R2; and wherein R2 is an optionally substituted 3- to 7- membered heterocycloalkyl;

1.105 The compound of F ormula I, or any of Compounds 1.1 - 1.102, wherein Ri is an optionally substituted 3- to 7-membered heterocycloalkyl;

1.106 The compound of any of F ormulas 1.103 -1.105, wherein said heterocycloalkyl is selected from aziridine, azetidine, oxirane, oxetane, pyrrolidine (e.g., 3,3-difluoropyrrolidin-l-yl), pyrrolidinone (e.g., 1- pyrrolidin-3-one), tetrahydrofuran, tetrahydropyran (e.g., tetrahydropyran- 4-yl), dihydropyran (e.g., 3,6-dihydropyran-4-yl), morpholine, piperidine, piperazine, and oxa-azaspiro[3.3]heptane (e.g., 2-oxa-6- azaspiro[3.3]heptan-6-yl), l,4-oxazepan-4-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, and 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, wherein each said heterocycloalkyl is optionally substituted;

1.107 The compound of Formula 1.106, wherein said heterocycloalkyl is optionally substituted morpholine (e.g., 2-methylmorpholin-4-yl, or 3- methylmorpholin-4-yl, or morpholin-4-yl (i.e., N-morpholinyl));

1.108 The compound of Formula 1.106, wherein said heterocycloalkyl is selected from (e.g., 3,3-difluoropyrrolidin-l-yl), l-pyrrolidin-3-one, and 2- oxa-6-azaspiro[3.3]heptan-6-yl;

1.109 The compound of any of Formulas 1.103-1.108, wherein said heterocycloalkyl is substituted with one or more groups selected from OH, CN, Ci-ealkyl (e.g., methyl), halogen (e.g., F), Ci-ealkoxy (e.g., methoxy), haloCi-ealkyl (e.g., CF3), and carboxy (COOH);

1.110 The compound of any of Formulas 1.103-1.108, wherein said heterocycloalkyl is unsubstituted (e.g., unsubstituted morpholin-4-yl);

1.111 The compound according to F ormula I or any of F ormulas 1.1-1.110, wherein the compound is selected from:

1.112 The compound according to F ormula I or any of F ormulas 1.1-1.110, wherein the compound is selected from the compounds listed in Table 1 below;

1.113 The compound according to F ormula I or any of F ormulas 1.1-1.110, wherein the compound is selected from the compounds listed in Table 2 below;

1.114 The compound according to F ormula I or any of F ormulas 1.1-1.113, wherein the compound is in free base form;

1.115 The compound according to F ormula I or any of F ormulas 1.1-1.113, wherein the compound is in the form of a pharmaceutically acceptable acid addition salt (e.g., hydrochloride);

1.116 The compound according to F ormula I or any of F ormulas 1.1-1.115, wherein the compound is an inhibitor of PIKFYVE (e.g., the compound having a Ki or IC50 of less than 10 pM, or less than 1 pM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 10 nM; and/or the compound provides >50% inhibition at a concentration of 1 //M, or > 75%, or > 85% or > 90% inhibition at said concentration; in free or pharmaceutically acceptable salt form.

In a second aspect, the invention provides a pharmaceutical composition comprising the compound of Formula I or any of 1.1-1.116 as described herein, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In some embodiments, the composition is a composition for oral administration, such as a tablet or capsule. In some embodiments, such an oral dosage form is an immediate-release composition, or a delayed release composition, or a sustained release composition. In other embodiments, the pharmaceutical composition is an injectable composition, such as for intravenous, intramuscular, intrathecal, intraabdominal, intraperitoneal, or subcutaneous injection. In other embodiments, the pharmaceutical composition may be an inhalational composition, including powdered and aerosol compositions (i.e., gas liquid/emulsions), such as an intranasal composition (e.g., spray) or an intrapulmonary composition (e.g., metered dose inhaler).

Pharmaceutical compositions include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for insomnia. For intramuscular injection, the dose is generally about one-half of the oral dose.

The unit oral dose may comprise from about 0.01 to about 1000 mg, preferably about 0.1 to about 100 mg of the compound, or 0.1 to 50 mg. The unit dose may be administered one or more times daily as needed to achieve the desired intended daily dosage.

The compounds of Formula I or any of 1.1-1.116 as described herein are highly effective inhibitors of PIKFYVE, preferably producing inhibition at nanomolar concentrations. In some embodiments the compounds are selective PIKFYVE inhibitors, e.g., the compounds have little or no inhibitory activity of other kinases, for example, other lipid kinases (e.g., other phosphoinositide kinases, such as phosphoinositide 3 -kinases, phosphoinositide 4-kinases, phosphoinositide 5-kinases, phosphoinositide-5-phosphate 4- kinases, and phosphatidyl inositol 4-phosphate 5-kinases), and protein kinases (e.g., tyrosine kinases and serine-threonine kinases). In some embodiments, the compounds have a Kd or IC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM, or greater than 50,000 nM against one or more of these other kinases, and/or the compound provides <50% inhibition at a concentration of 1 pM, or <25%, or <10%% or <5%, or < 1% inhibition at said concentration against one or more of these other kinases.

PIKFYVE inhibitors according to the invention are therefore useful for treatment and prophylaxis of diseases and disorders which may be ameliorated by modulating (e.g., inhibiting) PIKFYVE-dependent signaling pathways or by modulating (e.g., inhibiting) endosome formation or trafficking.

Therefore, in the third aspect, the invention provides a method for the treatment or prophylaxis of a disease or disorder characterized by dysregulation of phosphoinositide- mediated signal transduction pathways or which may be ameliorated by modulating (e.g., inhibiting) PIKFYVE-dependent signaling pathways or by modulating (e.g., inhibiting) endosome formation or trafficking, comprising administering to a patient in need thereof an effective amount of the compound of Formula I, or any of formulae 1.1-1.116 as described herein, in free or pharmaceutically acceptable salt form.

In some embodiments, the disease or disorder is a hyperproliferative disease (e.g., cancer, such as MET- or RAS- dependent cancers), an autoimmune disease (such as Crohn’s disease or rheumatoid arthritis), a neurological disease (such as amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD), and in particular C9FTD/ALS), diabetes or prediabetes, or Francois-Neetens corneal fleck dystrophy. In some embodiments, the disease or disorder is a cancer, such as a cancer having a genotype or phenotype indicative of PIKFYVE overactivity or Sacl underactivity. Cancer which may be amenable to treatment with a PIKFYVE inhibitor include, but are not limited to, nonHodgkin lymphoma, multiple myeloma, melanoma, liver cancer, glioblastoma, multiple myeloma, prostate cancer and breast cancer. In particular embodiments, the cancer is castration-resistant prostate cancer. In particular embodiments, the cancer having activated MET or RAS signaling pathways. In some embodiments the disease or disorder is infection by an enveloped virus, such as a virus which gains cellular entry by endocytosis. Such viruses include, but are not limited to, Ebola, influenza A, vesicular stomatitis virus, Lassa fever virus, lymphocytic choriomeningitis virus, and coronaviruses (including MERS-CoV, SARS-CoV and SARS-CoV-2). Thus, in another embodiment, the present disclosure provides a method for treating or preventing a viral infection by an enveloped virus, such as Ebola, influenza A, vesicular stomatitis virus, Lassa fever virus, lymphocytic choriomeningitis virus, and coronaviruses (including MERS-CoV, SARS- CoV and SARS-CoV-2).

The PIKFYVE inhibitor compounds described herein for the treatment or prophylaxis of a disease or disorder according to the foregoing methods may be used as a sole therapeutic agent or may be used in combination with one or more other therapeutic agents useful for the treatment of said diseases or disorders.

Such other agents include inhibitors of other protein kinases or other proteins associated with cancer development (for example, serine-threonine kinases, tyrosine kinases, growth factor receptors), traditional cytotoxic anticancer agents (e.g., DNA alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors, and cytotoxic antibiotics), and monoclonal antibody therapies (e.g., pembrolizumab, rituximab, trastuzumab, alemtuzumab, cetuximab, panitumumab, bevacizumab, and ipilimumab). Small molecule targeted therapies include inhibitors of such proteins as Bcr-Abl kinase, PDGFR, EGFR, VEGFR, RAF kinases, Ras-kinases, c-Kit, Src kinase, ephrin receptors, HER2/neu (ErbB2), proteasomes, estrogen receptors, JAK kinase, ALK, Bcl-2, PARP, PI3K, Braf, MEK, MAPK, CDK, HSP90, mTOR, inhibitors of checkpoint proteins (e.g., PD1, PDL1 and CTLA inhibitors), and modulators of the adaptive and innate immune system. Examples of these small molecule inhibitors include imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, lapatinib, nilotinib, bortezomib, tamoxifen, tofacitinib, crizotinib, obatoclax, navitoclax, gossypol, iniparib, olaparib, perifosine, apatinib, vemurafenib, dabrafenib, trametinib, CDK inhibitors, temsirolimus, everolimus, vemurafenib, and trametinib. Cytotoxic chemotherapeutic agents include cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, streptozotocin, busulfan, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin, procarbazine, altretamine, dacarbazine, temozolomide, 5- fluorouracil, 6-mercaptopurine, thioguanine, capecitabine, azacytidine, decitabine, nelarabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, pentostatin, hydroxycarbamide, methotrexate, pemetrexed, daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, mitoxantrone, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, topotecan, novobiocin, aclarubicin, pirarubicin, and aclarubicin. In some embodiments, particularly for the treatment of a cancer having activated MET or RAS signaling pathways, the compounds of the present disclosure are combined with compounds which inhibit MET activity or inhibit RAS activity, or inhibit upstream or downstream effectors in the MET or RAS signaling pathways, such as salirasib, tipifarnib, lonafarnib, crizotinib, cabozanitib, tivantinib, and tepotinib. In a particular embodiment, the cancer to eb treated is a prostate cancer (e.g., a castrationresistant prostate cancer and the compound of the present disclosure is combined with an anti-PD-1 antibody or a PD-1 inhibitor, such as pembrolizumab.

Such other agents also include small-molecule antiviral agents, such entry inhibitors, uncoating inhibitors, transcription or reverse transcription inhibitors, integrase inhibitors, translation inhibitors, protease inhibitors, assembly inhibitors, release inhibitors, and immune system stimulants (e.g., interferons). Examples of such agents include: abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol umfenovir, atazanavir, atripla, baloxavir marboxil, biktarvy, boceprovir, bulevirtide, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy, didanosine, docosanol, dolutegravir, doravirine, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, lamivudine, letermovir, lopinavir, lopinavir/ritonavir combination, loviride, maraviroc, methisazone, molnupiravir, moroxydine, nelfinavir, nevirapine, nexavir, nirmatrelvir, nirmatrelvir/ritonavir combination, nitazoxanide, norvir, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, ribavirin, rifampicin, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, taribavirin, telaprevir, telbivudine, tenofovir, tenofovir alafenamide, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada (emtricitabine/tenofovir combination), umifenovir, valaciclovir, valganciclovir, vicriviroc, vidarabine, zalcitabine, zanamivir, and zidovudine. In a preferred embodiment, especially when the treatment is directed to a coronavirus infection, the other agents may be selected from lopinavir, molnupiravir, nirmatrelvir, remdesivir, ritonavir, tenofovir, lopinavir/ritonavir combination, and nirmatrelvir/ritonavir combination.

Other agents that might be combined with the compounds of the present invention include: corticosteroids, methotrexate, thiopurine, chloroquine, hydroxychloroquine, sulfasalazine, leflunomide, certolizumab, infliximab, etanercept, abatacept, anakinra, rituximab, tocilizumab, cyclosporin, golimumab, adalimumab, insulin, exenatide, liraglutide, pramlintide, metformin, phenformin, buformin, rosiglitazone, pioglitazone, troglitazone, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, gilmepiride, gliclazide, glyclopyramide, gliquidone, meglitinide, repaglinide, nateglinide, miglitol, acarbose, voglibose, taspoglutide, lixisenatide, semaglutide, dulaglutide, vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, gemigliptin, dapagliflozin, canagliflozin, empagliflozin, and remogliflozin,

In another aspect, the invention provides the following:

(i) the compound of F ormula I or any of 1.1-1.116 as described herein, in free or pharmaceutically acceptable salt form, for use in any of the methods or in the treatment or prophylaxis of any disease or disorder as set forth herein,

(ii) a combination as described hereinbefore, comprising a compound of Formula I or any of 1.1-1.116 as described herein, in free or pharmaceutically acceptable salt form and a second therapeutic agent useful for the treatment or prophylaxis of any disease or disorder set forth herein;

(iii) use of the compound of F ormula I or any of 1.1 - 1.116, in free or pharmaceutically acceptable salt form, or the combination described herein, (in the manufacture of a medicament) for the treatment or prophylaxis of any disease or condition as set forth herein,

(iv) the compound of F ormula I or any of 1.1 - 1.116, in free or pharmaceutically acceptable salt form, the combination described herein or the pharmaceutical composition of the invention as hereinbefore described for use in the treatment or prophylaxis of any disease or condition as set forth herein.

If not otherwise specified or clear from context, the following terms herein have the following meanings:

(a) “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, in some embodiments, one to four carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro) or hydroxy. Exemplary “Ci-6 alkyl” groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /c/7-butyl, etc. Of course, other “Ci-6 alkyl” groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

(b) “Aryl” as used herein means any carbocyclic aromatic ring system, i.e., any aromatic ring system comprising only carbon atoms as ring atoms. This includes 6-membered monocyclic aryl ring systems and 9-membered or 10-membered fused bicyclic aryl ring systems, and larger fused ring systems, as long such ring systems comprise at least one 6-membered aromatic carbocyclic ring (i.e., a benzene ring) within the fused ring system, and as long as no ring-atoms are heteroatoms. Aryl includes phenyl and napthyl. (c) “Heteroaryl” as used herein means any cyclic heteroaromatic ring system, i.e., any aromatic ring system comprising at least one heteroatom (e.g., N, S, or O) ring atom. This includes 5-membered and 6-membered monocyclic heteroaryl ring systems and 9-membered or 10-membered fused bicyclic heteroaryl ring systems, and larger fused ring systems, as long such ring systems comprise at least one aromatic carbocyclic or aromatic heterocyclic ring within the fused ring system and at least one heteroatom (e.g., N, S or O) ring-atom within the fused ring system (either in an aromatic ring or non-aromatic ring). Heteroaryl therefore includes bicyclic fused ring system selected from aromatic-heteroaromatic, aromatic-heterocyclic, heteroaromatic-carbocyclic, heterocyclic-aromatic, and heteroaromatic-heteroaromatic, as well as larger fused ring systems comprising some combination of benzene, cycloalkane, heterocycloalkane and heteroaromatic rings. Exemplary heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3- triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-/>]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[l Jpyridinyl, benzo[/>]thiophenyl, 5, 6,7,8- tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianapthenyl, isothianapthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. It is understood that for heteroaryl systems in which the both ring carbon atoms and ring heteroatoms have open valencies, bonds can be formed to either such atom types (e.g., C-linked or N-linked). For example, where a pyrazolyl moiety is the group A, substituted at one atom to connect to the core of the compound of Formula I, and substituted at one or more other atoms with other substituent groups, either the core of the Compound of Formula I or any one or more other substituents may be atached to either a pyrazole ring nitrogen atom (N-linked) or a pyrazole ring carbon atom (C-linked).

(d) “Heterocycloalkyl” means any cyclic nonaromatic ring system comprising at least one heteroatom (e.g., N, S, or O) ring atom. This includes 3- to 12- membered monocyclic and fused bicyclic ring systems, and any larger multi-ring fused ring systems, as long such ring systems do not comprise any aromatic carbocyclic or aromatic heterocyclic ring. Exemplary heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl,

1.2-pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl,

1.2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1 ,2-tetrahydrodiazin-2-yl, 1,3- tetrahydrodiazin-l-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2- imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3- azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro- 2H-pyrido[l ,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3- azabicyclo[3.1.0]hexanyl, 2-azaspiro[4.4]nonanyl, 7-oxa-l-aza- spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro- IH-indolyl, etc. In general, the heterocycloalkyl group typically is atached to the main structure via a carbon atom or a nitrogen atom. Of course, other heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

(e) “Cycloalkyl” means a nonaromatic saturated or unsaturated free radical forming at least one ring consisting essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. The term “cycloalkyl” therefore includes cycloalkenyl groups, as further defined below. As such, cycloalkyl groups can be monocyclic or polycyclic. Individual rings of such polycyclic cycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1 ]octanyl, octahydro- pentalenyl, spiro[4.5]decanyl, cyclopropyl, adamantyl, substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc. Of course, other cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

It is understood that when describing the substituents attached in various positions to the core structure of Formula I, including substituents attached to substituents, in some cases, the substituent may be referred to using the name of the corresponding chemical compound, especially in the case of rings, whereas in some cases the same substituent may be referred to using the name of the corresponding chemical radical (e.g., having an “-yl” suffix), but these terms are interchangeable. For example, when referring to the substituent B, or a heteroaryl ring attached to a substituent A, the terms “pyridine” and “pyridyl” are equivalent, as are the terms “morpholine” and “morpholinyl.” The skilled artisan will recognize that such terms are used to denote attachment of, for example, pyridine or morpholine ring at the designated position, thus converting said ring to a pyridyl or morpholinyl substituent respectively. Absent an indication otherwise, such attachments may be made at any chemically permissible location of the attached ring.

Compounds of the Invention, e.g., the compound of Formula I or any of formulae 1.1- 1.116 as described herein, may exist in free or salt form, e.g., as acid addition salts (e.g., hydrochloride).

In this specification unless otherwise indicated, language such as “Compounds of the Invention” is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their pharmaceutically acceptable salts, are therefore also included.

The Compounds of the Invention include their enantiomers, diastereomers and racemates, as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of this invention may contain double bonds. Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond. In addition, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.

The Compounds of the present disclosure may comprise one or more chiral carbon atoms. The compounds thus exist in individual isomeric, e.g., enantiomeric or diaster eomeric form or as mixtures of individual forms, e.g., racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (Reconfiguration. The invention is to be understood as embracing both individual optically active isomers as well as mixtures (e.g., racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds of the Invention may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess (“e.e.”), preferably greater than 80% e.e., more preferably greater than 90% e.e., most preferably greater than 95% e.e. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like).

It is also intended that the Compounds of the Invention encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non- isotopic analogs. For example, the hydrogen atom at a certain position on the Compounds of the Invention may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but are not limited to, deuterium ( ² H), ¹³ C, ¹⁵ N, ¹⁸ O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., ¹²³ 1, ¹³¹ I, ¹²⁵ 1, ¹⁴ C, ¹⁸ F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the invention is the ⁿ C isotope. These radio isotopes are useful for radio-imaging and/or pharmacokinetic studies of the compounds of the invention.

Melting points are uncorrected and (dec) indicates decomposition. Temperatures are given in degrees Celsius (°C); unless otherwise stated, operations are carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 °C. Chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) is carried out on silica gel plates. NMR data is in the delta values of major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are given in Hz. For mass spectra (MS), the lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex, only diagnostic signals are reported.

The words "treatment" and "treating" are to be understood accordingly as embracing treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease. For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

The term “patient” includes human and non-human (i.e., animal) patients. In particular embodiments, the invention encompasses both human and nonhuman patients. In another embodiment, the invention encompasses non-human patients. In other embodiment, the term encompasses human patients.

The term “comprising” as used in this disclosure is intended to be open-ended and does not exclude additional, unrecited elements or method steps.

Compounds of the Invention, e.g., compounds of Formula I or any of formulas 1.1-1.116 as hereinbefore described, in free or pharmaceutically acceptable salt form, may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents.

Dosages employed in practicing the methods of present invention will of course vary depending, e.g., on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired. The compound may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g., for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 1000 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg or 300 mg, e.g., from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, 200 or 300 mg of the compound disclosed herein, together with a pharmaceutically acceptable diluent or carrier therefor.

The term “pharmaceutically acceptable diluent or carrier” is intended to mean diluents and carriers that are useful in pharmaceutical preparations, and that are free of substances that are allergenic, pyrogenic or pathogenic, and that are known to potentially cause or promote illness. Pharmaceutically acceptable diluents or carriers thus exclude bodily fluids such as example blood, urine, spinal fluid, saliva, and the like, as well as their constituent components such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well- known treatises on pharmaceutical formulations, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20 ^th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, including ranges, are approximations which are varied ( + ) or (-) by increments of 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about.” It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

Methods of Making Compounds of the Invention

The Compounds of the Invention and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and/or by methods similar thereto and/or by methods known in the chemical art. Such methods include, but not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds. Compounds of the present disclosure may be prepared according to the general procedures known in the art, including those found in the following references, which are incorporated herein by reference in their entireties: WO 2010/138589, WO 2012/104776, WO 2019/113523, WO 2001/083456, WO2013/076182, and U.S. Patent 7,750,556. As an example, compounds of the present disclosure having a thieno[3,2-d]pyrimidine core, can be prepared according to the synthetic scheme provided below, and as further shown in the Examples section below.

Terms and abbreviations:

DBU : 1 , 8-D iazabicy clo [5.4.0] undec-7- ene

DCM: Dichloromethane

DMF: Dimethylformamide

DMTMM: 4-(4, 6-Dimethoxy [ 1 , 3 , 5]triazin-2-yl)-4-methylmorpholinium chloride

EtOAc: Ethyl acetate

H2O: Water

MeOH: Methanol

MeCN: Acetonitrile

NaOH: Sodium Hydroxide

TBSC1: tert-Butyldimethylsilyl chloride

TBAF: Tetra-n-butylammonium fluoride

TEA: Triethylamine

T3P: Propylphosphonic anhydride

THF : T etrahy drofuran EXAMPLES

The compounds of Table 1 and Table 2 are prepared according to the synthetic methods detailed hereinbelow.

GENERAL SCHEMES

The compounds of Examples 1-7 are prepared according to the following scheme:

The compounds of Examples 9, 16, 30, 34, and 37 are prepared according to the following scheme:

The compounds of Examples 10, 11, 13, 14, 15, 35, 36, 40, and 43, are prepared according to the following scheme:

Step 3 Step 4

Step 5 Step 6

The compound of Example 12 is prepared according to the following scheme:

The compounds of Examples 17 and 26, are prepared according to the following scheme:

The compounds of Examples 18, 19, 20, 29, 31, 32, 33, 45, 50, and 51, are prepared according to the following scheme:

The compounds of Examples 21, 22, 23, 24, and 25, are prepared according to the following scheme: The compounds of Examples 27, 28, 38, 39, 41, 42, 46, 48, and 52, are prepared according to the following schemes:

The compounds of Examples 45, 47, 50, 51, and 52, are prepared according to the following scheme in conjunction with the previous schemes: The compound of Example 11 is prepared according to the following scheme: The compounds of Examples 53, 54, 55, 58, and 63, are prepared according to the following scheme:

The compounds of Examples 56, 57, and 62, are prepared according to the following scheme:

The compounds of Examples 59, 60, and 63, are prepared according to the following scheme: The compound of Example 64 is prepared according to the following scheme:

The compound of Example 65 is prepared according to the following scheme:

The compounds of Examples 66, 67, 68, 69, and 70, are prepared according to the following scheme:

The compound of Example 49 is prepared according to the following scheme:

The compound of Example 44 is prepared according to the following scheme:

The compound of Example 75 is prepared according to the following scheme:

ep 3

Step 6 Step 7

The compounds of Examples 72, 74, 76, and 79, are prepared according to the following scheme:

Step 3 Step 4

Step 5 Step 6

The compound of Example 78 is prepared according to the following scheme: The compounds of Examples 79-164 may be prepared according to analogous procedures to those set forth above and herein below.

Example 1:

Step _ l _ 4-(2-chloro-6-(Y4-(methylsulfonyl)piperazin-l-yl)methyl)thie no[3.,2- di pyrimidin-4-yl)morpholine: To a stirred solution of 2-chloro-4-morpholinothieno[3,2- d]pyrimidine-6-carbaldehyde (200 mg, 0.704 mmol, 1 eq.) in chloroform (10 ml) cooled to 0 °C is added l-(methylsulfonyl)piperazine (230 mg, 1.409 mmol, 2 eq.) followed by titanium tetraisopropoxide (0.6 ml, 1.056 mmol, 1.5 eq) and the reaction is allowed to stir at 65 °C for 12 hours (imine formation is monitored by TLC). The reaction mixture is evaporated under reduced pressure, and the obtained residue is re-dissolved in dichloroethane (DCE) (15 ml) and sodium cyanoborohydride is added (70 mg, 1.056 mmol, 1.5 eq.) at 0 °C. The reaction mixture is stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture is filtered through a Celite pad, washed with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layer is washed with brine solution (40 mL), dried over anhydrous sodium sulfate and evaporated under vacuum to obtain a crude product, which is further purified by silica gel (60-120 mesh) column chromatography using 3-5% MeOH:DCM as an eluents to afford the title product as a white solid (210 mg, 69%). 'H-NMR (400 MHz, DMSO-t/e): 5 7.19 (s, 1H), 3.99-3.97 (m, 4H), 3.85-3.82 (m, 6H), 3.29 (t, J= 4.8 Hz, 4H), 2.80 (s, 3H), 2.66 (t, J= 4.8 Hz, 4H). Mass (m/z): 432.0 [M+H] ⁺ .

Step 2: 4-(2-(3-(3-bromophenyl)-lH-pyrazol-l-yl)-6-((4-(methylsulfon yl)piperazin-l- yl)methyl)thieno[3,2-d1pyrimidin-4-yl)morpholine: To a stirred suspension of sodium hydride (57-63%) (7 mg, 0.174 mmol, 1.5 eq.) in THF (6 mL) is added 3-(3- bromophenyl)- IH-pyrazole (28 mg, 0.127 mmol, 1.1 eq.) at 0 °C under nitrogen atmosphere, and the mixture is stirred at the same temperature for 30 min. To this mixture, is added 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-l-yl)methyl)thie no[3,2- d]pyrimidin-4-yl)morpholine (50 mg, 0.116 mmol, 1 eq.) and the reaction is allowed to stir at 120 °C under microwave conditions (MW) for 2 hours. After completion, the reaction mixture is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer is washed brine solution (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude residue, which was purified from by preparative HPLC to give the product as a white fluffy solid (6 mg, 5%). ‘H-NMR (400 MHz, DMSO- e): 5 8.76 (d, J= 2.8 Hz,lH), 8.14 (s, 1H), 7.98 (d, J= 8 Hz,lH), 7.58 (d, J= 8.8 Hz, 1H), 7.47-7.42 (m, 2H), 7.14 (d, J= 2.8 Hz, 1H), 4.01 (t, J= 2.8 Hz, 4H), 3.95 (s, 2H), 3.80 (t, J= 4.8 Hz, 4H), 3.19-3.13 (m, 4H), 2.90 (s, 3H), 2.63-2.59 (m, 4H). Mass (m/z): 619.9 [M+H] ⁺ .

Example 2:

Step 2; 4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-2-(3-(m-toly l)-lH-pyrazol-l- yl)thieno[3.,2-d1pyrimidin-4-yl)morpholine: To a stirred suspension of sodium hydride (57-63%) (5.5 mg, 0.139 mmol, 1.5 eq.) in THF (5 mL) is added 3-(m-tolyl)-lH-pyrazole (16 mg, 0.102 mmol, 1.1 eq.) at 0 °C under nitrogen atmosphere and stirred at the same temperature for 30 minutes. Then 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-l- yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (40 mg, 0.09 mmol, 1 eq.) is added, and the reaction mixture is allowed to stir at 120 °C under microwave (MW) conditions for 2 hours. After completion, the reaction mixture is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer is washed brine solution (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product, which is purified by preparative HPLC to give the product as a white fluffy solid (11 mg, 22%). 'H-NMR (400 MHz, DMSO-t/e): 5 8.73 (d, 7=2.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.20 (d, 7=7.6 Hz, 1H), 7.03 (d, J= 2.8 Hz, 1H), 4.01 (t, 7=4.4 Hz, 4H), 3.95 (s, 2H), 3.80 (t, J= 4.8 Hz, 4H), 3.18-3.11 (m, 4H), 2.90 (s, 3H), 2.54-2.47 (m, 4H), 2.39 (s, 3H). Mass (m/z): 554.0 [M+H] ⁺ .

Example 3:

Step 2: 4-(2-(3-(3-methoxyphenyl)-lH-pyrazol-l-yl)-6-((4-(methylsulf onyl)piperazin- l-yl)methyl)thieno[3.,2-d1pyrimidin-4-yl)morpholine: To a stirred suspension of sodium hydride (57-63%) (7 mg, 0.174 mmol, 1.5 eq.) in THF (7 mL) is added 3-(3- methoxyphenyl)-lH-pyrazole (23 mg, 0.127 mmol, 1.1 eq.) at 0 °C under nitrogen atmosphere and stirred at the same temperature for 30 min. Then 4-(2-chloro-6-((4- (methylsulfonyl)piperazin-l -yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg, 0.116 mmol, 1 eq.) is added, and the reaction is allowed to stir at 120 °C under microwave (MW) conditions for 2 hours. After completion, the reaction mixture is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer is washed with brine solution (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude residue, which is purified by preparative HPLC to give the product as a white solid (12 mg, 18%). ¹ H- NMR (400 MHz, DMSO-t7 ₆ ): 5 8.73 (d, =2.4 Hz, 1H), 7.54 (d, =8.0 Hz, 1H), 7.49- 7.48 (m, 1H), 7.44 (s, 1H), 7.39 (t, 7=8 Hz, 1H), 7.06 (d, 7=2.8 Hz, 1H), 6.96 (dd, 7=8.0, 2.0 Hz, 1H), 4.01 (t, 7=4.4 Hz, 4H), 3.95 (s, 2H), 3.84 (s, 3H), 3.81 (t, 7=4.4 Hz, 4H), 3.16 (t, 7=4.8 Hz, 4H), 2.90 (s, 3H), 2.61 (t, 7=4.4 Hz, 4H). Mass (m/z): 570.0 [M+H] ⁺ .

Example 4:

Step _ L _ l-((2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)methyl) -N,N- dimethylpiperidin-4-amine: To a stirred solution of 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carbaldehyde (50 mg, 0.176 mmol, 1 eq) in chloroform (5 ml) at 0 °C is added 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (46 mg, 0.353 mmol, 2 eq) followed by titanium isopropoxide (60 pL, 0.264 mmol, 1.5 eq). The reaction mixture is stirred at 65 °C for 12 hours. After completion of the reaction, it is evaporated under reduced pressure to obtain a crude compound. This is dissolved in dichloroethane (DCE) (10 ml), and then sodium cyanoborohydride (13 mg, 0.264 mmol, 1.5 eq) is added at 0°C. The reaction mixture is allowed to warm to room temperature and it is stirred for 12 hours. After completion of the reaction, it is filtered through a Celite pad, followed by washing of the celite pad with DCM (50 mL). The filtrate is washed with water (10 mL). The organic layer is washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude title compound as a brown syrup. Mass (m/z): 396.2 [M+H] ⁺ .

Step 2: N, N-dimethyl-l-(Y4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)t hieno[3.,2- d1pyrimidin-6-yl)methyl)piperidin-4-amine: To a stirred suspension of sodium hydride (57-63%) (3.5 mg, 0.094 mmol, 1.5 eq) in THF (7 mL) is added 3-(m-tolyl)-lH-pyrazole (10 mg, 0.063 mmol, 1.1 eq) at 0 °C under nitrogen atmosphere and the mixture is stirred for 30 minutes. Then l-((2-chloro-4-morpholinothieno[3,2-d] pyrimidin-6-yl) methyl)-N, N-dimethylpiperidin-4-amine (25 mg, 0.063 mmol, 1 eq) is added at the same temperature. The reaction mixture is stirred at 120°C under micro wave irradiation for 2 hours. After completion of the reaction, it is quenched with ice-cold water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers are washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide a crude product, which is purified by preparative HPLC to give the title compound as a white fluffy solid. 'H NMR (400 MHz, DMSO-t/e): 8.72 (d, J=4 Hz,lH), 7.79 (bs, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.37 (t, J=15.2 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 4.01-3.99 (m, 4H), 3.83-3.79 (m, 6H), 2.95-2.92 (b s, 1H), 2.39 (s, 3H), 2.17(s, 6H), 2.10 (t, J=10.8 Hz, 3H), 1.75-1.72 (d, J=11.2 Hz, 2H), 1.45-1.40 (m, 2H). Mass (m/z): 518.2 [M+H] ⁺ .

Example 5:

Step 1: 2-(l-((2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)meth yl)piperidin- 4-yl)propan-2-ol :

The title compound is made according to the procedure used for Example 1, with 2-(4- piperidinyl)propane-2-ol in place of 1 -(methylsulfonyl)piperazine.

Step 2: 2-(l-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3. ,2-d1pyrimidin- 6-yl)methyl)piperidin-4-yl)propan-2-ol:

According to the procedure used for Example 1, 2-(l-((2-chloro-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol (25 mg) is reacted with 3-(m-tolyl)- IH-pyrazole (8 mg) to obtain the title compound (8 mg; 25%) as a white solid. Mass [m/z] = 533.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 5 8.71 (d, J= 2.4 Hz,lH), 7.79 (s, 1H), 7.73 (d, J= 8 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.18 (d, J= 7.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H) 4.06 (s, 1H), 4.00 (t, J = 4.8 Hz, 4H), 3.79-3.81 (m, 4H), 2.97 (d, J = 10.8 Hz, 2H), 2.97 (s, 3H), 1.98 (t, J = 11.6 Hz, 2H), 1.65 (d, J = 11.6 Hz, 2H), 1.20-1.29 (m, 4H), 1.04 (s, 5H).

Example 6:

Step 1: N-(l-((2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)meth yl)piperidin- 4-yl)-N-methylmethanesulfonamide:

The title compound is made according to the procedure used for Example 1, with N-(4- piperidinyl)-N-methylmethanesulfonamide in place of 1 -(methylsulfonyl)piperazine.

Step 2: N-methyl-N-(l-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl) thieno[3,2- d1pyrimidin-6-yl)methyl)piperidin-4-yl)methan esulfonamide:

According to the procedure used for Example 1, N-(l-((2-chloro-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl) -N- methylmethanesulfonamide (30 mg) is reacted with 10 mg of 3-(m-tolyl)-lH-pyrazole (10 mg)e to obtain the title compound (9 mg; 24%) as a white solid. Mass [m/z] = 533.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 5 8.72 (d, J= 2.8 Hz,lH), 7.79 (s, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.41 (s, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.18 (d, J= 8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H) 4.00 (t, J = 4.8 Hz, 4H), 3.87 (s, 2H), 3.79-3.80 (t, J = 3.6 Hz, 4H), 3.56-

3.62 (m, 1H), 2.97 (d, J = 12.8 Hz, 2H), 2.90 (s, 3H), 2.71 (s, 3H), 2.39 (s, 3H), 2.17 (t, J = 12.8, 2H), 1.73-1.77 (dd, J = 11.6 Hz, 8.8 Hz, 2H), 1.60 (d, J = 7.2 Hz, 2H).

Example 7:

Step 1: N-(l-((2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)meth yl)piperidin-

4-yl)-N-methylacetamide:

The title compound is made according to the procedure used for Example 1, with N-(4- piperidinyl)-N-methylacetamide in place of 1 -(methylsulfonyl)piperazine.

Step 2: N-methyl-N-(l-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl) thieno[3,2- d]pyrimidin-6-yl)methyl)piperidin-4-yl)acetamide:

According to the procedure used for Example 1, 25 mg of N-(l-((2-chloro-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl) -N-methylacetamide (25 mg) is reacted with 14 mg of 3-(m-tolyl)-lH-pyrazole (14 mg) to obtain the title compound (4 mg; 12%) as a white solid. Mass [m/z] = 546.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 5 8.75 (d, J= 2.8 Hz,lH), 7.79 (s, 1H), 7.74 (d, J= 3.6 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.21 (d, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.68-4.72 (br s, 2H), 4.04 (t, 4H), 3.82 (t, J = 4.8 Hz, 4H), 2.68 (s, 3H), 2.39 (s, 3H), 2.04 (s, 2H), 1.99 (s, 3H), 1.72 (br s, 1H).

Example 9:

Step 1: 4-(5-chlorothiazolo[5,4-d1pyrimidin-7-yl)morpholine: To a stirred solution of 5,7-dichlorothiazolo[5,4-d] pyrimidine (200 mg, 0.97 mmol, 1 eq) in MeOH (6 mL) is added morpholine (127 mg, 1.46 mmol, 1.5eq) at 0°C. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is filtered and the resulting solid washed with water (3 mL) and dried to give the title compound (200 mg; 80%) as an off white solid. Mass [m/z] 257 [M+H] ⁺ .

Step 2: 5-chloro-7-morpholinothiazolo[5.,4-d1 pyrimidine- 2-carbaldehyde:

To a stirred solution of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine (200 mg, 0.78 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (1.5 mL, 1.56 mmol, 2 eq). The reaction mixture is stirred at same temperature for 30 min. DMF (0.2 mL, 2.35 mmol, 3 eq.) is added and stirred for an additional 2h. The reaction is quenched with saturated NH4CI solution (15 mL) and extracted with ethyl acetate (2 x 30 mL). Finally, the combined organic layers are washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford the title compound (210 mg; 94%) as an off while solid. Mass [m/z] 285.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 9.97 (s, 1H), 4.74 (br s, 2H), 4.14-4.09 (m, 2H), 3.89-3.84 (m, 4H).

Step 3: (5-chloro-7-morpholinothiazolo[5,4-d1pyrimidin-2-yl)methanol :

To a stirred solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyd e (210 mg, 0.74 mmol, 1 eq) in THF (10 mL) is added NaBHi (56 mg, 1.48 mmol, 2 eq) at 0°C. The reaction temperature is raised to room temperature and stirred for an additional 5h. The progress of the reaction is monitored by TLC. After complete consumption of starting material, the reaction mixture is diluted with ethyl acetate (25 mL) and washed with water (10 mL). The organic layer is dried over Na2SO4, filtered and concentrated to obtain a brown solid that is triturated with n-pentane to afford the title compound (180 mg; 85%) as a white solid, this was used as such for the next reaction. Mass [m/z] 287.1 [M+H] ⁺ .

Step 4: (7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo[5,4-d1 pyrimidin-2- yllmethanol: To a stirred solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methanol (180 mg, 0.62 mmol, 1 eq) in 1,4 Dioxane: Toluene (4: 1) (4 mL) is added 3-(m-tolyl)- IH-pyrazole (99 mg, 0.62 mmol, 1 eq), K3PO4 (266 mg, 1.25 mmol, 2 eq). The resulting reaction mixture is degassed for 15 minutes under nitrogen, followed by addition of Pd2(dba)3 (115 mg, 0.12 mmol, 0.2 eq) and Tlu-XPhos (106 mg, 0.25 mmol, 0.4 eq) at room temperature. The reaction temperature was raised to 120°C and stirred for 6h. After completion, the reaction mixture is cooled to room temperature, filtered through celite pad, and washed with ethyl acetate (10 mL). The filtrate is concentrated to obtain a crude brown gummy liquid which is purified by silica gel chromatography (60-120 mesh) eluted with 5% MeOH/DCM to afford the title compound (110 mg; 43%) as an off-white solid. This was directly taken forward to next step. Mass [m/z] 409.1 [M+H] ⁺ .

Step 5 : 4-(2-(chloromethyl)-5-(3-(m-tolyl)- lH-pyrazol- l-yl)thiazolo [ 5,4-dl pyrimidin- 7-yl)morpholine:

To a stirred solution of (7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo[5,4- d]pyrimidin-2-yl)methanol (110 mg, 0.27 mmol, 1 eq) in DCM (5 mL) is added SOCh (0.2 mL) at 0°C, the reaction temperature is raised to room temperature and stirred for 2h. The progress of the reaction is monitored by TLC. After completion, the reaction mixture is concentrated under reduced pressure to obtain a crude solid which is triturated with diethyl ether to afford the title compound (100 mg; 87%) as an off-white solid. Mass [m/z] 427.1 [M+H] ⁺ . This compound is used to prepare the compounds of Examples 9, 16, 30, 31, 34, and 47.

Step 6: 4-(2-((4-(methylsulfonyl)piperazin-l-yl)methyl)-5-(3-(m-toly l)-lH-pyrazol-l- yl)thiazolo[5,4-d1pyrimidin-7-yl)morpholine:

To the solution of 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo[ 5,4- d]pyrimidin-7-yl)morpholine (20 mg, 1 eq) in THF (20 vol) is added 1- (methylsulfonyl)piperazine (8mg, 2 eq) and K2CO3 (3 eq) at room temperature, then the reaction mixture is heated to 80°C and stirred for 16h. The reaction mixture is quenched with cold water (10 vol) and extracted with ethyl acetate (2x 20 mL). The organic layer is dried over Na2SO4, filtered and concentrated to obtain a brown gummy solid which is purified by Prep HPLC (Method-B: GEMINI-C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/40, 20/65, 21/95), to afford the title compound (2.2 mg; 8%) as an off white solid. Mass [m/z] 555.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.75 (d, J= 2.8 Hz, 1H), 7.79 (s, 1H), 7.76 (d, J= 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 4.35 (br s, 4H), 4.01 (s, 2H), 3.79 (t, J = 4.8 Hz, 4H), 3.19 (t, J = 4.4 Hz, 4H), 2.93(s, 3H), 2.68 (br s, 2H), 2.46 (br s, 2H), 2.39 (s, 3H).

Example 10:

Step 1: 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl) morpholine:

To a solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2 g, 7.35 mmol, 1 eq) in MeOH (20 mL) is added morpholine (959 mg, 11.02 mmol, 1.5eq) at 0°C. The reaction mixture is brought to room temperature and stirred for 3h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered, and the solid washed with water (15 mL) and dried to obtain the title compound (1.2 g; 52%) as an off-white solid. Mass [m/z] 324.2 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 7.91 (s, 1H), 5.71 (dd, J=2 Hz, J= 10.4 Hz, 1H), 4.29-4.12 (m, 4H), 3.83-3.79 (m, 4H), 3.76- 3.73 (m, 1H), 2.1-2.02 (m, 2H), 1.91-1.87 (m, 1H), 1.79-1.61 (m, 3H).

Step 2: 2-chloro-6-morpholiiio-9-(tetrahydro-2H-pyran-2-yl)-9H-purin e-8- carbaldehyde:

To a stirred solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl) morpholine (1.2 g, 0.78 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (1.5 mL, 1.56 mmol, 2 eq), and the reaction is stirred for 30 min, then DMF (0.2 mL, 2.35 mmol, 3 eq.) is added and the reaction stirred for an additional 2h at the same temperature. The progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (30 mL) and extracted with EtOAc (2 x 50 mL). Finally, the combined organic layers are washed with water (25 mL) dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford the title compound (900 mg; 69%) as a sticky solid. Mass [m/z] 352.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 9.95 (s, 1H), 6.22-6.25 (dd, J = 2.4, 2.8 Hz, 1H), 4.65 (Br s, 2H), 4.00- 4.20 (m, 3H), 3.894 (t, J = 4.4 Hz, 4H). 3.70-3.78 (dt, J = 2.4, 12 Hz, 1H), 3.2 - 3.35 (m, 1H), 2.04-2.09 (m, 1H), 1.58-1.87 (m, 6H).

Step _ 3: _ (2-chloro-6-morpholino-9-(tetrahvdro-2H-pyran-2-yl)-9H-purin -8- yllmethanol:

To a solution of 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine -8- carbaldehyde (1.3 g, 3.70 mmol, 1 eq) in THF (10 mL) is added NaBHi (281 mg, 7.40 mmol, 2 eq) at 0°C the reaction temperature was raised to RT and stirred for 5h. The progress of the reaction is monitored by TLC. After complete consumption of starting material, the reaction is diluted with ethyl acetate (50 mL) and the organic layer washed with water (25 mL), dried over Na2SO4, filtered and concentrated to obtain a crude off white solid. The crude product is purified by silica gel column (60-120 mesh) eluting with 40-45% EtOAc/Hexane to afford the title compound (900 mg; 69%) as an off-white solid. Mass [m/z] 354.1 [M+H] ⁺ ;

Step 4: 4-(2-chloro-8-(chloromethyl)-9H-purin-6-yl)morpholine:

To a solution of (2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin -8- yl)methanol (500 mg, 1.41 mmol, 1 eq) in DCM (10 mL) is added SOCI2 (0.3 mL, 4.23 mmol, 3 eq) at 0°C then the reaction temperature is raised to 25°C and stirred for an additional 4h. The progress of the reaction is monitored by TLC. After completion, the reaction mixture is concentrated under reduced pressure to afford the title compound (520 mg; 52%). as a yellowish solid which was directly taken forward to the next step. Mass [m/z] 288.1 [M+H] ⁺ . Step 5: 4-(2-chloro-8-((4-(methylsulfonyl)piperazin-l-yl)methyl)-9H- purin-6- vDmorpholine:

4-(2-chloro-8-(chloromethyl)-9H-purin-6-yl)morpholine (50 mg) is reacted with 1- (methylsulfonyl)piperazine (42 mg, 1.5 eq.) in THF (20 vol) at room temperature, followed by K2CO3 (2 eq). The reaction mixture is heated to 70-80°C for 10-16 h. Progress of the reaction is monitored by TLC. After starting material consumption, the reaction mixture is diluted with water (10 vol) and extracted with EtOAc (2 xlO vol). The combined organics are dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain a crude product which is purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes, to provide the title compound (42 mg; 58%) as an off-white solid. Mass [m/z] 416.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 13.18 (br s, 1H), 4.15 (br s, 4H), 3.72 (m, 7H), 3.12 (t, J = 4.4 Hz, 4H), 2.87 (s, 3H).

Step 6; 4-(8-((4-(methylsulfonyl)piperazin-l-yl)methyl)-2-(3-(m-toly l)-lH-pyrazol-l- yl)-9H-purin-6-yl)morpholine:

4-(2-chloro-8-((4-(methylsulfonyl)piperazin-l-yl)methyl)- 9H-purin-6-yl)morpholine (19- 7) (40 mg) and 3-(m-tolyl)-lH-pyrazole (24 mg, 1.5 eq.) are dissolved in a mixture of toluene: dioxane (1 :1) (20 vol), to which is added Pd2(dba)3 (0.1 eq.), Tlu-XPhos (0.2 eq.), followed by K3PO4 (2 eq.), and degassed for 30 min. The resulting reaction mixture is stirred at 120°C for 6h, and the reaction monitored by TLC. After complete consumption of the starting material, the reaction mixture is passed through a celite pad and diluted with ethyl acetate (20 vol), and the organics are washed with water (25 vol). Finally, the organic layer is dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude product. The resulting crude was purified by flash RP column purification using Cl 8, 6 g column eluting with 65% of acetonitrile/water to give the title compound (15 mg; 23%) as an off white solid. Mass [m/z] 538.3 [M+H] ⁺ ; 'H- NMR (400 MHz, DMSO-t7 ₆ ): 13.18 (br s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 2.8 Hz), 4.27 (br s, 4H), 3.74-3.78 (m, 6H), 3.25 (t, J = 9.8 Hz, 4H), 2.88 (s, 3H), 2.66 (m, 4H).

2.49 (s, 3H).

Example 11:

Step 5: N-(l-((2-chloro-6-morpholino-9H-purin-8-yl)methyl)piperidin- 4-yl)-N- methylmethanesulfonamide:

Following the general procedure of Example 10, 4-(2-chloro-8-(chloromethyl)-9H-purin- 6-yl)morpholine (50 mg) is reacted with N-methyl-N-(piperidin-4-yl)methane sulfonamide (50 mg). The resulting crude is purified by silica gel chromatography eluting with 80% ethyl acetate/hexanes, to give the title compound (40 mg; 42%) as an off-white solid. Mass [m/z] 444.9 [M+H] ⁺ .

Step 6: N-methyl-N-(l-((6-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl) -9H-purin-8- yl)methyl)piperidin-4-yl)methanesulfonamide

Following the general procedure of Example 10, N-(l-((2-chloro-6-morpholino-9H- purin-8-yl)methyl)piperidin-4-yl)-N-methylmethanesulfonamide (40 mg) is reacted with 3-(m-tolyl)-lH-pyrazole (26 mg). The resulting crude is purified by flash RP column chromatography using C18, 6 g column, eluted with 50% of acetonitrile/water to give the title compound (10 mg; 19%) as an off white solid. Mass [m/z] 566.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.64 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 2.4 Hz), 4.25 (Br s, 4H), 3.76(t, J = 4.4 Hz, 4H), 3.62 (s 2H), 3.48-3.57 (m, 2H), 2.92 (d, J = 12Hz, 2H). 2.88 (s, 3H), 2.69 (s, 2H), 2.38 (s, 3H), 2.14 (t, J = 10.8 Hz, 2H), 1.75 (d, J = 7.2Hz, 2H), 1.56 (d, J = 10.4 Hz, 2H). Example 12:

Step 1: 5-chloro-7-morpholinothiazolo[5.,4-d1pyrimidine-2-carbaldehv de:

To a stirred solution of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine (400 mg, 1.56 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (3.1 mL, 3.12 mmol, 2 eq). The reaction mixture is stirred at same temperature for 30 min. DMF (0.38 mL, 4.68 mmol, 3 eq.) is added, stirred for another 2h at the same temperature and the progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (15 mL) and extracted with ethyl acetate (2 x 30 mL). Finally, the combined organic layers are washed with water (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford a crude compound as a sticky liquid. Then crude compound is purified through silica gel column (60-120 mesh) and compound eluted at 15-20% of EtOAc/Hexane to afford the title compound (230 mg; 52%) as an off-white solid. Mass [m/z] 284.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 9.97 (s, 1H), 4.76 (br s, 2H), 4.13 (br s, 2H), 3.88 (t, J= 4.8 Hz, 4H).

Step 2: l-(5-chloro-7-morpholinothiazolo[5,4-d1pyrimidin-2-yl)ethan- l-ol:

To a stirred solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyd e (230 mg, 0.80 mmol, 1 eq.) in THF (5 mL) at -78°C is added methylmagnesium bromide (2.4 mL, 2.42 mmol, 3 eq). Then reaction mixture is brought to room temperature and stirred for an additional 2h. The progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (20 mL) and extracted with ethyl acetate (2 x 35 mL). Finally, the combined organic layers are washed with water (10 mL) dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford crude compound as a sticky liquid. Then crude compound is purified using silica gel column (60-120 mesh) and product eluted with 25-30% EtOAc / Hexane to afford the title compound (110 mg; 45%) as an off-white solid. Mass [m/z] 301.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 6.50 (d, J=5.2 Hz, 1H), 5.01-4.95 (m, 1H), 4.24 (br s, 4H), 3.73(t, J=4.8 4H), 1.49(d, J=6.8 Hz, 3H).

Step 3: l-(7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo[5,4- d1pyrimidin-2- yllethan-l-ol:

To a stirred solution of l-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)ethan- l- ol (30 mg, 0.1 mmol, 1 eq.), and 3-(m-tolyl)-lH-pyrazole (24 mg, 0.15mmoL, 1.5 eq.) dissolved in a mixture of solvents toluene: dioxane (1 :1) (5 mL) is added Pd2(dba)3 (9 mg, 0.01 mmol, 0.1 eq.), and tBu-XPhos (8 mg, 0.02 mmol, 0.2 eq.), followed by K3PO4 (42 mg, 0.2 mmol, 2 eq.), and degassed for 30 min. The reaction mixture is stirred at 120°C for 6h. Progress of the reaction is monitored by TLC. After complete consumption of the starting material, the reaction is cooled and filtered through a celite pad to remove catalyst impurities. The filtrate is diluted with EtOAc (20 mL), and the organics are washed with water (8 mL x 2), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude (35 mg) as light brown solid. The crude compound is purified by silica gel (60-120 mesh) and eluted at 45-50% EtOAc / Hexane to afford the title compound (20 mg; 47%) as an off-white solid. Mass [m/z] 423.2 [M+H] ⁺ .

Step 4: 4-(2-(l-chloroethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo [5.,4-d1pyrimidin- 7-yl)morpholine:

To a stirred solution of l-(7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo[5,4- d]pyrimidin-2-yl)ethan-l-ol (20 mg, 0.42 mmol, 1 eq.), in DCM (5 mL) at 0°C is added SOCI2 (101 mg, 0.85mmol, 2 eq). The reaction temperature is allowed to raise to room temperature and stirred for 2h. The progress of the reaction is monitored by TLC and after completion, it is evaporated under reduced pressure to obtain the title compound (20 mg; 95%) as a yellowish solid. Mass [m/z] 441.1 [M+H] ⁺ ;

Step 5: 4-(2-(l-(4-(methylsulfonyl)piperazin-l-yl)ethyl)-5-(3-(m-tol yl)-lH-pyrazol-l- yl)thiazolo[5,4-d1pyrimidin-7-yl)morpholine: To a stirred solution of 4-(2-(l-chloroethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)thiazolo [5,4- d]pyrimidin-7-yl)morpholine (20 mg, 0.07 mmol, 1 eq.) in THF (4 mL) is added 1- (methylsulfonyl) piperazine (18 mg, 0.11 mmol, 1.5 eq) and K2CO3 (30 mg, 0.22 mmol, 3 eq) at room temperature. The reaction mixture is heated at reflux for 16h, and the progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with ethyl acetate (30 mL) and the organics are washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain an off- white solid. Purification of the crude by RP flash (C18-6g column) eluting with 55-60% of acetonitrile/water affords the title compound (8 mg; 30%) as an off-white solid. Mass [m/z] 569.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.73 (d, J = 2.8 Hz, 1H), 7.78 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.21 (d, J= 7.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.37 (br s, 4H), 4.27-4.24 (m, 1H), 3.79(t, J=4.4 Hz, 4H), 3.19-3.18(m, 4H), 2.92 (s, 3H), 2.69-2.67 (m, 4H), 2.39 (s, 3H), 1.44 (d, J=6.8 Hz, 3H).

Example 13:

Step 5: 2-(l-((2-chloro-6-morpholino-9H-purin-8-yl)methyl)piperidin- 4-yl)propan-2- ol:

Following the general procedure of Example 10, 4-(2-chloro-8-(chloromethyl)-9H-purin- 6-yl)morpholine (50mg) is reacted with 2-(piperidin-4-yl)propan-2-ol (37 mg). The resulting crude is purified by silica gel chromatography eluting with 60% ethyl acetate/hexanes, to give the title compound (50 mg; 44%) as an off-white solid. Mass [m/z] 339.9 [M+H] ⁺ .

Step 6: N-methyl-N-(l-((6-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl) -9H-purin-8- yl)methyl)piperidin-4-yl)methanesulfonamide Following the general procedure of Example 10, 2-(l-((2-chloro-6-morpholino-9H-purin- 8-yl)methyl)piperidin-4-yl)propan-2-ol (40 mg) is reacted with 3-(m-tolyl)-lH-pyrazole (24 mg). The resulting crude is purified by flash RP column chromatography using Cl 8, 6 g column, product eluted with 70% of acetonitrile/water to give the title compound (8 mg; 15%) as an off white solid. Mass [m/z] 517.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO- d ₆ ) 13.18 (br s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 2.4 Hz), 4.27 (Br s, 4H), 4.05 (s, 1H), 3.77 (t, J = 4.8 Hz, 4H), 3.62 (s 2H), 2.86 (Br s, 2H), 2.69 (s, 2H), 2.38 (s, 3H), 2.08 (br s, 2H), 1.63 (d, J = 9.6 Hz, 2H), 1.29-1.35 (m, 2H). 1.15 (d, J = 6.0 Hz, 1H), 1.02 (s, 6H).

Example 14:

Step 5: 4-((2-chloro-6-morpholino-9H-purin-8-yl)methyl)morpholine:

Following the general procedure of Example 10, 4-(2-chloro-8-(chloromethyl)-9H-purin- 6-yl)morpholine (50 mg) is reacted with 22.5 mg of morpholine (22.5 mg). The resulting crude product is purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes to give the title compound (26 mg; 45%) as an off-white solid. Mass [m/z] 339.9 [M+H] ⁺ .

Step 6: 4-((6-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)-9H-purin-8- yl)methyl) morpholine:

Following the general procedure of Example 10, 4-((2-chloro-6-morpholino-9H-purin-8- yl)methyl)morpholine (30 mg) is reacted with 3-(m-tolyl)-lH-pyrazole (14 mg). The resulting crude is purified by flash RP column chromatography using Cl 8, 6 g column, product eluted with 75% of acetonitrile/water to give the title compound (3 mg; 8%) as an off white solid. Mass [m/z] 459.1 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-t7 ₆ ): 13.20 (br s, 1H), 8.66 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 2.8 Hz), 4.23 (Br s, 4H), 3.77 (t, J = 4.4 Hz, 4H), 3.66 (s, 2H), 3.60 (t, J = 4.4 Hz, 4H), 2.45 (m, 4H). 2.38 (s, 3H).

Example 15:

Step 4: (6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-2-(3-(m-tolyl)-lH -pyrazol-l- yl)-9H-purin-8-yl)methanol:

The first three steps of the procedure according to Example 10 are carried out. To a solution of (2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin -8- yl)methanol (500 mg, 1.41 mmol, 1 eq) in 1,4 Dioxane : Toluene (4: 1) (5 mL) is added 3- (m-tolyl)-lH-pyrazole (268 mg, 1.69 mmol, 1.2 eq), K3PO4 (600 mg, 2.83 mmol, 2 eq). The resulting reaction mixture is degassed for 10 minutes under nitrogen, followed by addition of Pd2(dba)3 (129 mg, 0.141 mmol, 0.2 eq) and ^l Bu-XPhos (120 mg, 0.283 mmol, 0.4 eq) at room temperature. The reaction temperature is then raised to 120°C and mixture stirred for 6h. After completion, the reaction mixture is cooled to room temperature, filtered through a celite pad and washed with ethyl acetate (10 mL) and the filtrate is concentrated to obtain a crude brown gummy liquid. The crude product is purified by silica gel column (60-120 mesh) eluting with 2-5% MeOH/DCM to obtain the title compound (350 mg; 52%) as an off-white solid. Mass [m/z] 476.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.59 (d, J=2.8 Hz, 1H), 7.85 (br s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 6.1-6.07 (m, 1H), 5.0 (d, J=14 Hz, 1H), 4.86 (d, J=14.4 Hz, 1H), 4.37 (br s, 3H), 4.21-4.20 (m, 1H), 3.90- 3.84 (m, 5H), 3.48 (br s, 1H), 2.42 (s, 3H), 2.07-2.04 (m, 3H), 1.92-1.7 (m, 3H).

Step 5: 4-(8-(chloromethyl)-2-(3-(m-tolyl)-lH-pyrazol-l-yl)-9H-purin -6- yllmorpholine: To a solution of (6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-2-(3-(m-tolyl)-lH -pyrazol- l-yl)-9H-purin-8-yl) methanol (350 mg, 0.73 mmol, 1 eq) in DCM (5 mL) is added SOCh (0.2 mL) at 0°C and then the reaction temperature is raised to 25°C and stirred for an additional 2h. The progress of the reaction is monitored by TLC. After completion, the reaction mixture is concentrated under reduced pressure to afford the title compound (290 mg; 96%) as a yellowish solid. Mass [m/z] 410.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO- d ₆ ) 13.58 (Br s, 1H), 8.69 (d, J=2.8 Hz, 1H), 7.77 (Br s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.2 (d, J=7.2 Hz, 1H), 7.01 (d, J=2.8 Hz, 1H), 4.88 (s, 2H), 4.28 (t, J=7.6, 1H), 3.78 (t, J=7.0 Hz, 1H), 2.39 (s, 3H).

Step 6: N,N-dimethyl-l-((6-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl )-9H-purin-8- yl)methyl)piperidin-4- amine

To a solution of 4-(8-(chloromethyl)-9-methyl-2-(3-(m-tolyl)-lH-pyrazol-l-yl) -9H-purin- 6-yl)morpholine (30 mg, 1 eq.) in THF (3 mL) is added N,N-dimethylpiperidin-4-amine (17 mg, 2 eq.) and K2CO3 (3 eq) at room temperature, then the reaction mixture is heated to 80°C and stirred for 16h. The reaction mixture is quenched with cold water (20 vol) and extracted with ethyl acetate (20 vol x 2). The organic layer is dried over Na2SO4, filtered and concentrated to obtain a crude which is purified by Prep HPLC (Method-B: Kinetix, EVO, C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/55, 20/70, 21/95) eluted with 65-70% ACN/water to afford the title compound (8 mg); 22%) as a white solid. Mass [m/z] 502.4 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.67 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 4.27 (br s, 4H), 3.77 (t, J = 4.4 Hz, 4H), 3.68 (s, 3H), 2.84 (d, J = 12 Hz, 2H), 2.33 (s, 4H), 2.18 (s, 6H), 2.04 (t, J = 11.6 Hz, 3H), 1.70 (d, J = 12.4 Hz, 2H), 1.42 (m, 2H).

Example 16:

Step 6: N,N-dimethyl-l-((7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl )thiazolo[5.,4- d1pyrimidin-2-yl)methyl)piperidin-4-amine:

#

Following the general procedure of Example 9, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (40 mg) is reacted with N,N- dimethylpiperidin-4-amine (24 mg) and the resulting crude is purified by Prep HPLC (Method-B: GEMINI-C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/25, 10/55, 20/95), to afford the title compound (10 mg; 10%) as an off-white solid. Mass [m/z] 519.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.73 (d, J= 2.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.35 (br s, 4H), 3.88 (s, 2H), 3.78 (t, J = 4.4 Hz, 1H), 2.98 (d, J = 11.6 Hz, 1H), 2.39 (s, 3H), 2.08 (s, 6H), 1.77 (d, J=12.4 Hz, 2H), 1.45-1.43 (m, 2H), 1.23 (s, 1H).

Example 17:

Step 1: 2-chloro-4-morpholinothienof3.,2-d]pyrimidine-6-carbaldehvde :

To a stirred solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (200 mg, 0.78 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (1.5 mL, 1.56 mmol, 2 eq). The reaction mixture is stirred at same temperature for 30 min and then DMF (0.2 mL, 2.35 mmol, 3 eq.) is added at same temperature for 2h. The progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (15 mL) and extracted with EtOAc (2 x 30 mL). Finally, the combined organic layer is washed with water (20 mL) dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford a crude compound as a sticky liquid. Then crude is purified by silica gel column chromatography (60-120 mesh) and compound eluted at 15-20% EtOAc/Hexane, the product fractions are evaporated to afford the title compound (120 mg, 54%) as an off-white solid. Mass [m/z] 284.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 10.17 (s, 1H), 7.97 (s, 1H), 4.06 (t, J= 4.08 Hz, 4H), 3.86(t, 5.0Hz, 4H).

Step 2: l-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-l- ol: (26-1):

To a stirred solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (350 mg, 1.23 mmol, 1 eq.) in THF (5 mL) at -78°C is added methylmagnesium bromide (3.7 mL, 3.71 mmol, 3 eq). The reaction mixture as stirred at room temperature for 2h, and the progress of the reaction as monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (15 mL) and extracted with EtOAc (2 x 30 mL). Finally, the combined organic layers are washed with water (10 mL) dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford crude compound as a sticky liquid. Then, crude is purified by silica gel column chromatography (60-120 mesh) and compound eluted at 20-25% EtOAc/Hexane to afford the title compound (250 mg; 68%) as an off-white solid. Mass [m/z] 300.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 7.164 (s, 1H), 5.27-5.21 (m, 1H), 4.01-3.98 (m, 4H), 3.85- 3.82(m, 4H), 2.26(d, J=4.8 Hz, 1H), 1.66 (d, J=6.4 Hz, 3H).

Step 3: l-(4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3,2-d1 pyrimidin-6- yllethan-l-ol:

To a stirred solution of l-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-l- ol (250 mg, 0.83 mmol, 1 eq.) and 3-(m-tolyl)-lH-pyrazole (198 mg, 1.25mmoL, 1.5 eq.) dissolved in a mixture of toluene: dioxane (1:1) (5 mL) is added Pd2(dba)3 (77 mg, 0.083 mmol, 0.1 eq.), and tBu-XPhos (71 mg, 0.16 mmol, 0.2 eq.), followed by K3PO4 (353 mg, 0.19 mmol, 2 eq.), and degassed for 30 min. The reaction mixture is stirred at 120°C for 6h. Progress of the reaction is monitored by TLC. After completion consumption of the starting material, the catalyst is filtered and the filtrate diluted with EtOAc (30 mL), and washed with water (10 mL). Finally, the organic layer is dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain crude product (260 mg) as a light brown solid. The crude is purified by silica gel column chromatography (60-120 mesh) and compound eluted at 40% EtOAc/Hexane, to afford the title compound (180 mg; 51%) as an off white solid. Mass [m/z] 422.1 [M+H] ⁺ ;

Step 4: 4-(6-(l-chloroethyl)-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3 ,2-d1pyrimidin-4- vDmorpholine:

To a stirred solution of l-(4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3,2- d]pyrimidin-6-yl)ethan-l-ol (180 mg, 0.42 mmol, 1 eq.), in DCM (5 mL) at 0°C is added SOCh (101 mg, 0.85mmol, 2eq). The reaction temperature is raised to room temperature and stirred for 2h. The progress of the reaction is monitored by TLC and after completion, it is evaporated under reduced pressure to obtain the title compound (180 mg; 95%) as a white solid. Mass [m/z] 440.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.76 (d, J= 2.8 Hz, 1H), 7.8 (Brs, 1H), 7.76 (d, J= 8 Hz, 1H), 7.64 (s, 1H), 7.35 (t, J = 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 5.85-5.83(m, 1H), 4.04-4.02 (m, 4H), 3.81-3.78(m, 4H), 2.39 (s, 3H), 1.96 (d, J=6.8 Hz, 3H).

Step 5 ; N,N-dimethyl- 1-( l-(4-morpholino-2-(3-(m- tolyl)- lH-pyrazol- l-yl)thieno [ 3,2- d]pyrimidin-6-yl)ethyl)piperidin-4-amine:

To a solution of 4-(6-(l-chloroethyl)-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3 ,2- d]pyrimidin-4-yl)morpholine (50 mg, 1 eq.) in 1,4-dioxane (0.5 mL) is added N,N- dimethylpiperidin-4-amine (22 mg, 1.5 eq.) at room temperature and stirred at 150°C for 3h in a microwave vial. After completion, the reaction mixture is quenched with cold water (5 mL) and extracted with ethyl acetate (2x 15 mL). The organic layer is dried over Na2SO4 filtered and concentrated to obtain a crude off white solid (58 mg) which is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/10, 12/35, 15/60, 20/95.), which after lyophilization affords the title compound (15 mg; 25%) as an off-white solid. Mass [m/z] 440.2 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 9.70 (br s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 7.79 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.64 (s, 1H), 7.36 (t, J= 7.6 Hz 1H), 7.21 (d, J= 7.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.99-4.97 (m, 1H), 4.01-4.10 (m, 4H), 3.91-3.85(m, 4H), 3.75-3.5(m, 2H), 3.31-3.40 (m, 1H), 2.95-2.92 (m, 2H), 2.76 (s, 6H), 2.39 (s, 3H), 2.27-2.17 (m, 2H), 1.93-1.81 (m, 2H), 1.77 (d, J=6.8 Hz, 3H).

Example 18:

Step 1: 2-chloro-4-morpholinothieno[3.,2-d1pyrimidine-6-carbaldehvde :

To a stirred solution of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (200 mg, 0.78 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (1.5 mL, 1.56 mmol, 2 eq). The reaction mixture is stirred at the same temperature for 30 min, then DMF (0.2 mL, 2.35 mmol, 3 eq.) is added and stirred for another 2 hours at the same temperature. The progress of the reaction is monitored by TLC, after completion of the reaction, it is quenched with saturated NH4CI solution (15 mL) and extracted with ethyl acetate (2 x 30 mL). Finally, the combined organic layers are washed with water (20 mL) and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford crude compound as a sticky liquid. The crude compound is purified by silica gel (60-120 mesh) column chromatography, compound was eluted at 15-20% of EtOAc/Hexane to afford the title compound (120 mg; 120 mg; 54%) as an off-white solid. Mass [m/z] 284.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 10.17 (s, 1H), 7.97 (s, 1H), 4.06 (t, J= 4.08 Hz, 4H), 3.86(t, 5.0Hz, 4H).

Step 2: (2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)methanol:

To a stirred solution of 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carbaldehyde (1.5 g, 5.3 mmol, 1 eq.) in MeOH (20 mL) at 0°C is added NaBHi (402 mg, 10.6 mmol, 2 eq). The reaction mixture is allowed to reach room temperature and stirred for 4h. The progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with saturated NH4CI solution (30 mL) and extracted with EtOAc (2 x 50 mL). Finally, the combined organic layers are washed with water (20 mL) dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford crude compound as a sticky liquid. The crude compound is triturated with diethyl ether (2x10 mL) to afford the title compound (1.1 g; 73%) as a light brown solid. Mass [m/z] 286 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 7.20 (t, J = 1.2 Hz, 1H), 4.98 (d, J = 4.8 Hz, 2H), 4.0-3.98 (m, 4H), 3.85-3.82(m, 4H), 2.32 (br s, 1H).

Step 3: (4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3,2-d1py rimidin-6- yllmethanol:

To a stirred solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol (34-6) (1.1 g, 0.28 mmol,l eq.), and 3-(m-tolyl)-lH-pyrazole (550 mg, 1.5 eq.) in a mixture of toluene: dioxane (1 :1) (3 mL) is added Pd2(dba)3 (640 mg, 0.028 mmol, 0.1 eq.), and tBu-XPhos (600 mg, 0.056 mmol, 0.2 eq.), followed by K3PO4 (1.5 g, 0.56 mmol, 2 eq.), and degassed for 30 min. The reaction mixture is stirred at 120°C for 6h. Progress of the reaction is monitored by TLC. After completion of the reaction, the catalyst is filtered and the filtrate is diluted with EtOAc (100 mL), and washed with water (30 mL). Finally, the organic layer is dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain a crude (1.4 g) light brown solid. The crude is purified by flash RP using water/ACN as eluted at 55-60% ACN/water and after lyophilization to afford the title compound (350 mg; 22%) as an off white solid. Mass [m/z] 408.2 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.73 (d, J = 2.8 Hz, 1H), 7.79 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 5.94 (t, J= 5.6, 1H), 4.85-4.83 (m, 2H), 4.03-4.0 (m, 4H), 3.81-3.79(m, 4H), 2.39 (s, 3H).

Step 4: 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3, 2-d1pyrimidin-4- yllmorpholine:

To a stirred solution of (4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3,2- d]pyrimidin-6-yl)methanol (200 mg, 0.49 mmol, 1 eq.), in DCM (5 mL) at 0°C is added SOCh (116 mg, 0.98mmol, 2eq). The reaction is allowed to reach room temperature and then stirred for 2h. The progress of the reaction is monitored by TLC and after completion, it is evaporated under reduced pressure to give the title compound (200 mg; 96%) as a white solid. Mass [m/z] 426.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.65 (s, 1H), 8.47 (s, 1H), 7.95 (m, 2H), 7.38 (t, J= 7.6 Hz, 1H), 7.20 (d, J= 7.2 Hz, 1H), 6.86 (d, J= 2.4 Hz, 1H), 4.18 (brs, 4H), 3.94 (brs, 4H), 2.44 (s, 3H).

Step 5; (R)-N,N-dimethyl-l-(14-morpholino-2-(3-(m-tolyl)-lH-pyrazol- l-yl)thieno [3,2-d1pyrimidin-6-yl)methyl)pyrrolidin-3-amine

To a stirred solution of 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3, 2- d]pyrimidin-4-yl)morpholine (50 mg, 1 eq) in THF (20 vol) at room temperature is added (R)-N,N-dimethylpyrrolidin-3-amine (26.6 mg) followed by K2CO3 (3 eq). The reaction mixture is heated to 70-80°C for 8 to 12 h. Progress of the reaction is monitored by TLC. After starting material consumption, the reaction mixture is diluted with water (10 vol) and extracted with EtOAc (2 xlO vol). Combined organic fractions are dried over anhydrous Na2SO4 filtered and evaporated under reduced pressure to obtain crude product (65 mg) as an off white solid. The crude compound is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/10, 12/35, 15/60, 20/95.), and after lyophilization affords the title compound (10 mg; 17%) as an off-white solid. Mass [m/z] 504.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J = 2.8 Hz, 1H), 7.79 (Brs, 1H), 7.75 (d, J= 8 Hz, 1H), 7.40 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.01-3.97 (m, 4H), 3.88 (s, 2H), 3.81-3.78(m, 4H), 2.81-2.55(m, 4H), 2.43 (Brs, 1H), 2.39 (s, 3H), 2.12 (s, 6H), 1.85-1.95 (m, 1H), 1.7-1.66 (m, 1H).

Example 19: Step 5: (S)-N,N-dimethyl-l-((4-morDholino-2-(3-(m-tolyl)-lH-Dyrazol- l-yl)thieno [3,2-d1pyrimidin-6-yl)methyl)pyrrolidin-3-amine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with (S)-N,N- dimethylpyrrolidin-3 -amine (26.6 mg) to obtain crude (62 mg) as an off white solid. The crude compound is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/10, 12/35, 15/60, 20/95.), and after lyophilization affords the title product (12 mg; 20%) as an off- white solid. Mass [m/z] 504.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J = 2.8 Hz, 1H), 7.79 (Brs, 1H), 7.75 (d, J= 8 Hz, 1H), 7.38 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.01-3.97 (m, 4H), 3.88 (s, 2H), 3.81- 3.78(m, 4H), 2.81-2.58(m, 4H), 2.44-2.41 (m, 2H), 2.39 (s, 3H), 2.11 (s, 6H), 1.85-1.95 (m, 1H), 1.7-1.66 (m, 1H).

Example 20:

Step 5: N,N-dimethyl-3-(Y4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl )thieno[3.,2- d]pyrimidin-6-yl)methyl)-3-azabicvclof3.1.0]hexan-6-amine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with N,N- dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (29.6 mg) to obtain crude (69 mg) as an off white solid. The crude compound is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/10, 10/30, 15/55, 18/95.), and after lyophilization affords the title compound (8 mg; 14%) as off-white solid. Mass [m/z] 516.1 [M+H] ⁺ ; *H-NMR (400 MHz, DMSO- d ₆ ) 8.72 (d, J= 2.8 Hz, 1H), 7.78 (Brs, 1H), 7.75 (d, J= 8 Hz, 1H), 7.38 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.92 (s, 2H), 3.81-3.79(m, 4H), 3.33-2.3 (m„ 2H), 2.39 (s, 3H), 2.36-2.32 (m, 2H), 2.22 (s, 4H), 2.19 (s, 2H), 1.66 (br s, 2H).

Example 21:

Step 1: 2-chloro-4-morpholinothieno[3.,2-d1pyrimidine-6-carboxylic acid:

To a stirred solution of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (200 mg, 0.78 mmol, 1 eq.) in THF (5 mL) at -78°C is added LiHMDS (1.5 mL, 1.56 mmol, 2 eq). The reaction mixture is allowed to reach room temperature and is stirred for Ih and the progress of the reaction is monitored by TLC. The reaction is cooled to 0°C, dry ice is added and the reaction is stirred for Ih. The reaction is quenched with saturated NH4CI solution (10 mL) and extracted with EtOAc (2 x 30 mL). The organic layer is dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford the title compound (180 mg, 76%) as an off-white solid. Mass [m/z] 300.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 7.25 (s, IH), 3.90 (t, J=4.4 Hz, 4H), 3.74 (t, J= 5.2 Hz, 4H).

Step 2: (R)-(2-chloro-4-morpholinothienof3,2-d]pyrimidin-6-yl)(3-(di methylamino) pyrrolidin-l-yllmethanone:

To a stirred solution of 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carboxylic acid (40 mg, 1 eq.) in DMF (10 vol) is added (R)-N,N-dimethylpyrrolidin-3-amine (23 mg), HATU (1.5 eq.) and DIPEA (3.0 eq.). The reaction is stirred at room temperature for 18h and the progress of the reaction is monitored by TLC. After completion, it is diluted with ethyl acetate (20 vol), washed with ice cold water (2 X 15 vol) and brine solution (20 vol). Finally, the organic layers are dried over Na2SO4, filtered, and evaporated under vacuum to obtain a crude product which was purified by silica gel chromatography with 60% EtOAc/hexane gave the title compound (50 mg; 96%) as an off-white solid. Mass [m/z] 396.2 [M+H] ⁺ .

Step 3: fR)-(3-(dimethylamino)pyrrolidin-l-yl)(4-morpholino-2-(3-(m- tolyl)-lH- pyrazol-l-yl)thieno[3,2-d1pyrimidin-6-yl)methanone

To a stirred solution of (R)-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(3- (dimethylamino)pyrrolidin-l-yl)methanone (40 mg, 1 eq.), and 3-(m-tolyl)-lH-pyrazole (24 mg, 1.5 eq.) dissolved in mixture of toluene: dioxane (1 :1) (3 mL) is added Pd2(dba)3 (0.1 eq.), and tBu-XPhos (0.2 eq.), followed by K3PO4 (2 eq.), and the mixture degassed for 30 min. The resulting reaction is heated at 120°C for 6h and progress of the reaction is monitored by TLC. After complete consumption of the starting material, the reaction mixture is passed through a celite pad and diluted with ethyl acetate (20 vol), and the organics are washed with water (15 vol), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting crude solid was purified by Prep HPLC (Method-B: GEMINI-C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/25, 10/65, 15/95) to afford the title compound (10 mg; 19%) as an off white solid. Mass [m/z] 518.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.73 (d, J= 2.8 Hz, 1H), 7.79 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 5.94 (t, J= 5.6, 1H), 4.85-4.83 (m, 2H), 4.03-4.0 (m, 4H), 3.81-3.79(m, 4H), 2.39 (s, 3H).

Example 22: Step 2: (2-chloro-4-morpholinothieno[3.,2-d1pyrimidin-6-ylK4-(2-hydr oxypropan-2- yl)piperidin-l-yl)methanone:

Following the general procedure of Example 21, 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carboxylic acid (40 mg) is reacted with 2-(piperidin-4-yl)propan-2-ol (28 mg) to obtain the crude (49 mg) as a sticky liquid. After silica gel purification compound eluted at 60% EtOAc/hexane to obtain the title compound (40 mg; 71%) as an off-white solid. Mass [m/z] 425 [M+H] ⁺ .

Step 3: (4-(2-hvdroxypropan-2-yl)piperidin-l-yl)(4-morpholino-2-(3-( m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d1pyrimidin-6-yl)methanone:

Following the general procedure of Example 21, (2-chloro-4-morpholinothieno[3,2- d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-l-yl)met hanone (40 mg) is reacted with 3-(m-tolyl)-lH-pyrazole (22 mg). The resulting crude is purified by Prep HPLC (Method-B: GEMINI-C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/45, 10/65, 25/95) to afford the title compound (10 mg; 19% ) as an off white solid. Mass [m/z] 547.3 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.76 (d, J = 2.8 Hz, 1H), 7.80 (br s, 1H), 7.76 (d, J = 8 Hz, 1H), 7.35 (t, J = 11 Hz 1H), 7.21 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 4.55 (t, J= 5.6, 1H), 4.19(s, 1H), 4.05-4.31 (m, 2H), 3.83-3.81 (m, 4H), 3.5-3.4(m, 4H), 2.49 (s, 3H), 1.85-1.75(m,2H), 1.2-1.3(br s, 3H),1.07(s, 6H).

Example 23: Step 2: (2-chloro-4-morpholinothieno[3,2-d1pyrimidin-6-yl)(4- (dimethylamino)piperidin-l-yllmethanone:

Following the general procedure of Example 21, 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carboxylic acid (50 mg) is reacted with N,N-dimethylpiperidin-4-amine (32 mg) which after purification by silica gel chromatography eluted with 70% EtOAc/hexane to afford the title compound (35 mg; 51%) as an off-white solid. Mass [m/z] 382.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 7.41 (s, 1H), 4.01 (t, J = 4.8 Hz, 4H), 3.85 (t, J = 5.2 Hz, 4H), 2.28 (s, 6H), 1.93 (br s, 2H), 1.25(br s, 7H), 0.92-0.82 (m, 4H).

Step 3: (4-(dimethylamino)piperidin-l-yl)(4-morpholino-2-(3-(m-tolyl )-lH-pyrazol- l-yl)thieno[3,2-d]pyrimidin-6-yl)methanone:

Following the general procedure of Example 21, (2-chloro-4-morpholinothieno[3,2- d]pyrimidin-6-yl)(4-(dimethylamino)piperidin-l-yl)methanone (35 mg) is reacted with 3- (m-tolyl)-lH-pyrazole (20 mg). The resulting crude ias purified by Prep HPLC (Method- B: Kinetix, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/55, 20/70, 21/95) to afford the title product(5 mg; 11%) as an off white solid. Mass [m/z] 547.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.76 (d, J = 2.8 Hz, 1H), 7.8 (br s, 1H), 7.77-7.72 (m, 2H), 7.36 (t, J = 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.03 (t, J= 4.6 Hz, 1H), 3.81 (t, J= 4.4 Hz, 4H), 2.49 (s, 4H), 2.22 (s, 6H), 1.81-1.86(m, 2H).

Example 24: Step 2: (S)-(2-chloro-4-morpholinothieno[3.,2-dlpyrimidin-6-yl)(3- (dimethylaminolpyrrolidin-l-yllmethanone:

Following the general procedure of Example 21, 2-chloro-4-morpholinothieno[3,2-d] pyrimidine-6-carboxylic acid (40 mg) is reacted with (S)-N,N-dimethylpyrrolidin-3- amine (23 mg) which after silica gel chromatography eluted with 60% EtOAc/hexane afford the title compound (45 mg; 86%) as an off-white solid. Mass [m/z] 396.2 [M+H] ⁺ .

Step 3: (S)-(3-(dimethylamino)pyrrolidin-l-yl)(4-morpholino-2-(3-(m- tolyl)-lH- pyrazol-l-yl)thieno[3,2-d1pyrimidin-6-yl)methanone:

Following the general procedure of Example 21, (S)-(2-chloro-4-morpholinothieno[3,2- d]pyrimidin-6-yl)(3-(dimethylamino)pyrrolidin-l-yl)methanone (40 mg) is reacted with 3-(m-tolyl)-lH-pyrazole (22 mg). The resulting crude is purified by Prep HPLC (Method- 13: Kinetix, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/25, 20/95) to provide the title compound (10 mg; 19%) as an off white solid. Mass [m/z] 518.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.75 (s, 1H), 7.79 (br s, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.36 (t, J= 11.4 Hz 1H), 7.2 (d, J= 7.6 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.06 (t, J=7 Hz 4H), 3.829 (t, J= 4.8 Hz, 4H), 2.39 (s, 3H) 2.33-2.32 (m, 4H), 1.23 (s, 1H).

Example 25:

Step 2: (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-methylp iperazin-l- yllmethanone: Following the general procedure of Example 21, 2-chloro-4-morpholinothieno[3,2- d]pyrimidine-6-carboxylic acid (50 mg) is reacted with 1 -methylpiperazine (25 mg) which after purification by silica gel chromatography eluted with 45% EtOAc/hexane afford the title compound (50 mg; 79%) as an off-white solid. Mass [m/z] 382.1 [M+H] ⁺ .

Step 3: (4-methylpiperazin-l-yl)(4-morpholino-2-(3-(m-tolyl)-lH-pyra zol-l- yl)thieno[3,2-d]pyrimidin-6-yl)methanone:

Following the general procedure of Example 21, (2-chloro-4-morpholinothieno[3,2- d]pyrimidin-6-yl)(4-methylpiperazin-l-yl)methanone (50 mg) is reacted with 3-(m-tolyl)- IH-pyrazole (31 mg). The resulting crude is purified by Prep HPLC (Method-B: KINETIX EVO, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of formic acid in Water]; time/B%: 0/45, 10/65, 25/95) to afford the title compound (15 mg; 22%) as an off white solid. Mass [m/z] 504.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.75 (d, J = 2.8 Hz, 1H), 7.79 (br s, 1H), 7.77-7-73 (m, 2H), 7.36 (t, J = 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.03 (t, J= 4.8, 4H), 3.81 (t, J= 4.8 Hz, 4H), 3.67(t, J=4.8 Hz, 4H), 2.39 (br s, 7H), 2.22 (s, 3H).

Example 26:

Step 5: 4-(6-(l-(4-(methylsulfonyl)piperazin-l-yl)ethyl)-2-(3-(m-tol yl)-lH-pyrazol-l- yl)thieno[3,2-d1pyrimidin-4-yl)morpholine:

Following the general procedure of Example 17, 4-(6-(l-chloroethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine is treated with 1 -(methylsulfonyl) piperazine (28 mg) to obtain a crude (55 mg) which is purified by Flash RP chromatography (Cl 8, 6 g column) using water/acetonitrile as solvent system. The product is eluted at 50-55% acetonitrile/H2O and after evaporation produced the title compound (2 mg; 3%) as a white solid. Mass [m/z] 568.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.72 (d, J= 2.8 Hz, 1H), 7.78 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.41 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.20 (d, J= 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 4.18-4.17 (m, 1H), 3.4.05-3.95 (m, 4H), 3.81-3.72(m, 4H), 3.19-3.10(m, 4H), 2.9 (s, 3H), 2.65-2.57 (m, 4H), 2.39 (s, 3H), 1.46 (d, J=6.8 Hz, 3H)

Example 27:

Step 1: 4,6-dichloro-3-nitropyridin-2-amine:

To a stirred solution of 4,6-dichloropyridin-2-amine (3 g, 18.5 mmol, 1 eq.) at 0°C is added H2SO4 (16 mL) at same temperature for 30 min. Then added HNO3 (1 mL) dropwise at 0°C. Reaction is stirred at the same temperature for 5h. Progress of the reaction is monitored by TLC. After completion of the reaction, it is quenched with ice- cold water, obtained solid filtered to get crude (2.8 g) as yellow colored solid. This crude is purified by using silica gel (60-120 mesh) column chromatography using 12% EtOAc in Hexane as an eluent to afford the title compound (1.2 g; 31%) as a yellow solid. Mass [m/z] 208.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 6.83 (s, 1H), 6.29 (brs, 2H).

Step 2: 4,6-dichloropyridine-2,3-diamine:

To a stirred solution of 4,6-dichloro-3-nitropyridin-2-amine (1.2 g, 5.79 mmol, 1 eq.), dissolved in IPA (36 mL), is added iron (1.6 g, 28.9 mmol, 5 eq.), cooled to 0°C then added 6N HCL (6 mL) and stirred at room temperature for 3h. Progress of the reaction is monitored by TLC. After completion of the reaction, crude is Celite filtered, and the thus obtained filtrate is quenched with sat. NaHCCh solution and extracted with EtOAc (80 mL). The organic layers are washed with water (20 mL) and dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain crude (980 mg) as brown solid. This crude is purified by using silica gel (60-120 mesh) column chromatography using 45% EtOAc in Hexane as an eluent to afford the title compound (750 mg; 75%) as a brown solid. Mass [m/z] 170.0 [M+H] ⁺ ; 'H-NMR (400 MHz, CDCh): 6.756 (s, 1H), 4.46 (brs, 2H), 3.57 (brs, 2H).

Step 3; 2-(benzyloxy)methyl)-5.,7-dichloro-3H-iniidazo[4.,5-b1 pyridine:

To a stirred solution of 4,6-dichloropyridine-2,3-diamine (700 mg, 3.95 mmol, 1 eq.), 2- (benzyloxy) acetic acid (1.3 g, 7.91 mmol, 2 eq.), is added, this neat reaction is stirred at 150°C for 4h. Progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with EtOAc (55 mb). Organic layer is washed with aq. NaHCOs (20 mb) first then washed with water (15 mb). Finally, the organic layers are dried over anhydrous Na2SO4 filtered and evaporated under reduced pressure to obtain crude (1.1 g) as brown liquid. Crude is purified by using silica gel (60-120 mesh) column chromatography using 25% EtOAc in Hexane as an eluent to afford the title compound (750 mg; 62%) as an ash color solid. Mass [m/z] 308.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 13.75 (brs, 1H), 7.56 (s, 1H), 7.41-7-29 (m,5H), 4.77 (s, 2H), 4.62 (s, 1H).

Step 4: 2-((benzyloxy)methyl)-5.,7-dichloro-3-(tetrahvdro-2H-pyran-2 -yl)-3H- imidazo [ 4,5-bl pyridine

To a stirred solution of 2-((benzyloxy)methyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine (500 mg, 1.62 mmol, 1 eq.) in DCM (10 mb) is added pyridinium p-toluenesulfonate (PPTS) (41 mg, 0.16 mmol, 0.1 eq), followed by 3,4-dihydropyran (DHP) (0.5 mL, 6.49 mmol, 4 eq). The reaction mixture is stirred at room temperature for 18h. Progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with EtOAc (60 mL). Separated organic layer is washed with aq. NaHCO3 (20 mL) followed by water (15 mL). Finally, the organic layers are dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain crude (550 mg) as colorless liquid. Crude is purified by using silica gel (60-120) column chromatography using 20% EtOAc in Hexane as an eluent to afford the title compound (450 mg; 71%) as an off-white solid. Mass [m/z] 392.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 7.36-7.26 (m, 6H), 5.03 (d, J=12.4 Hz, 1H), 4.86 (d, J = 12.4 Hz 1H), 4.67-4.60 (m, 2H), 4.13-4.09 (m, 1H), 3.64-3.63 (m, 1H), 2.62-2.70 (m, 1H), 1.63-2.13 (m, 6H). Step 5: 4-(2-((benzyloxy)methyl)-5-chloro-3-(tetrahydro-2H-pyran-2-y l)-3H- imidazo [ 4,5-b] pyridin-7-yllmorpholine

To a stirred solution of 2-((benzyloxy)methyl)-5,7-dichloro-3-(tetrahydro-2H-pyran-2- yl)-3H-imidazo[4,5-b]pyridine (200 mg, 0.51 mmol, 1 eq.) in methanol (5 mL) is added morpholine (2 mL, 1 vol), The reaction mixture is stirred at 80°C for 12h. Progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with EtOAc (35 mL). Separated organic layer is washed with IN HC1 (15 mL), and washed with water (15 mL). Finally, the organic layer is dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain crude (230 mg) as colorless liquid. Crude is purified by using silica gel (60-120) column chromatography using 15-20% EtOAc in Hexane as an eluent to afford the title compound (130 mg; 58%) as a light-yellow solid. Mass [m/z] 443.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 7.40-7.29 (m, 5H), 6.59 (s, 1H), 5.69- 5.66 (dd, J = 2 Hz, J = 2.4 Hz, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.58 (d, J=1.2 Hz, 2H), 4.03-4.0 (m, 1H), 3.91-3.89 (m, 4H), 3.75-3.73 (m, 4H), 3.6-3.58 (m, 1H), 2.56-2.51 (m, 1H), 1.90-1.89 (m, 1H), 1.76-1.72 (m, 1H), 1.50 (brs, 1H). 1.26 (s, 2H).

Step 6: 4-(2-((benzyloxy)methyl)-3-(tetrahydro-2H-pyran-2-yl)-5-(3-( m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b1pyridin-7-yl)morpholine

A solution of t-Butyl-Xphos (57 mg, 0.13 mmol, 0.2 eq), Pd2(dba)3 (62 mg, 0.067 mmol, 0.1 eq) in toluene (3 mL) is degassed for 10 min and heated to 100°C for 5 min until solution turns clear, this mixture at 100 °C is added slowly to a degassed mixture of 4-(2- ((benzyloxy)methyl)-5-chloro-3-(tetrahydro-2H-pyran-2-yl)-3H -imidazo[4,5-b] pyridin- 7-yl) morpholine (300 mg, 0.67 mmol, 1 eq.), 3-(m-tolyl)-lH-pyrazole (160 mg, 1.01 mmol, 1.5 eq) and K3PO4 (430 mg, 1.35 mmol, 2 eq) in 1,4-dioxane (5 mL) taken in another flask (at 100 °C). The resulting reaction mixture is heated to 120°C and stirred for 5h. The progress of the reaction is monitored by TLC and after completion it is diluted with EtOAc (50 mL) and washed with water (20 mL). Finally, the organic layer is dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain crude (400 mg) as a brownish gummy material. The crude compound is purified by RP flash purification (Cl 8-6 g column in 55% of CH3CN & water) isolated to afford the title compound (180 mg; 47%) as an off-white solid; Mass [m/z] 563.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.59 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.4- 7.3 (m, 8H), 7.17 (d, J= 7.6 Hz 1H), 6.75 (d, J= 2.4 Hz, 1H), 5.83 (dd, J=2.4 Hz, J=11.2 Hz, 1H), 4.94 (d, J=12.4 Hz, 1H), 4.78 (d, J=12 Hz, 1H), 4.63 (d, J=2.8 Hz, 1H), 4.16- 4.13 (m, 1H), 4.03-4.01 (m, 4H), 3.94-3.92 (m, 4H), 3.66-3.65 (m, 1H), 2.75-2.85 (m, 1H), 2.43 (s, 3H), 2.05 (Brs, 1H), 1.91 (d, J=13.6 Hz, 1H), 1.71 (t, J=8.8 Hz, 2H).

Step 7: (7-morpholino-3-(tetrahydro-2H-pyran-2-yl)-5-(3-(m-tolyl)-lH -pyrazol-l- yl)-3H-imidazo[4.,5-b1 pyridin-2-yl) methanol

To a stirred solution of 4-(2-((benzyloxy)methyl)-3-(tetrahydro-2H-pyran-2-yl)-5-(3-( m- tolyl)-lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpho line (150 mg, 0.51 mmol, 1 eq.) in EtOAc (3 mL) is added 10% Pd/C (50% wet) (120 mg). The reaction mixture is stirred at room temperature for 18h under hydrogen atmosphere (30psi). Progress of the reaction is monitored by TLC. After completion of the reaction, it ias diluted with EtOAc (35 mL) and filtered under nitrogen atmosphere though Celite pad. Filtrate is evaporated under reduced pressure to obtain crude (100 mg) as colorless liquid. Crude is purified by using silica gel (60-120) column chromatography using 45% EtOAc in Hexane as an eluent to afford the title compound (80 mg; 63%) as an off white solid. Mass [m/z] 475.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.58 (d, J= 2.8 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.35-7.31 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.96 (dd, J=2.4 Hz, J=11.2 Hz, 1H), 5.0 (d, J=12.4 Hz, 1H), 4.89 (m, 1H), 4.27 (d, J=11.6 Hz, 1H), 4.03-4.00 (m, 4H), 3.95-3.92 (m, 4H), 3.81-3.79 (m, 1H), 3.45-3.42 (m, 1H), 2.43 (s, 3H), 1.82-1.76 (m, 3H).

Step 8: 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)-3H-imida zo[4,5- bl pyridin-7-yl)morpholine

To a stirred solution of (5-chloro-7-morpholinopyrazolo[l,5-a]pyrimidin-2-yl)methanol (280 mg, 0.59 mmol, 1 eq.), in DCM (6 mL) at 0°C is added SOCh (0.2 mL). The reaction mass is allowed to raise to room temperature and stirred for 2h. The progress of the reaction is monitored by TLC. After starting material consumption, it is evaporated under reduced pressure to afford the title compound (220 mg; 91%) as a white solid. Mass [m/z] 409.1 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.79 (brs, 1H), 7.73 (d, J=8 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz 1H), 6.87 (brs, 1H), 4.75 (s, 2H), 4.25 (brs, 4H), 3.95 (brs, 4H), 2.45 (s, 3H).

Step 9: 4-(2-((4-(methyl sulfonyl) piperazin-l-yl) methyl)-5-(3-(m-tolyl)-lH-pyrazol- l-yl)-3H-imidazo[4,5-b1 pyridin-7-yl) morpholine

To a stirred solution of 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)-3H- imidazo[4,5-b]pyridin-7-yl)morpholine (30 mg, 1 eq) in THF (20 vol) at room temperature is added 1-piperazinylsufonylmethane (1.5 eq) followed by K2CO3 (3 eq). The reaction mixture is heated to 70-80°C for 8 to 12 h. Progress of the reaction is monitored by TLC. After starting material consumption, the reaction mixture is diluted with water (10 vol) and extracted twice with EtOAc (2 xlO vol). Combined organic fractions were dried over anhydrous Na2SO4 filtered and evaporated under reduced pressure to obtain crude product (45 mg) which is purified by RP flash column chromatography (Cl 8-6 g, product elutes at 52% of Acetonitrile and water) to afford the title compound (15 mg; 38%) as an off white solid. Mass [m/z] 409.1 [M+H] ⁺ ; 'H-NMR

(400 MHz, DMSO-t/e): 12.78 (Brs, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.78 (Brs, 2H), 7.36- 7.33 (t, J= 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz 1H), 7.00 (d, J= 2.4 Hz, 1H), 3.94 (Brs, 4H), 3.83-3.82 (m, 4H), 3.72 (s, 2H), 3.15 (t, J=4.4 Hz, 4H), 2.88 (s, 3H), 2.67 (Brs, 4H), 2.39 (s, 3H).

Example 28:

Step 9: N,N-dimethyl-l-(Y7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl )-3H- imidazo[4.,5-b]pyridin-2-yl)methyl)piperidin-4-amine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (40 mg) gave crude product (50 mg) which is purified by RP flash column chromatography (Cl 8-6 g, product elutes at 65% of Acetonitrile and water) to afford the title compund (18 mg; 37%) as an off white solid. Mass [m/z] 409.1 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 12.85 (Brs, 1H), 8.51 (d, J= 2.4 Hz, 1H), 7.77 (Brs, 2H), 7.35 (t, J= 7.6 Hz, 1H), 7.19 (d, J= 7.6 Hz 1H), 7.01 (d, J= 2.4 Hz, 1H), 3.94 (Brs, 4H), 3.83-3.82 (m, 4H), 3.68 (s, 2H), 2.98 (d, J= 11.6 Hz 1H), 2.63 (Brs, 6H), 2.39 (s, 3H), 2.12 (t, J=11.6 Hz, 2H), 1.92 (d, J=10.4 Hz, 2H), 1.61 (m, 2H).

Example 29:

Step 9: 4-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol- l-yl)thieno [3,2-dl pyrimidin-6- vDmethyllmorpholine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with morpholine (20 mg) to obtain crude (58 mg) as an off white solid. The crude compound is purified by flash RP chromatography, and product eluted with 70-75% acetonitrile/water. Product fractions are lyophilized to obtain the title compound (15 mg; 27%) as an off-white solid. Mass [m/z] 477.3 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J = 2.8 Hz, 1H), 7.78 (br s, 1H), 7.75 (d, J = 8 Hz, 1H), 7.42 (s, 1H), 7.35 (t, J = 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.01 (t, J=4.4 Hz, 4H), 3.87 (s, 2H), 3.81(t, J=4.8 Hz, 4H), 3.62(t, J=4.4 Hz, 4H), 2.39 (s, 3H).

Example 30:

Step 6: 4-(Y7-morpholino-5-(3-(m-tolyl)-lH-pyrazolyl)thiazolo[5.,4-d 1pyrimidin-2- vDmethyllmorpholine:

Following the general procedure of Example 9, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (60 mg) is reacted with morpholine (24 mg) and the resulting crude (68 mg) is purified by Flash RP chromatography (Cl 8, 6 g column) eluting with 70-75% ACN/water to afford the title compound (11 mg; 16%) as a white solid. Mass [m/z] 478.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.73 (d, J= 2.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.35 (Brs, 4H), 3.92 (s, 2H), 3.79 (t, J= 4.8 Hz, 4H), 3.64 (t, J= 4.4 Hz, 4H), 2.57 (t, J= 4 Hz, 4H), 2.39 (s, 3H).

Example 31:

Step 5: 4-(6-((4-methylpiperazin-l-yl)methyl)-2-(3-(m-tolyl)-lH-pyra zol-l-yl)thieno [3,2-d1pyrimidin-4-yl)morpholine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with 1-methyl- piperizine (24 mg) to obtain crude (56 mg) as an off white solid. The crude compound is purified by flash RP product eluted with 68% acetonitrile/water which after lyophilization affords the title compound (15 mg; 26%) as an off-white solid. Mass [m/z] 490.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J= 2.8 Hz, 1H), 7.79 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.40 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.86 (s, 2H), 3.81-3.79(m, 4H), 2.39 (s, 3H), 2.19 (br s, 3H), 1.23 (s, 2H).

Example 32:

Step 5; N,N-dimethyl-l-(Y4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl )thieno[3.,2- d1pyrimidin-6-yl)methyl)azetidin-3-amine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with N,N- dimethyl-azetidine-3 -amine (23.5 mg) to obtain crude (54 mg) as an off-white solid. The crude compound is purified by flash RP product eluted with 50-55% acetonitrile/water which after lyophilization affords the title compound (11 mg; 19%) as an off-white solid. Mass [m/z] 490.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J = 2.8 Hz, 1H), 7.79 (Brs, 1H), 7.75 (d, J = 8 Hz, 1H), 7.38 (s, 1H), 7.35 (t, J = 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.95 (s, 2H), 3.81-3.78(m, 4H), 3.5 (Brs, 2H), 2.99-2.92 (m, 2H), 2.39 (s, 3H), 2.14-1.95 (m, 4H).

Example 33:

Step 5; 4-(l-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3, 2-d1pyrimidin-

6-yl)methyl)piperidin-4-yl)morpholine: Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with 4- (piperidin-4-yl)morpholine (39.9 mg) to obtain crude (69 mg) as an off white solid. The crude compound was purified by flash RP product eluted with 65-70% acetonitrile/water, which after lyophilization affords the title compound (15 mg; 26%) as an off-white solid. Mass [m/z] 560.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J = 2.8 Hz, 1H), 7.78 (Brs, 1H), 7.75 (d, J = 8 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J = 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.95 (s, 2H), 3.81-3.78(m, 4H), 3.55-3.61 (m, 4H), 2.99-2.92 (m, 2H), 2.39 (s, 3H), 2.14-1.95 (m, 4H), 1.77-1.75 (m,

1H), 1.47-1..43 (m, 1H).

Example 34:

Step 6; 4-(2-((4-methylpiperazin-l-yl)methyl)-5-(3-(m-tolyl)-lH-pyra zol-l- yl)thiazolo[5,4-d1pyrimidin-7-yl)morpholine:

Following the general procedure of Example 9, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (40 mg) is reacted with 1- methylpiperazine (19 mg) and the resulting crude is purified by Flash RP chromatography (Cl 8, 6 g column) eluting with 75-80% ACN/water to afford the title compound (13 mg; 28%) as a white solid. Mass [m/z] 491.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.73 (d, J= 2.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.35 (br s, 4H), 3.91 (s, 2H), 3.78 (t, J= 4.8 Hz, 4H), 2.67 (br s, 4H), 2.39 (s, 3H), 2.22 (s, 4H), 1.23 (s, 3H).

Example 35:

Step 6: 4-(8-((4-methylpiperazin-l-yl)methyl)-2-(3-(m-tolyl)-lH-pyra zol-l-yl)-9H- purin-6-yl)morpholine:

Following the general procedure of Example 15, 4-(8-(chloromethyl)-9-methyl-2-(3-(m- tolyl)-lH-pyrazol-l-yl)-9H-purin-6-yl)morpholine (30 mg) is reacted with 1- methylpiperazine (27 mg) and the resulting crude product is purified by Prep HPLC (Method-B: Kinetix, EVO, C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/55, 20/70, 21/95.), eluted with 60% ACN/water to afford the title compound (4 mg; 20%) as a white solid. Mass [m/z] 474.3 [M+H] ⁺ ; 'H-NMR (400 MHz, CDC13): 10.00 (br s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 3,2 Hz, 1H), 7.52 (s, 1H), 7.29 (m. 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.38 (br s, 4H), 3.86 (t, J = 4.8 Hz, 4H), 3.71 (s, 2H), 2.56 (s, 4H), 2.45 (s, 6H), 2.31 (s, 3H).

Example 36:

Step 6: 4-(8-((3-(pyrrolidin-l-yl)azetidin-l-yl)methyl)-2-(3-(m-toly l)-lH-pyrazol-l- yl)-9H-purin-6-yl)morpholine:

Following the general procedure of Example 15, 4-(8-(chloromethyl)-9-methyl-2-(3-(m- tolyl)-lH-pyrazol-l-yl)-9H-purin-6-yl)morpholine (30 mg) is reacted with l-(azetidin-3- yl)pyrrolidine (32 mg) and the resulting crude product is purified by Prep HPLC (Method-B: Kinetix, EVO, C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/55, 20/70, 21/95.) eluted with 60% ACN/water to afford the title product (5 mg; 30%) as a white solid. Mass [m/z] 500.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.50 (d, J= 2.4 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J= 3.6 Hz, 1H), 7.31 (m, 1H), 7.14 (d, J = 7.8Hz, 1H), 6.74 (d, J= 2.4 Hz, 1H), 4.34 (s, 4H), 3.86-3.89 (m, 6H), 3.56 (t, J = 5.6 Hz, 2H), 3.32-3.37 (m, 2H), 2.66 (Br s, 3H), 2.40 (s, 3H), 1.89 (s, 5H).

Example 38:

Step 9; 4-((7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)-3H-imidazo[ 4.,5-b1pyridin- 2-yl)methyl)morpholine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (35 mg) gave crude product (42 mg) which is purified by RP flash column chromatography (Cl 8-6 g, product elutes at 70% of Acetonitrile and water) to provide the title compound (15 mg; 38%) as an off white solid. Mass [m/z] 460.4 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 9.70 (Brs, 1H), 8.48 (d, J= 2.8 Hz, 1H), 7.77 (Brs, 1H), 7.73 (d, J= 8 Hz, 1H), 7.34-7.31 (m, 2H), 7.17 (d, J= 7.6 Hz 1H), 6.76 (d, J= 2.4 Hz, 1H), 4.01- 3.99 (m, 4H), 3.95-3.93(m, 4H), 3.75- 3.73 (m, 6H), 2.56 (t, J=4.4 Hz, 4H), 2.43 (s, 3H).

Example 39:

Step 9; 4-(2-((4-methylpiperazin-l-yl)methyl)-5-(3-(m-tolyl)-lH-pyra zol-l-yl)-3H- imidazo [ 4,5-bl pyridin-7-yl)morpholine: Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (35 mg), gave crude product (42 mg) which is purified by RP flash column chromatography (Cl 8-6 g, product elutes at 75% of Acetonitrile and water) to afford the title compound (12 mg; 30%) as an off white solid. Mass [m/z] 473.4 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 9.83 (brs, 1H), 8.48 (d, J= 2.8 Hz, 1H), 7.77 (brs, 1H), 7.73 (d, J= 8 Hz, 1H), 7.34-7.31 (m, 2H), 7.17 (d, J= 7.6 Hz 1H), 6.76 (d, J= 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.95-3.93(m, 4H), 3.77 (s, 2H), 2.65 (brs, 4H), 2.56 (brs, 3H), 2.43 (s, 3H), 2.37 (s, 3H).

Example 40:

Step 6; 4-(8-((4-isopropylpiperazin-l-yl)methyl)-2-(3-(m-tolyl)-lH-p yrazol-l-yl)-9H- purin-6-yl)morpholine:

Following the general procedure of Example 15, 4-(8-(chloromethyl)-9-methyl-2-(3-(m- tolyl)-lH-pyrazol-l-yl)-9H-purin-6-yl)morpholine (40 mg) is reacted with 1- isopropylpiperazine (25 mg) and the resulting crude product is purified by Flash RP chromatography (Cl 8, 6 g column) eluted with 75% ACN/water to produce the title compound (7 mg; 14%) as a white solid. Mass [m/z] 500.2 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.66 (d, J= 4.0 Hz, 1H), 8.32 (s, 1H), 7.79 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.34 (t, J= 7.6 Hz, 1H), 7.19 (d, J= 7.6 Hz, 1H), 7.0 (d, J= 2.4 Hz, 1H), 4.27 (Br s, 4H), 3.77 (t, J = 4.8 Hz, 4H), 3.63 (s, 2H), 2.56-2.63 (m, 3H), 2.45 (s, 6H), 2.38 (s, 3H), 0.94 (d, J = 6.4 Hz, 6H).

Example 41:

Step 9: (R)-N,N-dimethyl-l-(Y7-morpholino-5-(3-(m-tolyl)-lH-pyrazol- l-yl)-3H- imidazo[4,5-b]pyridin-2-yl)methyl)pyrrolidin-3-amine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (30 mg) gave crude (32 mg) which is subjected to Prep HPLC purification (Column: Kinetex EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/15, 12/40, 15/50, 17/95.), to afford the title product (3 mg; 8%) as an off-white solid. Mass [m/z] 487.5 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.62 (brs, 1H), 8.56 (d, J= 2.8 Hz, 1H), 7.77 (brs, 1H), 7.73 (d, J = 8 Hz, 1H), 7.32 (t, J=7.6, 2H), 7.16 (d, J = 7.6 Hz 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.01-4.03 (m, 1H), 3.96-3.92(m, 9H), 3.22-3.09 (m, 3H), 2.76-2.73 (m, 2H), 2.66 (s, 6H), 2.43 (s, 3H), 2.20-2.13 (m, 6H).

Example 42:

Step 9: 4-(l-((7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl)-3H-imida zo[4,5- b1pyridin-2-yl)methyl)piperidin-4-yl)morpholine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (30mg) gave crude product (36 mg) which is purified by Prep HPLC (Column: Gemini Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/40, 14/55, 25/90, 26/95.), to afford the title compound (5 mg; 13%) as off-white solid. Mass [m/z] 543.4 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.65 (brs, 1H), 8.56 (d, J = 2.8 Hz, 1H), 7.77 (brs, 1H), 7.73 (d, J= 8 Hz, 1H), 7.34 (t, J=7.6, 2H), 7.16 (d, J = 7.6 Hz 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.06 (m, 1H), 3.95-3.91(m, 7H), 3.22-3.08 (m, 3H), 2.75-2.67 (m, 2H), 2.65 (s, 6H), 2.43 (s, 3H), 2.27-2.12 (m, 2H).

Example 43:

Step 6; 4-(8-((4-(azetidin-l-yl)-3-fluoropiperidin-l-yl)methyl)-2-(3 -(m-tolyl)-lH- Pyrazol-l-yl)-9H-purin-6-yl)morpholine:

Following the general procedure of Example 15, 4-(8-(chloromethyl)-9-methyl-2-(3-(m- tolyl)-lH-pyrazol-l-yl)-9H-purin-6-yl)morpholine (40 mg) is reacted with 4-(azetidin-l- yl)-3-fluoropiperidine (30.9 mg) and the resulting crude is purified by Prep HPLC (Method-B: Kinetix, EVO, C18, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/55, 20/70, 21/95.) eluted with 55% ACN/water to give the title compound (2 mg; 4%) as a white solid. Mass [m/z] 532.4 [M+H] ⁺ ; ¹ H- NMR (400 MHz, DMSO-t7 ₆ ): 13.18 (br s, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 2.8 Hz), 4.54-4.67 (m, 1H), 4.27 (br s, 4H), 3.76-3.78 (t, J = 4.8 Hz, 4H), 3.70 (s, 2H), 3.10-3.16 (t, J = 9.8 Hz, 4H), 2.92 (m, 1H), 2.65 (m, 1H). 2.41 (s, 3H), 2.22 (m, 1H), 2.06 (m, 2H), 1.5 (m, 2H).

Example 45: Step 5: 4-(l-((4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thieno[3, 2-d1pyrimidin- 6-yl)methyl)piperidin-4-yl)morpholine:

Following the general procedure of Example 18, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (40 mg, 1 eq.) in IPA (4 mL) is treated with 4-(azeti din- l-yl)-3-fluoropiperi dine (29.5 mg, 2 eq.) and DIPEA (36 mg, 0.28 mmol, 3 eq) at room temperature. The reaction mixture is refluxed for 6-8h, progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with ethyl acetate (2 xlO mL) and washed with water (10 mL). Finally, the organic layers are dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude product (55 mg) as an off-white solid. The crude compound is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/15, 12/40, 15/50, 17/95.), which after lyophilization affords the title compound (8 mg; 16%) as an off-white solid. Mass [m/z] 548.4 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.72 (d, J= 2.8 Hz, 1H), 7.79 (Brs, 1H), 7.75 (d, J= 8 Hz, 1H), 7.40 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J= 7.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.01-3.99 (m, 4H), 3.86 (s, 2H), 3.81-3.79(m, 4H), 2.39 (s, 3H), 2.19 (Brs, 3H), 1.23 (s, 2H).

Example 46:

Step 9: (S)-N.,N-dimethyl-l-((7-morpholino-5-(3-(m-tolyl)-lH-pyrazol -l-yl)-3H- imidazo[4,5-b1pyridin-2-yl)methyl)pyrrolidin-3-amine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (30 mg) gave crude product (34 mg) which is subjected to Prep HPLC purification (Column: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/15, 12/40, 15/50, 17/95.), to afford the title compound (2.1 mg; 6%) as an off-white solid. Mass [m/z] 543.4 [M+H] ⁺ ; *H-NMR (400 MHz, DMSO-t7 ₆ ): ): 8.65 (brs, 1H), 8.56 (d, J = 2.8 Hz, 1H), 7.77 (brs, 1H), 7.73 (d, J= 8 Hz, 1H), 7.34 (t, J=7.6, 2H), 7.16 (d, J= 7.6 Hz 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.06 (m, 1H), 3.95-3.91(m, 7H), 3.22-3.08 (m, 3H), 2.75-2.67 (m, 2H), 2.65 (s, 6H), 2.43 (s, 3H), 2.27-2.12 (m, 2H).

Example 47:

Step 6: 4-(2-((4-(azetidin-l-yl)-3-fluoropiperidin-l-yl)methyl)-5-(3 -(m-tolyl)-lH- pyrazol-l-yl)thiazolo[5,4-d1pyrimidin-7-yl)morpholine:

#

Following the general procedure of Example 9, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (40 mg) is reacted with 4- (azetidin-l-yl)-3-fluoropiperidine (30 mg) and the resulting crude is purified by Prep HPLC (Method-B: X-Bridge-C18, 250 x 19.1 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/20, 15/50, 25/60, 26/95) to afford the title compound (11 mg; 21%) as an off white solid. Mass [m/z] 549.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.75 (d, J = 2.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J= 7.6 Hz, 1H), 7.07 (d, J= 2.8 Hz, 1H), 5.12 (d, J=50.4 1H), 4.34- 4.20 (m, 6H), 4.04 (s, 4H), 3.8-3.78 (m, 6H), 3.41-3.35 (m, 1H), 3.09 (d, J= 11.6, 1H), 2.39 (s, 3H), 2.33-2.08 (m, 2H), 1.9-1.88 (m, 1H), 1.68-1.64 (m, 1H), 1.23 (s, 1H).

Example 48:

Step 9: N,N-dimethyl-l-((7-morpholino-5-(3-(m-tolyl)-lH-pyrazol-l-yl )-3H- imidazo[4.,5-b1pyridin-2-yl)methyl)azetidin-3-amine:

Following the general procedure of Example 27, 4-(2-(chloromethyl)-5-(3-(m-tolyl)-lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (30 mg) gave crude product (34 mg) which is purified by Prep HPLC (Column: Gemini Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/40, 14/55, 20/80, 26/95.) to afford TME-0159 (2 mg; 6%) as off-white solid. Mass [m/z] 543.4 [M+H] ⁺ ; ‘H-NMR (400 MHz, DMSO-t7 ₆ ): 8.65 (Brs, 1H), 8.56 (d, J= 2.8 Hz, 1H), 7.77 (Brs, 1H), 7.73 (d, J = 8 Hz, 1H), 7.34 (t, J=7.6, 2H), 7.16 (d, J = 7.6 Hz 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.06 (m, 1H), 3.95-3.91(m, 7H), 3.22-3.08 (m, 3H), 2.75-2.67 (m, 2H), 2.65 (s, 6H), 2.43 (s, 3H), 2.27-2.12 (m, 2H).

Example 50:

Step 5: 6-fluoro-8-(Y4-morpholino-2-(3-(m-tolyl)-lH-pyrazol-l-yl)thi eno [3,2-d1pyrimidin-6-yl)methyl)-l.,4-dioxa-8-azaspiro[4.51deca ne:

Following the general procedure of Example 45, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (50 mg) is treated with 6-fluoro- l,4-dioxa-8-azaspiro[4.5]decane (37.4 mg) to obtain crude (62 mg) as an off-white solid. The crude compound is purified by flash RP column chromatography (Cl 8, 6 g column), product is eluted with 65-70% acetonitrile/water and after lyophilization affords the title compound (15 mg; 26%) as an off-white solid. Mass [m/z] 551.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t/e): 8.73 (s, 1H), 7.79 (s, 1H), 7.73 (d, J= 8 Hz, 1H), 7.42 (s, 1H), 7.35 (t, J = 7.6 Hz 1H), 7.20 (d, J = 2.4 Hz, 1H), 4.01-3.80 (m, 10H), 3.93-3.78 (m, 4H), 3.75- 3.73 (m, 6H), 2.85 (br m, 2H), 2.43 (s, 3H), 1.84 (br m, 1H), 1.65 (br m, 1H).

Example 51:

Step 5; 3-fluoro-N,N-dimethyl-l-((4-morpholino-2-(3-(m-tolyl)-lH-pyr azol-l- yl)thieno[3,2-d1pyrimidin-6-yl)methyl)piperidin-4-amine:

Following the general procedure of Example 45, 4-(6-(chloromethyl)-2-(3-(m-tolyl)-lH- pyrazol-l-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (25 mg) is treated with 3-fluoro- N,N-dimethylpiperidin-4-amine (17.5 mg) to obtain crude (40 mg) as an off-white solid. The crude compound is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/10, 12/35, 15/60, 20/95.), and after lyophilization affords the title compound (2.4 mg) as off- white solid. Mass [m/z] 536.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 8.73 (d, J = 2.8 Hz, 1H), 7.79 (br s, 1H), 7.75 (d, J= 8 Hz, 1H), 7.41 (s, 1H), 7.35 (t, J= 7.6 Hz 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.03 (d, J= 2.4 Hz, 1H), 4.98-4.86 (m, 1H), 4.01-3.99 (m, 4H), 3.95 (s, 2H), 3.81-3.78 (m, 4H), 3.13-3.33 (m, 1H), 2.99-2.96 (m, 1H), 2.39 (s, 3H), 2.24 (s, 6H), 2.14-2.22 (m, 2H), 1.8-1.77 (m, 1H), 1.6-1.69(m, 1H).

Example 52: Step 9: 3-fluoro-N,N-dimethyl-l-((7-morpholino-5-(3-(m-tolyl)-lH-pyr azol-l-yl)-3H- imidazof4,5-b]pyridin-2-yl)methyl)piperidin-4-amine:

Following the procedure of Example 27 for steps 1 to 8, to a stirred solution of 4-(2- (chloromethyl)-5-(3-(m-tolyl)-lH-pyrazol-l-yl)-3H-imidazo[4, 5-b]pyridin-7- yl)morpholine (50 mg, 0.12 mmol, 1 eq.) in IPA (5 mL) is added 3-fluoro-N,N- dimethylpiperidin-4-amine (27 mg, 0.18 mmol, 1.5 eq) and DIPEA (47 mg, 0.36 mmol, 3 eq) at room temperature. The reaction mixture is heated at reflux for 16h and progress of the reaction is monitored by TLC. After completion of the reaction, it is diluted with EtOAc (30 mL) and washed with water (10 mL). Finally, the organic layer is dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain crude as an off white solid. The crude product is purified by Prep HPLC (Method-B: Kinetex, EVO, Cl 8, 250 x 21.2 mm, 5 pm; Mobile phase: [ACN: 0.1% of Formic acid in Water]; time/B%: 0/15, 12/40, 15/50, 17/95.), and after lyophilization affords the title compound (9.5 mg;15%) as an off-white solid. Mass [m/z] 519.3 [M+H] ⁺ ; 'H-NMR (400 MHz, DMSO-t7 ₆ ): 12.89 (Brs, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.78 (brs, 1H), 7.75 (brs, 1H), 7.35 (t, J=7.6, 2H), 7.19 (d, J= 7.6 Hz 1H), 7.01 (d, J= 2.4 Hz, 1H), 4.96 (d, J= 49.6 Hz, 1H), 3.94(Brs, 4H), 3.83-3.82 (m, 4H), 3.67 (s, 2H), 3.08 (t, J=12.4, 1H), 2.94 (d, J=11.2, 1H), 2.34 (s, 3H), 2.22 (s, 6H), 2.19-2.05 (m, 2H), 1.81-1.72 (m, 2H).

Example 165: In vitro inhibitory activity

Compounds were tested for PIKFYVE inhibitory activity using the KINOMEsca/?™ Kinase Assay (Eurofins).

Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage, and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris. Alternatively, some kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin- coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads are blocked with excess biotin and washed with blocking buffer (Sea Block, 1% BSA, 0.05% Tween-20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% Sea Block, 0.17x PBS, 0.05% Tween-20, 6mM DTT). Test compounds are prepared as 11 lx stocks in DMSO. Kd values are determined using an 11 -point, 3-fold compound dilution series with three DMSO control points. Compounds are distributed by non-contact acoustic transfer and are then directly diluted into the assay for a final concentration of DMSO of 0.9%, with a final volume in each well of 0.02 m . Assay plates are incubated at room temperature with shaking for one hour, and the affinity beads are then washed with wash buffer (1% PBS, 0.05% Tween-20). The beads are then resuspended in elution buffer (lx PBS, 0.05% Tween-20, 0.05 M non-biotinylated affinity ligand) and incubated with shaking for 30 minutes. The concentration of kinase in the eluates is measured by qPCR. Binding constants (Kd) are calculated with a standard dose-response curve using the Hill equation, fitted using non-linear least squares fit with the Levenberg-Marquedt algorithm.

The KINOME.sca/?™ experiments provide the following results:

These results demonstrate that the Compounds of the Invention are highly potent inhibitors of PIKFYVE. Example 166: Anti-viral activity

Selected compounds are evaluated for their inhibitory activity against SARS-CoV-2, influenza A, Ebola, and Marburg using the immunofluorescence assay (IF A).

SARS-CoV-2 IFA: Test compounds are solubilized in DMSO to prepare 20 mg/mL stock solutions. Compounds are then serially diluted using eight half-log dilutions in test media so that the starting (high) test concentration is 100 pg/mL. Each dilution is added to 5 wells of a 96- well plate with 80-100% confluent MDCK cells. Three wells of each dilution are infected with virus (strain USA-WA1/2020 or Delta strain B.1.617), and two wells remain uninfected as toxicity controls. As virus controls, six wells are infected but untreated, and as cell controls, six wells are uninfected and untreated. Each virus is prepared to achieve an MOI (multiplicity of infection) of 0.001. A positive control compound is tested in parallel. Plates are incubated at 37 °C under 5% CO2 atmosphere. On day 3 post-infection (once untreated virus control cells reached maximum cytopathic effect, CPE), plates are stained with neutral red dye for 2 hours. Supernatant dye is removed and the wells are rinsed with PBS. The incorporated dye is extracted using 50:50 Sorensen citrate buffer/ethanol for at least 30 minutes, and the optical density is read at 450 nM on a spectrophotometer. Optical densities are converted to percent of cell controls and normalized to virus control, then the concentration of test compound required to inhibit CPE by 50% (ECso) is calculated by regression analysis. The concentration of compound that causes 50% cell death in the absence of virus is also calculated (CCso). The selectivity index (SI) is calculated as CC50 divided by ECso.

Influenza A: The procedure above is followed using influenza A strain California/07/09 (HlNl)pdmO9. Alternatively, the procedure above is followed, with the following minor modifications: Test compound is solubilized to form a 2 mg/mL DMSO stock solution; serial dilutions are prepared using a starting (high) test concentration of 10 pg/mL; maximum CPE is reached on day 5 post-infection.

Ebola and Marburg: Neutralization activity (IC50) is evaluated against the Ebola virus (Mayinga strain) and Marburg virus (Angola strain) glycoproteins using an rVSV- pseudotype-based neutralization assay in Vero cells, with cytotoxicity run in parallel. The assays are performed in serum- free medium (GIBCO VP-SFM # 11681-020). The neutralization assays are luciferase-based microneutralization assays. Vero cells are seeded in black 96- well plates on day -1 at 50,000 cells per well. Eight semi-log serial dilutions are prepared and incubated for 1-hour with approximately 30,000 RLU of rVSV-EBOV-GP or rVSV-MARV-GP. Virus-only and cells-only are added as controls for calculation, as well as an internal assay control for assay validation. The test article formulation is 330 pM in DMSO. The test article/virus mixture is then added in triplicate to the Vero cells and the plates are incubated for 24-hours at 37°C. Firefly Luciferase activity is detected using the Bright-Glo™ Assay System kit (Promega). Fifty percent inhibition concentration (IC50) is calculated using XLfit dose response model. For the cytotoxicity assay, Vero cells are seeded in black 96-well plates on day -1 at 50,000 cells per well. The same dilutions of the TAs are prepared in triplicate and added to Vero cells for one-day incubation at 37°C; cells-only and medium-only wells are also tested in parallel. On Day 1, cells are lysed for evaluation of the ATP content using Promega’s CellTiter-Glo® kit. Luciferase luminescence in relative light unit (RLU) is read and 50% cytotoxicity concentration (CC50) is calculated using the XLFit dose response model.

The results are summarized in the table below, with comparison to the reference compound remdesivir for the SARS-CoV2 assay (remdesivir EC50 5.6 pM and CC50 > 100 pM), and ribavirin for the influenza A assay (ribavirin EC50 3.8 pM and CC50 > 1000 pM):

Example 167: Anti-proliferative activity

Selected compounds are evaluated for their anti-proliferative activity against human cutaneous T-cell lymphoma and multiple myeloma cell lines.

HuT-78 (T cell lymphoma) cells or JJN3 (multiple myeloma) cells are cultured in RPMI- 1640 with 10% FBS and 1% penicillin/streptomycin. 45 pL suspensions of cells are transferred to the wells of 384-well plate for a density of 1,000 cells per well. The plates are incubated overnight at 37 °C under 5% CO2 atmosphere. Test compounds are dissolved in 100% DMSO at a 2 mM concentration, then diluted 20x in assay medium for to provide a 5% DMSO concentration and 100 pM compound concentration. 5 pL of this compound solution is added to the 45 pL cell suspension in the assay plate for a top plate concentration of 10 pM and 0.5% DMSO concentration. For positive controls, 10 pM APY0201 is added instead of the compound solution. After spinning at 1000 rpm for 1 minutes, the cell plate is placed in the incubator overnight at 37 °C under 5% CO2 atmosphere. After incubation for six days, the cell plate is equilibrated to room temperature for 20 minutes. 25 L of CellTiter-Glo (CTG) reagent (Promega Cat No. G7572) is added to each well, and the plate is shaken for 15 minutes at 300 rpm.

Luminescence is read on an Envision plate reader. The results are shown in the table below: