WO2008132502A1

WO2008132502A1 - Pyrazolyl-amino-substituted pyrimidines and their use for the treatment of cancer

Info

Publication number: WO2008132502A1
Application number: PCT/GB2008/050290
Authority: WO
Inventors: Huiping Guan; Barry Raymond Hayter; Shan Huang; Stephanos Ioannidis; Jeffrey Johannes; Michelle Lamb; Bo Peng; Bin Yang
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2007-04-25
Filing date: 2008-04-24
Publication date: 2008-11-06
Also published as: PE20090210A1; AR066147A1; TW200846344A; UY31048A1

Abstract

The present invention relates to compounds of Formula (I) and to their pharmaceutical compositions, and to their methods of use. These compounds provide a treatment for myeloproliferative disorders and cancer.

Description

PYRAZOLYL-AMINO-SUBSTITUTED PYRIMIDINES AND THEIR USE FOR THE TREATMENT OF CANCER

Field of the Invention

The present invention relates to novel compounds, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.

Background of the Invention

The JAK (Janus-associated kinase)/STAT (signal transducers and activators of transcription) signalling pathway is involved in a variety of hyperproliferative and cancer related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system (Haura et al, Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al, Cancer and Metastasis Reviews, 2003, 22, 423-434).

The JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl, JAK2, and JAK3, which play a critical role in cytokine- and growth factor mediated signal transduction. Cytokine and/or growth factor binding to cell-surface receptor(s), promotes receptor dimerization and facilitates activation of receptor-associated JAK by autophosphorylation. Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl, 2, 3, 4, 5a, 5b and 6). Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including, but not limited to, genes encoding apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).

Over the past decade, a considerable amount of scientific literature linking constitutive JAK and/or STAT signalling with hyperproliferative disorders and cancer has been published. Constitutive activation of the STAT family, in particular STAT3 and STAT5, has been detected in a wide range of cancers and hyperproliferative disorders (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324). Furthermore, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, impairment of negative regulatory proteins, such as the suppressors of cytokine signalling (SOCS) proteins, can also influence the activation status of the JAK/STAT signalling pathway in disease (JC Tan and Rabkin R, Pediatric Nephrology 2005, 20, 567-575).

Several mutated forms of JAK2 have been identified in a variety of disease settings. For example, translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL- JAK2, Bcr-JAK2 and PCM1-JAK2, have been implicated in the pathogenesis of various hematologic malignancies (SD Turner and Alesander DR, Leukemia, 2006, 20, 572-582). More recently, a unique acquired mutation encoding a valine-to-phenylalanine (V617F) substitution in JAK2 was detected in a significant number of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis patients and to a lesser extent in several other diseases. The mutant JAK2 protein is able to activate downstream signalling in the absence of cytokine stimulation, resulting in autonomous growth and/or hypersensitivity to cytokines and is believed to play a critical role in driving these diseases (MJ Percy and McMullin MF, Hematological Oncology 2005, 23(3-4), 91-93).

JAKs (in particular JAK3) play an important biological roles in the immunosuppressive field and there are reports of using JAK kinase inhibitors as tools to prevent organ transplant rejections (Changelian, P.S. et al, Science, 2003, 302, 875-878). Merck (Thompson, J. E. et al Bioorg. Med. Chem. Lett. 2002, 12, 1219-1223) and Incyte (WO2005/105814) reported imidazole based JAK2/3 inhibitors with enzyme potency at single nM levels. Recent Vertex PCT publications have described azaindoles as JAK inhibitors (WO2005/95400). AstraZeneca has published quinoline-3-carboxamides as JAK3 inhibitors (WO2002/92571). In addition to the above, Vertex Pharmaceuticals has described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in WO2002/50065, WO2002/62789, WO2003/027111 and WO2004/37814; and AstraZeneca has reported pyrazole compounds as inhibitors against IGF-I receptor kinase - WO2003/48133 - and Trk in WO2005/049033, WO2005/103010, WO2006/082392.

Summary of the Invention

In accordance with the present invention, applicants have hereby discovered compounds of Formula (I):

or pharmaceutically acceptable salts thereof.

It is expected that the compounds of Formula (I) may possess beneficial efficacious, metabolic, and/or pharmacodynamic properties.

The compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man. Also in accordance with the present invention the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.

The properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinases, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.

Furthermore, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia; particularly myeloma, leukemia, ovarian cancer, breast cancer and prostate cancer. Detailed Description of the Invention

The present invention relates to compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein:

Ring A may be selected from phenyl and 5- or 6-membered heterocyclyl, wherein said phenyl and 5- or 6-membered heterocyclyl may be optionally substituted with one or more R ;

X may be selected from -NH-, -O-, and -S-;

R¹ may be selected from H, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -N(R^la)N(R^la)₂,

-NO₂, -C(O)H, -C(O)R^lb, -C(O)₂R¹³, -C(O)N(R^la)₂, -OC(O)N(R^la)₂, -N(R^la)C(0)₂R^la,

-N(R^la)C(0)N(R^la)₂, -OC(O)R^lb, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, -N(R^la)S(O)₂R^lb,

-C(R^la)=N(R^la), and -C(R^la)=N(0R^la), wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5- membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R¹⁰;

R^la in each occurrence may be independently selected from H, Ci_₆alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl wherein said Ci-βalkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R¹⁰;

R^lb in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl,

C₂_6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R io ;.

R² in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -N(R^2a)N(R^2a)₂,

-NO₂, -C(O)H, -C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂, -OC(O)N(R^2a)₂, -N(R^2a)C(O)₂R^2a,

-N(R^2a)C(O)N(R^2a)₂, -OC(O)R^2b, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, -N(R^2a)S(O)₂R^2b,

-C(R^2a)=N(R^2a), and -C(R^2a)=N(OR^2a), wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R ;

R^2a in each occurrence may be independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R^2b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R³ may be selected from H, halo, -CN, Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -N(R^3a)N(R^3a)₂, -NO₂, -C(O)H, -C(O)R^3b,

-C(O)₂R^3a, -C(O)N(R^3a)₂, -OC(O)N(R^3a)₂, -N(R^3a)C(O)₂R^3a, -N(R^3a)C(O)N(R^3a)₂, -OC(O)R^3b,

-S(O)R^3b, -S(O)₂R^3b, -S(O)₂N(R^3a)₂, -N(R^3a)S(O)₂R^3b, -C(R^3a)=N(R^3a), and -C(R^3a)=N(OR^3a), wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R³⁰;

R^3a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

R^3b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

R⁴ may be selected from -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl,

-N(R^4a)C(O)R^4b, -N(R^4a)N(R^4a)₂, -NO₂, -C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂,

-OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a, -N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b,

-S(O)₂N(R^4a)₂, -N(R^4a)S(O)₂R^4b, -C(R^4a)=N(R^4a), and -C(R^4a)=N(OR^4a), wherein said d_₆alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R⁴⁰;

R^4a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰;

R^4b in each occurrence may be independently selected from Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -N(R^5a)N(R^5a)₂,

-NO₂, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)N(R^5a)₂, -N(R^5a)C(O)₂R^5a,

-N(R^5a)C(O)N(R^5a)₂, -OC(O)R^5b, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, -N(R^5a)S(O)₂R^5b,

-C(R^5a)=N(R^5a), and -C(R^5a)=N(OR^5a), wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally substituted with one or more

R⁵⁰;

R^5a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R¹⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b,

-N(R^10a)N(R^10a)₂, -NO₂, -C(O)H, -C(O)R^10b, -C(O)₂R^10a, -C(O)N(R^10a)₂, -OC(O)N(R^10a)₂,

-N(R^10a)C(O)₂R^10a, -N(R^10a)C(O)N(R^10a)₂, -OC(O)R^10b, -S(O)R^10b, -S(O)₂R^10b, -S(O)₂N(R^10a)₂,

-N(R^10a)S(O)₂R^10b, -C(R^1Oa)=N(R^1Oa), and -C(R^10a)=N(OR^10a), wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^a;

R^1Oa in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^a;

R^1Ob in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^a;

R²⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^20a)₂, -N(R^20a)C(O)R^20b,

-N(R^20a)N(R^20a)₂, -NO₂, -C(O)H, -C(O)R^20b, -C(O)₂R^20a, -C(O)N(R^20a)₂, -OC(O)N(R^20a)₂,

-N(R^20a)C(O)₂R^20a, -N(R^20a)C(O)N(R^20a)₂, -OC(O)R^20b, -S(O)R^20b, -S(O)₂R^20b, -S(O)₂N(R^20a)₂,

-N(R^20a)S(O)₂R^20b, -C(R^20a)=N(R^20a), and -C(R^20a)=N(OR^20a), wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^20b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^b;

R³⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^3Oa, -N(R^30a)₂, -N(R^30a)C(O)R^30b,

-N(R^3Oa)N(R^3Oa)₂, -NO₂, -C(O)H, -C(O)R^30b, -C(O)₂R^30a, -C(O)N(R^30a)₂, -OC(O)N(R^30a)₂,

-N(R^30a)C(O)₂R^30a, -N(R^30a)C(O)N(R^30a)₂, -OC(O)R^30b, -S(O)R^30b, -S(O)₂R^30b, -S(O)₂N(R^30a)₂,

-N(R^30a)S(O)₂R^30b, -C(R^3Oa)=N(R^3Oa), and -C(R^30a)=N(OR^30a), wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^c;

R^30a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^c;

R^30b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^c;

R⁴⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^40a)₂, -N(R^40a)C(O)R^40b,

-N(R^40a)N(R^40a)₂, -NO₂, -C(O)H, -C(O)R^40b, -C(O)₂R^40a, -C(O)N(R^40a)₂, -OC(O)N(R^40a)₂,

-N(R^40a)C(O)₂R^40a, -N(R^40a)C(O)N(R^40a)₂, -OC(O)R^40b, -S(O)R^40b, -S(O)₂R^40b, -S(O)₂N(R^40a)₂,

-N(R^40a)S(O)₂R^40b, -C(R^40a)=N(R^40a), and -C(R^40a)=N(OR^40a), wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^d;

R^40a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^40b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^d;

R⁵⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^50a, -SR^5Oa, -N(R^50a)₂, -N(R^50a)C(O)R^50b,

-N(R^50a)N(R^50a)₂, -NO₂, -C(O)H, -C(O)R^50b, -C(O)₂R^50a, -C(O)N(R^50a)₂, -OC(O)N(R^50a)₂,

-N(R^50a)C(O)₂R^50a, -N(R^50a)C(O)N(R^50a)₂, -OC(O)R^50b, -S(O)R^50b, -S(O)₂R^50b, -S(O)₂N(R^50a)₂,

-N(R^50a)S(O)₂R^50b, -C(R^5Oa)=N(R^5Oa), and -C(R^50a)=N(OR^50a), wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^e;

R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^e;

R^50b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^e; R^a, R^b, R^c, R^d, and R^e in each occurrence may be independently selected from halo, -CN,

Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂,

-N(R^m)C(O)Rⁿ, -N(R^m)N(R^m)₂, -NO₂, -C(O)H, -C(O)R", -C(O)₂R¹", -C(0)N(R^m)₂,

-0C(0)N(R^m)₂, -N(R^m)C(O)₂R^m, -N(R^m)C(0)N(R^m)₂, -OC(O)R", -S(O)R", -S(O)₂R",

-S(O)₂N(R^m)₂, -N(R^m)S(0)₂R", -C(R^m)=N(R^m), and -C(R^m)=N(0R^m);

R^m in each occurrence may be independently selected from H and Ci_₆alkyl; and

R" may be Ci_₆alkyl.

In this specification the prefix C_x__y as used in terms such as C_x__yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, Ci-₄alkyl includes Cialkyl (methyl), C₂alkyl (ethyl), Csalkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and ϊ-butyl).

Alkyl - As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.

Alkenyl - As used herein, the term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C₂_6alkenyl" includes, but is not limited to, groups such as C₂_₆alkenyl, C₂_₄alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

Alkvnyl - As used herein, the term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C₂_6alkynyl" includes, but is not limited to, groups such as C₂_₆alkynyl, C₂_₄alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl. Halo - As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo.

Carbocvclyl - As used herein, the term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH₂- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl. In one aspect, "carbocyclyl" may be cyclopropyl.

3- to 5-Membered Carbocvclyl - In one aspect, "carbocyclyl" may be "3- to 5-membered carbocyclyl." The term "3- to 5-membered carbocyclyl" refers to a saturated or partially saturated monocyclic carbon ring containing 3 to 5 ring atoms, of which one or more -CH₂- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "3- to 5-membered carbocyclyl" include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, and cyclopentenyl. In one aspect, "3- to 5-membered carbocyclyl" may be cyclopropyl.

Heterocyclyl - As used herein, the term "heterocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, pyridine-N-oxidyl and quinoline-N-oxidyl. 5- to 8-Membered Heterocyclyl - In one aspect, "heterocyclyl" may be "5- to 8-membered heterocyclyl," which refers to a saturated, partially saturated, or unsaturated, monocyclic or bicyclic ring containing 5 to 8 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH₂- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "5- to 8- membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "5- to 8- membered heterocyclyl" include, but are not limited to, azepanyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2- oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, pyridine -N-oxidyl.

5- or 6-Membered Ηeterocvclyl - In another aspect, "heterocyclyl" and "5- to 8-membered heterocyclyl" may be "5- or 6-membered heterocyclyl," which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH₂- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "5- or 6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "5- or 6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, oxazolyl, 2- oxopyrrolidinyl, 2-oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, pyridine-N-oxidyl.

6-Membered Ηeterocvclyl - In still another aspect, "heterocyclyl," "5- to 8-membered heterocyclyl," and "5- or 6-membered heterocyclyl" may be "6-membered heterocyclyl," which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH₂- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "6- membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperidinyl, morpholino, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.

6-Membered Ηeteroaryl - In yet another aspect, "heterocyclyl," "5- to 8-membered heterocyclyl," "5- or 6-membered heterocyclyl," and "6-membered heterocyclyl" may be "6-membered heteroaryl." The term "6-membered heteroaryl" is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. Illustrative examples of the term "6-membered heteroaryl" include, but are not limited to, pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.

5-Membered Ηeterocyclyl - In a further aspect, "heterocyclyl," "5- to 8-membered heterocyclyl," and "5- or 6-membered heterocyclyl" may be "5-membered heterocyclyl," which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH₂- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "5-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "5-membered heterocyclyl" include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl, thiazolyl, and thiophenyl.

Where a particular R group (e.g. R^la, R¹⁰, etc.) is present in a compound of Formula (I) more than once, it is intended that each selection for that R group is independent at each occurrence of any selection at any other occurrence. For example, the -N(R)₂ group is intended to encompass: 1) those -N(R)₂ groups in which both R substituents are the same, such as those in which both R substituents are, for example, Ci_6alkyl; and 2) those -N(R)₂ groups in which each R substituent is different, such as those in which one R substituent is, for example, H, and the other R substituent is, for example, carbocyclyl.

Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.

Effective Amount - As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

In particular, an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.

Leaving Group - As used herein, the phrase "leaving group" is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile. Examples of suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.

Optionally substituted - As used herein, the phrase "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound. One or More - In one aspect, when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted. In another aspect, the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the particular group may bear three substituents. In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents.

Pharmaceutically Acceptable - As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Protecting Group - As used herein, the term "protecting group" is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.

Illustrative examples of suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl. The deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.

Illustrative examples of suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ϊ-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl. The deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a ϊ-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

With reference to substituent R¹ for illustrative purposes, the following substituent definitions have the indicated meanings:

The compounds discussed herein in many instances were named and/or checked with ACD/Name by ACD/Labs®.

Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2 -hydroxy ethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.

Some compounds of Formula (I) may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers. The invention further relates to any and all tautomeric forms of the compounds of Formula (I).

It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.

Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

Ring A

In one aspect, Ring A may be selected from phenyl and 5- or 6-membered heterocyclyl, wherein said phenyl and 5- or 6-membered heterocyclyl may be optionally substituted with one or more

R⁵;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^5a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰; R^5b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R⁵⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, and heterocyclyl, -OR^50a, -SR^5Oa, -N(R^50a)₂, -N(R^50a)C(O)R^50b, -C(O)H,

-C(O)R^50b, -C(O)₂R⁵⁰³, -C(O)N(R^50a)₂, -OC(O)R^50a, -N(R^50a)C(O)N(R^50a)₂, -S(O)R^50b, -S(O)₂R^50b,

-S(O)₂N(R^50a)₂, and -N(R^50a)S(O)₂R^50b;

R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R^50b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In another aspect, Ring A may be 5- or 6-membered heterocyclyl, wherein said 5- or 6- membered heterocyclyl may be optionally substituted with one or more R⁵;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci-βalkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H,

-C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b,

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^5a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ;

R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -OR^50a, -SR^5Oa, -N(R^50a)₂, -N(R^50a)C(O)R^50b, -C(O)H,

-C(O)R^50b, -C(O)₂R⁵⁰³, -C(O)N(R^50a)₂, -OC(O)R⁵⁰³, -N(R^50a)C(O)N(R⁵°³)₂, -S(O)R^50b, -S(O)₂R^50b, -S(O)₂N(R > 5^0a\)₂, and j - ΛN.τ(rRr> 5^0a\)cSv(/O~»\)₂ rR> 5³0b. RR^5500aa iinn eeaacchh ooccccurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and RR^5500bb iinn eeaacchh ooccccuurrence may be independently selected from C_halky!, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl.

In still another aspect, Ring A may be selected from phenyl and 5- or 6-membered heterocyclyl, wherein said phenyl and 5- or 6-membered heterocyclyl may be optionally substituted with one or more R⁵;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, and

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H,

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ;

R^5a in each occurrence may be independently selected from H and Ci_₆alkyl, wherein said

Ci-βalkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂-₆alkenyl, and

C₂-₆alkynyl, wherein said Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

C₂-₆alkynyl, carbocyclyl, and heterocyclyl, -OR^50a, -SR^5Oa, and -N(R^50a)₂; and

R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl.

In yet another aspect, Ring A may be 5- or 6-membered heterocyclyl, wherein said 5- or 6- membered heterocyclyl may be optionally substituted with one or more R ; R⁵ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, and C₂-₆alkynyl, carbocyclyl, heterocyclyl, -0R^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

Ci-βalkyl, C₂-₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ;

R^5b in each occurrence may be independently selected from Ci-₆alkyl, C₂_₆alkenyl, and

C₂_₆alkynyl, wherein said Ci^alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -OR^50a, -SR^5Oa, and -N(R^50a)₂; and

In a further aspect, Ring A may be selected from phenyl and 6-membered heterocyclyl, wherein said phenyl and 6-membered heterocyclyl may be optionally substituted with one or more R⁵; R⁵ in each occurrence may be independently selected from halo, -CN, Ci-βalkyl, C₂_₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^5a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ; R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R⁵⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -OR^50a, -SR^5Oa, and -N(R^50a)₂; and R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl.

In still a further aspect, Ring A may be 6-membered heterocyclyl, wherein said 6-membered heterocyclyl may be optionally substituted with one or more R ;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci-βalkyl, C₂-₆alkenyl,

R^5a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ;

In yet a further aspect, Ring A may be selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl may be optionally substituted with one or more R ; R⁵ in each occurrence may be independently selected from halo, -CN, Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰; R^5a in each occurrence may be independently selected from H and Ci_₆alkyl, wherein said

R^5b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^50a in each occurrence may be independently selected from H and Ci_₆alkyl.

In one aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R ;

Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^50a in each occurrence may be independently selected from H and Ci_₆alkyl.

In another aspect, Ring A may be selected from phenyl and 6-membered heterocyclyl, wherein said phenyl and 6-membered heterocyclyl may be optionally substituted with one or more R ;

R »5 in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b;

R^5a in each occurrence may be independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl;

R in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In still another aspect, Ring A may be 6-membered heterocyclyl, wherein said 6-membered heterocyclyl may be optionally substituted with one or more R⁵;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H,

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b;

R^5a in each occurrence may be independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl;

R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In yet another aspect, Ring A may be selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl may be optionally substituted with one or more R ;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H,

-C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R⁵³, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b,

-S(O)₂N(R⁵³),, and -N(R^5a)S(O)₂R^5b;

R^5a in each occurrence may be independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl; and

R^5b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl. In a further aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R ;

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b;

R^5a in each occurrence may be independently selected from H, Chalky 1, carbocyclyl, and heterocyclyl; and

In still a further aspect, Ring A may be selected from phenyl and 6-membered heterocyclyl, wherein said phenyl and 6-membered heterocyclyl may be optionally substituted with one or more R⁵;

R in each occurrence may be independently selected from halo, -CN, Ci_6alkyl, -OR ^a, -SR ^a, and -N(R , 5a )₂, wherein said Ci_₆alkyl in each occurrence may be optionally and independently substituted with one or more R ;

R^5a in each occurrence may be independently selected from H and Ci_₆alkyl; and

R⁵⁰ may be halo.

In yet a further aspect, Ring A may be selected from phenyl and 6-membered heterocyclyl, wherein said phenyl and 6-membered heterocyclyl may be optionally substituted with one or more R⁵; and R⁵ may be halo.

In one aspect, Ring A may be 6-membered heterocyclyl, wherein said 6-membered heterocyclyl may be optionally substituted with one or more R ; and R⁵ may be halo.

In another aspect, Ring A may be selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl may be optionally substituted with one or more R⁵; and

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_6alkyl, -OR^5a, -SR^5a, and -N(R^5a)2, wherein said Ci_6alkyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R⁵⁰ may be halo.

In still another aspect, Ring A may be selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl may be optionally substituted with one or more R⁵; and R⁵ may be halo.

In yet another aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R⁵; and R⁵ may be halo.

In a further aspect, Ring A may be selected from phenyl and 6-membered heteroaryl, wherein said phenyl and 6-membered heteroaryl may be optionally substituted with one or more R ; and R⁵ may be fluoro.

In still a further aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R⁵; and R⁵ may be fluoro.

In yet a further aspect, Ring A may be selected from 6-membered heteroaryl, wherein said 6- membered heteroaryl may be optionally substituted with one or more R ; and R⁵ may be halo.

In one aspect, Ring A may be selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl may be optionally substituted with one or more R⁵; and R⁵ in each occurrence may be independently selected from halo, -CN, Ci_6alkyl, -OR^5a, -SR^5a, and -N(R^5a)2, wherein said Ci_6alkyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R⁵⁰ may be halo.

In another aspect, Ring A may be selected from phenyl, pyridinyl, and pyrimidinyl, wherein said phenyl, pyridinyl, and pyrimidinyl may be optionally substituted with one or more R⁵; and R⁵ may be fluoro.

In still another aspect, Ring A may be selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl may be optionally substituted with one or more R⁵; and R⁵ may be fluoro.

In yet another aspect, Ring A may be selected from phenyl, wherein said phenyl may be optionally substituted with one or more R ; and R⁵ may be halo.

In a further aspect, Ring A may be selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl may be optionally substituted with one or more R ; and R⁵ may be halo.

In still a further aspect, Ring A may be selected from pyridinyl, wherein said pyridinyl may be optionally substituted with one or more R⁵; and R⁵ may be halo.

In yet a further aspect, Ring A may be selected from pyrimidinyl, wherein said pyrimidinyl may be optionally substituted with one or more R ; and R⁵ may be halo.

In one aspect, Ring A may be selected from 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5- fluoropyrimidin-2-yl. In another aspect, Ring A may be selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl.

In still another further aspect, Ring A may be 4-fluorophenyl.

In yet another aspect, Ring A may be 5-fluoropyridin-2-yl.

In a further aspect, Ring A may be 3,5-difluoropyridin-2-yl.

In still a further aspect, Ring A may be 5-fluoropyrimidin-2-yl.

X

In one aspect, X may be selected from -NH- and -O- .

In another aspect, X may be selected from -NH-.

In still another aspect, X may be selected from -O- .

In one aspect, R¹ may be selected from -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, 3- to 5- membered carbocyclyl, 5-membered heterocyclyl, -0R^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -NO₂, -C(O)H, -C(O)R^lb, -C(O)₂R¹³, -C(0)N(R^la)₂, -OC(O)R^lb, -N(R^la)C(0)N(R^la)₂, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(O)₂R^lb, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R¹⁰;

R^la in each occurrence may be independently selected from H, Ci_₆alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci_6alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R¹⁰;

R^lb in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl wherein said Ci_6alkyl, C₂_6alkenyl, C₂-6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R 10 ;

R¹⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b, -C(O)H,

-C(O)R^10b, -C(O)₂R¹⁰³, -C(O)N(R^10a)₂, -OC(O)R^10b, -N(R^10a)C(O)N(R^10a)₂, -S(O)R^10b, -S(O)₂R^10b,

-S(O)₂N(R^10a)₂, and -N(R^10a)S(O)₂R^10b;

R^1Oa in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R^1Ob in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, and heterocyclyl.

In another aspect, R¹ may be selected from -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5- membered carbocyclyl, 5-membered heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -NO₂,

-C(O)H, -C(O)R^lb, -C(O)₂R¹³, -C(0)N(R^la)₂, -OC(O)R^lb, -N(R^la)C(0)N(R^la)₂, -S(O)R^lb,

-S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(O)₂R^lb, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl,

3- to 5-membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R¹⁰;

R^la in each occurrence may be independently selected from H and Ci_₆alkyl, wherein said

Ci_₆alkyl in each occurrence may be optionally and independently substituted with one or more

R¹⁰;

R^lb in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, and

C₂_₆alkynyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl in each occurrence may be optionally and independently substituted with one or more R¹⁰;

C₂_₆alkynyl, -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b, -C(O)H, -C(O)R^10b, -C(O)₂R^10a,

-C(O)N(R^10a)₂, -OC(O)R^10b, -N(R^10a)C(O)N(R^10a)₂, -S(O)R^10b, -S(O)₂R^10b, -S(O)₂N(R^10a)₂, and

-N(R^10a)S(O)₂R^10b;

R^1Oa in each occurrence may be independently selected from H and Ci_₆alkyl; and

R^1Ob in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, and

C₂_₆alkynyl. In still another aspect, R¹ may be selected from -CN, Ci_6alkyl, 3- to 5-membered carbocyclyl, 5- membered heterocyclyl, -OR^la, and -N(R^la)₂; and

R^la in each occurrence may be independently selected from H and Ci_₆alkyl.

In yet another aspect, R¹ may be selected from Ci^alkyl, 3- to 5-membered carbocyclyl, and

-OR^la; and

R^la may be Ci_₆alkyl.

In a further aspect, R¹ may be 3- to 5-membered carbocyclyl.

In still a further aspect, R¹ may be selected from -CN, Ci_₆alkyl, cyclopropyl, -OR^la, and

-N(R^la)₂; and

R ,1a^a in each occurrence may be independently selected from H and Ci_₆alkyl.

In yet a further aspect, R¹ may be selected from Ci-βalkyl, cyclopropyl, and -OR^la; and

R »l^la^a may be Ci_₆alkyl.

In one aspect, R may be selected from methyl, methoxy, and cyclopropyl.

In another aspect, R¹ may be selected from Ci_₆alkyl and -OR^la; and R^la may be Ci_₆alkyl.

In still another aspect, R¹ may be selected from methyl and methoxy.

E!

In one aspect, R² may be selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -C(O)H, -C(O)R^22b, -C(O)₂R²³, -C(O)N(R^2a)₂, -OC(O)R^2a, -N(R^2a)C(O)N(R^2a)₂, -S(O)R^2b, -S(O)₂R²", -S(O)₂N(R^2a)₂, and -N(R^2a)S(O)₂R^2b, wherein said Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R²⁰; R^2a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R 20 ;

R^2b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^20a)₂, -N(R^20a)C(O)R^20b, -C(O)H,

-C(O)R^20b, -C(O)₂R^20a, -C(O)N(R^20a)₂, -OC(O)R^20b, -N(R^20a)C(O)N(R^20a)₂, -S(O)R^20b, -S(O)₂R^20b,

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R^b;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^b in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂, -N(R^m)C(O)Rⁿ, -C(O)H, -C(O)R",

-C(O)₂R¹¹¹, -C(0)N(R^m)₂, -OC(O)R", -N(R^m)C(0)N(R^m)₂, -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂, and

-N(R^m)S(O)₂R";

R^m in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R" in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In another aspect, R² may be selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂, -OC(O)R^2a, -N(R^2a)C(O)N(R^2a)₂, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, and -N(R^2a)S(O)₂R^2b, wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R²⁰;

R^2a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl;

R^2b in each occurrence may be independently selected from Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl;

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl; and

R^20b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In still another aspect, R² may be selected from 5- to 8-membered heterocyclyl, -OR^2a, and

-N(R^2a)₂, wherein said 5- to 8-membered heterocyclyl may be optionally substituted with one or more R²⁰;

R^2a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^20a)₂, -N(R^20a)C(O)R^20b, -C(O)H,

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R ;

R^20b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^b;

R^b in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂, -N(R^m)C(O)Rⁿ, -C(O)H, -C(O)R",

-C(O)₂R¹¹¹, -C(O)N(R^m)₂, -OC(O)R", -N(R^m)C(0)N(R^m)₂, -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂, and

-N(R^m)S(O)₂R";

In yet another aspect, R² may be selected from heterocyclyl, -0R^2a, and -N(R^2a)₂, wherein said heterocyclyl may be optionally substituted with one or more R²⁰;

R^2a in each occurrence may be independently selected from H, d_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

In a further aspect, R² may be selected from 5- to 8-membered heterocyclyl, -0R^2a, and -N(R^2a)₂, wherein said 5- to 8-membered heterocyclyl may be optionally substituted with one or more R²⁰; R^2a in each occurrence may be independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^20a)₂, -N(R^20a)C(O)R^20b, -C(O)H, -C(O)R^20b, -C(O)₂R²⁰³, -C(O)N(R^20a)₂, -OC(O)R^20b, -N(R^20a)C(O)N(R^20a)₂, -S(O)R^20b, -S(O)₂R^20b,

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b;

R^20b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In still a further aspect, R² may be selected from heterocyclyl, -0R^2a, and -N(R^2a)₂, wherein said heterocyclyl may be optionally substituted with one or more R²⁰;

R^2a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence may be independently selected from Ci_₆alkyl and -S(O)₂R^20b; and

R^20b may be C_1-6alkyl.

In yet a further aspect, R² may be selected from heterocyclyl, -OR^2a, and -N(R^2a)₂, wherein said heterocyclyl may be optionally substituted with one or more R ;

R ^a in each occurrence may be independently selected from H and Ci_₆alkyl;

R^20b may be C_1-6alkyl.

In one aspect, R may be selected from heterocyclyl, -OR ^a, and -N(R ^a)₂, wherein said heterocyclyl may be optionally substituted with one or more R ₂o ;

R^2a in each occurrence may be independently selected from H, Ci_₆alkyl, wherein said Ci_₆alkyl, in each occurrence may be optionally and independently substituted with one or more R ;

R²⁰ in each occurrence may be independently selected from -CN, Ci-βalkyl, -OR^20a, and

-S(O)₂R^20b, wherein said C_halky 1 in each occurrence may be optionally and independently substituted with one or more R ;

R^20a in each occurrence may be independently selected from H and Ci^alkyl;

R^20b may be C_1-6alkyl;

R^b may be -OR^m; and R^m in each occurrence may be independently selected from H and Ci_₆alkyl.

In another aspect, R may be selected from 5- to 8-membered heterocyclyl, -OR ^a, and -N(R ^a)2, wherein said 5- to 8-membered heterocyclyl may be optionally substituted with one or more R²⁰; R ^a in each occurrence may be independently selected from H and Ci_₆alkyl; R²⁰ in each occurrence may be independently selected from Ci_6alkyl and -S(O)2R^20b; and R^20b may be C_1-6alkyl.

In still another aspect, R may be selected from 5- to 8-membered heterocyclyl, -OR ^a, and -N(R^2a)2, wherein said 5- to 8-membered heterocyclyl may be optionally substituted with one or more R²⁰;

R ,2a^a in each occurrence may be independently selected from H, Ci_₆alkyl, wherein said Ci_₆alkyl, in each occurrence may be optionally and independently substituted with one or more R 20 ;.

R²⁰ in each occurrence may be independently selected from -CN, Ci^alkyl, -OR^20a, and

-S(O)2R^20b, wherein said Ci_6alkyl in each occurrence may be optionally and independently substituted with one or more R ;

R^20a in each occurrence may be independently selected from H and Ci_₆alkyl;

R^20b may be d_₆alkyl;

R^b may be -OR^m; and

R^m in each occurrence may be independently selected from H and Ci_₆alkyl.

In yet another aspect, R² may be selected from morpholin-4-yl, 4-methyl-3-oxopiperazin-l-yl, A- methylpiperazin-1-yl, piperazin-1-yl, 4-(methylsulfonyl)piperazin-l-yl, 1,1- dioxidothiomorpholin-4-yl, 2-oxa-5-azabicycylo[2.2.1]hept-5-yl, ethoxy, and methylamino.

In one aspect, R² may be selected from 4-cyanopiperidin-l-yl, l,l-dioxidothiomorpholin-4-yl, ethoxy, 3-(hydroxymethyl)morpholin-4-yl 4-hydroxy-4-methylpiperidin-l-yl, 3- methoxyazetidin-1-yl, 4-methoxypiperidin-l-yl, methylamino, 4-methyl-3-oxopiperazin-l-yl, 4- methylpiperazin-1-yl, 4-(methylsulfonyl)piperazin-l-yl, morpholin-4-yl, 2-oxa-5- azabicycylo[2.2.1]hept-5-yl, and piperazin-1-yl. In another aspect, R² may morpholin-4-yl.

E!

In one aspect, R³ may be selected from H, halo, -CN, C_halky 1, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

-C(O)N(R^3a)₂, -OC(O)R^3a, -N(R^3a)C(O)N(R^3a)₂, -S(O)R^3b, -S(O)₂R^3b, -S(O)₂N(R^3a)₂, and

-N(R^3a)S(O)₂R^3b, wherein said C_halky 1, C₂_6alkenyl, and C₂_6alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R³⁰;

R^3b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^3Oa, -N(R^30a)₂, -N(R^30a)C(O)R^30b, -C(O)H,

-C(O)R^30b, -C(O)₂R^30a, -C(O)N(R^30a)₂, -OC(O)R^30a, -N(R^30a)C(O)N(R^30a)₂, -S(O)R^30b, -S(O)₂R^30b,

-S(O)₂N(R^30a)₂, and -N(R^30a)S(O)₂R^30b;

R^30a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R^30b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In another aspect, R³ may be selected from H, halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

-N(R^3a)S(O)₂R^3b;

R^3a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R^3b may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In still another aspect, R »3 may be selected from H, halo, and Ci_₆alkyl.

In yet another aspect, R »3 may be selected from H and halo.

In a further aspect, R³ may be selected from H, fluoro, and chloro.

In still a further aspect, R³ may be selected from H and fluoro.

In yet a further aspect, R³ may be selected from H.

In one aspect, R³ may be selected from halo.

In another aspect, R³ may be selected from fluoro.

E!

In one aspect, R⁴ may be selected from -CN, Ci-βalkyl, C₂-₆alkenyl, and C₂-₆alkynyl,

-N(R^4a)C(O)R^4b, -NO₂, -C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂,

-N(R^4a)C(O)₂R^4a, -N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b, -S(O)₂N(R^4a)₂, and

-N(R^4a)S(O)₂R^4b, wherein said Ci_₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl may be optionally substituted with one or more R⁴⁰;

R^4b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰;

R⁴⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^40a)₂, -N(R^40a)C(O)R^40b, -NO₂, -C(O)H, -C(O)R^40b, -C(O)₂R⁴⁰³, -C(O)N(R^40a)₂, -OC(O)R^40a, -N(R^40a)C(O)N(R^40a)₂, -S(O)R^40b,

-S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

R^40a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and RR^4400bb iinn eeaacchh ooccccuurrence may be independently selected from C_halky!, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In another aspect, R⁴ may be selected from Ci-₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl, wherein said

Ci_₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl may be optionally substituted with one or more R⁴⁰;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^40a)₂, -N(R^40a)C(O)R^40b, -NO₂,

-C(O)H, -C(O)R^40b, -C(O)₂R^40a, -C(O)N(R^40a)₂, -OC(O)R^40a, -N(R^40a)C(O)N(R^40a)₂, -S(O)R^40b,

-S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

In still another aspect, R⁴ may be selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, wherein said

Ci-βalkyl, C₂_₆alkenyl, and C₂_₆alkynyl may be optionally substituted with one or more R⁴⁰;

R⁴⁰ in each occurrence may be independently selected from halo, -CN, -OR^40a, -SR^40a, -N(R^40a)₂; and

R^40a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl.

In yet another aspect, R⁴ may be Ci_₆alkyl, wherein said Ci_₆alkyl may be optionally substituted with one or more R⁴⁰;

R^40a in each occurrence may be independently selected from H and Ci_₆alkyl. In a further aspect, R⁴ may be Ci_₆alkyl, wherein said Ci_₆alkyl may be optionally substituted with one or more -OR 40 ; and R⁴⁰ may be C_1-6alkyl.

In still a further aspect, R⁴ may be Ci_₆alkyl.

In yet a further aspect, R⁴ may be selected from methyl and methoxymethyl.

In one aspect, R⁴ may be methyl.

In another aspect, R⁴ may be methoxymethyl.

Ring A, X, R¹. R², R³, R⁴ and R⁵

R⁵;

X may be selected from -NH- and -O- ;

R¹ may be selected from -CN, Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, 3- to 5-membered carbocyclyl,

5-membered heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -NO₂, -C(O)H, -C(O)R^lb,

-C(O)₂R¹³, -C(O)N(R^la)₂, -OC(O)R^lb, -N(R^la)C(0)N(R^la)₂, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(O)₂R^lb, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R¹⁰;

R^la in each occurrence may be independently selected from H, C_halky 1, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci-βalkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^lb in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl wherein said Ci_6alkyl, C₂_6alkenyl,

C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R¹⁰;

R² may be selected from halo, -CN, Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -C(O)H, -C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂,

-OC(O)R^2a, -N(R^2a)C(O)N(R^2a)₂, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, and -N(R^2a)S(O)₂R^2b, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R ;

R^2a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^2b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R³ may be selected from H, halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

R^3a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

R⁴ may be selected from -CN, C_1-6alkyl, C₂_₆alkenyl, and C₂_₆alkynyl, -N(R^4a)C(O)R^4b, -NO₂,

-C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a,

-N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b, -S(O)₂N(R^4a)₂, and -N(R^4a)S(O)₂R^4b, wherein said Ci_₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl may be optionally substituted with one or more R⁴⁰;

R^4a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰; R^4b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci^alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, and heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H,

R^5b in each occurrence may be independently selected from Ci-₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b, -C(O)H,

-C(O)R^10b, -C(O)₂R^10a, -C(O)N(R^10a)₂, -OC(O)R^10b, -N(R^10a)C(O)N(R^10a)₂, -S(O)R^10b, -S(O)₂R^10b,

-S(O)₂N(R^10a)₂, and -N(R^10a)S(O)₂R^10b;

R^1Oa in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl;

R^1Ob in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R b ;

R^20b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^b;

R³⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^3Oa, -N(R^30a)₂, -N(R^30a)C(O)R^30b, -C(O)H,

-C(O)R^30b, -C(O)₂R³⁰³, -C(O)N(R^30a)₂, -OC(O)R^30a, -N(R^30a)C(O)N(R^30a)₂, -S(O)R^30b, -S(O)₂R^30b,

-S(O)₂N(R^30a)₂, and -N(R^30a)S(O)₂R^30b;

R^30a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl;

R^30b in each occurrence may be independently selected from d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

-S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

R^40a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl;

R^40b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

R⁵⁰ in each occurrence may be independently selected from halo, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl -CN, -OR^50a, -SR^5Oa, -N(R^50a)₂, -N(R^50a)C(O)R^50b, -C(O)H,

-C(O)R^50b, -C(O)₂R^50a, -C(O)N(R^50a)₂, -OC(O)R^50a, -N(R^50a)C(O)N(R^50a)₂, -S(O)R^50b, -S(O)₂R^50b,

-S(O)₂N(R^50a)₂, and -N(R^50a)S(O)₂R^50b;

R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl;

R^50b in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

R^b in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂, -N(R^m)C(0)Rⁿ, -C(O)H, -C(O)R",

-C(O)₂R¹", -C(0)N(R^m)₂, -OC(O)R", -N(R^m)C(0)N(R^m)₂, -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂, and

-N(R^m)S(0)₂R";

R" in each occurrence may be independently selected from Ci-₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl.

In another aspect, Ring A may be 6-membered heterocyclyl, wherein said 6-membered heterocyclyl may be optionally substituted with one or more R⁵;

X may be selected from -NH- and -O- ;

R¹ may be selected from -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl,

5-membered heterocyclyl, -0R^la, -SR^la, -N(R^la)₂, -N(R^la)C(0)R^lb, -NO₂, -C(O)H, -C(0)R^lb,

-C(O)₂R¹³, -C(0)N(R^la)₂, -0C(0)R^lb, -N(R^la)C(O)N(R^la)₂, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(0)₂R^lb, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R ;

R^lb in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl wherein said Ci_6alkyl, C₂_6alkenyl,

C₂_6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence may be optionally and independently substituted with one or more R¹⁰;

R² may be selected from halo, -CN, Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, heterocyclyl,

-0R^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -C(O)H, -C(0)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂,

-0C(0)R^2a, -N(R^2a)C(O)N(R^2a)₂, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, and -N(R^2a)S(O)₂R^2b, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R²⁰;

R^2b in each occurrence may be independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R²⁰;

R³ may be selected from H, halo, -CN, Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

-C(O)N(R^3a)₂, -OC(O)R^3a, -N(R^3a)C(O)N(R^3a)₂, -S(O)R^3b, -S(O)₂R³", -S(O)₂N(R^3a)₂, and

-N(R^3a)S(O)₂R^3b, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R³⁰;

R^3a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl, wherein said C_halky 1, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

R^3b in each occurrence may be independently selected from Ci_₆alkyl, C_2-6alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R³⁰;

C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -0R^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b,

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵ ;

R in each occurrence may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

-S(O)₂N(R^10a)₂, and -N(R^10a)S(O)₂R^10b;

R^20b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^b; R³⁰ in each occurrence may be independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

-S(O)₂N(R^30a)₂, and -N(R^30a)S(O)₂R^30b;

R^30b in each occurrence may be independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

-S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

-S(O)₂N(R^50a)₂, and -N(R^50a)S(O)₂R^50b;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^m, -SR^m, -N(R^m)₂, -N(R^m)C(0)Rⁿ, -C(O)H, -C(O)R",

-N(R^m)S(O)₂R";

X may be selected from -NH- and -O- ;

-C(O)₂R¹³, -C(0)N(R^la)₂, -OC(O)R^lb, -N(R^la)C(0)N(R^la)₂, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(O)₂R^lb, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl may be optionally substituted with one or more R¹⁰;

R¹⁰;

R² may be selected from 5- to 8-membered heterocyclyl, -0R^2a, and -N(R^2a)₂, wherein said 5- to

8-membered heterocyclyl may be optionally substituted with one or more R²⁰;

R³ may be selected from H, halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

-N(R^3a)S(O)₂R^3b;

R^3a in each occurrence may be independently selected from H, C_halky 1, carbocyclyl, and heterocyclyl;

R^3b may be independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl;

R⁴ may be selected from Ci_₆alkyl, C₂_₆alkenyl, and C₂_₆alkynyl, wherein said Ci_₆alkyl, C₂-₆alkenyl, and C₂-₆alkynyl may be optionally substituted with one or more R 40 ;.

-S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R ;

R^5a in each occurrence may be independently selected from H, Ci^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl and C₂_₆alkynyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

C₂_₆alkynyl -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b, -C(O)H, -C(O)R^10b, -C(O)₂R^10a,

-N(R^10a)S(O)₂R^10b;

R^1Oa in each occurrence may be independently selected from H and Ci_₆alkyl;

C₂_₆alkynyl;

-S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted with one or more R ;

R^20a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R^b;

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^40a)₂, -N(R^40a)C(O)R^40b, -NO₂,

-S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -CN, -OR^50a, -SR^5Oa, and -N(R^50a)₂;

R^50a in each occurrence may be independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, ;

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^m, -SR^m, -N(R^m)₂, -N(R^m)C(O)Rⁿ, -C(O)H, -C(O)R",

-N(R^m)S(O)₂R";

In yet another aspect, Ring A may be selected from phenyl and 6-membered heterocyclyl, wherein said phenyl and 6-membered heterocyclyl may be optionally substituted with one or more R⁵;

X may be selected from -NH- and -O- ;

R¹ may be selected from -CN, Ci-βalkyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, -0R^la, and -N(R^la)₂;

R^la in each occurrence may be independently selected from H and Ci_₆alkyl;

R² may be selected from heterocyclyl, -0R^2a, and -N(R^2a)₂, wherein said heterocyclyl may be optionally substituted with one or more R²⁰;

R³ may be selected from H, halo, and Ci-βalkyl;

R⁴ may be Ci_₆alkyl, wherein said Ci_₆alkyl may be optionally substituted with one or more R⁴⁰;

R⁵ in each occurrence may be independently selected from halo, -CN, Ci_6alkyl, -OR^5a, -SR^5a, and -N(R^5a)₂, wherein said Ci_6alkyl in each occurrence may be optionally and independently substituted with one or more R⁵⁰;

R^5a in each occurrence may be independently selected from H and Ci_₆alkyl;

R²⁰ in each occurrence may be independently selected from Ci_6alkyl and -S(O)₂R^20b; and

R^20b may be C_1-6alkyl;

R⁴⁰ in each occurrence may be independently selected from halo, -CN, -OR^40a, -SR^40a, -N(R^40a)₂;

R^40a in each occurrence may be independently selected from H and Ci_₆alkyl; and

R⁵⁰ may be halo.

In a further aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R ;

X may be selected from -NH- and -O- ;

R¹ may be selected from -CN, 3- to 5-membered carbocyclyl, Ci_6alkyl, and -OR^la;

R^la may be selected from H and Ci_₆alkyl;

R² may be selected from 5- to 8-membered heterocyclyl, -OR^2a, and -N(R^2a)₂, wherein said 5- to

8-membered heterocyclyl may be optionally substituted with one or more R²⁰;

R ^a in each occurrence may be independently selected from H and Ci_₆alkyl;

R³ may be selected from H and halo;

R⁴ may be Ci-βalkyl;

R⁵ may be halo;

R^20b may be C_1-6alkyl.

In still a further aspect, Ring A may be 6-membered heteroaryl, wherein said 6-membered heteroaryl may be optionally substituted with one or more R⁵;

X may be selected from -NH- and -O- .

R¹ may be selected from Ci_6alkyl and -OR^la; and

R^la may be C_1-6alkyl;

R² may be selected from 5- to 8-membered heterocyclyl, -OR^2a, and -N(R^2a)2, wherein said 5- to

8-membered heterocyclyl may be optionally substituted with one or more R ;

R³ may be selected from H and halo;

R⁴ may be Ci_₆alkyl, wherein said Ci_₆alkyl may be optionally substituted with one or more

-OR⁴⁰;

R⁵ may be halo;

R²⁰ in each occurrence may be independently selected from -CN, Ci_₆alkyl, -OR^20a, and

R^20a in each occurrence may be independently selected from H and Ci_₆alkyl;

R^20b may be C_1-6alkyl;

R⁴⁰ may be Ci_₆alkyl

R^b may be -OR^m; and

R^m in each occurrence may be independently selected from H and Ci_₆alkyl.

In yet a further aspect, Ring A may be selected from 4-fluorophenyl, 5-fluoropyridin-2-yl, and 5- fluoropyrimidin-2-yl;

X may be -NH-;

R¹ may be selected from methyl and methoxy;

R² may be selected from morpholin-4-yl, 4-methyl-3-oxopiperazin-l-yl, 4-methylpiperazin-l-yl, piperazin-1-yl, 4-(methylsulfonyl)piperazin-l-yl, l,l-dioxidothiomorpholin-4-yl, 2-oxa-5- azabicycylo[2.2.1]hept-5-yl, ethoxy, and methylamino;

R³ may be selected from H and fluoro; and

R⁴ may be methyl. In one aspect, Ring A may be selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5- fluoropyrimidin-2-yl;

X may be selected from -NH- and -O- ;

R¹ may be selected from methyl and methoxy;

R² may be selected from 4-cyanopiperidin-l-yl, l,l-dioxidothiomorpholin-4-yl, ethoxy, 3-

(hydroxymethyl)morpholin-4-yl 4-hydroxy-4-methylpiperidin-l-yl, 3-methoxyazetidin-l-yl, 4- methoxypiperidin- 1 -yl, methylamino, 4-methyl-3-oxopiperazin-l-yl, 4-methylpiperazin-l-yl, 4-

(methylsulfonyl)piperazin-l-yl, morpholin-4-yl, 2-oxa-5-azabicycylo[2.2.1]hept-5-yl, and piperazin-1-yl;

R³ may be selected from H, fluoro, and chloro; and

R⁴ may be selected from methyl and methoxymethyl.

In another aspect, the compound of Formula (I) may be a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein Ring A, X, R¹, R², R³, and R⁴ are as defined hereinabove.

In one aspect of the invention, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.

In another aspect, the present invention provides a compound of Formula (I) selected from: 5-Fluoro-N⁴-[(S)-l-(5-fluoro-pyrimidin-2-yl)-ethyl]-N²-(5-methoxy-lH-pyrazol-3-yl)-6- morpholin-4-yl-pyrimidine-2,4-diamine;

5-Fluoro-Λ^/4-[(l₁S^l)-l-(5-fluoropyrimidin-2-yl)ethyl]-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholin- 4-ylpyrimidine-2,4-diamine;

N^-[(S)- 1 -(5-Fluoro-pyridin-2-yl)-ethyl]-N²-(5-methoxy- lH-pyrazol-3-yl)-6-morpholin-4-yl- pyrimidine-2,4-diamine;

4-[6-[(5)- 1 -(5-Fluoro-pyridin-2-yl)-ethylamino]-2-(5-methoxy- lH-pyrazol-3-ylamino)- pyrimidin-4-yl] - 1 -methyl-piperazin-2-one;

N⁴-[(₁S)-l-(5-Fluoro-pyridin-2-yl)-ethyl]-N²-(5-methoxy-lH-pyrazol-3-yl)-6-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl)-pyrimidine-2,4-diamine;

5-Fluoro-N⁴-[(₁S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N²-(5-methoxy-lH-pyrazol-3-yl)-6-(2-oxa-5- aza-bicyclo[2.2.1]hept-5-yl)-pyrimidine-2,4-diamine;

5-Fluoro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH-pyrazol-3-yl)-6-morpholin-

4-yl-pyrimidine-2,4-diamine; l-{6-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}piperidine-4-carbonitrile; l-{5-Fluoro-6-[(l₁S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}piperidine-4-carbonitrile;

5-Fluoro-4-[(l₁S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-6-(4-methoxypiperidin-l-yl)-N-(5-methyl- lH-pyrazol-3-yl)pyrimidin-2-amine; l-{5-fluoro-6-[(l₁S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}-4-methylpiperidin-4-ol;

5-Fluoro-4-[(l₁S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-6-(3-methoxyazetidin-l-yl)-N-(5-methyl-lH- pyrazol-3-yl)pyrimidin-2-amine;

[(3i?)-4-{6-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-2-[(5-methyl-lH- pyrazol-3-yl)amino]pyrimidin-4-yl}morpholin-3-yl]methanol;

[(3i?)-4-{5-Fluoro-6-[(l₁S)-l-(5-fluoropyrimidin-2-yl)ethoxy]-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}morpholin-3-yl]methanol;

4-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-6-(4-methoxypiperidin-l-yl)-N- (5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine; l-{6-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}-4-methylpiperidin-4-ol;

4-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-6-(3-methoxyazetidin-l-yl)-N-

(5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine;

^-[(l^-l-CS^-Difluoropyridin^-yOethyll-S-fluoro-N^CS-methyl-lH-pyrazol-S-yO-β- morpholin-4-ylpyrimidine-2,4-diamine;

N⁴-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl]-5-fluoro-N²-(5-methyl-lH-pyrazol-3-yl)-

6-morpholin-4-ylpyrimidine-2,4-diamine;

5-Fluoro-N⁴-[(li?)-l-(5-Fluoropyridin-2-yl)-2-methoxyethyl]-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholin-4-ylpyrimidine-2,4-diamine;

5-Fluoro-Λ^/4-[(li?)-l-(5-Fluoropyrimidin-2-yl)-2-methoxyethyl]-N²-(5-methyl-lH-pyrazol-3-yl)-

6-morpholin-4-ylpyrimidine-2,4-diamine;

(S)-5-Fluoro-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine;

5-Fluoro-4-[(l₁S)-l-(5-Fluoropyrimidin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)-6-morpholin-

4-y lpyrimidin-2 -amine ;

5-Fluoro-4-[(l₁S)-l-(5-Fluoropyridin-2-yl)ethoxy]-N-(5-methyl-lH-pyrazol-3-yl)-6-morpholin-4- ylpyrimidin-2-amine;

4-[(l₁S)-l-(3,5-Difluoropyridin-2-yl)ethoxy]-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholin-4-y lpyrimidin-2 -amine ;

4-[(li?)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy]-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-

6-morpholin-4-ylpyrimidin-2-amine; l-(6-{[(l₁S)-l-(3,5-Difluoropyridin-2-yl)ethyl]amino}-5-fluoro-2-[(5-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl)-4-methylpiperidin-4-ol;

(R)- 1 -(6-( 1 -(3 ,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-5-fluoro-2-(5-methyl- lH-pyrazol-

3-ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol;

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4-

(methylsulfonyl)piperazin-l-yl)pyrimidine-2,4-diamine;

(S)-5-Fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(piperazin-l- yl)pyrimidine-2,4-diamine hydrochloride; 6-( 1 , l-Dioxidothiomorpholin-4-yl)-5-fluoro-N⁴-[(l₁S)- 1 -(5-fluoropyridin-2-yl)ethyl]-N²-(5- methyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine;

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methyl-N²-(5-methyl-lH-pyrazol-3- yl)pyrimidine-2,4,6-triamine;

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4- methylpiperazin- 1 -yl)pyrimidine-2,4-diamine;

N⁴-[(li?)-l-(5-Fluoropyridin-2-yl)-2-methoxyethyl]-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholin-

4-ylpyrimidine-2,4-diamine;

(S)-N⁴-( 1 -(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl- lH-pyrazol-3 -yl)-6-(piperazin- 1 - yl)pyrimidine-2,4-diamine;

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4-methylpiperazin-l- yl)pyrimidine-2,4-diamine;

(S)-A^-(I -(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholinopyrimidine-

2,4-diamine;

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N^ά-methyl-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-

2,4,6-triamine;

6-( 1 , l-Dioxidothiomorpholin-4-yl)-N⁴-[(l,S)- 1 -(5-fluoropyridin-2-yl)ethyl]-N²-(5 -methyl- IH- pyrazol-3-yl)pyrimidine-2,4-diamine;

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4-

(methylsulfonyl)piperazin-l-yl)pyrimidine-2,4-diamine;

(S)-N⁴-(l-(5-Fluoropyrimidin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine;

6-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N⁴-((S)-l-(5-fluoropyrimidin-2-yl)ethyl)-N²-(5- methyl- lH-pyrazol-3-yl)pyrimidine-2,4-diamine;

(S)-5-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine;

6-((lS,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N⁴-((S)-l-(5-fluoropyridin-2-yl)ethyl)-N²-(5- methyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine;

5-Fluoro-4-[(li?)-l-(5-fluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholin-4-ylpyrimidin-2-amine; and

(S)-6-Ethoxy-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine, or a pharmaceutically acceptable salt thereof.

Utility

JAK2

The compounds of Formula (I) have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinase, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.

The compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.

The compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.

JAK2 kinase activity was determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).

To measure JAK2 kinase activity, a commercially available purified enzyme may be used. The enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in SGl cells (Upstate Biotechnology MA). After incubation of the kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 60 minutes at room temperature, the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA). The reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specific antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature. "Tween 20" is a registered trademark of ICI Americas, Inc.

Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, in general, activity possessed by compounds of the Formula (I) may be demonstrated at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 μM.

When tested in the above in-vitro assay the JAK inhibitory activity of the following examples was measured at the indicated IC50. A dash indicates that an IC50 was not obtained for that particular compound.

Examples 1 to 10

Examples 11 to 20

Examples 21 to 30

Examples 31 to 40

Examples 41 to 51

Thus, in one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.

In still another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.

In yet another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplasia syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.

In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of an anti-proliferative effect, in a warm-blooded animal such as man.

In still a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of a JAK inhibitory effect.

In yet a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

In one aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In still another aspect, there is provided a method for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In yet another aspect, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In a further aspect, there is provided a method for producing a JAK inhibitory effect in a warmblooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In still a further aspect, there is provided a method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In yet a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.

In one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.

In another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.

In still another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti-proliferative effect, in a warm-blooded animal such as man.

In yet another further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.

In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man.

In still a further aspect, where reference is made to the treatment (or prophylaxis) of cancer, it may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous system, melanoma, fibrosarcoma including congenital fibrosarcoma and osteosarcoma. More particularly it refers to prostate cancer. In addition, more particularly it refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and / or breast cancer. In a further aspect it may refer to hormone refractory prostate cancer.

In yet a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as poly oxy ethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.

The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti -tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); and proteosome inhibitors (for example bortezomib [Velcade^®]); and the agent anegrilide [Agrylin®]; and the agent alpha-interferon;

(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis

(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3- kinase (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (Gleevec™); and any agents that modify STAT signalling;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine -transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid^R]; and (x) other treatment regimes including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies, targeted radiation therapy with 1311-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply.

In one aspect, the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.

Process

If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5^X Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove.

Compounds of Formula (I) may be prepared in a variety of ways. The Processes and Scheme shown below illustrate some methods for synthesizing compounds of Formula (I) and intermediates which may be used for the synthesis of compounds of Formula (I) (wherein Ring A, X, R¹, R², R³, and R⁴, unless otherwise defined, are as defined hereinabove). Where a particular solvent or reagent is shown in a Scheme or referred to in the accompanying text, it is to be understood that the chemist of ordinary skill in the art will be able to modify that solvent or reagent as necessary. The Processes and Scheme are not intended to present an exhaustive list of methods for preparing the compounds of Formula (I); rather, additional techniques of which the skilled chemist is aware may be also be used for the compounds' synthesis. The claims are not intended to be limited to the structures shown in the Processes and Scheme.

The skilled chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples and Scheme herein, to obtain necessary starting materials and products. In one aspect, compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be prepared by:

1) Process A - reacting a compound of Formula (A):

with a compound of Formula (B):

• _or

2) Process B - reacting a compound of Formula (C):

with a compound of Formula (D):

and thereafter if appropriate: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L and L are leaving groups.

More particularly, with regard to Process A, the pyrimidine of Formula (A) and the pyrazole of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one. Such reaction may advantageously occur in the presence of a suitable acid, examples of which include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and formic acid, and Lewis acids. The reaction is advantageously performed at a temperature in a range from 0⁰C to reflux.

In another aspect, pyrimidine of Formula (A) and the pyrazole of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base. Examples of suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ϊ-butoxide. Such a reaction may be advantageously occur in the presence of palladium acetate. Solvents suitable for such a reaction include aromatic solvents such as toluene, benzene, or xylene. Use of a protecting group for the compound of Formula (B) may help facilitate the reaction.

The pyrimidine of Formula (C) may be prepared according to Scheme 1: Scheme 1

The skilled chemist will be able to choose the substituents and leaving groups of the compound of Formula (E) so as to effect replacement of the desired leaving group by the compound of Formula (D). For example, in some instances it may be advantageous for the chemist to choose a different leaving group for L¹ than is used for L².

It should be noted that upon reaction of a compound of Formula (D) with a compound of Formula (E), two regioisomers may result, as is depicted in Scheme 2.

Scheme 2

The compounds of Formulas (A) and (G) in many instances may be separated via column chromatography. In those instances in which such a separation is difficult or inconvenient, a mixture of the two compounds may be used for the subsequent step in which a compound of Formula (A) is coupled with a compound of Formula (B).

Similarly, it is possible that upon the conditions indicated in Scheme 3, a mixture of two compounds (Formulas (H) and (I)) may result.

Scheme 3

The compounds of Formula (H) and (I) may be separated by column chromatography.

Examples

The invention will now be further described with reference to the following illustrative Examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (⁰C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 ⁰C;

(ii) organic solutions were dried over anhydrous magnesium sulfate unless other wise stated; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 ⁰C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC or liquid chromatography/mass spectroscopy and reaction times are given for illustration only;

(v) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectra data;

(vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;

(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in DMSO-dβ unless otherwise stated;

(viii) chemical symbols have their usual meanings;

(ix) solvent ratio was given in volume : volume (v/v) terms.

(x) "ISCO" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12 g, 40 g etc.), used according to the manufacturer's instructions, obtained from ISCO, Inc, 4700 Superior Street Lincoln, NE, USA.

(xi) A "Gilson column" refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H₂OMeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A.

(xii) "Biotage" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12g, 4Og, 80 g etc.), used according to the manufacturer's instructions, obtained from Biotage Inc, 1725 Discovery Drive Charlotteville, Virginia 22911, USA.

(xiii) "SFC (super critical fluid chromatography)" refers to Analytical SFC (ASC-1000 Analytical SFC System with Diode Array Detector) and/or Preparative SFC (APS- 1000 AutoPrep Preparative SFC),used according to the manufacturer's instruction, obtained from SFC Mettler Toledo AutoChem, Inc. 7075 Samuel Morse Drive Columbia MD 21046, U.S.A.

(xiv) Conditions (A) for Preparative SFC: Oven 40⁰C; Flow: 60ml/min; Outlet Pressure: 100 bar; Wavelength: 254nm unless specified otherwise.

(xv) Conditions (B) for Analytical SFC for chiral determination: Oven 35°C, Flow: 5ml/min; Outlet Pressure: 120 bar;, Wavelength for e.e. determination: 254nm unless otherwise stated, (xvi) Chiral column and solvent conditions: AD, AS, OJ, and OD correspond to the chiral column (see below); the number (from 1 to 4) immediately after the chiral column designation corresponds to the mobile phase modifier (see xvii below). For example:

AD-3-20 indicates Chiralpak AD with 20% methanol and 0.4%dimethylethylamine, used for chiral purification or e.e. determination, (xvii) Mobile phase modifier: l=Methanol, 2=isopropanol, 3=methanol,

0.4%dimethylethylamine, and 4=isopropanol, 0.4%dimethylethylamine. (xviii) Chiralcel^® OJ and OD or Chiralpak^® AS and AD columns are used according to the manufacturer's instructions, obtained from Chiral Technologies,Inc. 800

NorthFivePointsRoad WestChester, PA19380, USA. (xix) Conditions (Cl) for Preparative HPLC: Chiralpak-AD^® 5x50cm; diameter 20μ; Flow

120ml/min unless otherwise stated, (xx) Conditions (C2) for Preparative HPLC: Chiralcel-OJ^® 5x50cm; diameter 20μ; Flow

120ml/min unless otherwise stated, (xxi) Conditions (D) for Analytical HPLC for chiral determination: Chiralpak-AD^®

5x50cm; diameter 20μ; Flow lml/min unless otherwise stated, (xxii) Enantiomeric excess for each individual enantiomer (e.e.): > % calculated using area percent at 220 nm or 254nm.

(xxiii) After chiral purification, all Examples have e.e. >98% unless otherwise stated, (xxiv) The Examples depicted in this application have been characterized by the use of n.O.e

(nuclear Overhauser effect) studies, 2D ¹H n.m.r., ¹H n.m.r., ¹⁹F n.m.r. and other spectroscopic studies, (xxv) Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres

(60 psi) and temperatures to 80 ⁰C. (xxvi) the following abbreviations have been used:

BINAP 2,2'-bis(diphenylphosphino)-l,l '-binapthyl

BOC2O di-fert-butyl-dicarbonate

DCM dichloromethane DIPEA N, N-diisopropylethylamine

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethylsulfoxide dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene

EtOAc ethyl acetate

Et₂O diethyl ether

GC gas chromatography

HPLC high-performance liquid chromatography

LCMS liquid chromatography/mass spectroscopy

Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (O)

THF tetrahydrofuran

TFA trifluoroacetic acid e.e. enantiomeric excess

Intermediate 1

S-Fluoropyrimidine^-carbonitrile

A 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd₂(dba)₃ (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol). The flask was evacuated and backfilled with N₂, and anhydrous dimethylacetamide. The vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 ⁰C for 10 hours. The reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness. The dried residue was purified by silica gel chromatography (By ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a creamy solid (1.50 g, 80%). GC-MS: 123 [M]; ¹H NMR (CDCl₃) δ: 8.80 (s, 2H).

Intermediate 2

N-( 1 -(5-Fluoropyrimidin-2-yl)vinyl)acetamide

5-Fluoropyrimidine-2-carbonitrile (Intermediate 1, 1.0 g, 8.1 mmol) in THF (10 ml) was added to a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0 ⁰C. After addition, the reaction was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction was stirred at room temperature for 1 hour and 40 ⁰C for 1 hour. Saturated sodium bicarbonate solution (10 ml) was added and extracted with EtOAc (2x20 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 2.5 : 1) to give the title compound as a white solid (0.38 g, 26%). ¹H NMR (400 MHz) δ: 9.34 (s, IH), 8.95 (s, 2H), 6.25 (s, IH), 6.03 (s, IH), 2.11 (s, 3H). LCMS: 182 [M+H]⁺ 182.

Intermediate 3

N-[(15Vl-(5-Fluoropyrimidin-2-yl)ethyllacetamide

N-(l-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Intermediate 2, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-l,2-bis((25^l, 55)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction was stirred at room temperature for 4 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (0.096 g, 95%). ¹H NMR (400 MHz) δ: 8.84 (d, 2H), 8.34 (d, IH), 5.00 (m, IH), 1.84 (s, 3H), 1.37 (d, 3H). LCMS: 184 [M+H]. Enantiomeric excess determined by HPLC (Chiralpak IA; 95:5 CO₂MeOH), >99% ee.

Intermediate 4 tert-Butyl [(15Vl-(5-fluoropyrimidin-2-yl)ethyl^"|carbamate

N-[(l,S)-l-(5-Fluoropyrimidin-2-yl)ethyl]acetamide (Intermediate 3, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and BoC₂O (0.60 g, 2.73 mmol) in THF (10 ml) was stirred at 50 ⁰C for 40 hours. After cooling to room temperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) and water (10 ml) was added. The reaction was stirred at room temperature for 9 hours. Ether (30 ml) was added, organic layer was separated, washed with brine (20 ml) and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (Hex-EtOAc=5:l) to give the title compound as a pale yellow oil (0.21 g, 80%). ¹H NMR (400 MHz) δ: 8.84 (s, 2H), 7.24 (d, IH), 4.74 (m, IH), 1.35 (s, 12H). LCMS: 242 [M+H].

Intermediate 5

(IS)-I -(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride

To a solution of tert-butyl [(l₁S)-l-(5-fluoropyrimidin-2-yl)ethyl]carbamate (Intermediate 4, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed to give the title compound as white solid (quantitative). LCMS: 142 [M+H].

Intermediate 6

4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine

A round-bottom flask was charged with 2,4,6-trichloro-5-fluoropyrimidine (WO200549033, 2.0 g, 10 mmol), in EtOH (100ml) and was cooled to -20⁰C. Morpholine (0.95 g, 11 mmol) in EtOH (20 ml) was added drop-wise to the reaction mixture in the course of 1 hour. The reaction was stirred at -20⁰C for 30 minutes and at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between DCM and H₂O. Organic phase was concentrated under reduced pressure to give a solid. Recrystallization from EtOH afforded the title compound (1.75 g, 86%). ¹U NMR (δ) 6.76 (s, IH), 3.69 (m, 8H). LCMS: 252 [M+H].

Intermediate 7

2-Chloro-5-fluoro-N-[(15^f)-l-(5-fluoropyrimidin-2-yl)ethyl]-6-morpholin-4-ylpyrimidin-4-amine A round-bottom flask was charged with 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6, 1.45 g, 5.75 mmol), (15)-l-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 1.23 g, 5.75 mmol), DIPEA (4.0 ml, 23 mmol) in n-BuOH (20ml). The reaction was heated at 130⁰C overnight. Solvent was removed and the mixture was purified by silica gel chromatography (ISCO Combiflash with gradient EtOAc and Hexane with 1% Et₃N) to afford the title compound 1.20 g (58 %). ¹H NMR (δ) 8.85 (s, 2H), 7.69 (m, IH), 5.21 (m, IH), 3.65 (m, 4H), 3.53 (br, 4H), 1.54 (d, 3H) . LCMS: 357 [M+H].

Intermediate 8

5-Methoxy- lH-pyrazol-3 -amine To a solution of 3-amino-5-hydroxypyrazole (50.00 g) in CH2CI2 (800 ml) was added triphenylphosphine (155.64 g) and the resulting mixture was cooled to 0⁰C. Diisopropyl azodicarboxylate (117.64 ml) was added drop-wise over a period of 35 minutes (temp < 2°C) to give a dark brown, mobile slurry. The reaction mixture was then held at 0⁰C for lhr. A beige precipitate came out of solution after 20 minutes. MeOH (50 ml) was then added drop-wise over a period of 15 minutes at 0⁰C as the slurry thinned considerably to give a lighter yellow slurry. The reaction mixture was then held at 0⁰C for lhr. The reaction was warmed slowly to ambient temperature over a period of 2 hours. The reaction mixture was then held at ambient temp for 22 hours. The reaction mixture was filtered to remove undissolved solids. The filtrate was dried (MgSO₄) and concentrated under reduced pressure to give a yellow-orange oil. Purification by column chromatography (5%-> 10% MeOHZCH₂Cb) afforded the title compound as a waxy solid. ¹H NMR (300 MHz) δ: 4.67 (s, 1 H) 3.61 (s, 3 H); LCMS: 114 [M+H].

Intermediate 9 tert-Butyl S-amino-S-methoxy-lH-pyrazole-l-carboxylate

To a solution of 5-methoxy-lH-pyrazol-3-amine (Intermediate 8, 2.48 g, 17.6 mmol) in DCM (70 ml) was added BoC₂O (4.0 g, 18.5 mmol) followed by a 4.5 M solution of KOΗ (31 ml, 140.8 mmol) at 0⁰C. The resulting mixture was stirred at ambient temperature overnight, diluted with more DCM. The combined organic layers dried (MgSO₄) and evaporated to give a yellow oil. Purification by column chromatography (Biotage, 20%->30% EtOAc/hexanes) afforded the title compound as solid. LCMS: 214 [M+Η].

Intermediate 10 tert-Butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate

5-Methyl-lH-pyrazol-3-amine and BoC₂O were reacted using a procedure similar to the one described for the synthesis of Intermediate 9, providing the title compound.

LCMS: 198 [M+Η].

Intermediate 11

5-Fluoropyridine-2-carbonitrile

2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), dppf (11.7 g, 21.1 mmol) and Pd₂dba₃ (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 ⁰C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1:1) to give the title compound as a white solid (49 g, 72%). ¹H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH).

Intermediate 12

N-ri-(5-Fluoropyridin-2-yl)vinvHacetamide

A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 ⁰C. 5-Fluoropyridine-2-carbonitrile (Intermediate 11, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 ⁰C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added drop-wise at 0 ⁰C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). ¹H NMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). LCMS: 181 [M+H].

Intermediate 13

N-\( IS)- 1 -(5-Fluoropyridin-2-yl)ethyll acetamide

To a solution of N-(l-(5-fluoropyridin-2-yl)vinyl)acetamide (Intermediate 12, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N₂ was added (+)-l,2-bis((2₁S,55)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H₂. The reaction stirred at room temperature and maintained inside pressure between 120-150 psi for 7 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (9.8 g, 88%). ¹H NMR (400 MHz) δ: 8.49 (d, J= 2.4 Hz, IH), 8.32 (d, J = 7.6 Hz, IH), 7.66 (m, IH), 7.39 (dd, J= 4.4 and 8.8 Hz, IH), 4.95 (m, IH), 1.85 (s, 3H), 1.34 (d, J = 7.2 Hz, 3H). LCMS: 183 [M+H]. Enantiomeric excess determined by HPLC (Chiralpak IA; 70:30 CO₂MeOH), 95.3% ee.

Intermediate 14 tert-Butyl [(l»S^-l-(5-fluoropyridin-2-yl)ethyllcarbamate

A solution of N-[(15)-l-(5-fluoropyridin-2-yl)ethyl]acetamide (Intermediate 13, 11.0 g, 60.37 mmol), DMAP (1.48 g, 12.07 mmol) and di-fert-butyl-dicarbonate (26.35 g, 120.7 mmol) in THF (100 ml) was stirred at 50 ⁰C for 20 hours. After cooled to room temperature, lithium hydroxide monohydrate (5.19 g, 123.8 mmol) and water (100 ml) were added. The reaction was stirred at room temperature for 5 hours and diluted with ether (200 ml). The organic layer was separated, washed with brine (100 ml), and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 5:1) to give the title compound as a pale yellow oil (13.6 g, 94%). ¹U NMR (400 MHz) δ: 8.46 (d, IH), 7.69 (m, IH), 7.35-7.41 (m, 2H), 4.67 (m, IH), 1.37 (s, 9H), 1.32 (d, 3H). LCMS: 241 [M+H].

Intermediate 15 r(15yi-(5-Fluoropyridin-2-yl)ethyl^"|amine

To a solution of tert-butyl [(l.S^<)-l-(5-fluoropyridin-2-yl)ethyl]carbamate (Intermediate 14, 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxane solution (107 ml, 4 N, 428 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed and 50 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6 x 400 ml), dried over sodium sulfate and concentrated to give the title compound (7.30 g, 98%) as pale yellow oil. ¹H NMR (400 MHz) δ: 8.44 (d, IH), 7.66 (m, IH), 7.53 (m, IH), 4.01 (q, IH), 1.94 (b, 2H), 1.26 (d, 3H). LCMS: 141 [M+H].

The hydrochloride salt of the title compound may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvent provides the hydrochloride salt of the title compound as a tan solid.

Intermediate 16 2,6-Dichloro-N-r(15)-l-(5-fluoropyridin-2-yl)ethyllpyrimidin-4-amine

A solution of [(15)-l-(5-Fluoropyridin-2-yl)ethyrjamine (Intermediate 15, 556mg, 4mmol) in EtOH (6ml) was added into a solution of 2,4,6-trichloropyrimidine (Aldrich, 372mg, 4mmol) and DIPEA (1.39ml, 8mmol) in EtOH (10ml) at -30⁰C. The mixture was allowed to warm to 0⁰C whereupon it was stirred for 4 hours and then at ambient temperature for 24 hours. Evaporation of the solvents under reduced pressure gave a residue. This residue was purified by silica gel chromatography (ISCO, DCM/MeOH/NH₄OH: 100/0/0^ 100/2/0.2) to give the title compound (620mg, 54%). LCMS: 289 [M+H].

Intermediate 17

(4,6-Dichloro-5-fluoro-pyrimidin-2-yl)-(5-methoxy-lH-pyrazol-3-yl)-amine To the solution of 2,4,6-trichloro-5-fluoro-pyrimidine (PCT Pub. No. WO200549033, 1.66 g, 8.26 mmol) in EtOH (3OmL) at -30⁰C was added 5-methoxy-lH-pyrazol-3-amine (Intermediate 8, 1.Og, 9.08 mmol). DIPEA (4.3 mL, 25 mmol) was added to the solution and the reaction mixture was naturally warmed to 0⁰C for 3 hours and then at room temperature overnight. Evaporation of the solvents under reduced pressure, a white precipitate was removed by filtration. The mother liquid was evaporated to dryness and purified by silica gel chromatography (ISCO, DCM/MeOΗ/NΗ₄OΗ: 100/0/0-100/3/0.3) to give the title compound (221mg, 10%). LCMS: 279 [M+H].

Intermediate 18

3,5-Difluoro-2-hvdrazinylpyridine

In a 250 mL round-bottomed flask was added hydrazine monohydrate (17.69 mL, 563.61 mmol) and 2,3,5-trifluoropyridine (25.0 g, 187.87 mmol) in THF (150 mL) to give a colorless solution. The reaction was heated over 72 h at 50 ⁰C. Concentration removed THF, and EtOAc (80 mL) was added. Filtration afforded the first crop of product as a solid which was washed with water (50 mL). The aqueous layer was extracted with EtOAc (3 X 30 mL). Concentration of the organic layer afforded the second crop of the product. The crude product was loaded into silica gel chromatography and eluted with EtOAc/hexane (30%). The collected fractions were concentrated to give the product (23.0 g, 84% yield). ¹H NMR δ 4.09 (s, 2 H), 7.62 (ddd, 1 H), 7.75 (s, 1 H), 7.96 (d, 1 H). Intermediate 19

2-Bromo-3,5-difluoropyridine

In a 500 mL round-bottomed flask was added 3,5-difluoro-2-hydrazinylpyridine (Intermediate 18, 16.0 g, 110.26 mmol) in CHCI3 (158 ml) to give a brown suspension. The reaction was heated to 40 ⁰C, and bromine (14.20 ml, 275.65 mmol) was added drop-wise over 15 min. The reaction mixture was refluxed at 60 ⁰C for 1 hour. After cooling down to rt, the flask was placed in a ice bath, and sat. NaHCO₃ was added very slowly to quench the reaction. Partition, extraction with DCM (2 X 80 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexane (0-20%). Collected fractions were concentrated to give the product (12.0 g, 56% yield). ¹H NMR δ 8.18 (td, 1 H), 8.46 (d, 1 H).

Intermediate 20

2-Bromo-3,5-difluoro-4-(trimethylsilyl)pyridine

In a 250 mL round-bottomed flask was added 2-bromo-3,5-difluoropyridine (Intermediate 19, 5.35 g, 27.58 mmol) in THF (55.2 ml) to give a yellow solution. The solution was cooled to -78 ⁰C and LDA (22.98 ml, 41.37 mmol) was added. The solution turned dark immediately, and after stirring at rt for 10 min, chlorotrimethylsilane (3.66 ml, 28.96 mmol) was added. After 0.5 h, sat. NH₄Cl was added to quench the reaction. Partition, extraction with EtOAc (2 X 30 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexane (0-20%). Collected fractions were concentrated to give the product (5.90 g, 80% yield). ¹U NMR δ 0.40 (s, 9 H), 8.34 (s, 1 H).

Intermediate 21

N-(2-(tert-Butyldimethylsilyloxy)-l-(3,5-difluoro-4-(trimethylsilyl)pyridin-2-yl)ethyl)-2- methylpropane-2-sulfϊnamide

In a 250 mL round-bottomed flask was 2-bromo-3,5-difluoro-4-(trimethylsilyl)pyridine

(Intermediate 20, 5.9 g, 22.17 mmol) in THF (36.9 ml) to give a yellow solution. The solution was cooled to -78 ⁰C, and H-BuLi (13.85 ml, 22.17 mmol) was added. After stirring at that temperature for 10 min, N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2- sulfinamide (Intermediate 25, 7.38 g, 26.60 mmol) was added. The reaction was stirred for another 20 min, and sat. NH₄Cl (40 mL) was added to quench the reaction. Warming up to rt, partition, extraction with EtOAc (2 X 20 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAC/hexane (0-60%). Collected fractions were concentrated to give the product (5.0 g, 48.5% yield). IH NMR δ -0.17 (s, 3 H), -0.06 (s, 3 H), 0.37 (s, 9 H), 0.71 (s, 9 H), 1.05 (s, 9 H), 3.92 (m, 2 H), 4.67 (m, 1 H), 5.50 (d, J= 7.91 Hz, 1 H), 8.44 (s, 1 H).

The title compound may also be prepared by the following procedure:

In a 500 mL round-bottomed flask was added 3,5-difluoropyridine (4.22 g, 36.67 mmol) in tetrahydrofuran (147 ml) to give a colorless solution. The solution was cooled to -78 ⁰C before LDA (20.37 ml, 36.67 mmol) was added. After kept at -78 ⁰C for 10 min, chlorotrimethylsilane (4.64 ml, 36.67 mmol) was added slowly. The reaction mixture was kept at -78 ⁰C for another 10 min, LDA (50.9 ml, 91.67 mmol) was slowly added and the mixture was allowed to stir for 0.5 h before (R)-(E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (10.18 g, 36.67 mmol) was added in THF (20 mL). Sat. NH₄Cl (80 mL) was added to quench the reaction after 0.5 hours. Partition, extraction with EtOAc (2 X 50 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexanes (0-40%). Collected fractions were concentrated to give the product at 41.1% yield.

Intermediate 22 tert-Butyl 1 -(3 ,5-difluoropyridin-2-yl)-2-hvdroxyethylcarbamate

In a 200 mL round-bottomed flask was N-(2-(tert-butyldimethylsilyloxy)-l-(3,5-difluoro-4- (trimethylsilyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 21, 5.0 g, 10.76 mmol) in methanol (45 ml) to give a brown solution. Cool the solution to 0 ⁰C, and HCl (4 M in dioxane) (10.76 ml, 43.03 mmol) was added. The reaction was stirred at 0 ⁰C for 1 hour. The solution was concentrated in a 250 mL of round-bottomed flask to give a residue (2.65 g). To the residue was added water (35 mL) to give a yellow solution. The reaction mixture was diluted with THF (70 mL). At rt, BoC₂O (3.00 mL, 12.91 mmol) and NaOH (8.61 mL, 5 M aq solution) were added. The reaction was allowed to stir at rt for 1 hour. Extraction with EtOAc (2 X 40 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was loaded into a silica gel chromatography and eluted with EtOAc/hexane (20-80%). Collected fractions were concentrated to give the product (1.80 g, 61% yield). LCMS (M + Na) = 297.

Intermediate 23 tert-Butyl 1 -(3 ,5-difluoropyridin-2-yl)-2-methoxyethylcarbamate

In a 200 mL round-bottomed flask was tert-butyl l-(3,5-difluoropyridin-2-yl)-2- hydroxyethylcarbamate (Intermediate 22, 1.80 g, 6.60 mmol) in THF (25 mL) to give a brown solution. The solution was cooled to -15 ⁰C using NaCl-ice bath. Potassium tert-butoxide (1.481 g, 13.2 mmol) was added. The reaction was kept at that temp and after 20 min, iodomethane (0.413 mL, 6.6 mmol) was added. The reaction was stirred at that temp for 1.5 hours. TLC monitor showed a little starting material left, additional 0.3 g of KOt-Bu was added, followed by 0.05 mL of iodomethane. After another 10 min, sat. NH₄Cl was added to work up the reaction. Partition, extraction (EtOAc, 2 X 15 mL), drying (Na₂SO₄), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAC/hexane (0-40%). Collected fractions were concentrated to give the product (1.0 g, 53%). ¹H NMR δ 1.34 (s, 9 H), 3.21 (s, 3 H), 3.57 (d, 2 H), 5.06 (d, 1 H), 7.28 (d, 1 H), 7.90 (m, 1 H), 8.49 (m, 1 H).

Intermediate 24

1 -(3 ,5-Difruoropyridin-2-yl)-2-methoxyethanamine hydrochloride

In a 100 mL round-bottomed flask was tert-butyl l-(3,5-difluoropyridin-2-yl)-2- methoxyethylcarbamate (Intermediate 23, 1.10 g, 3.82 mmol) in MeOH (5.0 mL) to give a colorless solution. To the solution at rt HCl in dioxane (1.908 mL, 7.63 mmol) was added. The reaction was stirred at rt for 2 hours. Concentration removed MeOH, and to the residue was added dry ether (10 mL). Decanting removed ether, and concentration gave the product as a solid (0.7 g, 97%). ¹H NMR O 3.29 (s, 3 H), 3.72 (m, 2 H), 4.83 (s, 1 H), 8.13 (m, 1 H), 8.65 (m, 3 H).

Intermediate 25

N-(2-(fer?-Butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfϊnamide To a suspension of rac-2-methylpropane-2-sulfinamide (3.1Og, 26 mmol) and CuSO₄ (8.3g, 52 mmol) in 60 mL DCM, was added fert-butyldimethylsilyloxy acetaldehyde (5.Og, 26 mmol) at rt. The mixture was stirred at rt for 18h and then filtered through a Celite® pad followed by washing with DCM. The filtrate was concentrated in vacuo and then purified by column chromatography (20 to 40% EtOAc/π-hexane) to give the title compound (6.59g, 92%) as a pale yellow oil.

Intermediate 26

5 -F luoro-2 - vinylpyrimidine

To a stirred solution of potassium vinyltrifluoroborate (9.80 g, 73.19 mmol), 2-chloro-5- fluoropyrimidine (9.32 mL, 73.19 mmol), PPh₃ (2.304 g, 8.78 mmol), and Cs2CO₃ (71.5 g, 219.58 mmol) in THF (144 mL) and water (16 mL) was added PdCl₂ (0.519 g, 2.93 mmol) in one portion. The reaction mixture was heated to 85 ⁰C for 48 hours. After cooling, the reaction mixture was filtered through a pad of celite with the aid of DCM (10OmL). The solids that remained in the flask were triturated with DCM and filtered. The resulting filtrate was carefully concentrated to give 5-fluoro-2-vinylpyrimidine as a heterogeneous brown oil, which was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ 5.70 (d, 1 H) 6.53 (dd, 1 H) 6.86 (dd, 1 H) 8.55 (s, 2 H); LCMS: [M+H] = 124.36.

Intermediate 27

5-Fluoro-2-(oxiran-2-yl)pyrimidine

To a stirred solution of 5-fluoro-2-vinylpyrimidine (Intermediate 26, 9.06 g, 73 mmol), (S, S)- (+)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-l,2-cyclohexanediamino-manganese(III) chloride (0.927 g, 1.46 mmol), and 4-Phenylpropyl pyridine N-oxide (1.246 g, 5.84 mmol), and sodium phosphate, dibasic (1.036 g, 7.30 mmol) in water (76 ml) and DCM (106 ml) was added NaOCl solution 5.65-6% (380 ml, 255.50 mmol) in one portion. The reaction mixture was stirred for 48 hours. The reaction was filtered through a pad of celite with the aid of DCM. The aqueous layer was extracted with DCM. The combined organic extracts were dried (Na₂SO₄) and concentrated. Purification via ISCO chromatography (0% to 10% to 20% EtOAc-hexanes, DCM load, SiO₂) gave 5-fluoro-2-(oxiran-2-yl)pyrimidine (2.80 g, 27.4 %) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.20 (ddd, 2 H) 4.12 (dd, 1 H) 8.58 (s, 2 H); LCMS: [M+H] = 140.61. Intermediate 28

2-Azido-2-(5-fluoropyrimidin-2-yr)ethanol

To a stirred solution of 5-fluoro-2-(oxiran-2-yl)pyrimidine (Intermediate 27, 2.8 g, 19.98 mmol) and ammonium chloride (1.817 g, 33.97 mmol) in MeOH (200 mL) was added NaN₃ (3.25 g, 49.96 mmol) in one portion. The reaction mixture was heated to 50 ⁰C for 8 h, After cooling, the MeOH was removed via rotary evaporation and the resulting solids were partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na₂SO₄) and concentrated. Purification via ISCO chromatography (0% to 23% to 50% EtOAc-hexanes, DCM load, SiO2) gave 2-azido-2-(5-fluoropyrimidin-2-yl)ethanol (0.500 g, 13.66 %) and 2-azido-l-(5-fluoropyrimidin-2-yl)ethanol (1.600 g, 43.7 %) as yellow oils. ¹H NMR (400 MHz, CDCl₃) δ (for 2-Azido-2-(5-fluoropyrimidin-2-yl)ethanol): 3.02 (t, 1 H) 4.07 (t, 2 H) 4.74 (t, 1 H) 8.64 (s, 2 H); LCMS: [M-N2-H] = 154.42.

Intermediate 29

2-(l-Azido-2-methoxyethyl)-5-fluoropyrimidine

To a stirred solution of 2-azido-2-(5-fluoropyrimidin-2-yl)ethanol (Intermediate 28, 360 mg, 1.97 mmol) and proton-sponge (l,8-Bis-(dimethylamino)-naphthalene) (421 mg, 1.97 mmol) in DCM (19 ml) at 0 ⁰C was added trimethyloxonium tetrafluoroborate (291 mg, 1.97 mmol) in one portion. The reaction was monitored by TLC. The reaction proceeded to 60% conversion, then stalled. Additional Proton-sponge (l,8-Bis-(dimethylamino)-naphthalene) (211 mg, 0.98 mmol) and Trimethyloxonium tetrafluoroborate (116 mg, 0.79 mmol) were added. The reaction reached 85% conversion. Water was added and the reaction mixture was partitioned between EtOAc and 0.5 M (aq) CuSO4 to give a partial emulsion. This biphasic mixture was filtered though a fritted funnel with the aid of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. Purification via ISCO chromatography (0% to 10% to 20% EtOAc-hexanes, DCM load, SiO₂) gave 2-(l-azido-2- methoxyethyl)-5-fluoropyrimidine (243 mg, 62.7 %) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.41 (s, 3 H) 3.85 - 3.94 (m, 2 H) 4.80 (dd, 1 H) 8.62 (s, 2 H); LCMS: [M+H] = 198.01.

Intermediate 30

1 -(5-Fluoropyrimidin-2-yl)-2-methoxyethanamine hydrochloride To a stirred solution of 2-(l-azido-2-methoxyethyl)-5-fluoropyrimidine (Intermediate 29, 243 mg, 1.23 mmol) in THF (10.6 mL) and water (1.767 mL) was added 4-diphenylphosphino polystyrene resin (998 mg, 1.85 mmol) in one portion. The reaction mixture was heated to 65 ⁰C for 2 hours. After cooling, the reaction mixture was filtered with the aid of EtOAc and concentrated to give l-(5-fluoropyrimidin-2-yl)-2-methoxyethanamine (196 mg, 93 %) as a yellow oil which was used without further purification. IH NMR (400 MHz, CDCl₃) δ 3.35 (s, 3 H) 3.64 (dd, 1 H) 3.76 (dd, 1 H) 4.34 (dd, 1 H) 8.57 (s, 2 H); LCMS: [M+H] = 171.82. The hydrochloride salt was prepared by the addition of 4N HCl in dioxane to a methanolic solution of the amine followed by evaporation of the solvents to dryness.

Intermediate 31 l-(5-fluoropyridin-2-yl)ethanol

To a solution of 5-fluoropyridine-2-carbaldehyde (2.5 g) in Et₂O (50 ml) at 0⁰C was added drop- wise a solution of MeMgBr (8 ml, 3.0M in Et₂O). The resulting solution was stirred at this temperature for 30 minutes and then it was allowed to warm to ambient temperature over 1 hour. The mixture was quenched with a solution of saturated NH₄Cl(_aq) and extracted with Et₂O. The organic extracts dried and evaporation gave the title compound (2.6 g). ¹H NMR δ 8.43 (s, IH), 7.69 (m, IH), 7.55 (m, IH), 5.40 (d, IH), 4.71 (m, IH), 1.33 (d, 3H).

Intermediate 32 l-(5-fluoropyrimidin-2-yl)ethanone

To a solution of 5-fluoropyrimidine-2-carbonitrile (Intermediate 1, 2.5 g) in Et₂O (50 ml) at 0⁰C was added drop-wise a solution of MeMgBr (12 ml, 3.0M in Et₂O). The resulting solution was stirred at this temperature for 30 minutes and then it was allowed to warm to ambient temperature o/n. The mixture was quenched with a solution of saturated NH₄C^q) and extracted with Et₂O. The organic extracts dried and evaporation gave a colored residue. Purification by column chromatography (ISCO, 3% MeOH/DCM) to afford the title compound (800 mg). ¹H NMR (CDCl₃) δ 8.75 (s, 2H), 2.77 (s, 3H).

Intermediate 33 l-(5-fluoropyrimidin-2-vP)ethanol To a solution of l-(5-fluoropyrimidin-2-yl)ethanone (Intermediate 32, 800 mg) in MeOH (40 ml) at 0⁰C was added portion-wise NaBH₄ (12 ml, 3.0M in Et₂O). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between H₂O and DCM. The organic layer was washed with saturated NH₄Cl(_aq) solution, H₂O and brine. The organic extracts dried and evaporation gave the tile compound (330 mg). ¹H NMR (CDCl₃) δ 8.59 (s, 2H), 4.96 (m, IH), 3.79 (br s, IH), 1.54 (d, 3H).

Intermediate 34

N-(2-(fer?-Butyldimethylsilyloxy)-l-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfϊnamide To a solution of 2-bromo-5-fluoropyridine (5.2g, 29 mmol) in 80 mL of anhydrous MTBE was slowly added 1.7M solution of LDA in pentane (21 mL, 36 mmol) at -78⁰C. After being stirred for 30 min at -78⁰C, a solution of N-(2-(fert-butyldimethylsilyloxy)ethylidene)-2-methylpropane- 2-sulfϊnamide (Intermediate 25, 6.59 g, 24 mmol) in 15 mL of anhydrous MTBE was slowly added into the reaction mixture and stirred additional 2h at the same temperature. The reaction was quenched with saturated NH₄Cl (aq) solution, extracted with EtOAc, dried over anhydrous Na₂SO₄. The collected organic layer was concentrated in vacuo and then purified by column chromatography (30% EtOAc/hexanes) to give the title compound (8.Og, 90%) as a viscous oil. LC-MS: 375 [M+H].

Intermediate 35 fert-butyl [l-(5-fluoropyridin-2-yl)-2-hvdroxyethyl^"|carbamate

To a solution of N-(2-(fert-butyldimethylsilyloxy)-l-(5-fluoropyridin-2-yl)ethyl)-2- methylpropane-2-sulfϊnamide (Intermediate 34, 1.59g, 6 mmol) in 50 mL of EtOAc, was slowly added a 4M solution of HCl in dioxane (4.6 mL) at rt. The reaction mixture was turned into a cloudy solution and then white solid started to precipitate out. After 2h at rt, diethyl ether (5OmL) was added for complete precipitation of a desired product. After being stood for 30 min at rt, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum, and used to next step. The solid was added into 2OmL of water, 4OmL of THF and 4.8mL of 5N-NaOH followed by BoC₂O (1.7g) at rt. After being stirred at rt for 2h, the reaction was extracted with EtOAc, dried over anhydrous Na₂SO₄. The collected organic layer was concentrated in vacuo and then purified by column chromatography (40% EtOAc/hexanes) to give the title compound (1.29g, 84%) as a pale yellow oil. LC-MS: 257 [M+H].

Intermediate 36

1 -(5-Fluoropyridin-2-yl)-2-methoxyethanamine hydrochloride

To a solution of a fert-butyl [l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate (Intermediate 35, 1.27g, 5 mmol) in 18 mL of anhydrous THF, was slowly added 20% potassium-ϊ-butoxide solution in THF at -15⁰C. After being stirred for 20 min at the same temperature, was added 0.32 mL of MeI, and then allowed to warm up to rt. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SU4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (20-30% EtOAc/hexanes) to give fert-butyl [l-(5-fluoropyridin-2-yl)-2-methoxyethyl] carbamate (0.58g, 45%) as viscous oil. The resulting oil was dissolved in EtOAc (1OmL) and treated with 4M HCl in dioxane. After 2 hours at rt, diethyl ether (2OmL) was added for completion of precipitation of a desired product. After being stood for 30 min at rt, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum to give a highly moisture sensitive title compound (267 mg, 72% as mono hydrochloride salt) as colorless solid. LC-MS: 171 [M+H]. ¹U NMR (500 MHz) δ 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, IH), 7.67 (m, IH), 7.82 (m, IH) 8.59 (d, IH) 8.65 (br, 2H).

Alternatively the title compound could be prepared according to the procedure described below: To a stirred solution of 4-diphenylphosphino polystyrene resin (21.57 g, 39.91 mmol) in THF (120 ml)and water (20 ml) was added 2-(l-azido-2-methoxyethyl)-5-fluoropyridine (Intermediate 54, 5.22 g, 26.61 mmol). The reaction mixture was heated to 65 ⁰C for lhr and monitored by TLC. Upon completion, the reaction mixture was filtered with the aid of EtOAc and concentrated to give l-(5-fluoropyridin-2-yl)-2-methoxyethanamine (5.14 g) as a yellow oil. The hydrochloride salt (if it was required) was prepared by treatment of a methanol solution of the amine with HCl (4N in dioxane) and subsequent evaporation to dryness under reduced pressure.

Intermediate 37 2,4-Dichloro-5-fluoro-6-(4-methoxypiperidin-l-yl)pyrimidine

2,4,6-Trichloro-5-fluoropyrimidine and 4-methoxy piperidine were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 281 [M+H]. ¹H NMR (400 MHz, CHLOROFORM-t/) δ ppm 1.65 - 1.80 (m, J=10.36, 10.36, 7.33, 3.54 Hz, 2 H) 1.87 - 2.05 (m, 2 H) 3.41 (s, 3 H) 3.53 (td, J=7.01, 3.41 Hz, 1 H) 3.69 (ddd, J=13.45, 7.89, 3.66 Hz, 2 H) 3.88 - 4.19 (m, 2 H)

Intermediate 38

(R)-(4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholin-3-yl)methanol

2,4,6-Trichloro-5-fluoropyrimidine and 3-(R)-hydroxymorpholine were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 283 [M+H]. ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 3.20 - 3.41 (m, 1 H) 3.54 - 3.81 (m, 3 H) 3.95 - 4.20 (m, 4 H) 4.40 - 4.53 (m, 1 H).

Intermediate 39 l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)piperidine-4-carbonitrile

2,4,6-Trichloro-5-fluoropyrimidine and piperidine-4-carbonitrile hydrochloride (Intermediate 42) were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 276 [M+H]. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.00 (m, 4H) 2.98 (m, IH) 3.82 (m, 2H) 3.94 (m, 2H).

Intermediate 40

2,4-Dichloro-5-fluoro-6-(3-methoxyazetidin-l-yl)pyrimidine

2,4,6-Trichloro-5-fluoropyrimidine and 3-methoxyazetidine were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 253 [M+H].

Intermediate 41 l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-4-methylpiperidin-4-ol

2,4,6-Trichloro-5-fluoropyrimidine and 4-methylpiperidin-4-ol hydrochloride (Intermediate 44) were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 281 [M+H].

Intermediate 42

Piperidine-4-carbonitrile hydrochloride tert-Butyl 4-cyanopiperidine-l-carboxylate (2.100 g, 9.99 mmol) in methanol (15 ml) was added with HCl in z^'-PrOH(3 ml, 5-6N solution). The reaction was stirred at room temperature overnight. Solvent was removed to get 1.56 g product as HCl salt. The material was directly used for the next step reaction without further purification. IH NMR (300 MHz, MeOD) δ ppm 1.82 - 2.03 (m, 2 H) 2.04 - 2.21 (m, 2 H) 3.00 - 3.15 (m, 3 H) 3.17 - 3.32 (m, 2 H).

Intermediate 43 tert-Butyl 4-hvdroxy-4-methylpiperidine- 1 -carboxylate

Methylmagnesium bromide (1.795 g, 15.06 mmol) (3M solution in ether) was cooled at an dry- ice bath, tert-butyl 4-oxopiperidine-l -carboxylate (3.00 g, 15.06 mmol) in THF was added to the reaction mixture drop-wise. The reaction was stirred at -78°C for Ih, and quenched with saturated NH₄Cl solution at the same temperature. Ethyl acetate was added, and the organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by ISCO (80 g column, 35-65 EtOAc/hexanes) afforded 1.86 g of the title compound. IH NMR (300 MHz, DICHLOROMETHANE-J₂) δ ppm 1.15 (s, 3 H) 1.35 (s, 9 H) 1.37 - 1.46 (m, 4 H) 2.92 - 3.24 (m, 2 H) 3.46 - 3.66 (m, 2 H).

Intermediate 44

4-Methylpiperidin-4-ol hydrochloride tert-Butyl 4-hydroxy-4-methylpiperidine-l -carboxylate (Intermediate 43, 1.82 g, 8.45 mmol) in methanol (10 ml) was cooled to 0⁰C. HCl (7 ml, 4N in dioxane) was added to the reaction. Ice- bath was removed, and the reaction was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure to afford 1.26 g product as HCl salt. ¹H NMR (300 MHz, DICHLOROMETHANE-J₂) δ ppm 0.66 - 0.93 (m, 2 H) 1.08 - 1.32 (m, 4 H) 1.64 - 1.74 (m, 1 H) 1.87 - 2.08 (m, 2 H) 3.06 - 3.31 (m, 2 H). Intermediate 45 l-(3,5-Difluoropyridin-2-yr)ethanone

A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N₂ and cooled to -78°C. 3,5-difluoropicolinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temp, was kept below -4°C. After the addition was complete, the reaction was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction was stirred at 0⁰C for 30 minutes and r.t. for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aqueous phase was neutralized to pH9 with NaHCO₃ and extracted with EtOAc (2 X 20 ml). The organic phase were combined and the volatiles were removed under reduced pressure. Purification by ISCO (0-10% EtOAc- hexanes) gave the title compound as light yellow oil. LC-MS: 158 [M+H].

Intermediate 46

1 -(3 ,5-Difluoropyridin-2-yl)ethanone oxime

To a solution of l-(3,5-difluoropyridin-2-yl)ethanone (Intermediate 45, 12.91 g, 82.17 mmol) in ethanol (164 ml) was added hydroxylamine hydrochloride (8.56 g, 123.25 mmol) followed by Et₃N (17.18 ml, 123.25 mmol) and the resulting mixture was stirred o/n at r.t. The volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAcZH₂O. The organic extracts washed with brine and dried. Orange yellow solid was obtained and purification by ISCO (10%EtOAc/hexanes->25% EtOAc/hexanes) gave l-(3,5-difluoropyridin- 2-yl)ethanone oxime (9.73 g, 68.8 %) as yellow solid (color turned from white to light yellow/brown after stay under vacuum over night). ¹H NMR (300 MHz, OMSO-dβ) δ ppm 2.19 (s, 3 H) 7.98 (ddd, J=10.97, 8.81, 2.26 Hz, 1 H) 8.55 (d, J=2.26 Hz, 1 H) 11.70 (s, 1 H) LC-MS: 173 [M+H].

Intermediate 47

1 -(3 ,5-Difluoropyridin-2-yl)ethanamine l-(3,5-Difluoropyridin-2-yl)ethanone oxime (Intermediate 46, 9.73 g, 56.53 mmol) was added to water (113 ml) to form a suspension. Ammonium hydroxide (22.01 ml, 565.26 mmol) was added to the above solution, followed by ammonium acetate (5.23 g, 67.83 mmol). The mixture was heated at 50⁰C and subsequently zinc (14.79 g, 226.11 mmol) was added portion wise while maintain the internal temperature below 65°C. After the addition was complete, the reaction was stirred at 50⁰C for 3 hr. Solid NaCl and EtOAc was added to quench the reaction, stirred for lhr at r.t, was then filtered through celite pad and rinsed with EtOAc. The organic layer was washed with 5 ml 2.5% NaOH (aq.) then 10 ml NH₄OH. The organic layer was then washed with brine and dried with Na2SO₄. The organic layer was concentrated down under reduced pressure to obtain the title compound as light yellow oil. ¹H NMR (400 MHz, MeOD) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.86 (q, J=6.82 Hz, 1 H) 7.75 (ddd, J=10.11, 8.34, 2.27 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H).

Intermediate 48 l-(3,5-Difluoropyridin-2-yl)ethanol

In a 250 mL round-bottomed flask, l-(3,5-difluoropyridin-2-yl)ethanone (Intermediate 45, 1.0 g, 6.36 mmol) was dissolved in MeOH (30 ml) to give a colorless solution. Cooled to -10 ⁰C (ice in MeOH) and sodium borohydride (0.060 g, 1.59 mmol) was added to the above solution at - 10⁰C. The reaction was stirred for 30 min. Concentration under reduced pressure removed MeOH, and to the residue was added sat. NaHCO₃, and extracted with EtOAc. The crude product was added to a silica gel column and was eluted with EtOAc/DCM (20-50%). The title compound was obtained as colorless oil (600 mg). LCMS: 160 [M+H]⁺.

Intermediate 49 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone

3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -80⁰C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 3°C during addition. The reaction turned into a deep brownish, thick phase. The reaction was stirred for 30 minutes. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop- wise in a quicker version, and the reaction was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction was quenched at - 78°C by adding 20 ml of saturated NH₄Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0-25% EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]⁺. Intermediate 50 l-(3,5-Difluoropyridin-2-vP)-2-methoxyethanol l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone (Intermediate 49, 2.78 g, 14.85 mmol) in MeOH was cooled to -72°C. NaBH₄ was added portion wise. The reaction was complete almost instantly after the addition OfNaBH₄ (monitored by TLC 25% EtOAc/hexanes). NH₄Cl solution (Ig in 2 ml H₂O) was added to quench the reaction. Solvent was removed under reduced pressure and the residue was partitioned between DCM and H2O. Organic layer was dried over Na2SO₄ and concentrated under reduced pressure to afford a yellow oil. ISCO purification (25% EtOAc/Hexanes) gave the title compound (2.0 g). LCMS: 190

[M+H]⁺.

Intermediate 51 l-(5-Fruoropyridin-2-yl)-2-methoxyethanone

To a solution of 2-bromo-5-fluoropyridine (15.0 g, 85.23 mmol) in methyl t-butyl ether (250 ml) at -78 ⁰C was added tert-butyllithium (60.2 ml, 102.28 mmol) with caution.

After the addition of the organolithium was completed, the resulting black solution was stirred at

-78 ⁰C for 15 minutes whereupon methyl 2-methoxyacetate (8.43 ml, 85.23 mmol) in 10 ml

MTBE was added to the solution. The mixture was stirred for 3 hours at -78 ⁰C whereupon saturated NH₄Cl was added in order to quench the reaction.

The mixture was partitioned between EtOAc and brine and the organic extract was dried and evaporated under reduced pressure. Purification by column chromatography (20% ->40%

EtOAc/hexanes) gave the titled compound as a yellowish solid 6.19 g (43% yield). LCMS: 170

[M+H]⁺.

Intermediate 52 l-(5-Fluoropyridin-2-yl)-2-methoxyethanol

In a 50OmL round-bottomed flask, l-(5-fluoropyridin-2-yl)-2-methoxyethanone (Intermediate 51, 6.19 g, 36.59 mmol) was dissolved in MeOH (183 ml) to give a yellow solution at 0 ⁰C. Sodium borohydride (1.383 g, 36.59 mmol) was added to the above solution at 0⁰C. The reaction was allowed to warm up to rt and stirred for 30 min. Concentration under reduced pressure removed the MeOH, and to the residue was added sat. NaHCO₃, and extracted with EtOAc. The crude was added to a silica gel column and was eluted with EtOAc/DCM (20->50%). The title compound was obtained yellow oil 5.61g (90% yield). LCMS: 172 [M+H]⁺.

Intermediate 53

1 -(5-Fluoropyridin-2-yl)-2-methoxyethyl methanesulfonate l-(5-Fluoropyridin-2-yl)-2-methoxyethanol (Intermediate 52, 5.60 g, 32.72 mmol) and triethylamine (13.68 ml, 98.15 mmol) were dissolved in DCM (100 ml) to give a clear solution at -78 ⁰C. Methanesulfonyl chloride (3.81 ml, 49.07 mmol) was added to above solution at -78°C. After 5 min, water (10 mL) was added to quench the reaction, and DCM (2 X 20 mL) was used for extraction. Evaporation of the volatiles under reduced pressure gave a yellow oil. ISCO purification (35% EtOAc/hexanes) gave the title compound (7.37g, 90%) as light yellow oil.

Intermediate 54

2-(l-Azido-2-methoxyethyl)-5-fruoropyridine l-(5-Fluoropyridin-2-yl)-2-methoxyethyl methanesulfonate (Intermediate 53, 7.37 g, 29.57 mmol) was dissolved in DMF (100 mL) to give a colorless solution. Sodium azide (5.77 g, 88.70 mmol) was added to the above solution. The reaction was stirred at 60 ⁰C for 3.5 h, Water was added to quench the reaction. Ether extraction (4 x 100 mL), and concentration under reduced pressure gave the title compound that was used in a subsequent step without any further purification.

Intermediate 55 l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4- yl)piperidine-4-carbonitrile

In a microwave tube was added l-(3,5-difluoropyridin-2-yl)-2-methoxyethanol (Intermediate

50, 275 mg, 1.45 mmol), 3 mL t-BuOH and sodium tert-butoxide (140 mg, 1.45 mmol), stirred at r.t. for lhr under N2. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)piperidine-4-carbonitrile

(Intermediate 39, 400 mg, 1.45 mmol) in 2 mL t-BuOH was added to the above at r.t. The reaction mixture was stirred at 50⁰C under N2 overnight. The volatiles were removed under reduced pressure to yield a colored residue. ISCO purification (25% EtOAc/hexanes) gave the title compound (370 mg) as colorless sticky oil. LCMS: 428 [M+H]⁺.

Intermediate 56 l-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)piperidine-4- carbonitrile l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)piperidine-4-carbonitrile (Intermediate 39) and l-(5- fluoropyrimidin-2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 381 [M+H]⁺. ¹U NMR (400 MHz, CHLOROFORM-t/) δ ppm 1.79 (d, J=6.57 Hz, 3 H) 1.89 - 2.15 (m, 4 H) 2.86 - 3.00 (m, 1 H) 3.63 - 3.76 (m, 2 H) 3.97 (ddd, J=13.96, 7.52, 3.28 Hz, 2 H) 6.23 (q, J=6.82 Hz, 1 H) 8.61 (s, 2 H).

Intermediate 57

2-Chloro-5-fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxy)-6-(4-methoxypiperidin-l-yl)pyrimidine 2,4-Dichloro-5-fluoro-6-(4-methoxypiperidin-l-yl)pyrimidine (Intermediate 37) and l-(5- fluoropyrimidin-2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 386 [M+H]⁺. IH NMR (400 MHz, CHLOROFORM-^) δ ppm 1.57 - 1.71 (m, 2 H) 1.78 (d, J=6.82 Hz, 3 H) 1.94 (dq/=12.85, 3.55 Hz, 2 H) 3.39 (s, 3 H) 3.48 (ddd, J=I 1.62, 7.83, 3.28 Hz, 2 H) 4.04 (ddd, J=13.45, 7.01, 3.79 Hz, 2 H) 5.17 - 5.49 (m, 1 H) 6.22 (q, J=6.82 Hz, 1 H) 8.61 (s, 2 H).

Intermediate 58 l-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)-4-methylpiperidin-4- Pi l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-4-methylpiperidin-4-ol (Intermediate 41) and l-(5- fluoropyrimidin-2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 386 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 1.30 (s, 3 H) 1.61 - 1.73 (m, 4 H) 1.78 (d, J=6.82 Hz, 3 H) 3.49 (ddd, J=13.83, 9.92, 4.55 Hz, 2 H) 4.01 - 4.24 (m, 2 H) 6.22 (q, J=6.74 Hz, 1 H) 8.61 (s, 2 H). Intermediate 59

2-Chloro-5-fluoro-4-( 1 -(5 -fruoropyrimidin-2-vP)ethoxy)-6-(3 -methoxyazetidin- 1 -vDpyrimidine 2,4-Dichloro-5-fluoro-6-(3-methoxyazetidin-l-yl)pyrimidine (Intermediate 40) and l-(5- fluoropyrimidin-2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 358[M+H]⁺. IH NMR (400 MHz, CHLOROFORM-t/) δ ppm 1.78 (d, J=6.82 Hz, 3 H) 3.35 (s, 3 H) 4.15 (dd, 2 H) 4.27 - 4.37 (m, 1 H) 4.42 (d, J=8.59 Hz, 2 H) 6.22 (q, J=6.65 Hz, 1 H) 8.60 (s, 2 H).

Intermediate 60

(S)-3-((tert-Butyldimethylsilyloxy)methyl)-4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (R)-(4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholin-3-yl)methanol (Intermediate 38, 1724 mg, 6.11 mmol), tert-butylchlorodimethylsilane (1197 mg, 7.94 mmol), DMAP (74.7 mg, 0.61 mmol), and pyridine (1934 mg, 24.45 mmol) in DCM (20 ml) was stirred at ambient temperature overnight. Additional 1.2 g of tert-butylchlorodimethylsilane and 1 ml of pyridine was added to the reaction mixture. The reaction mixture was allowed to stir at ambient temperature for 3 additional hours. The volatiles were removed under reduced pressure to give a residue that was purified by ISCO (10^30 EtOAc/ hexanes) to give the title compound. ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm -0.03 (s, 3 H) 0.00 (s, 3 H) 0.76 (s, 9 H) 3.20 - 3.41 (m, 1 H) 3.54 - 3.81 (m, 3 H) 3.86 - 4.21 (m, 4 H) 4.40 - 4.53 (m, 1 H).

Intermediate 61

(3S)-3-((tert-Butyldimethylsilyloxy)methyl)-4-(2-chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2- yl)ethoxy)pyrimidin-4-yl)morpholine

(S)-3-((tert-Butyldimethylsilyloxy)methyl)-4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 60) and l-(5-fluoropyrimidin-2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 503 [M+H]⁺.

¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 0.00 (s, 6H) 0.79 (s, 9 H) 1.73 (d, 3H) 3.34- 3.94 (m, 8H) 4.36 (m, IH) 5.29 (m, IH) 6.19 (br.s., IH) 8.57 (s, 2 H). Intermediate 62 r3^-3-r(rtert-Butvirdimethvnsilyl1oxylmethylV4-(2-chloro-6-ri-r3.5-difluoropyridin-2-ylV2- methoxyethoxy1-5-fluoropyrimidin-4-yl}morpholine

(S)-3-((tert-Butyldimethylsilyloxy)methyl)-4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 60) and l-(3,5-difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 50) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound.

LCMS: 550 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-t/) δ ppm 0.05 (s, 3 H) 0.11 (s, 3H) 0.75 (s, 9 H) 3.31 (td, ./=13.07, 3.41 Hz,l H) 3.43 (s, 3 H) 3.50 - 3.71 (m, 2 H) 3.77 - 4.10 (m, 7 H) 4.27 - 4.46 (m, 1 H) 6.18 - 6.66 (m, 1 H) 7.13 -7.26 (m, 1 H) 8.34 (s, 1 H).

Intermediate 63

2-Chloro-4-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(4-methoxypiperidin-l- vDpyrimidine

2,4-Dichloro-5-fluoro-6-(4-methoxypiperidin-l-yl)pyrimidine (Intermediate 37) and l-(3,5- difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 50) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 433 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-tf) δ ppm 1.48 - 1.78 (m, 2 H) 1.83 - 1.99 (m, 2 H) 3.39 (s, 3 H) 3.41 -3.54 (m, 6 H) 3.81 - 4.09 (m, 4 H) 6.27 - 6.56 (m, 1 H) 7.19 - 7.26 (m, 1 H) 8.36 (d, J=2.27 Hz, 1 H).

Intermediate 64 l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4-yl)-4- methylpiperidin-4-ol l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-4-methylpiperidin-4-ol (Intermediate 41) and l-(3,5- difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 50) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 433 [M+H]⁺. IH NMR (400 MHz, CHLOROFORM-^) δ ppm 1.29 (s, 3 H) 1.60 - 1.71 (m, 4 H) 3.37 - 3.54 (m, 5 H) 3.89 (dd, J=10.61, 5.05 Hz, 1 H) 3.98 - 4.21 (m, 3 H) 6.39 - 6.55 (m, 1 H) 7.14 - 7.27 (m, 1 H) 8.36 (d, J=2.27 Hz, 1 H). Intermediate 65

2-Chloro-4-(l-(3,5-difluoropyridin-2-yl^N)-2-methoxyethoxy^N)-5-fluoro-6-(3-methoxyazetidin-l- vDpyrimidine

2,4-Dichloro-5-fluoro-6-(3-methoxyazetidin-l-yl)pyrimidine (Intermediate 40) and l-(3,5- difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 50) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound.

LCMS: 405[M+H]⁺.

Intermediate 66

2-Chloro-N-(l-(3,5-difluoropyridin-2-yl)ethyl)-5-fluoro-6-morpholinopyrimidin-4-amine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(3,5- difluoropyridin-2-yl)ethanamine (Intermediate 47) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. ¹H NMR (400 MHz, CHLOROFORM-J) δ ppm 1.51 (d, J=6.82 Hz, 3 H) 3.59 - 3.71 (m, 4 H) 3.72 - 3.86 (m, 4 H) 5.61 (t, J=6.82 Hz, 1 H) 6.24 (d, J=6.06 Hz, 1 H) 7.04 - 7.35 (m, 1 H) 8.31 (d, J=2.53 Hz, 1 H). LCMS: 374 [M+H]⁺.

Intermediate 67

2-Chloro-N-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-5-fluoro-6-morpholinopyrimidin-4- amine

4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(3,5- difluoropyridin-2-yl)-2-methoxyethanamine hydrochloride (Intermediate 24) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound.

LCMS: 404 [M+H]⁺.

Intermediate 68

2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-6-morpholinopyrimidin-4-amine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(5-Fluoropyridin-2- yl)-2-methoxyethanamine hydrochloride (Intermediate 36) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 386[M+H]⁺.

Intermediate 69

2-Chloro-5-fluoro-N-(l-(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-6-morpholinopyrimidin-4- amine

4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(5-fluoropyrimidin-

2-yl)-2-methoxyethanamine hydrochloride (Intermediate 30) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound.

LCMS: 387 [M+H]⁺.

Intermediate 70

(S)-2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-morpholinopyrimidin-4-amine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and [( I₁S)-I -(5- Fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 15) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 356 [M+H]⁺.

Intermediate 71

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)morpholine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(5-fluoropyrimidin- 2-yl)ethanol (Intermediate 33) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 358[M+H]⁺.

Intermediate 72

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(5-fluoropyridin-2- yl)ethanol (Intermediate 31) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 357 [M+H]⁺. Intermediate 73

4-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl^N)ethoxy^N)-5-fluoropyrimidin-4-yl^N)morpholine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(3,5- difluoropyridin-2-yl)ethanol (Intermediate 48) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 375 [M+H]⁺.

Intermediate 74

4-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4- vDmorpholine

4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(3,5- difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 50) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound.

LCMS: 405 [M+H]⁺.

Intermediate 75 l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)ethylamino)-5-fluoropyrimidin-4-yl)-4- methylpiperidin-4-ol l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-4-methylpiperidin-4-ol (Intermediate 41) and l-(3,5- difluoropyridin-2-yl)ethanamine (Intermediate 47) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 402

[M+H]⁺.

Intermediate 76

(R)-l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethylamino)-5-fluoropyrimidin-4-yl)-

4-methylpiperidin-4-ol l-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-4-methylpiperidin-4-ol (Intermediate 41) and (IR)-I-

(3,5-Difluoropyridin-2-yl)-2-methoxyethanamine (L)-mandelic acid salt (Intermediate 88) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 433[M+H]⁺.

Intermediate 77

2,6-Dichloro-N-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)pyrimidin-4-amine 2,4,6-Trichloropyrimidine (0.734 g) and l-(5-fluoropyridin-2-yl)-2-methoxyethanamine hydrochloride (Intermediate 36) were reacted using a procedure similar to the one described for the synthesis of Intermediate 16, providing the title compound. LCMS: 318 [M+H]⁺.

Intermediate 78

(S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine 2,4,6-Trichloro-5-fluoropyrimidine and [(lS)-l-(5-fluoropyridin-2-yl)ethylamine (Intermediate 15) were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 306 [M+H]⁺.

Intermediate 79

(S)-2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-(4-(methylsulfonyl)piperazin-l- yl)pyrimidin-4-amine

(S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 78) and l-(methylsulfonyl)piperazine were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 433 [M+H]⁺.

Intermediate 80

(S)-tert-Butyl 4-(2-chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-4- vDpiperazine- 1 -carboxylate

(S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 78) and tert-butyl piperazine-1 -carboxylate were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 455[M+H]⁺. Intermediate 81

2-Chloro-6-(l,l-dioxidothiomorpholin-4-yl^N)-5-fluoro-N-[(15^f)-l-(5-fluoropyridin-2- yl)ethyl^"|pyrimidin-4-amine

(S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 78) and thiomorpholine- 1 , 1 -dioxide were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 404 [M+H]⁺.

Intermediate 82

(S)-2-Chloro-5-fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methylpyrimidine-4,6-diamine (S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 78) and methylamine were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 300 [M+H]⁺.

Intermediate 83

(S)-2-Chloro-5-fluoro-N^/-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methylpyrimidine-4,6-diamine (S)-2,6-Dichloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 78) and 1-methylpiperazine were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 369 [M+H]⁺.

Intermediate 84

(S)-2,6-Dichloro-N-(l-(5-fluoropyrimidin-2-yl)ethyl)pyrimidin-4-amine

(lS)-l-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5), were reacted using a procedure similar to the one described for the synthesis of Intermediate 16, providing the title compound.

LCMS: 289[M+H]⁺.

Intermediate 85

4-(2,5,6-Trichloropyrimidin-4-yl)morpholine

2,4,5, 6-Tetrachloropyrimidine and morpholine were reacted using a procedure similar to the one described for the synthesis of Intermediate 6, providing the title compound. LCMS: 269 [M+H]⁺.

Intermediate 86

(S)-2,5-Dichloro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-morpholinopyrimidin-4-amine 4-(2,5,6-Trichloropyrimidin-4-yl)morpholine (Intermediate 85) and [( IS)-I -(5-fluoropyri din-2- yl)ethyl] amine (Intermediate 15) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7, providing the title compound. LCMS: 373 [M+H]⁺.

Intermediate 87

1 -(3 ,5-Difluoropyridin-2-yl)-2-methoxyethanone oxime l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone (Intermediate 49) dissolved in ethanol (255 ml, 10 vol). Hydroxylamine hydrochloride (14.22 g, 204.61 mmol) was added, followed by drop-wise by triethylamine (28.5 ml, 204.61 mmol). The resulting colored mixture was heated to 50° C for 2 hours. The volatiles were evaporated under reduced pressure and the residue left was partitioned between water (255 ml) and ethyl acetate (255 ml). The separated aqueous layer was further extracted into 2 x ethyl acetate (255 ml). The combined organic extracts washed with water (255 ml), saturated brine (255 ml), dried over MgSO₄, filtered and concentrated in vacuo to give 42g of a brown oil. Purification by column chromatography (25- 40% EtOAc in isohexanes) gave 32g of the title compound as yellow oily solid (-3:1 mixture of isomers). Trituration in MTBE to gave the title compound (12.3 g, 60.84 mmol, 44.6 %, single isomer) as white solid. The liquor was evaporated under reduced pressure and the residue was re- columned using the previous conditions followed by trituration with EtOAc/isohexanes to give additional l-(3,5-difluoropyridin-2-yl)-2-methoxyethanone oxime (7.2 g, 35.62 mmol, 26.1 %). LCMS: 203 [M+H]⁺.

Intermediate 88

(lR)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanamine (L)-mandelic acid salt l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone oxime (Intermediate 87) was dissolved in EtOAc (0.4M) and was subsequently subjected to catalytic hydrogenation (Pd on C) in a Parr Hydrogenator (Pressure 5 bar at 40⁰C) for 1 hour. The catalyst was filtered via Celite and the filtrate of l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (0.4 M in ethyl acetate) (180 mL, 72.00 mmol) was treated with (L)-(+)-Mandelic acid (5.81 g, 38.16 mmol). Precipitation was observed almost instantaneously and the resulting mixture was allowed to stir o/n. (R)- 1 -(3,5- difluoropyridin-2-yl)-2-methoxyethanamine (L)-mandelate salt was collected via filtration (8.5 g, 69.4 %). The other enantiomer was recovered after evaporation of the mother liquor. ¹H NMR (400 MHz) δ ppm 8.6 (s, IH) 8.01 (m, IH) 7.41 (t, 2H) 7.36 (t, 2H) 7.19 (m ,1H) 4.81 (s, IH) 4.50 (m, IH) 3.57 (d, 2H) 3.23 (s, 3H). LCMS: 188 [M-H]⁺.

Intermediate 89

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)-2-methoxyethoxy)pyrimidin-4-yl)morpholine 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine (Intermediate 6) and l-(5-fluoropyridin-2- yl)-2-methoxyethanol (Intermediate 52) were reacted using a procedure similar to the one described for the synthesis of Intermediate 55, providing the title compound. LCMS: 387 [M+H]⁺. IH NMR (400 MHz, DICHLOROMETHANE-d

2) δ ppm 3.41 (s, 3 H) 3.72 - 3.81 (m, 8 H) 3.84 - 3.93 (m, IH) 3.92 - 4.03 (m, 1 H) 6.31 (dd, J=7.07, 3.54 Hz, 1 H) 7.28 - 7.65 (m, 2 H) 8.48 (d, J=2.53 Hz, 1 H).

Intermediate 90

(S)-4-(3-((tert-Butyldimethylsilyloxy)methyl)morpholino)-6-(l-(3,5-difluoropyridin-2-vD-2- methoxyethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine (3,S^<)-3-({[fert-Butyl(dimethyl)silyl]oxy}methyl)-4-{2-chloro-6-[l-(3,5-difluoropyridin-2-yl)-2- methoxyethoxy]-5-fluoropyrimidin-4-yl}morpholine (Intermediate 62), tert-butyl 3-amino-5- methyl-lH-pyrazole-1-carboxylate (Intermediate 10), BINAP, Pd2(dba)3, and CS2CO3 in dioxane (2 ml) was heated at 95⁰C for 8h. LCMS indicated complete reaction. Methanol (1 ml) was added and the reaction was stirred at r.t for Ih. Solvent was removed under reduced pressure and the reaction mixture was purified by ISCO column. The material obtained was directly used in the subsequent step without further purification. LCMS: 610[M+Η]⁺.

Intermediate 91

S-4-(3-((tert-Butyldimethylsilyloxy)methyl)morpholino)-5-fluoro-6-(l-(5-fluoropyrimidin-2- yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine

(3S)-3-((tert-Butyldimethylsilyloxy)methyl)-4-(2-chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2- yl)ethoxy)pyrimidin-4-yl)morpholine (Intermediate 61), tert-butyl 3-amino-5-methyl-lH- pyrazole-1-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. LCMS: 564 [M+Η]⁺.

Example 1

5-Fluoro-N⁴-[(S)-l-(5-fluoro-pyrimidin-2-yl)-ethyll-N²-(5-methoxy-lH-pyrazol-3-yl)-6- morpholin-4-yl-pyrimidine-2.4-diamine

A microwave reaction vessel was charged with tert-butyl 3-amino-5-methoxy-lH-pyrazole-l- carboxylate (Intermediate 9, 66mg, 0.31mmol), 2-chloro-5-fluoro-N-[(15)-l-(5-fluoropyrimidin- 2-yl)ethyl]-6-morpholin-4-ylpyrimidin-4-amine (Intermediate 7, 74 mg, 0.21mmol), Pd2(dba)3 (27 mg), BINAP (36 mg), and CSCO3 (250 mg) in dioxane. The reaction vessel was degassed and heated at 95°C under an inert atmosphere for 6 hours. MeOH was added and the mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified using an ISCO column (DCM/MeOΗ/NEUOΗ), providing the title compound as a light, pale solid (29mg, 32%). ¹H NMR (CDCl₃) δ 11.86 (br, 3H), 8.63 (s, 2H), 5.62 (s, IH), 5.49 (m, IH), 3.98 (s, 3H), 3.79 (m, 4H), 3.65 (m, 4H), 1.68 (d, 3H). LCMS: 434 [M+H].

Example 2

5-Fluoro-Λ^/4-r(l»S)-l-(5-fluoropyrimidin-2-yl)ethyll-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholin- 4-ylpyrimidine-2,4-diamine tert-Butyl 3 -amino-5 -methyl- lH-pyrazo Ie- 1-carboxylate (Intermediate 10, 66mg, 0.31mmol) and 2-chloro-5-fluoro-N-[(l.S^<)-l-(5-fluoropyrimidin-2-yl)ethyl]-6-morpholin-4-ylpyrimidin-4- amine (Intermediate 7) were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound (26mg, 30%) as a mixture of enantiomers. LCMS: 418 [M+Η]. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.55 (d, J=6.82 Hz, 3 H) 2.15 (s, 3 H) 3.50 (m, 4 H) 3.66 (m, 4 H) 5.28 (m, 1 H) 6.01 (br.s, 0.5 H) 6.94 (br.s, 0.5 H) 8.86 (s, 2 H).

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with OJ-I- 20

Column particle size (μ): 5

Column dimensions (mm): 4.6x100

Post purification purity check

Sample purity was checked using Conditions (B) with OJ- 1-20

Example 2(a), First Eluting Compound

5-Fluoro-Λ^/4-r(l»S)-l-(5-fluoropyrimidin-2-yl)ethyll-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholin-

4-ylpyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 0.73 minutes.

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.55 (d, J=7.07 Hz, 3 H) 2.13 (s, 3 H) 3.50 (m, 4 H) 3.67

(m, 4 H) 5.28 (m, 1 H) 6.01 (br.s, 0.5 H) 6.94 (br.s, 0.5 H) 8.86 (s, 2 H). LCMS: 418 [M+H]

Example 2(b), Second Eluting Compound

4-ylpyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 1.69 minutes.

Example 3

6-Chloro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyll-N -(5-methoxy-lH-pyrazol-3-yl)-pyrimidine- 2,4-diamine

A 2ml microwave reaction vessel was charged with tert-Butyl 3-amino-5-methoxy-lH-pyrazole- 1-carboxylate (Intermediate 9, 371mg, 1.76mmol), 2,6-Dichloro-N-[(15)-l-(5-fluoropyridin-2- yl)ethyl]pyrimidin-4-amine (Intermediate 16, 400 mg, 1.4mmol), Pd2(dba)₃ (63 mg), BINAP (84mg), CS2CO3 (1.12 g), 1,4-dioxane (2ml), and NMP (2ml). The vessel was capped, degassed and then charged with an Argon balloon. The reaction mixture was heated to 100⁰C. MeOH (ImI) was added and the resulting mixture was heated to 6O⁰C for another 1 hour. The reaction mixture was then partitioned between DCM and H2O and the organic phase was concentrated under reduced pressure. Purification by silica gel column (ISCO, DCM/MeOH/NH₄OH: 100/0/0 tolOO/5/0.5) afforded the title compound (184mg, 36%). LCMS: 367 [M+H].

Example 4

N^-\(S)- 1 -(5-Fluoro-pyridin-2-yl)-ethyl1-N²-(5-methoxy- lH-pyrazol-3-yl)-6-morphorin-4-yl- pyrimidine-2,4-diamine

A mixture of 6-chloro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH-pyrazol-3-yl)- pyrimidine-2,4-diamine (Example 3, 61mg, 0.17 mmol), morpholine (22mg, 0.25 mmol) and DIPEA (0.088ml, 0.5 mmol) in n-BuOΗ (0.7 ml) was heated in a microwave reactor to 180⁰C for 4 hours. After evaporation of the solvents, the residue was purified by Gilson (30-70% MeCN/H₂O with 0.1% TFA) to afford the TFA salt of the title compound (44mg, 40%). ¹H NMR (δ) 10.39 (br, IH), 8.55 (s, IH), 8.42 (br, IH), 7.74 (m, IH), 7.54 (m, IH), 5.41 (m, IH), 5.00 (br, IH), 3.80 (s, 3H), 3.64 (m, 4H), 3.51 (m, 4H), 1.49 (d, 3H). LCMS: 415 [M+H].

Example 5

4-\6-\(S)- 1 -(5-Fluoro-pyridin-2-vD-ethylamino1-2-(5-methoxy- lH-pyrazol-3-ylamino)- pyrimidin-4-yll- 1 -methyl-piperazin-2-one

6-Chloro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH-pyrazol-3-yl)-pyrimidine- 2,4-diamine (Example 3) and l-methylpiperazin-2-one hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 4, providing the TFA salt of the title compound (28mg, 25%). ¹H NMR (MeOD) δ 8.33 (s, IH), 7.50 (m, IH), 7.42 (m, IH), 5.30 (s, IH), 4.07 (m, 2H), 3.79 (s, 3H), 3.75 (m, 2H), 3.36 (m, 2H), 2.89 (s, 3H), 1.50 (d, 3H). LCMS: 442 [M+H].

Example 6

N⁴-[(y)-l-(5-Fluoro-pyridin-2-yl)-ethyl1-N²-(5-methoxy-lH-pyrazol-3-yl)-6-(2-oxa-5-aza- bicvclo[2.2.11hept-5-yl)-pyrimidine-2,4-diamine

6-Chloro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH-pyrazol-3-yl)-pyrimidine- 2,4-diamine (Example 3) and (l₁S^l,4₁S')-2-oxa-5-aza-bicyclo[2.2.1]heptane hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 4, providing the TFA salt of the title compound the TFA salt of the title compound (32mg, 29%). ¹H NMR (MeOD) δ 8.28 (s, IH), 7.45 (m, IH), 7.36 (m, IH), 4.80 (br, IH), 4.55 (s, IH), 3.72 (s, 3H), 3.66 (m, 4H), 3.35 (m, 2H), 1.82 (m, 2H), 1.42 (d, 3H). LCMS: 427 [M+H].

Example 7

6-Chloro-5-fluoro-N⁴-r(S)-l-(5-fluoro-pyridin-2-yl)-ethyl1-N²-(5-methoxy-lH-pyrazol-3-yl)- pyrimidine-2,4-diamine

A round-bottom flask was charged with (4,6-dichloro-5-fluoro-pyrimidin-2-yl)-(5-methoxy-lH- pyrazol-3-yl)-amine (Intermediate 17, 221 mg, 0.8 mmol), (l.S)-l-(5-fluoropyridin-2- yl)ethanamine hydrochloride (Intermediate 15, 167 mg, 0.8 mmol), DIPEA (0.695 ml, 4 mmol) in π-BuOΗ (4ml). The reaction was heated at 100⁰C overnight. Solvent was removed under reduced pressure and the mixture was purified by silica gel chromatography (ISCO, DCM/MeOH/NH₄OH: 100/0/0-100/4/0.4) to give the title compound (21Og, 69 %). LCMS: 382 [M+H].

Example 8

5-Fluoro-N⁴-r(»y)-l-(5-fluoro-pyridin-2-yl)-ethyl1-N²-(5-methoxy-lH-pyrazol-3-yl)-6-(2-oxa-5- aza-bicvclo[2.2.11hept-5-yl)-pyrimidine-2,4-diamine

A mixture of 6-chloro-5-fluoro-Λ^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH- pyrazol-3-yl)-pyrimidine-2,4-diamine (Example 7, 70mg, 0.18 mmol), (l₁S',4₁S)-2-oxa-5-aza- bicyclo[2.2.1]heptane hydrochloride (40mg, 0.3 mmol) and DIPEA (0.088ml, 0.5 mmol) in n- BuOH (0.8 ml) was heated in a microwave reactor at 150⁰C for 4 hours. Evaporation of the solvents under reduced pressure gave a residue. This residue was purified by silica gel chromatography (ISCO, DCMZMeOHZNH₄OH: IOOZOZO tol00Z4Z0.4) to afford the title compound (24mg, 30%). ¹H NMR (CDCl₃) δ 8.40 (s, IH), 7.37 (m, IH), 7.28 (m, IH), 5.96 (m, IH), 5.26 (m, IH), 5.10 (s, IH), 4.86 (br, IH), 4.59(s, IH), 3.85 (s, 3H), 3.80 (m, 2H), 3.46 (m, 3H), 1.83 (s, 2H), 1.54 (d, 3H). LCMS: 445 [M+H].

Example 9 5-Fluoro-Λ^-r(S)-l-(5-fluoro-pyridin-2-yl)-ethyll-N -(5-methoxy-lH-pyrazol-3-yl)-6-morpholin- 4-yl-pyrimidine-2,4-diamine

6-Chloro-5-fluoro-N⁴-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N²-(5-methoxy-lH-pyrazol-3-yl)- pyrimidine-2,4-diamine (Example 7) and morpholine (0.026ml, 0.3mmol) were reacted using a procedure similar to the one described for the synthesis of Example 4, providing the TFA salt of the title compound (51mg, 43%). ¹H NMR (CDCl₃) δ 10.64 (br, IH), 8.65 (s, IH), 7.85 (m, IH), 7.70 (m, IH), 6.58 (m, IH), 5.39 (m, IH), 4.04 (s, 3H), 3.67 (m, 4H), 3.58 (m, 4H), 1.72 (d, 3H). LCMS: 434 [M+H].

Example 10 l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)piperidine-4-carbonitrile l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4- yl)piperidine-4-carbonitrile (Intermediate 55), tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 489 [M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with AS-I-

40

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using Conditions (B) with AS- 1-20

Example 10(a), First Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)piperidine-4-carbonitrile, Enantiomer A The first eluting compound had a retention time of 2.21 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.69 - 1.78 (m, 2 H) 1.86 - 1.94 (m, J=6.79, 6.79, 6.51, 3.41 Hz, 2 H) 2.31 (s, 3 H) 2.97 (dt, J=8.40, 4.26 Hz, IH) 3.33 (s, 3 H) 3.41 - 3.50 (m, 2 H) 3.86 - 3.94 (m, 3 H) 3.99 - 4.06 (m, 1 H) 5.99 (s, 1 H) 6.32 (dd, J=7.58, 4.80 Hz, 1 H) 7.58 (ddd, ./=10.29, 8.40, 2.27 Hz, 1 H) 8.29 (d, J=2.27 Hz, 1 H)

Example 10(b), Second Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)piperidine-4-carbonitrile, Enantiomer B The second eluting compound had a retention time of 3.15 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.69 - 1.78 (m, 2 H) 1.86 - 1.94 (m, J=6.79, 6.79, 6.51, 3.41 Hz, 2 H) 2.31 (s, 3 H) 2.97 (dt, J=8.40, 4.26 Hz, IH) 3.33 (s, 3 H) 3.41 - 3.50 (m, 2 H) 3.86 - 3.94 (m, 3 H) 3.99 - 4.06 (m, 1 H) 5.99 (s, 1 H) 6.32 (dd, J=7.58, 4.80 Hz, 1 H) 7.58 (ddd, ./=10.29, 8.40, 2.27 Hz, 1 H) 8.29 (d, J=2.27 Hz, 1 H).

Example 11 l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin- 4-yl)piperidine-4-carbonitrile l-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)piperidine-4- carbonitrile (Intermediate 56), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 442 [M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (C2) with a

Chiralpak AD.

Column dimensions: 25O x 20mm, lOμ

Mobile phase: 100% 1:1 (v/v) ethanobmethanol, 0.1% diethylamine

Flow rate (ml/min): 1 mL/min

Detection (nm): 254 Post purification purity check

Sample purity was checked with a Chiralpak AD.

Column dimensions: 4.6 x 250 mm, 10 um

Mobile phase: 100% 1:1 (v/v) ethanobmethanol, 0.1% diethylamine

Flow: 1 mL/min

Detection: 254 nm

Example 1 Ka), First Eluting Compound l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin-

4-yl)piperidine-4-carbonitrile, Enantiomer A

The first eluting compound had a retention time of 7.59 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.75 (d, J=6.82 Hz, 3 H) 1.79 - 1.93 (m, 2 H) 2.02 (dt,

J=UAA, 3.16 Hz,2 H) 2.25 (s, 3 H) 2.95 - 3.12 (m, 1 H) 3.45 - 3.62 (m, 2 H) 3.87 - 4.10 (m, 2 H)

5.86 (br. s., 1 H) 6.14 (q/=6.82 Hz, 1 H) 8.75 (s, 2 H)

Example 1 Kb), Second Eluting Compound l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin-

4-yl)piperidine-4-carbonitrile, Enantiomer B

The second eluting compound had a retention time of 10.97 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.75 (J=6.82 Hz, 3 H) 1.81 - 1.92 (m, 2 H) 1.94 - 2.12 (m, 2

H) 2.25 (s,3 H) 2.94 - 3.13 (m, 1 H) 3.48 - 3.57 (m, 2 H) 3.89 - 4.10 (m, 2 H) 6.14 (q, J=6.82 Hz,

1 H) 8.75 (s, 2 H)d,

Example 12

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(4-methoxypiperidin- 1 -yl)-N-(5 -methyl- IH- Pyrazol-3-yl)pyrimidin-2-amine

2-Chloro-5-fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxy)-6-(4-methoxypiperidin-l-yl)pyrimidine (Intermediate 57), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 447[M+Η]⁺. Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with OD-I-

15.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using Conditions (B) with OD- 1-20

Example 12(a), First Eluting Compound

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(4-methoxypiperidin- 1 -yl)-N-(5 -methyl- IH- pyrazol-3-yl)pyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 7.52 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.50 - 1.61 (m, 2 H) 1.75 (d, J=6.06 Hz, 3 H) 1.92 - 2.06 (m,

2 H) 2.22 (br. s., 3 H) 3.28 - 3.42 (m, 5 H) 3.46 - 3.57 (m, J=8.08, 8.08, 4.04, 3.79 Hz, 1 H) 3.99 -

4.21 (m, 2 H) 5.55 (br.s., 0 H) 5.95 - 6.23 (m, 1 H) 8.74 (br. s., 2 H)

Example 12(b), Second Eluting Compound

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(4-methoxypiperidin- 1 -yl)-N-(5 -methyl- IH- pyrazol-3-yl)pyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 8.77 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.49 - 1.65 (m, 2 H) 1.75 (d, 3 H) 1.91 - 2.07 (m, 2 H) 2.26

(br. s., 3 H) 3.34 - 3.43 (m, 5 H) 3.45 - 3.58 (m, 1 H) 3.91 - 4.17 (m, 2 H) 5.54 (br. s., 1 H) 5.99 -

6.21 (m, 1 H) 8.73 (br. s., 2 H)

Example 13 l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin- 4-yl)-4-methylpiperidin-4-ol l-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)-4-methylpiperidin-4- ol (Intermediate 58), tert-butyl 3 -amino-5 -methyl- lH-pyrazo Ie- 1-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 447 [M+H]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with AD-3-

25.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with AD-4-20.

Example 13 (a). First Eluting Compound l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin-

4-yl)-4-methylpiperidin-4-oL Enantiomer A

The first eluting compound had a retention time of 2.57 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.14 (s, 3 H) 1.48 - 1.55 (m, 4 H) 1.63 (d, 3 H) 2.12 (s, 3 H)

3.30 - 3.44 (m, 2 H) 3.82 - 4.04 (m, 2 H) 6.00 (q, 1 H) 8.63 (s, 2 H).

Example 13(b), Second Eluting Compound l-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3-ylamino)pyrimidin-

4-yl)-4-methylpiperidin-4-ol, Enantiomer B

The second eluting compound had a retention time of 3.79 minutes.

3.30 - 3.44 (m, 2 H) 3.82 - 4.04 (m, 2 H) 6.00 (q, 1 H) 8.63 (s, 2 H).

Example 14

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(3 -methoxyazetidin- 1 -yl)-N-(5 -methyl- IH- pyrazol-3-yl)pyrimidin-2-amine

2-Chloro-5-fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxy)-6-(3-methoxyazetidin-l-yl)pyrimidine (Intermediate 59), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 419[M+H]⁺.

Column and solvent conditions

Chiralcel OJ.

Column dimensions: 25O x 20mm, lOμ

Mobile phase: 1:1 ethanohmethanol, 0.1% diethylamine (v/v/v)

Flow rate (ml/min): 10

Detection (nm): 254

Post purification purity check

Sample purity was checked with a Chiralcel OJ.

Column dimensions: 4.6 x 250 mm, 10 um

Mobile Phase: 50:50:0.1 Ethanol:Methanol:Diethlylamine

Flow: 0.5 mL/min

Detection: 254 nm

Example 14(a), First Eluting Compound

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(3 -methoxyazetidin- 1 -yl)-N-(5 -methyl- IH- pyrazol-3-yl)pyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 11.58 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.74 (d, J=6.32 Hz, 3 H) 2.22 (s, 3 H) 3.35 (s, 3 H) 3.89 -

4.11 (m, 2 H) 4.27 - 4.50 (m, 3 H) 5.53 (br. s., 0 H) 5.99 - 6.36 (m, 1 H) 8.73 (br. s., 2 H)

Example 14(b), Second Eluting Compound

5-Fluoro-4-( 1 -(5-fluoropyrimidin-2-yl)ethoxy)-6-(3 -methoxyazetidin- 1 -yl)-N-(5 -methyl- IH- pyrazol-3-yl)pyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 15.79 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.74 (d, J=6.32 Hz, 3 H) 2.21 (s, 3 H) 3.37 (s, 3 H) 4.02 (dd,

J=6.57, 1.26 Hz, 2 H) 4.27 - 4.53 (m, 3 H) 5.53 (br. s., 0 H) 6.13 (q, 1 H) 8.73 (br. s., 2 H). Example 15

[(3i?^N)-4-{6-[l-(3,5-difluoropyridin-2-yl^N)-2-methoxyethoxyl-5-fluoro-2-[(5-methyl-lH-pyrazol-3- yl^N)aminolpyrimidin-4-vUmorpholin-3-yllmethanol

(S)-4-(3 -((tert-Butyldimethylsilyloxy)methyl)morpholino)-6-( 1 -(3 ,5-difluoropyridin-2-yl)-2- methoxyethoxy)-5-fluoro-N-(5 -methyl- lH-pyrazol-3-yl)pyrimidin-2-amine (Intermediate 90, 0.695 g, 1.14 mmol) in TΗF (10 ml) was treated with TBAF (3ml, IM in TΗF). The reaction was stirred at r.t overnight. Solvent was removed under reduced pressure and purification by ISCO column (20-40% solvent B/DCM, solvent B: 10 methanol/ 1⁰ZoNH₄OU in DCM) to give the title compound as a mixture of diastereomers.

Column and solvent conditions

The diastereomers of the title compound were separated using Conditions (Cl) with a Chiralpak

AD.

Column dimensions: 20 x 250 mm, 10 um

Mobile Phase: 50:50:0.1 Ethanol:Methanol:Diethlylamine (v/v/v)

Flow: 20 mL/min

Detection: 254 nm

Post purification purity check

Sample purity was checked using a Chiralpak AD.

Column dimensions: 4.6 x 250 mm, 10 μm

Mobile Phase: 50:50:0.1 Ethanol:Methanol:Diethlylamine

Flow: 1 mL/min

Detection: 254 nm

Example 15(a), First Eluting Compound r(3i?)-4-(6-ri-(3.5-difluoropyridin-2-yl)-2-methoxyethoxy1-5-fluoro-2-r(5-methyl-lH-pyrazol-3- yl)aminolpyrimidin-4-vUmorpholin-3-yllmethanol, Diastereomer A

The first eluting compound had a retention time of 5.0 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 2.23 (s, 3 H) 3.44 (s, 3 H) 3.56 - 4.16 (m, 10 H) 4.28 - 4.42

(m, 1 H) 6.04 (br. s., 1 H) 6.43 (dd, J=6.82, 5.31 Hz, 1 H) 7.62 (ddd, J=10.29, 8.40, 2.27 Hz, 1 H) 8.38 (d, J=2.27 Hz, I H)

Example 15(b), Second Eluting Compound r(3i?)-4-{6-ri-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy1-5-fluoro-2-r(5-methyl-lH-pyrazol-3- yl)aminolpyrimidin-4-vUmorpholin-3-yl1methanoL Diastereomer B

The second eluting compound had a retention time of 8.4 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 2.27 (br. s., 3 H) 3.44 (s, 3 H) 3.55 - 4.16 (m, 10 H) 4.22 -

4.45 (m, 1 H) 5.63 (br. s., 0.5 H) 6.21 (br. s., 0.5 H) 6.33 - 6.51 (m, 1 H) 7.62 (t, J=8.21 Hz, 1 H)

8.37 (br. s., 1 H).

Example 16

(R)-(4-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)morpholin-3-yl)methanol

S-4-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)-5-fluoro-6-(l-(5-fluoropyrimidin-2- yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-2-amine (Intermediate 91) and TBAF were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. LCMS: 449[M+Η]⁺.

Column and solvent conditions

The title compound was chirally purified using Conditions (A) with OJ- 1-20. Column particle size (μ): 5 Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with OJ- 1-20.

Example 16(a), First Eluting Compound

(R)-(4-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)morpholin-3-yl)methanoL Diastereomer A

The first eluting compound had a retention time of 0.60 minutes.

¹H NMR (400 MHz, DMSO- dβ) δ ppm 1.47 (d, J=6.82 Hz, 3 H) 1.94 (br. s., 3 H) 2.94 - 3.14 (m, 1 H) 3.20 -3.48 (m, 3 H) 3.52 - 3.69 (m, 2 H) 3.71 - 3.84 (m, 2 H) 3.93 - 4.10 (m, 1 H) 4.34 (br. s., 1 H) 5.73 (br. s., 1 H) 5.94 (q, J=6.82 Hz, 1 H) 8.62 (s, 2 H)

Example 16(b), Second Eluting Compound

(R)-(4-(5-Fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)morpholin-3-yl)methanoL Diastereomer B

The second eluting compound had a retention time of 1.02 minutes.

¹H NMR (400 MHz, DMSO-^6) δ ppm 1.69 (d, J=6.82 Hz, 3 H) 2.16 (s, 3 H) 3.20 - 3.36 (m, 1

H) 3.44 - 3.70(m, 3 H) 3.73 - 3.90 (m, 2 H) 3.91 - 4.03 (m, 2 H) 4.15 - 4.26 (m, 1 H) 5.87 (br. s.,

1 H) 6.16 (q, J=6.82 Hz, IH) 8.83 (s, 2 H).

Example 17

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(4-methoxypiperidin-l-yl)-N-(5- methyl- lH-pyrazol-3-yl)pyrimidin-2-amine

2-Chloro-4-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(4-methoxypiperidin-l- yl)pyrimidine (Intermediate 63), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 494 [M+Η]⁺.

Column and solvent conditions

The title compound was chirally purified using Conditions (A) with AS-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250

Post purification purity check.

Sample purity was checked using Conditions (B) and AS-3-20

Example 17(a), First Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(4-methoxypiperidin-l-yl)-N-(5- methyl- lH-pyrazo 1-3 -yl)pyrimidin-2-amine, Enantiomer A The first eluting compound had a retention time of 1.04 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.46 - 1.70 (m, 2 H) 1.90 - 2.04 (m, 2 H) 2.23 (br. s., 3 H) 3.44 (s, 3 H) 3.48 - 3.58 (m, 1 H) 3.85 - 3.97 (m, 1 H) 4.00 - 4.13 (m, 3 H) 5.64 (br. s., 0 H) 6.23 (br. s., 1 H) 6.35 - 6.53 (m, 1 H) 7.50 - 7.70 (m, 1 H) 8.37 (br. s., 1 H)

Example 17(b), Second Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(4-methoxypiperidin-l-yl)-N-(5- methyl-lH-pyrazol-3-yl)pyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 1.35 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.43 - 1.70 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.26 (br. s., 3 H)

3.44 (s, 3 H) 3.48 - 3.53 (m, 1 H) 3.83 - 3.98 (m, 1 H) 3.98 - 4.13 (m, 3 H) 6.22 (br. s., 1 H) 6.36

- 6.51 (m, 1 H) 7.33 - 7.76 (m, 1 H) 8.38 (br. s., 1 H).

Example 18 l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4-yl)-4- methylpiperidin-4-ol (Intermediate 64), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 494 [M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with AS-3-

15.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with AS-3-15.

Example 18(a), First Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol, Enantiomer A

The first eluting compound had a retention time of 6.27 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.14 (s, 3H) 1.53 (m, 4H) 2.15 (br.s, 3H) 3.32 (s, 3H) 3.38

(m, 4H) 3.82 (br.s, IH) 3.88 (m, 2H) 5.51 (br.s, 0.5H) 6.13 (br.s, 0.5H) 6.31 (m, IH) 7.50 (m,

IH) 8.26 (br.s IH).

Example 18(b), Second Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol, Enantiomer B

The second eluting compound had a retention time of 8.08 minutes.

IH) 8.26 (br.s IH).

Example 19

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(3-methoxyazetidin-l-yl)-N-(5- methyl-lH-pyrazol-3-yl)pyrimidin-2-amine

2-Chloro-4-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(3-methoxyazetidin-l- yl)pyrimidine (Intermediate 65) and tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 466 [M+Η]⁺.

Column and solvent conditions

The title compound was chirally purified using Conditions (A) with AD-3-30. Column particle size (μ): 5 Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with AD-3-30. Example 19(a), First Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl^N)-2-methoxyethoxy^N)-5-fluoro-6-(3-methoxyazetidin-l-yl^N)-N-(5- methyl- lH-pyrazo 1-3 -vP)pyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 0.97 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 2.24 (s, 3 H) 3.16 (s, 3 H) 3.26 (s, 3 H) 3.80 - 3.85 (m, 1 H)

3.91 (dd, J=13.26, 9.22 Hz, 3 H) 4.16 - 4.27 (m, 3H) 5.91 (s, 1 H) 6.26 (dd, J=7.45, 4.93 Hz, 1 H)

7.50 (ddd, J=10.29, 8.40, 2.27 Hz, 1 H) 8.22 (d, J=2.27 Hz, 1 H)

Example 19(b), Second Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-6-(3-methoxyazetidin-l-yl)-N-(5- methyl-lH-pyrazol-3-yl)pyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 1.56 minutes.

7.50 (ddd, J=10.29, 8.40, 2.27 Hz, 1 H) 8.22 (d, J=2.27 Hz, 1 H).

Example 20

N⁴-(l-(3,5-Difluoropyridin-2-yl)ethyl)-5-fluoro-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2 ,4-diamine

2-Chloro-N-(l-(3,5-difluoropyridin-2-yl)ethyl)-5-fluoro-6-morpholinopyrimidin-4-amine (Intermediate 66) and tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 435 [M+Η]⁺.

Column and solvent conditions

Post purification purity check

Sample purity was checked using Conditions (B) with AD-3-30 Example 20(a), First Eluting Compound y-ri-r3.5-Difluoropyridin-2-vnethylV5-fluoro-N²-r5-methyl-lH-pyrazol-3-ylV6- morpholinopyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 1.05 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.45 (d, J=6.82 Hz, 3 H) 2.12 (s, 3 H) 3.41 (m, 4H) 3.59 (m,

4 H) 5.40 (d, J=6.32 Hz, 1 H) 6.17 (m, 1 H) 7.40 (ddd, ./=10.30, 8.40, 2.27 Hz, 1 H) 8.22 (d,

J=2.27 Hz, 1 H)

Example 20(b), Second Eluting Compound

N⁴-(l-(3,5-Difluoropyridin-2-yl)ethyl)-5-fluoro-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 2.12 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.46 (d, 3 H) 2.13 (s, 3 H) 3.45 (s, 1 H) 3.46 (m, 4H) 3.63

(m, 4 H) 5.42 (s, 1 H) 6.17 (m, 1 H) 7.44 (ddd, J=10.29, 8.40, 2.27 Hz, 1 H) 8.24 (d, J=1.77 Hz, 1

H).

Example 21

N^/-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-5-fluoro-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2 ,4-diamine

2-Chloro-N-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-5-fluoro-6-morpholinopyrimidin-4- amine (Intermediate 67), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as mixture of enantiomers. LCMS: 465 [M+Η]⁺.

Column and solvent conditions

Post purification purity check Sample purity was checked using Conditions (B) with AD-1-30.

Example 2 Ka), First Eluting Compound

A^-(l-(3.,5-Difluoropyridin-2-vD-2-methoxyethylV5-fluoro-N²-(5-methyl-lH-pyrazol-3-vD-6- morpholinopyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 1.05 minutes.

2.23 (br.s., 3Η) 3.33 (s, 3H), 3.58 (m, 4H) 3.75 (m, 4H) 3.81 (m, 2H) 5.76 (m, IH) 6.33 (br.s.,

IH) 7.56 (m, IH) 8.37 (s, IH)

Example 2Kb), Second Eluting Compound

Λ^/4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-5-fluoro-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 1.86 minutes.

2.22 (br.s., 3Η) 3.33 (s, 3H), 3.58 (m, 4H) 3.72 (m, 4H) 3.81 (m, 2H) 5.75 (m, IH) 6.31 (br.s.,

IH) 7.56 (m, IH) 8.37 (s, IH).

Example 22

5-Fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2 ,4-diamine

2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-6-morpholinopyrimidin-4-amine (Intermediate 68), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 447[M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using conditions (Cl). Mobile phase: 1:1 (v/v) ethanol/methanol, 0.1% diethylamine

Column particle size (μ): 10 Column dimensions (mm): 2x25

Post purification purity check Sample purity was checked using conditions (D).

Column dimensions (mm): 4.6x250

Column particle size (μ): 10

Mobile phase: 1:1 (v/v) ethanol/methanol, 0.1% diethylamine

Example 22(a), First Eluting Compound

5-Fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 8.50 minutes.

¹H NMR (400 mHz CD₃OD) δ 8.49 (s, IH), 7.55-7.58 (m, 2H), 6.05 (br.s., 0.5H) 5.55 (br.s.,

0.5H) 5.34-5.36 (m, IH), 3.85-3.83 (m, 2H), 3.77 (m, 4H), 3.62 (m, 2H) 3.60 (m, 2H), 3.37 (s,

3H), 2.22 (s, 3H).

Example 22(b), Second Eluting Compound

5-Fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 15.47 minutes.

¹H NMR (400 mHz CD₃OD) δ 8.47 (s, IH), 7.50 (m, 2H), 6.05 (br.s., 0.5H) 5.55 (br.s., 0.5H)

5.34(m, IH), 3.83 (m, 2H), 3.74 (m, 4H), 3.58 (m, 4H), 3.37 (s, 3H), 2.20 (s, 3H).

Example 23

5-FIuQrQ-A^-(I -(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2 ,4-diamine

2-Chloro-5-fluoro-N-(l-(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-6-morpholinopyrimidin-4- amine (Intermediate 69), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 448[M+Η]⁺.

Column and solvent conditions

The title compound was chirally purified using Conditions (A) with AD-3-25. Column particle size (μ): 5 Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using Conditions (B) with AD- 1-20.

Example 23 (a). First Eluting Compound

5-Fluoro-Λ^/4-(l-(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 3.29 minutes.

¹H NMR (400 mHz, CD₃OD) δ 8.68 (s, 2H) 6.20 (br.s., IH) 5.44 (m, IH), 3.90 (m, 2H), 3.69

(m, 4H), 3.54 (m, 4H) 3.30 (s, 3H), 2.17 (s, 3H).

Example 23(b), Second Eluting Compound

5-Fluoro-Λ^/4-(l-(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 4.59 minutes.

(m, 4H), 3.54 (m, 4H) 3.30 (s, 3H), 2.17 (s, 3H).

Example 24

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-vnethvn-N²-(5-methyl-lH-pyrazol-3-vn-6- morpholinopyrimidine-2.4-diamine

(S)-2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-morpholinopyrimidin-4-amine (Intermediate 70), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.59 (d, J=6.82 Hz, 3 H) 2.22 (s, 3 H) 3.59 (d, J=9.35 Hz, 4 H) 3.76 (d, J=9.09 Hz, 4 H) 5.22 (s, 1 H) 5.51 (br.s, 0.5H) 6.09 (br.s, 0.5H) 7.49 -7.60 (m, 2 H) 8.45 (s, 1 H). LCMS: 417 [M+H]⁺.

Example 25

5-Fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (Intermediate 71), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (C2). Mobile Phase: 1:1 (v/v) ethanohmethanol, 0.1%diethylamine

Post purification purity check

Sample purity was checked using Chiralcel OJ Column dimensions (mm): 4.6x250 mm Diameter: lOμ

Mobile Phase: 1:1 (v/v) ethanohmethanol

Flow rate: 0.5ml/min.

Example 25(a), First Eluting Compound

5-Fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxyVN-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 11.12 minutes.

¹H NMR (400 MHz) δ ppm 1.66 (d, J=6.82 Hz, 3 H) 2.15 (s, 3 H) 3.60 (s, 4 H) 3.68 (s, 5 H) 5.84

(s, 1 H) 6.10 (q, J=6.48 Hz, 1 H) 8.90 (s, 2 H) 11.69 (s, 1 H). LCMS: 419 [M+H]⁺.

Example 25(b), Second Eluting Compound

5-Fluoro-4-(l-(5-fluoropyrimidin-2-yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 15.74 minutes.

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.66 (d, J=6.82 Hz, 3 H) 2.15 (s, 3 H) 3.58 (s, 1 H) 3.59

(d, J=4.80 Hz, 3 H) 3.67 (d, J=4.80 Hz, 3 H) 3.69 (s, 1 H) 5.84 (s, 1 H) 6.10 (d, J=6.82 Hz, 1 H)

8.77 (s, 1 H) 8.90 (s, 2 H) 11.69 (s, 1 H). LCMS: 419 [M+H]⁺. Example 26

5-Fluoro-4-(l-(5-fluoropyridin-2-yl^N)ethoxy^N)-N-(5-methyl-lH-pyrazol-3-yl^N)-6- morpholinopyrimidin-2-amine

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine (Intermediate 72), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 418 [M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (Cl). Mobile phase: 80% Hexane, 20% 1:1 (v/v) ethanobmethanol, 0.1% diethylamine

Post purification purity check

Sample purity was checked using Conditions (D)

Mobile phase: 80% Hexane, 20% 1:1 (v/v) ethanobmethanol, 0.1% diethylamine

Example 26(a), First Eluting Compound

5-Fluoro-4-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 10.81 minutes.

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.62 (d, J=6.57 Hz, 3 H) 2.17 (s, 3 H) 3.59 (d, J=5.05

Hz, 4 H) 3.67 (d, J=4.80 Hz, 5 H) 5.99 (s, 1 H) 6.13 (d, J=6.82 Hz, 1 H) 7.55 (s, 1 H) 7.73 (s, 1

H) 8.56 (s, 1 H) 8.93 (s, 1 H) 11.74 (s, 1 H). [M+H]+: 418.07

Example 26(b), Second Eluting Compound

5-Fluoro-4-(l-(5-fluoropyridin-2-yl)ethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine. Enantiomer B

The second eluting compound had a retention time of 1.94 minutes.

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.62 (d, J=6.57 Hz, 3 H) 2.17 (s, 3 H) 3.59 (s, 4 H) 3.68

(s, 5 H) 5.99 (s, 1 H) 6.13 (d, J=6.57 Hz, 1 H) 7.53 (dd, J=8.72, 4.67 Hz, 1 H) 7.69 - 7.76 (m, 1 H) 8.56 (s, 1 H) 8.93 (s, 1 H) 11.74 (s, 1 H). [M+H]+: 418

Example 27

4-(l-(3,5-Difluoropyridin-2-yl)ethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine

4-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)ethoxy)-5-fluoropyrimidin-4-yl)morpholine (Intermediate 73), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 436[M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (Cl) with a

Chiralpak AD.

Column dimensions: 20 x 250 mm, 10 μm

Mobile Phase: 85:15:0.1 Hexanes:Isopropanol:Diethylamine

Flow rate: 20 mL/min

Detection: 295 nm

Post purification purity check

Sample purity was checked with a Chiralpak AD.

Column dimensions: 4.6 x 250 mm, 10 um

Mobile Phase: 85:15:0.1 Hexanes:Isopropanol:Diethylamine (v/v/v)

Flow rate: 1 mL/min

Detection: 295 nm

Example 27(a), First Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl)ethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine. Enantiomer A

The first eluting compound had a retention time of 14.2 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.55 (d, J=6.57 Hz, 3 H) 2.17 (s, 3 H) 3.48 (m, 4 H) 3.58 (m,

4 H) 5.98 - 6.08 (m, 2 H) 7.45 - 7.55 (m, 1 H) 8.21 (s, 1 H) Example 27(b), Second Eluting Compound

4-(l-(3,5-Difluoropyridin-2-yl)ethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time ofl8.7 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.58 (d, J=6.57 Hz, 3 H) 2.21 (s, 3 H) 3.50-3.52 (m, 4 H)

3.58-3.63 (m, 4 H) 6.00 (s, IH) 6.07 (m, 1 H) 7.54 - 7.50 (m, 1 H) 8.21 (s, 1 H)

Example 28

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine

4-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoropyrimidin-4- yl)morpholine (Intermediate 74), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 466 [M+Η]⁺.

Column and solvent conditions

The R and S Enantiomers of the title compound were separated using Conditions (A) with AD-I-

20.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) and AD- 1-30

Example 28(a), First Eluting compound

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine. Enantiomer A

The first eluting compound had a retention time of 0.87 minutes.

¹H NMR (400 MHz, MeOD) d ppm 2.14 (s, 3 H) 3.25 (s, 3 H) 3.52 - 3.59 (m, 4 H) 3.61 - 3.66

(m, 4 H) 3.80 (dd, J=10.48, 4.93 Hz, 1 H) 3.87 - 3.97 (m, 1 H) 5.91 (br.s., IH) 6.31 (dd, J=6.57, 5.31 Hz, 1 H) 7.50 (ddd, J=10.11, 8.34, 2.27 Hz, 1 H) 8.26 (d, 1=1.11 Hz, 1 H)

Example 28(b), Second Eluting compound

4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxy)-5-fluoro-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 1.31 minutes.

(m, 4 H) 3.80 (dd, J=10.48, 4.93 Hz, 1 H) 3.87 - 3.97 (m, 1 H) 5.91 (br.s., IH) 6.31 (dd, J=6.57,

5.31 Hz, 1 H) 7.50 (ddd, J=10.11, 8.34, 2.27 Hz, 1 H) 8.26 (d, 1=1.11 Hz, 1 H)

Example 29 l-(6-(l-(3,5-Difluoropyridin-2-yl)ethylamino)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)ethylamino)-5-fluoropyrimidin-4-yl)-4- methylpiperidin-4-ol (Intermediate 75) and tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 463 [M+Η]⁺.

Column and solvent conditions

The title compound was chirally purified using Conditions (A) with OJ- 1-30. Column particle size (μ): 5 Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with OJ- 1-30.

Example 29(a), First Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)ethylamino)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-oL Enantiomer A The first eluting compound had a retention time of 2.21 minutes. ¹H NMR (400 MHz, MeOD) δ ppm 1.24 (s, 3 H) 1.53 - 1.65 (m, 6 H) 2.23 (s, 3 H) 3.39 - 3.49 (m, 2 H) 3.83 - 3.92 (m, 2 H) 5.52 (s, 1 H) 7.55 (ddd, J=I 0.29, 8.40, 2.27 Hz, 1 H) 8.35 (s, 1 H).

Example 29(b), Second Eluting Compound l-(6-(l-(3,5-Difluoropyridin-2-yl)ethylamino)-5-fluoro-2-(5-methyl-lH-pyrazol-3- ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-oL Enantiomer B

The second eluting compound had a retention time of 4.21 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 1.13 (s, 3 H) 1.44 - 1.54 (m, 7 H) 2.12 (s, 3 H) 3.29 - 3.38

(m, 2 H) 3.73 - 3.81 (m, 2 H) 5.41 (s, 1 H) 7.40 -7.47 (m, 1 H) 8.24 (d, J=2.02 Hz, 1 H).

Example 30

(R)-l-(6-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-5-fluoro-2-(5-methyl-lH-pyrazol- 3-ylamino)pyrimidin-4-yl)-4-methylpiperidin-4-ol

(R)-l-(2-Chloro-6-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethylamino)-5-fluoropyrimidin-4-yl)- 4-methylpiperidin-4-ol (Intermediate 76, tert-butyl 3 -amino-5 -methyl- lH-pyrazo Ie-I- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Examplel, providing the title compound.

¹H NMR (400 MHz, MeOD) δ ppm 1.10 - 1.16 (m, 3 H) 1.52 (s, 2 H) 1.54 (d, J=4.04 Hz, 1 H) 2.13 (s, 3 H) 3.22 - 3.26 (m, 3 H) 3.35 (ddd, ./=13.39, 9.35, 4.04 Hz, 2 H) 3.67 - 3.74 (m, 1 H) 3.79 (dt, ./=13.39, 3.79 Hz, 2 H) 5.62 (s, 1 H) 7.46 (ddd, J=9.85, 8.59, 2.27 Hz, 1 H) 8.28 (d, J=2.27 Hz, 1 H). LCMS: 493 [M+H]⁺.

Example 31

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4- (methylsulfonyl)piperazin- 1 -yl)pyrimidine-2,4-diamine

(S)-2-Chloro-5-fluoro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-(4-(methylsulfonyl)piperazin-l- yl)pyrimidin-4-amine (Intermediate 79), tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. ¹H NMR (400 MHz, CHLOROFORM-D) d ppm 1.50 (d, J=7.33 Hz, 3 H) 2.24 (s, 3 H) 2.72 (s, 3 H) 3.18 - 3.26 (m, 3 H) 3.61 - 3.71 (m, 4 H) 5.14 - 5.24 (m, 1 H) 5.64 (br.s, 0.5 H) 5.79 (br. s, 0.5 H) 7.27 - 7.37 (m, 2 H) 8.39 (d, J=2.27 Hz, 1 H). LCMS: 494 [M+H]⁺.

Example 32

(S)-5-Fluoro-N^/-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(piperazin-l- yl)pyrimidine-2,4-diamine hydrochloride

(S)-tert- Butyl 4-(2-chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-4- yl)piperazine-l-carboxylate (Intermediate 80), tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1. The title compound was obtained as an HCl salt after treatment with HCl (4N in dioxane). ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.51 (d, 3 H) 2.19 (s, 3H) 2.95 (m, 4H) 3.60 (m, 4H) 5.15-5.18 (m, IH) 5.56 (br.s IH) 7.27-7.32 (m, 2H) 8.38 (d, IH). LCMS: 416 [M+H]⁺.

Example 33

6-( 1 , l-Dioxidothiomorpholin-4-yl)-5-fluoro-N⁴-|Yl,S^f)- 1 -(5-fluoropyridin-2-yl)ethyll-N²-(5- methyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine

2-Chloro-6-(l,l-dioxidothiomorpholin-4-yl)-5-fluoro-N-[(l.S)-l-(5-fluoropyridin-2- yl)ethyl]pyrimidin-4-amine (Intermediate 81), tert-butyl 3-amino-5-methyl-lH-pyrazole-l- carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.48 (d, J=6.82 Hz, 3 H) 2.11 (s, 3 H) 3.01 - 3.10 (m, 4 H) 3.99 (m, 4 H) 5.13 (q, 1 H) 5.42 (br. s, 0.5 H) 5.91 (br. s, 0.5 H) 7.44 (dd, J=8.34, 2.53 Hz, 2 H) 8.33 (s, 1 H). LCMS: 466 [M+H]⁺.

Example 34

(S)-5-Fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methyl-N²-(5-methyl-lH-pyrazol-3- yl)pyrimidine-2,4,6-triamine

(S)-2-Chloro-5-fluoro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methylpyrimidine-4,6-diamine (Intermediate 82), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. LCMS: 361 [M+Η]⁺. Example 35

(Sl-S-Fluoro-y-d-fS-fluoropyridin-l-vnethvn-N^-fS-methyl-lH-pyrazol-S-vn-β-^- methylpiperazin-l-vP)pyrimidine-2,,4-diamine

(S)-2-Chloro-5-fluoro-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N⁵-methylpyrimidine-4,6-diamine (Intermediate 83) and tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.51 (d, J=6.82 Hz, 3 H) 2.12 (s, 3 H) 2.19 (s, 3 H) 2.37 (s, 4 H) 3.52 (s, 4 H) 5.15 - 5.26 (m, 1 H) 7.09 (s, 1 H) 7.49 (dd, J=8.08, 4.29 Hz, 1 H) 7.67 (t, J=7.45 Hz, 1 H) 8.50 (s, 1 H). LCMS: 430 [M+H]⁺.

Example 36

6-Chloro-N^/-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3- yl)pyrimidine-2 ,4-diamine

2,6-Dichloro-N-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)pyrimidin-4-amine (Intermediate 77), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound.

LCMS: 378 [M+Η]⁺.

Example 37

N⁴ -(I -(5-Fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2 ,4-diamine

6-Chloro-Λ^/4-(l-(5-fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3- yl)pyrimidine-2,4-diamine (Example 36, contaminated with small amount of 2-chloro-N4-(l-(5- fluoropyridin-2-yl)-2-methoxyethyl)-N6-(5-methyl-lH-pyrazol-3-yl)pyrimidine-4,6-diamine, 180mg, 0.47mmol) and morpholine in BuOH (1.5 mL) was heated in microwave oven for 6h at 18O⁰C. Evaporation of the volatiles followed by purification by ISCO

(DCM/MeOΗ/Η₂O=100/0/0^ 100/3/0.3) to give the title compound (200mg) as a mixture of enantiomers. LCMS: 429 [M+H]⁺.

Column and solvent conditions The R and S enantiomers of the title compound were separated using Conditions (A) with AD-3-

50.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with AD-3-50

Example 37(a), First Eluting Compound

Λ^/4-(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer A

The first eluting compound had a retention time of 1.49 minutes.

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, IH) 7.54 (m, 2H) 5.29 (br.s., IH) 5.16 (m, IH), 3.77 (m,

2H), 3.71 (m, 4H), 3.44 (m, 4H) 3.35 (s, 3H), 2.20 (s, 3H).

Example 37(b), Second Eluting Compound

Λ^/4-(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidine-2,4-diamine, Enantiomer B

The second eluting compound had a retention time of 3.31 minutes.

2H), 3.71 (m, 4H), 3.44 (m, 4H) 3.35 (s, 3H), 2.20 (s, 3H).

Example 38

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine

2,6-Dichloro-N-[(l₁S)-l-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (Intermediate 16), tert- butyl 3 -amino-5 -methyl- lH-pyrazo Ie- 1-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 36, providing the title compound.

LCMS: 348 [M+Η]⁺. Example 39

(S)-N⁴ -( 1 -(5-fluoropyridin-2-ylkthviyN²-(5-methyl- lH-pyrazol-3 -ylV 6-f piperazin- 1 - yl)pyrimidine-2,,4-diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and piperazine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.42 (d, J=7.07 Hz, 3 H) 2.10 (s, 3 H) 2.82 (m, 4 H) 3.40 (m, 4 H) 4.89 (m, 1 H) 5.70 (br.s, IH) 7.35 - 7.46 (m, 2 H) 8.31 (s, 1 H). LCMS: 398 [M+H]⁺.

Example 40

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4-methylpiperazin-l- yl)pyrimidine-2 ,4-diamine

(S)-6-Chloro-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and 1 -methyl piperazine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.54 (d, J=7.07 Hz, 3 H) 2.22 (s, 43H) 2.32 (s, 3 H) 2.47 (m, 4H) 3.50 (m, 4H) 5.01 (m, 1 H) 5.23 (s, 1 H) 5.53 (br.s, IH) 7.49 -7.55 (m, 2 H) 8.44 (s, 1 H). LCMS: 412 [M+H]⁺.

Example 41

(S)-A^-(I -(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-morpholinopyrimidine- 2,4-diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.57 (d, J=7.07 Hz, 3 H) 2.25 (s, 3 H) 3.48 (m, 4 H) 3.73 (m, 4 H) 5.01 (m, 1 H) 5.79 (s, 1 H) 7.50 (s, 1 H) 7.59 (s, 1 H) 8.37 - 8.48 (m, 2 H). LCMS: 399 [M+H]⁺.

Example 42

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N^d-methyl-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-

2,4.6-triamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and methylamine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.54 (d, J=7.07 Hz, 3 H) 2.22 (s, 3 H) 2.77 (s, 3 H) 4.96 (m, 2 H) 7.50-7.57 (m, 1 H) 8.43 (s, 1 H). LCMS: 343 [M+H]⁺.

Example 43

6-( 1 , l-Dioxidothiomorpholin-4-yl)-N⁴-r(l»y)- 1 -(5-fluoropyridin-2-yl)ethyl1-N²-(5 -methyl- IH- Pyrazol-3-yl)pyrimidine-2,4-diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and thiomorpho line 1,1 -dioxide were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.55 (d, J=6.82 Hz, 4 H) 2.23 (s, 3 H) 3.05 (m, 4 H) 4.06 (m, 4 H) 5.07 (m 1 H) 5.40 (s, 1 H) 6.12 (br.s, IH) 7.59-7.51 (m, 2 H) 8.44 (s, 1 H). LCMS: 447 [M+H]⁺.

Example 44

(S)-N⁴-(l-(5-Fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)-6-(4- (methylsulfonyl)piperazin- 1 -yl)pyrimidine-2,4-diamine

(S)-6-Chloro-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and l-(methylsulfonyl)piperazine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) d ppm 1.55 (d, J=7.07 Hz, 3 H) 2.23 (s, 3 H) 2.85 (s, 3 H) 3.24 (m, 4 H) 3.61 (m, 4 H) 5.03 (m, 1 H) 5.29 (s, 1 H) 5.76 (br.s, IH) 7.50- 7.57 (m, 2 H) 8.44 (s, 1 H). LCMS: 476 [M+H]⁺.

Example 45

(S)-6-Chloro-Λ^/4-(l-(5-fluoropyrimidin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-

2,4-diamine

(S)-2,6-Dichloro-N-(l-(5-fluoropyrimidin-2-yl)ethyl)pyrimidin-4-amine (Intermediate 84), tert- butyl 3 -amino-5 -methyl- lH-pyrazo Ie- 1-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 36, providing the title compound. LCMS: 349[M+H]⁺.

Example 46

(Sl-Λ^-d-rS-Fluoropyrimidin-l-vnethvD-N^-rS-methyl-lH-pyrazol-S-vD-β- morpholinopyrimidine-2,4-diamine

(S)-6-Chloro-Λ^/4-(l-(5-fluoropyrimidin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine- 2,4-diamine (Example 45) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, DMSO) δ ppm 1.55 (d,3 H) 2.23 (br.s., 3 H) 3.69 (m, 8H) 5.35 (m, 1 H) 5.53 (br.s, IH) 6.14 (br.s., IH) 8.92 (s, 2 H).

Example 47

6-(2-Oxa-5-azabicvclor2.2.11heptan-5-yl)-N^/-((S)-l-(5-fluoropyrimidin-2-yl)ethyl)-N²-(5- methyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyrimidin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine- 2,4-diamine (Example 45) and (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. LCMS: 412 [M+Η]⁺. ¹U NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (d, 3 H) 1.81 (m, 2H) 2.19 (br.s., 3 H) 3.17-3.27 (m, 2H) 3.75 (s, IH) 4.55 (s, IH) 4.75 (m, IH) 5.31-5.33 (m, 3H) 5.73 (br.s., IH) 8.52 (s, 2H).

Example 48

(S)-5-Chloro-N⁴-(l-(5-fluoropyridin-2-vnethvn-N²-(5-methyl-lH-pyrazol-3-vn-6- morpholinopyrimidine-2,4-diamine

(S)-2,5-Dichloro-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-morpholinopyrimidin-4-amine (Intermediate 86), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound. LCMS: 433 [M+Η]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (d, 3 H) 2.29 (br.s., 3 H) 3.46(m, 4H) 3.78 (m, 4H) 5.96 (br.s., IH) 6.06 (m, IH) 7.32 (m, 2H) 8.41 (s, IH). Example 49

6-rriSΛSV2-Oxa-5-azabiwclor22Jlheirtan-5-ylVJV^-rrSVl-r5-fluorop\τidin-2-vnethvn-JV²-r5- methyl-lH-pyrazol-3-yl)pyrimidine-2,,4-diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38) and (lS,4S)-2-oxa-5-azabicyclo[2.2.1] heptane were reacted using a procedure similar to the one described for the synthesis of Example 37, providing the title compound. ¹H NMR (400 MHz, MeOD) δ ppm 1.56 (d, J=7.07 Hz, 3 H) 1.93-1.97 (m, 4 H) 2.23 (s, 3 H) 3.42-3.45 (m, 1 H) 3.78 - 3.84 (m, 2 H) 4.62 (s, IH) 4.98 (m, 1 H) 5.80 (s, 1 H) 7.39-7.46 (m, 2 H) 8.33 (s, 1 H). LCMS: 411 [M+H]⁺.

Example 50

5-Fluoro-4-(l-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine

4-(2-Chloro-5-fluoro-6-(l-(5-fluoropyridin-2-yl)-2-methoxyethoxy)pyrimidin-4-yl)morpholine (Intermediate 89), tert-butyl S-amino-S-methyl-lH-pyrazole-l-carboxylate (Intermediate 10), were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title compound as a mixture of enantiomers. LCMS: 448[M+Η]⁺.

Column and solvent conditions

The R and S enantiomers of the title compound were separated using Conditions (A) with AS-4-

20.

Column particle size (μ): 5

Column dimensions (mm): 21x250

Post purification purity check

Sample purity was checked using conditions (B) with AD-4-15.

Example 50(a), First Eluting Compound

5-Fluoro-4-(l-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer A

The first eluting compound had a retention time of 1.39 minutes. ¹H NMR (400 MHz, MeOD) δ ppm 2.13 (s, 3 H) 3.31 (s, 3 H) 3.49 - 3.58 (m, 4 H) 3.60 - 3.68 (m, 4 H) 3.74 -3.95 (m, 2 H) 5.81 (s, 1 H) 6.10 (dd, J=6.82, 3.79 Hz, 1 H) 7.33 - 7.59 (m, 2 H) 8.37 (d, J=2.53 Hz, I H).

Example 50(b), Second Eluting Compound

5-Fluoro-4-(l-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-N-(5-methyl-lH-pyrazol-3-yl)-6- morpholinopyrimidin-2-amine, Enantiomer B

The second eluting compound had a retention time of 1.96 minutes.

¹H NMR (400 MHz, MeOD) δ ppm 2.12 (s, 3 H) 3.29 (s, 3 H) 3.50 - 3.56 (m, 4 H) 3.60 - 3.65

(m, 4 H) 3.72 - 4.02 (m, 2 H) 5.81 (s, 1 H) 6.10 (dd, J=6.82, 3.79 Hz, 1 H) 7.20 - 7.69 (m, 2 H)

8.37 (d, J=2.78 Hz, I H).

Example 51

(S)-6-Ethoxy-Λ^/4-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine

(S)-6-Chloro-N⁴-(l-(5-fluoropyridin-2-yl)ethyl)-N²-(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4- diamine (Example 38, 100 mg, 0.29 mmol), sodium ϊ-butoxide (27.6 mg) ethanol (1 mL) in 2- methylpropan-2-ol (2 ml) were heated in a sealed tube at 90⁰C. Overnight evaporation of the volatiles under reduced pressure afforded a brown solid. ISCO purification (3% to 6% MeOH, 0.3% to 0.6% NH₄OH in DCM), followed by preparative TLC purification (5% MeOH, 0.5%

NH₄OH in DCM) and further purification afforded the title compound (14.2 mg) as white solid. LCMS: 358 [M+H]⁺.

¹H NMR (400 MHz, MeOD) δ ppm 1.33 (t, 3 H) 1.55 (d, 3 H) 2.23 (s, 4 H) 4.23 (q, 2 H) 5.03 (m, 1 H) 5.28 (s, IH) 7.49 (m, 1 H) 7.57 (m, 1 H) 8.44 (s, 1 H).

Claims

ClaimsWhat is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl is optionally substituted with one or more R⁵;

X is selected from -NH-, -O-, and -S-;

R¹ is selected from H, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb,

-N(R^la)N(R^la)₂, -NO₂, -C(O)H, -C(O)R^lb, -C(O)₂R^la, -C(O)N(R^la)₂, -OC(O)N(R^la)₂,

-N(R^la)C(O)₂R^la, -N(R^la)C(0)N(R^la)₂, -OC(O)R^lb, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂,

-N(R^la)S(O)₂R^lb, -C(R^la)=N(R^la), and -C(R^la)=N(OR^la), wherein said d_₆alkyl,

C₂_6alkenyl, C₂_6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl are optionally substituted with one or more R¹⁰;

R^la in each occurrence is independently selected from H, Ci-βalkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci_6alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence is optionally and independently substituted with one or more R¹⁰;

R^lb in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl,

3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci_6alkyl, C₂-6alkenyl, C₂-6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, in

10 each occurrence are optionally and independently substituted with one or more R ;

R² in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b,

-N(R^2a)N(R^2a)₂, -NO₂, -C(O)H, -C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂, -OC(O)N(R^2a)₂,

-N(R^2a)C(O)₂R^2a, -N(R^2a)C(O)N(R^2a)₂, -OC(O)R^2b, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂,

-N(R^2a)S(O)₂R^2b, -C(R^2a)=N(R^2a), and -C(R^2a)=N(OR^2a), wherein said C_1-6alkyl,

C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R²⁰;

R^2a in each occurrence is independently selected from H, Ci-₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R²⁰;

R^2b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R²⁰;

R³ is selected from H, halo, -CN, Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -N(R^3a)N(R^3a)₂, -NO₂, -C(O)H,

-C(O)R^3b, -C(O)₂R^3a, -C(O)N(R^3a)₂, -OC(O)N(R^3a)₂, -N(R^3a)C(O)₂R^3a,

-N(R^3a)C(O)N(R^3a)₂, -OC(O)R^3b, -S(O)R^3b, -S(O)₂R^3b, -S(O)₂N(R^3a)₂, -N(R^3a)S(O)₂R^3b,

-C(R^3a)=N(R^3a), and -C(R^3a)=N(OR^3a), wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R³⁰;

R^3a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R³⁰;

R^3b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R³⁰;

R⁴ is selected from -CN, Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, heterocyclyl,

-N(R^4a)C(O)R^4b, -N(R^4a)N(R^4a)₂, -NO₂, -C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a, -N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b,

-S(O)₂N(R^4a)₂, -N(R^4a)S(O)₂R^4b, -C(R^4a)=N(R^4a), and -C(R^4a)=N(OR^4a), wherein said

Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;

R ^a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁴⁰;

R^4b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁴⁰;

R⁵ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b,

-N(R^5a)N(R^5a)₂, -NO₂, -C(O)H, -C(O)R^5b, -C(O)₂R^5a, -C(O)N(R^5a)₂, -OC(O)N(R^5a)₂,

-N(R^5a)C(O)₂R^5a, -N(R^5a)C(O)N(R^5a)₂, -OC(O)R^5b, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂,

-N(R^5a)S(O)₂R^5b, -C(R^5a)=N(R^5a), and -C(R^5a)=N(OR^5a), wherein said C_1-6alkyl,

C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally substituted with one or more R⁵⁰;

R^5a in each occurrence is independently selected from H, Ci-₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁵⁰;

R^5b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁵⁰;

R¹⁰ in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C₂_6alkenyl,

-N(R^10a)C(O)₂R^10a, -N(R^10a)C(O)N(R^10a)₂, -OC(O)R^10b, -S(O)R^10b, -S(O)₂R^10b,

-S(O)₂N(R^10a)₂, -N(R^10a)S(O)₂R^10b, -C(R^1Oa)=N(R^1Oa), and -C(R^10a)=N(OR^10a), wherein said Ci-6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^a;

R^1Oa in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^a;

R^1Ob in each occurrence is independently selected from Ci-βalkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^a;

R²⁰ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

-N(R^20a)C(O)₂R^20a, -N(R^20a)C(O)N(R^20a)₂, -OC(O)R^20b, -S(O)R^20b, -S(O)₂R^20b,

-S(O)₂N(R^20a)₂, -N(R^20a)S(O)₂R^20b, -C(R^20a)=N(R^20a), and -C(R^20a)=N(OR^20a), wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R ;

R^20a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^b;

R^20b in each occurrence is independently selected from Ci-₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^b;

R³⁰ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

-N(R^30a)C(O)₂R^30a, -N(R^30a)C(O)N(R^30a)₂, -OC(O)R^30b, -S(O)R^30b, -S(O)₂R^30b,

-S(O)₂N(R^30a)₂, -N(R^30a)S(O)₂R^30b, -C(R^3Oa)=N(R^3Oa), and -C(R^30a)=N(OR^30a), wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^c;

R^30a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^c;

R^30b in each occurrence is independently selected from Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^c;

R⁴⁰ in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C₂-6alkenyl,

-N(R^40a)C(O)₂R^40a, -N(R^40a)C(O)N(R^40a)₂, -OC(O)R^40b, -S(O)R^40b, -S(O)₂R^40b,

-S(O)₂N(R^40a)₂, -N(R^40a)S(O)₂R^40b, -C(R^40a)=N(R^40a), and -C(R^40a)=N(OR^40a), wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^d;

R^40a in each occurrence is independently selected from H, d_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^d;

R^40b in each occurrence is independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^d;

R⁵⁰ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

-N(R^50a)C(O)₂R^50a, -N(R^50a)C(O)N(R^50a)₂, -OC(O)R^50b, -S(O)R^50b, -S(O)₂R^50b,

-S(O)₂N(R^50a)₂, -N(R^50a)S(O)₂R^50b, -C(R^5Oa)=N(R^5Oa), and -C(R^50a)=N(OR^50a), wherein said Ci_6alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^e;

R^50a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^e;

R^50b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^e;

R^a, R^b, R^c, R^d, and R^e in each occurrence are independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂, -N(R^m)C(O)Rⁿ, -N(R^m)N(R^m)₂, -NO₂, -C(O)H, -C(O)R", -C(O)₂R¹", -C(0)N(R^m)₂, -0C(0)N(R^m)₂, -N(R^m)C(O)₂R^m, -N(R^m)C(0)N(R^m)₂, -OC(O)R", -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂, -N(R^m)S(0)₂R", -C(R^m)=N(R^m), and -C(R^m)=N(0R^m); R^m in each occurrence is independently selected from H and Ci_₆alkyl; and R" is Ci_₆alkyl.

2. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein

Ring A is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl are optionally substituted with one or more R ;

R⁵ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, -0R^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -C(O)H, -C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -0C(0)R^5a, -N(R^5a)C(O)N(R^5a)₂, -S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, and -N(R^5a)S(O)₂R^5b, wherein said d_₆alkyl, C₂_₆alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁵⁰;

R^5a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁵⁰;

R^5b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R⁵⁰; R⁵⁰ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂-₆alkynyl, carbocyclyl, and heterocyclyl, -OR Λ 5³0a , - rSi TRi 5³0a , - _ΛN.TY(DR 5³0^υa^a\)₂, - _ΛN.TY(DR 5³0^υa^a\)C /~i( /rO\\)τR> 5³0b

-C(O)H i,, --CC((OO))RR^5500bb,, --CC((OO))₂₂RR^5500aa,, --CC((OO))NN((RR^5500aa))₂₂,, --OOCC((OO))BR^50a, -N(R^50a)C(O)N(R^50a)₂, -S(O)R^50b, -S(O)₂R^50b, -S(O)₂N(R^50a)₂, and -N(R^50a)S(O)₂R^50b; R^50a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R^50b in each occurrence is independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl.

3. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in either of claim 1 or claim 2, wherein

R¹ is selected from -CN, Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -NO₂,

-S(O)₂R^lb, -S(O)₂N(R^la)₂, and -N(R^la)S(O)₂R^lb, wherein said C_1-6alkyl, C₂_₆alkenyl,

C₂_6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl are optionally substituted with one or more R¹⁰;

R^la in each occurrence is independently selected from H, C_halky 1, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said Ci_6alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R¹⁰;

3- to 5-membered carbocyclyl, and 5-membered heterocyclyl wherein said Ci_6alkyl,

C₂_6alkenyl, C₂_6alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R¹⁰;

R¹⁰ in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

-C(O)H, -C(O)R^10b, -C(O)₂R^10a, -C(O)N(R^10a)₂, -OC(O)R^10b, -N(R^10a)C(O)N(R^10a)₂,

-S(O)R^10b, -S(O)₂R^10b, -S(O)₂N(R^10a)₂, and -N(R^10a)S(O)₂R^10b;

R^1Oa in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl; and

R^1Ob in each occurrence is independently selected from Ci-βalkyl, C₂_₆alkenyl, C₂_₆alkynyl, and heterocyclyl.

4. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein

R² is selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -C(O)H, -C(O)R^22b, -C(O)₂R^2a,

-C(O)N(R^2a)₂, -OC(O)R^2a, -N(R^2a)C(O)N(R^2a)₂, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, and

-N(R^2a)S(O)₂R^2b, wherein said C_1-6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R ;

R^2a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R²⁰;

R^2b in each occurrence is independently selected from Ci-₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R²⁰;

R²⁰ in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C₂_6alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^20a)₂, -N(R^20a)C(O)R^20b,

-C(O)H, -C(O)R^20b, -C(O)₂R^20a, -C(O)N(R^20a)₂, -OC(O)R^20b, -N(R^20a)C(O)N(R^20a)₂,

-S(O)R^20b, -S(O)₂R^20b, -S(O)₂N(R^20a)₂, and -N(R^20a)S(O)₂R^20b, wherein said C_1-6alkyl,

C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R^b;

R^20a in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^b;

R^20b in each occurrence is independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R^b;

R^b in each occurrence is independently selected from halo, -CN, Ci_₆alkyl, C₂_₆alkenyl,

C₂_₆alkynyl, carbocyclyl, heterocyclyl, -0R^m, -SR^m, -N(R^m)₂, -N(R^m)C(0)Rⁿ, -C(O)H,

-C(O)R", -C(O)₂R¹¹¹, -C(0)N(R^m)₂, -OC(O)R", -N(R^m)C(0)N(R^m)₂, -S(O)R", -S(O)₂R",

-S(O)₂N(R^m)₂, and -N(R^m)S(0)₂R";

R^m in each occurrence is independently selected from H, Ci_₆alkyl, carbocyclyl, and heterocyclyl; and

R" in each occurrence is independently selected from Ci-₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl.

5. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein

R³ is selected from H, halo, -CN, Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, -N(R^3a)C(O)R^3b, -C(O)H, -C(O)R^3b, -C(O)₂R^3a,

-N(R^3a)S(O)₂R^3b, wherein said Ci_-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R³⁰;

R^3a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R³⁰;

R^3b in each occurrence is independently selected from Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R³⁰;

R³⁰ in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C_2-6alkenyl,

C₂-₆alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^3Oa, -N(R^30a)₂, -N(R^30a)C(O)R^30b,

-C(O)H, -C(O)R^30b, -C(O)₂R³⁰³, -C(O)N(R^30a)₂, -OC(O)R^30a, -N(R^30a)C(O)N(R^30a)₂,

-S(O)R^30b, -S(O)₂R^30b, -S(O)₂N(R^30a)₂, and -N(R^30a)S(O)₂R^30b;

R^30a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl; and

R^30b in each occurrence is independently selected from Ci-βalkyl, C₂_6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl.

6. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein

R⁴ is selected from -CN, C_1-6alkyl, C₂_₆alkenyl, and C₂_₆alkynyl, -N(R^4a)C(O)R^4b, -NO₂, -C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a, -N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b, -S(O)₂N(R^4a)₂, and

-N(R^4a)S(O)₂R^4b, wherein said Ci_6alkyl, C₂-6alkenyl, and C₂-6alkynyl are optionally substituted with one or more R⁴⁰;

R^4b in each occurrence is independently selected from Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence may be optionally and independently substituted with one or more R⁴⁰;

R⁴⁰ in each occurrence are independently selected from halo, -CN, Ci_₆alkyl, C₂-₆alkenyl,

-C(O)H, -C(O)R^40b, -C(O)₂R^40a, -C(O)N(R^40a)₂, -OC(O)R^40a, -N(R^40a)C(O)N(R^40a)₂,

-S(O)R^40b, -S(O)₂R^40b, -S(O)₂N(R^40a)₂, and -N(R^40a)S(O)₂R^40b;

R^40a in each occurrence is independently selected from H, C_halky!, carbocyclyl, and heterocyclyl; and RR^4400bb iinn eeaacchh ooccccuuirrence is independently selected from C_halky!, C₂-₆alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl.

7. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5- fluoropyrimidin-2-yl;

X is selected from -NH- and -O- ;

R¹ is selected from methyl and methoxy;

R² is selected from 4-cyanopiperidin-l-yl, l,l-dioxidothiomorpholin-4-yl, ethoxy, 3-

(hydroxymethyl)morpholin-4-yl 4-hydroxy-4-methylpiperidin- 1 -yl, 3 -methoxyazetidin-

1-yl, 4-methoxypiperidin-l-yl, methylamino, 4-methyl-3-oxopiperazin-l-yl, 4- methylpiperazin-1-yl, 4-(methylsulfonyl)piperazin-l-yl, morpholin-4-yl, 2-oxa-5- azabicycylo[2.2.1]hept-5-yl, and piperazin-1-yl;

R³ is selected from H, fluoro, and chloro; and

R⁴ is selected from methyl and methoxymethyl.

8. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use as a medicament.

9. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the production of a JAK inhibitory effect.

10. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the treatment of cancer.

11. A method for producing an anti-proliferative effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

12. A method for producing a JAK inhibitory effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

13. A method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

14. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the production of an anti-proliferative effect, in a warm-blooded animal such as man.

15. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the production of a JAK inhibitory effect in a warmblooded animal such as man.

16. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

17. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, said process comprising reacting a compound of Formula (A):

with a compound of Formula (B):

. _and

and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt,

wherein L¹ is a leaving group.

18. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, said process comprising reacting a compound of Formula (C):

with a compound of Formula (D):

and thereafter if appropriate: i. converting a compound of Formula (I) into another compound of Formula (I); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt, wherein L² is a leaving group.