WO2012066065A1

WO2012066065A1 - Phenyl-heteroaryl amine compounds and their uses

Info

Publication number: WO2012066065A1
Application number: PCT/EP2011/070322
Authority: WO
Inventors: William R. Antonios-Mccrea; Paul A. Barsanti; Cheng Hu; Xianming Jin; Eric J. Martin; Yue Pan; Keith B. Pfister; Martin Sendzik; James Sutton; Lifeng Wan
Original assignee: Novartis Ag
Priority date: 2010-11-17
Filing date: 2011-11-17
Publication date: 2012-05-24

Abstract

The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I, and pharmaceutical compositions comprising such compounds.

Description

PHENYL-HETEROARYL AMINE COMPOUNDS AND THEIR USES

BACKGROUND

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (Hardie, G. and Hanks, S., THE PROTEIN KINASE FACTS BOOK, I AND II, Academic Press, San Diego, Calif : 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein- tyrosine, protein- serine/threonine, lipids, etc.).

Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K, Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al,

Science 1991, 253, 407-414; Hiles et al, Cell 1992, 70, 419-429; Kunz et al, Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO J. 1994, 13, 2352-2361).

Many diseases are associated with abnormal cellular responses triggered by the protein kinase-mediated events described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma,

Alzheimer's disease, viral diseases, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

The cyclin-dependent kinase (CDK) complexes are a class of kinases that are targets of interest. These complexes comprise at least a catalytic (the CDK itself) and a regulatory (cyclin) subunit. Some of the more important complexes for cell cycle regulation include cyclin A (CDKl-also known as cdc2, and CDK2), cyclin B1-B3 (CDK1) and cyclin D1-D3 (CDK2, CDK4, CDK5, CDK6), cyclin E (CDK2). Each of these complexes is involved in a particular phase of the cell cycle. Additionally, CDKs 7, 8, and 9 are implicated in the regulation of transcription. The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localization. Tumor development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for, e.g., cyclin A/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cytotoxic and cytostatic drugs. While inhibition of cell cycle- related CDKs is clearly relevant in, e.g., oncology applications, inhibition of RNA polymerase-regulating CDKs may also be highly relevant in cancer indications.

The CDKs have been shown to participate in cell cycle progression and cellular transcription, and loss of growth control is linked to abnormal cell proliferation in disease (see e.g., Malumbres and Barbacid, Nat. Rev. Cancer 2001, 1 :222). Increased activity or temporally abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors (Sherr C. J., Science 1996, 274 : 1672-1677). Indeed, human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C, Am. J. Path. 1995; 147: 545-560; Karp J. E. and Broder S., Nat. Med. 1995; 1 : 309-320; Hall M. et al, Adv. Cancer Res. 1996; 68: 67-108).

Naturally occurring protein inhibitors of CDKs such as pl6 and p27 cause growth inhibition in vitro in lung cancer cell lines (Kamb A., Curr. Top. Microbiol. Immunol. 1998; 227: 139-148).

CDKs 7 and 9 seem to play key roles in transcription initiation and elongation, respectively (see, e.g., Peterlin and Price, Cell 23: 297-305, 2006, Shapiro, J. Clin. Oncol. 24: 1770-83, 2006). Inhibition of CDK9 has been linked to direct induction of apoptosis in tumor cells of hematopoietic lineages through down-regulation of transcription of antiapoptotic proteins such as Mcll (Chao, S.-H. et al. J. Biol. Chem. 2000;275:28345-28348; Chao, S.-H. et al. J. Biol. Chem. 2001;276:31793-31799; Lam et. al. Genome Biology 2: 0041.1-11, 2001 ; Chen et al. Blood 2005; 106:2513; MacCallum et al. Cancer Res. 2005;65:5399; and Alvi et al. Blood 2005; 105:4484). In solid tumor cells, transcriptional inhibition by downregulation of CDK9 activity synergizes with inhibition of cell cycle CDKs, for example CDK1 and 2, to induce apoptosis (Cai, D.-P., Cancer Res 2006, 66:9270. Inhibition of transcription through CDK9 or CDK7 may have selective non-proliferative effect on the tumor cell types that are dependent on the transcription of mRNAs with short half lives, for example Cyclin Dl in Mantle Cell Lymphoma. Some transcription factors such as Myc and NF-kB selectively recruit CDK9 to their promoters, and tumors dependent on activation of these signalling pathways may be sensitive to CDK9 inhibition.

Small molecule CDK inhibitors may also be used in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders that are due to aberrant cell proliferation. Vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty are inhibited by over-expression of the cyclin-dependent kinase inhibitor protein. Moreover, the purine CDK2 inhibitor CVT-313 (Ki = 95 nM) resulted in greater than 80% inhibition of neointima formation in rats.

CDK inhibitors can be used to treat diseases caused by a variety of infectious agents, including fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses. For example, cyclin-dependent kinases are required for viral replication following infection by herpes simplex virus (HSV) (Schang L. M. et al, J. Virol. 1998; 72: 5626) and CDK homologs are known to play essential roles in yeast.

Inhibition of CDK9/cyclin T function was recently linked to prevention of HIV replication and the discovery of new CDK biology thus continues to open up new therapeutic indications for CDK inhibitors (Sausville, E. A., Trends Molec. Med. 2002, 8, S32-S37).

CDKs are important in neutrophil-mediated inflammation and CDK inhibitors promote the resolution of inflammation in animal models. (Rossi, A.G. et al., Nature Med. 2006, 12: 1056). Thus CDK inhibitors, including CDK9 inhibitors, may act as anti-inflammatory agents.

Selective CDK inhibitors can be used to ameliorate the effects of various autoimmune disorders. The chronic inflammatory disease rheumatoid arthritis is characterized by synovial tissue hyperplasia; inhibition of synovial tissue proliferation should minimize inflammation and prevent joint destruction. In a rat model of arthritis, joint swelling was substantially inhibited by treatment with an adenovirus expressing a CDK inhibitor protein p 16. CDK inhibitors are effective against other disorders of cell proliferation including psoriasis (characterized by keratinocyte hyperproliferation), glomerulonephritis, chronic inflammation, and lupus.

Certain CDK inhibitors are useful as chemoprotective agents through their ability to inhibit cell cycle progression of normal untransformed cells (Chen, et al. J. Natl. Cancer

Institute, 2000; 92: 1999-2008). Pre-treatment of a cancer patient with a CDK inhibitor prior to the use of cytotoxic agents can reduce the side effects commonly associated with chemotherapy. Normal proliferating tissues are protected from the cytotoxic effects by the action of the selective CDK inhibitor.

Accordingly, there is a great need to develop inhibitors of protein kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as combinations thereof.

Summary of the Invention

There remains a need for new treatments and therapies for protein kinase-associated disorders. There is also a need for compounds useful in the treatment or prevention or amelioration of one or more symptoms of cancer, inflammation, cardiac hypertrophy, and HIV. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, and combinations thereof, and the present invention provides such methods, using novel compounds described herein.

In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or deuterated version thereof, as further described herein, as well as pharmaceutical compositions containing these compounds and methods to use the compounds and compositions for treatment of protein kinase- associated disorders, particularly disorders associated with excessive or undesired levels of CDK activity and especially CDK9 activity. Disorders treatable by the compounds and methods described herein include various cancers. In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or deuterated version thereof, wherein:

Ai is N or CRs;

A₃ is N or CR₈;

A₄ is selected from a bond, S0₂, CO-NR9, -SO2-NR9-, NR₉, and O; L is selected from a bond, optionally substituted Ci_-4alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, or C_2-4 alkenyl;

Ri is -X-Rie;

X is a bond, or C_1-4 alkylene;

Ri₆ is selected from the group consisting of Ci-₆ alkyl, C3-₆branched alkyl, C3- ₈Cycloalkyl, C3-10 heterocycloalkyl, C3-8-partially unsaturated cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C₆-io aryl- or C₅_6-heteroaryl-fused C₅-7 heterocycloalkyl, and C3-10 partially unsaturated heterocycloalkyl wherein R½ is substituted with up to three groups independently selected from halogen, Ci-₆alkyl, Ci-₆haloalkyl, C₃_₆branched alkyl, C₃_₆branched haloalkyl, OH, oxo, Ci-₆alkoxy, heterocycloalkyl, Ci_-2alkyl-heterocycloalkyl, Ci_-2alkyl-heteroaryl, -R₂₂-ORi_2i S(0)o-2Ri2, -R₂2-S(0)o-₂Ri2, S(0)₂NRi3Ri₄, -R₂₂-S(0)₂NRi₃Ri₄, -C(0)ORi₂, -R₂₂-C(0)ORi₂, C(0)Ri9, -R₂₂-C(0)Ri9, 0-Ci_-3 alkyl, OCi_-3 haloalkyl, OC(0)Ri₉, -R₂₂-OC(0)Ri₉, C(0)NRi₃Ri₄, -R₂₂-C(0)NRi₃Ri₄, NRi₅S(0)₂Ri2, -R₂₂-NRi₅S(0)₂Ri₂, -NR₁₇R₁₈, -R₂₂-NRi₇Ri₈,

NRi₅C(0)Ri9, -R₂₂-NRi₅C(0)Ri9, NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)OCH₂Ph, NRi₅C(0)ORi₂, -R₂₂-NR₁₅C(0)OR₁₂, NR₁₅C(0)NR₁3Ri₄, and -R₂₂-NR₁₅C(0)NR₁₃Ri₄; Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, hydroxyl, Ci-₆alkyl, Ci-₆haloalkyl, C3-₆branched alkyl, C3-8 cycloalkyl, Ci-4-alkyl-C3-8-cycloalkyl, C3 -8 heterocycloalkyl, Ci-4-alkyl-C3-8 heterocycloalkyl, R22-OR12_, R22-S(0)o-2Ri2_, -R22- S(0)₂NRi₃Ri4, -R₂₂-C(0)ORi2, -R₂₂-C(0)Ri₉, -R₂₂-OC(0)Ri₉, -R₂₂-C(0)NRi3Ri₄, -R22- NRi₅S(0)₂Ri2, -R22-NR₂3R₂₄, -R₂2-NRi₅C(0)Ri₉, .R22-NRi₅C(0)OCH₂Ph, -R₂2-NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)NRi₃Ri₄, -R₂₂-cycloalkyl, -R₂₂-heterocycloalkyl, heteroaryl, and -R₂₂-heteroaryl; wherein each alkyl, cycloalkyl, branched alkyl, heterocycloalkyl, and heteroaryl can be substituted with up to two groups selected from R²⁰;

alternatively, R17 and Ri₈ along with the nitrogen atom to which they are attached can be taken together to form a four to six or seven or eight-membered heterocyclic ring containing up to two heteroatoms selected from N, O and S as ring members and optionally fused to an optionally substituted 5-6 membered aryl or heteroaryl ring, wherein the carbon atoms of said rings are optionally substituted with R20, and the nitrogen atoms of said rings are optionally substituted with R21;

Ri₉ is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R20 is selected from the group consisting of oxo (=0), halo, amino, hydroxy, Ci_-6 alkoxy, Ci-6 alkyl and Ci-6 haloalkyl;

and where two R²⁰ on the same or adjacent connected atoms can be taken together with the atoms to which they are attached to form a 3-8 membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from N, O and S as ring members and optionally substituted with up to two groups selected from halo, oxo, Me, OMe, CN, hydroxy, amino, and dimethylamino;

R21 is selected from the group consisting of Ci-₆alkyl, Ci-₆haloalkyl, C(0)Ri2, C(0)ORi2, and S(0)₂Ri₂;

R22 is selected from the group consisting of Ci-₆ alkylene, Ci-₆haloalkylene, C3-6 branched alkylene, C3_₆branched haloalkylene;

R23 and R2₄ are each, independently, selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-₆ acyl, Ci-₆haloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl; R₂ is selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C3-8 branched alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted C₆-io aryl, and optionally substituted C_5- 10 heteroaryl;

R4_a, R4b, R5, and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C_1-4 alkyl, Ci_-4haloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, amino, NR10R11, and alkoxy;

R3, R7 and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, NR10R11, C(0)Ri₂, C(0)ORi2, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(0)o-₂NRi₃Ri₄, morpholino, tetrazolyl, and optionally substituted C3_-4 cycloalkyl;

R9 is selected from the group consisting of hydrogen, Ci_-4 alkyl, alkoxy, C(0)Ri₂, C(0)ORi5_, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(0)o-₂NRi₃Ri₄, optionally substituted C_3-4 cycloalkyl, and optionally substituted heterocycloalkyl;

Rio and Rn are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(0)Ri₂, C(0)ORi_2, C(0)NRi₃Ri₄, S(O)_0-2Ri₂, and S(O)₀-₂NRi₃Ri₄; alternatively, Rio and Rn along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non- aromatic heterocyclic ring;

Ri₂ and R15 are each, individually, selected from the group consisting of hydrogen, alkyl, branched alkyl, haloalkyl, branched haloalkyl, hydroxyalkyl, alkoxyalkyl, (CH₂)o-3-cycloalkyl, (CH₂)o-3-heterocycloalkyl, (CH₂)o-3-aryl, and heteroaryl;

Ri3 and Ri₄ are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, branched alkyl, haloalkyl, branched haloalkyl, alkoxy, cycloalkyl or heterocycloalkyl; and alternatively, R13 and Ri₄ along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or non-aromatic heterocyclic ring.

Selected embodiments of these compounds are further described herein.

In certain embodiments, the compound is a compound of Formula II:

wherein:

Ai is N or CH;

Rs is selected from F, CI and Me;

R₇ is selected from H, CI, F, CN;

R₃ is selected from H, halo, CN, Me and OMe;

X is a bond, CH₂ or (CH₂)₂;

Ri6 is optionally substituted cyclohexyl;

A₄ is NH or O;

and R₂ is selected from optionally substituted C3-6 cycloalkyl, tetrahydropyran, optionally substituted phenyl, and optionally substituted pyridyl;

or a pharmaceutically acceptable salt thereof.

Specific embodiments of these compounds are further described below. The invention includes each isomer, tautomer, atropisomer, and diastereomer of such compounds.

The invention also includes pharmaceutically acceptable salts of the compounds described herein, as well as pharmaceutical compositions that comprise a compound of the invention or a pharmaceutically acceptable salt admixed with at least one pharmaceutically acceptable excipient, carrier or diluent.

These compounds and compositions are useful to treat disorders mediated by CDK9 activity.

Another aspect of the present invention provides a compound of Formula I or II, or pharmaceutically acceptable salt or solvate thereof, for use in therapy. Yet another aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a disease or condition mediated by CDK9. Yet another aspect of the present invention provides a method of treating a disease or condition mediated by CDK9 comprising administration to a subject in need thereof a therapeutically effective amount of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof. Provided in yet another aspect of the present invention is a compound of Formula I for use in a method of treating a disease or condition mediated by CDK9 is selected from cancer, cardiac hypertrophy, HIV and inflammatory diseases.

Another aspect of the present invention provides a method of treating a cancer selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.

Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the invention provides a method of regulating, modulating, or inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of the invention. In one embodiment, the protein kinase is selected from the group consisting of CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, or any combination thereof. In another embodiment, the protein kinase is selected from the group consisting of CDKl, CDK2 and CDK9, or any combination thereof. In still another embodiment, the protein kinase is in a cell culture. In yet another embodiment, the protein kinase is in a mammal.

In another aspect, the invention provides a method of treating a protein kinase-associated disorder comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention such that the protein kinase-associated disorder is treated. In one embodiment, the protein kinase is selected from the group consisting of CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9. In some embodiments, the protein kinase is CDK9.

In one embodiment, the protein kinase-associated disorder is cancer. In still another embodiment, the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system,

genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer. In one embodiment, the protein kinase-associated disorder is inflammation. In another embodiment, the inflammation is related to rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic inflammation, and organ transplant rejections.

In another embodiment, the protein kinase-associated disorder is a viral infection. In one embodiment, the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxvirus virus, Epstein-Barr virus, Sindbis virus, or adenovirus.

In still another embodiment, the protein kinase-associated disorder is cardiac hypertrophy.

In another aspect, the invention provides a method of treating cancer comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention such that the cancer is treated. In one embodiment, the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer.

In another aspect, the invention provides a method of treating inflammation comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the inflammation is treated, wherein the compound is a compound of the invention. In one embodiment, the inflammation is related to rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic inflammation, and organ transplant rejections.

In another aspect, the invention provides a method of treating cardiac hypertrophy comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the cardiac hypertrophy is treated, wherein the compound is a compound of the invention.

In another aspect, the invention provides a method of treating a viral infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the viral infection is treated, wherein the compound is a compound of the invention. In one embodiment, the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxvirus virus, Epstein-Barr virus, Sindbis virus, or adenovirus.

In one embodiment, the subject to be treated by the compounds of the invention is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a preferred embodiment, the mammal is a human. In some embodiments, the subject is a human who has been diagnosed as in need of treatment for one of the conditions described herein.

In another aspect, the compounds of the invention is administered, simultaneously or sequentially, with an antiinflammatory, antiproliferative, chemotherapeutic agent,

immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitor or salt thereof. In one embodiment, the compound, or salt thereof, is administered, simultaneously or sequentially, with one or more of a PTK inhibitor, cyclosporin A, CTLA4-Ig, antibodies selected from anti-ICAM- 3, anti-IL-2 receptor, anti-CD45RB, anti-CD2, anti-CD3, anti-CD4, anti-CD80, anti-CD86, and monoclonal antibody OKT3, CVT-313, agents blocking the interaction between CD40 and gp39, fusion proteins constructed from CD40 and gp39, inhibitors of NF-kappa B function, nonsteroidal antiinflammatory drugs, steroids, gold compounds, FK506, mycophenolate mofetil, cytotoxic drugs, TNF-a inhibitors, anti-TNF antibodies or soluble TNF receptor, rapamycin, leflunimide, cyclooxygenase-2 inhibitors, paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, epothilone, vindesine, leurosine, or derivatives thereof.

In another aspect, the invention provides a packaged protein kinase-associated disorder treatment, comprising a protein kinase-modulating compound of the Formula I or Formula II, packaged with instructions for using an effective amount of the protein kinase-modulating compound to treat a protein kinase-associated disorder.

In certain embodiments, the compound of the present invention is further characterized as a modulator of a protein kinase, including, but not limited to, protein kinases selected from the group consisting of abl, ATK, Bcr-abl, Blk, Brk, Btk, c-fms, e-kit, c-met, c-src, CDK, cRafl, CSFIR, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFRI, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK, Gst-Flkl, Hck, Her-2, Her-4, IGF- lR, INS-R, Jak, INK, KDR, Lck, Lyn, MEK, p38, panHER, PDGFR, PLK, PKC, PYK2, Raf, Rho, ros, SRC, TRK, TYK2, UL97, VEGFR, Yes, Zap70, Aurora- A, GSK3-alpha, fflPKl, ΓΠΡΚ2, ΓΠΡ3, IRAKI , JNK1 , JNK2, JNK3, TRKB, CAMKII, CK1 , CK2, RAF, GSK3Beta, MAPKl , MKK4, MKK7, MST2, NEK2, AAKl, PKCalpha, PKD, RIPK2 and ROCK-II. In a preferred embodiment, the compounds of the invention modulate a protein kinase selected from the group consisting of CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 and any combination thereof, as well as any other CDK, as well as any CDK not yet identified. In a particularly preferred embodiment, the protein kinase is selected from the group consisting of CDKl, CDK2 and CDK9. In a particularly preferred embodiment, the protein kinase is selected from the group consisting of CDK9.

In a particular embodiment, CDK combinations of interest include CDK4 and CDK9; CDKl, CDK2 and CDK9; CDK9 and CDK7; CDK9 and CDKl; CDK9 and CDK2; CDK4, CDK6 and CDK9; CDKl, CDK2, CDK3, CDK4, CDK6 and CDK9. In some embodiments, the compounds of the invention are active on at least one of these combinations with IC-50 levels below about 1 micromolar on each such CDK, and preferably below about 100 nM on each CDK in one of these combinations. In some embodiments, the compounds are selectively active on CDK9, with at least a 5-fold or 10-fold lower IC-50 on CDK9 than on CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, or CDK8.

In other embodiments, the compounds of the present invention are used for the treatment of protein kinase-associated disorders. As used herein, the term "protein kinase-associated disorder" includes disorders and states (e.g., a disease state) that are associated with the activity of a protein kinase, e.g., the CDKs, e.g., CDKl, CDK2 and/or CDK9. Non-limiting examples of protein kinase-associated disorders include abnormal cell proliferation (including protein kinase- associated cancers), viral infections, fungal infections, autoimmune diseases and

neurodegenerative disorders.

Non-limiting examples of protein-kinase associated disorders include proliferative diseases, such as viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, chronic inflammation, neurodegenerative disorders, such as Alzheimer's disease, and post-surgical stenosis and restenosis. Protein kinase-associated diseases also include diseases related to abnormal cell proliferation, including, but not limited to, cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary passages, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, and leukemia.

Additional non-limiting examples of protein kinase-associated cancers include carcinomas, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Protein kinase-associated disorders include diseases associated with apoptosis, including, but not limited to, cancer, viral infections, autoimmune diseases and neurodegenerative disorders.

Non-limiting examples of protein-kinase associated disorders include viral infections in a patient in need thereof, wherein the viral infections include, but are not limited to, HIV, human papilloma virus, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.

Non-limiting examples of protein-kinase associated disorders include tumor angiogenesis and metastasis. Non-limiting examples of protein-kinase associated disorders also include vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis and restenosis, and endometriosis.

Further non-limiting examples of protein-kinase associated disorders include those associated with infectious agents, including yeast, fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses.

In another embodiment, the compound of the present invention is further characterized as a modulator of a combination of protein kinases, e.g., the CDKs, e.g., CDKl, CDK2 and/or CDK9.

In certain embodiments, a compound of the present invention is used for protein kinase- associated diseases, and/or as an inhibitor of any one or more protein kinases. It is envisioned that a use can be a treatment of inhibiting one or more isoforms of protein kinases.

The compounds of the invention are inhibitors of cyclin-dependent kinase enzymes.

Without being bound by theory, inhibition of the CDK4/cyclin Dl complex blocks

phosphorylation of the Rb/inactive E2F complex, thereby preventing release of activated E2F and ultimately blocking E2F-dependent DNA transcription. This has the effect of inducing Gi cell cycle arrest. In particular, the CDK4 pathway has been shown to have tumor- specific deregulation and cytotoxic effects. Accordingly, the ability to inhibit the activity of combinations of CDKs will be of beneficial therapeutic use.

Furthermore, the cell's ability to respond and survive chemotherapeutic assault may depend on rapid changes in transcription or on activation of pathways which are highly sensitive to CDK9/cyclinTl (PTEF-b) activity. CDK9 inhibition may sensitize cells to TNFalpha or TRAIL stimulation by inhibition of NF-kB, or may block growth of cells by reducing myc- dependent gene expression. CDK9 inhibition may also sensitize cells to genotoxic

chemotherapies, HDAC inhibition, or other signal transduction based therapies.

As such, the compounds of the invention can lead to depletion of anti-apoptotic proteins, which can directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition. Depletion of anti- apoptotic proteins by the compounds of the invention may directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition.

The compounds of the invention can be effective in combination with chemotherapy,

DNA damage arresting agents, or other cell cycle arresting agents. The compounds of the invention can also be effective for use in chemotherapy-resistant cells.

The present invention includes treatment of one or more symptoms of cancer, inflammation, cardiac hypertrophy, and HIV infection, as well as protein kinase-associated disorders as described above, but the invention is not intended to be limited to the manner by which the compound performs its intended function of treatment of a disease. The present invention includes treatment of diseases described herein in any manner that allows treatment to occur, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection.

In certain embodiments, the invention provides a pharmaceutical composition of any of the compounds of the present invention. In a related embodiment, the invention provides a pharmaceutical composition of any of the compounds of the present invention and a

pharmaceutically acceptable carrier or excipient of any of these compounds. In certain embodiments, the invention includes the compounds as novel chemical entities.

In one embodiment, the invention includes a packaged protein kinase-associated disorder treatment. The packaged treatment includes a compound of the invention packaged with instructions for using an effective amount of the compound of the invention for an intended use. The compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating protein kinase-associated disorders, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection. The pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like. In certain embodiments, the excipient is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.

The phrase, "pharmaceutically effective amount" as used herein indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially the regulating, modulating, or inhibiting protein kinase activity, e.g., inhibition of the activity of a protein kinase, or treatment of cancer, inflammation, cardiac hypertrophy, and HIV infection.

In other embodiments, the present invention provides a method for inhibiting the activity of a protein kinase. The method includes contacting a cell with any of the compounds of the present invention. In a related embodiment, the method further provides that the compound is present in an amount effective to selectively inhibit the activity of a protein kinase.

In other embodiments, the present invention provides a use of any of the compounds of the invention for manufacture of a medicament to treat cancer, inflammation, cardiac

hypertrophy, and HIV infection in a subject.

In other embodiments, the invention provides a method of manufacture of a medicament, including formulating any of the compounds of the present invention for treatment of a subject. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The term "treat," "treated," "treating" or "treatment" includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises the induction of a protein kinase- associated disorder, followed by the activation of the compound of the invention, which would in turn diminish or alleviate at least one symptom associated or caused by the protein kinase- associated disorder being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

The term "use" includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-associated disorders; the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the manufacture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases; as appropriate and expedient, if not stated otherwise. In particular, diseases to be treated and are thus preferred for use of a compound of the present invention are selected from cancer, inflammation, cardiac hypertrophy, and HIV infection, as well as those diseases that depend on the activity of protein kinases. The term "use" further includes embodiments of compositions herein which bind to a protein kinase sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent.

The term "subject" is intended to include organisms, e.g., prokaryotes and eukaryotes, which are capable of suffering from or afflicted with a disease, disorder or condition associated with the activity of a protein kinase. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer, inflammation, cardiac hypertrophy, and HIV infection, and other diseases or conditions described herein (e.g., a protein kinase-associated disorder). In another embodiment, the subject is a cell. The language "protein kinase-modulating compound," "modulator of protein kinase" or "protein kinase inhibitor" refers to compounds that modulate, e.g., inhibit, or otherwise alter, the activity of a protein kinase. Examples of protein kinase-modulating compounds include compounds of the invention, i.e., Formula I and Formula II, as well as the compounds of Table A, Table B, and Table C (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof).

Additionally, a method of the invention includes administering to a subject an effective amount of a protein kinase-modulating compound of the invention, e.g., protein kinase- modulating compounds of Formula I and Formula II, as well as Table 1 or Table IB, including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof.

Where linking groups are specified by their conventional chemical formula herein, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH₂O- is intended to

include -OCH₂- for this purpose only.

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a fully saturated straight-chain (linear; unbranched) or branched chain, or a combination thereof, having the number of carbon atoms specified, if designated {i.e. C₁-C₁₀ means one to ten carbons). Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. If no size is designated, the alkyl groups mentioned herein contain 1-10 carbon atoms, typically 1-8 carbon atoms, and often 1-6 or 1-4 carbon atoms, and preferably 1-2 carbon atoms. If the alkyl group is a branched alkyl group, and the number of carbon atoms is not mentioned, the branched alkyl group will consist of 3-8 carbon atoms, typically about 3-6 carbon atoms, and particularly 3-4 carbon atoms.

The term "alkenyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranched), branched-chain groups, and combinations thereof, having the number of carbon atoms specified, if designated, which contain at least one double bond (-C=C-). All double bonds may be independently either (E) or (Z) geometry, as well as mixtures thereof. Examples of alkenyl groups include, but are not limited to, -CH₂-CH=CH-CH₃; -CH=CH-CH=CH₂ and -CH₂-CH=CH-CH(CH₃)-CH₂-CH₃. If no size is specified, the alkenyl groups discussed herein contain 2-6 carbon atoms.

The term "alkynyl" refers to unsaturated aliphatic groups including straight-chain (linear; unbranched), branched-chain groups, and combinations thereof, having the number of carbon atoms specified, if designated, which contain at least one carbon-carbon triple bond (-C≡C-). Examples of alkynyl groups include, but are not limited to, -CH₂-C≡C-CI¾; -C≡C-C≡CH and -CH₂-C≡C-CH(CI¾)-CH₂-CH₃. If no size is specified, the alkynyl groups discussed herein contain 2-6 carbon atoms.

Alkynyl and alkenyl groups can contain more than one unsaturated bond, or a mixture of double and triple bonds, and can be otherwise substituted as described for alkyl groups.

Where the context indicates that an alkyl, alkenyl or alkynyl group or a cycloalkyl or heterocycloalkyl group serves as a linking group (such as -X- and L and R₂₂ in Formula I), the alkyl, alkenyl or alkynyl group is divalent, as would be apparent to the person of skill in the art. Examples of such groups include methylene, (0¼)_η where n = 1-4, -CH(CI¾)-, 1,1- cyclopropane-diyl, and the like.

The terms "alkoxy," "alkenyloxy," and "alkynyloxy" refer to -O-alkyl, -O-alkenyl, and -O-alkynyl, respectively.

The term "cycloalkyl" by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of alkyl, alkenyl, or alkynyl, or mixtures thereof. Additionally, cycloalkyl may contain fused rings, but excludes fused aryl and heteroaryl groups, and cycloalkyl groups can be substituted unless specifically described as unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 - cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, and the like. If no ring size is specified, the cycloalkyl groups described herein contain 3-8 ring members, or 3-6 ring members.

The term "heterocyclic" or "heterocycloaklyl" or "heterocyclyl," by itself or in combination with other terms, represents a cycloalkyl radical containing at least one annular carbon atom and at least one annular heteroatom selected from the group consisting of O, N, P, Si and S, preferably from N, O and S, wherein the ring is not aromatic but can contain unsaturations. The nitrogen and sulfur atoms in a heterocyclic group may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In many embodiments, the annular heteroatoms are selected from N, O and S. The heterocyclic groups discussed herein, if not otherwise specified, contain 3-10 ring members, and at least one ring member is a heteroatom selected from N, O and S; commonly not more than three of these heteroatoms are included in a heterocyclic group, and generally not more than two of these heteroatoms are present in a single ring of the heterocyclic group. The heterocyclic group can be fused to an additional carbocyclic, heterocyclic, or aryl ring. A heterocyclic group can be attached to the remainder of the molecule at an annular carbon or annular heteroatom, and the heterocyclic groups can be substituted as described for alkyl groups. Additionally, heterocyclic may contain fused rings, but excludes fused systems containing a heteroaryl group as part of the fused ring system. Examples of heterocyclic groups include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4- tetrahydropyridyl, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

As with other moieties described herein, heterocycloalkyl moieties can be unsubstituted, or substituted with various substituents known in the art, e.g., hydroxy, halo, oxo (C=0), alkylimino (RN=, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl. Non-limiting examples of substituted heterocycloalkyl groups include the following, where each moiety may be attached to the parent molecule at any available valence, and in some of these substructures, a preferred attachment point is indicated by a bond having a wavy line across it:

Also included within heterocyclic are piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, tetrahydrofuran, oxetane, oxepane, oxirane, tetrahydrothiofuran, thiepane, thiirane, and optionally substituted versions of each of these.

The terms "cycloalkyloxy" and "heterocycloalkyloxy" refer to -O-cycloalkyl

and -O-heterocycloalkyl groups, respectively (e.g., cyclopropoxy, 2-piperidinyloxy, and the

The term 'acyl' as used herein takes its conventional meaning, and refers to a group of the formula -C(=0)R, where R represents an alkyl group or other group of suitable size and composition. For example, a C_1-6 acyl would include R = C1-C5 alkyl, wherein the alkyl may be substituted as described herein for typical alkyl groups.

The term "aryl" means, unless otherwise stated, an aromatic hydrocarbon group which can be a single ring or multiple rings (e.g., from 1 to 3 rings) which are fused together. Aryl may contain fused rings, wherein one or more of the rings is optionally cycloalkyl, but not including heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is described as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is described herein as a heterocyclic group. An aryl group will include a fused ring system wherein a phenyl ring is fused to a cycloalkyl ring. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, tetrahydro-naphthalene, dihydro-lH-indene, 2-naphthyl, tetrahydronaphthyl and the like.

The term "heteroaryl" as used herein refers to groups comprising a single ring or two or three fused rings, where at least one of the rings is an aromatic ring that contain from one to four heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one

heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through an annular carbon or annular heteroatom, and it can be attached through any ring of the heteroaryl moiety, if that moiety is bicyclic or tricyclic. Heteroaryl may contain fused rings, wherein one or more of the rings is optionally cycloalkyl or heterocycloalkyl or aryl, provided at least one of the rings is a heteroaromatic ring. Non-limiting examples of heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Aryl and/or heteroaryl groups commonly contain up to four substituents per ring (0-4), and sometimes contain 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroaryloxy" refer to aryl and heteroaryl groups, respectively, attached to the remainder of the molecule via an oxygen linker (-0-).

The term "arylalkyl" or "aralkyl" designates an alkyl-linked aryl group, where the alkyl portion is attached to the parent structure and the aryl is attached to the alkyl portion of the arylalkyl moiety. Examples are benzyl, phenethyl, and the like. "Heteroarylalkyl" or

"heteroaralkyl" designates a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl, and the like.

Aralkyl and heteroaralkyl also include substituents in which at least one carbon atom of the alkyl group is present in the alkyl group and wherein another carbon of the alkyl group has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridylmethoxy, 3-(l - naphthyloxy)propyl, and the like).

The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and perhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The prefix "perhalo" refers to the respective group wherein all available valences are replaced by halo groups. For example "perhaloalkyl" includes -CCI₃, -CF₃, -CCI₂CF₃, and the like. The terms "perfluoroalkyl" and "perchloroalkyF'are a subsets of perhaloalkyl wherein all available valences are replaced by fluoro and chloro groups, respectively. Non limiting examples of perfluoroalkyl include -CF₃ and -CF₂CF₃. Non limiting examples of perchloroalkyl include -CCI₃ and -CCI₂CCI₃.

"Amino" refers herein to the group -NH₂ or -NRR', where R and R are each independently selected from hydrogen or an alkyl (e.g, lower alkyl). The term "arylamino" refers herein to the group -NRR' where R is aryl and R is hydrogen, alkyl, or an aryl. The term "aralkylamino" refers herein to the group -NRR' where R is an aralkyl and R is hydrogen, an alkyl, an aryl, or an aralkyl. "Substituted amino" refers to an amino wherein at least one of R and R' is not H, i.e., the amino has at least one substituent group on it. The term alkylamino refers to -alkyl-NRR' where R and R are each independently selected from hydrogen or an alkyl (e.g, lower alkyl).

The term "aminocarbonyl" refers herein to the group -C(0)-NH₂ , i.e., it is attached to the base structure through the carbonyl carbon atom. "Substituted aminocarbonyl" refers herein to the group -C(0)-NRR where R is alkyl and R is hydrogen or an alkyl. The term

"arylaminocarbonyl" refers herein to the group -C(0)-NRR where R is an aryl and R is hydrogen, alkyl or aryl. "Aralkylaminocarbonyl" refers herein to the group -C(0)-NRR where R is aralkyl and R is hydrogen, alkyl, aryl, or aralkyl.

"Aminosulfonyl" refers herein to the group -S(0)₂-NH₂. "Substituted aminosulfonyl" refers herein to the group -S(0)₂-NRR where R is alkyl and R is hydrogen or an alkyl. The term "aralkylaminosulfonlyaryl" refers herein to the group -aryl-S(0)₂-NH-aralkyl.

"Carbonyl" refers to the divalent group -C(O)-. The term "sulfonyl" refers herein to the group -S0₂-. "Alkylsulfonyl" refers to a substituted sulfonyl of the structure -S0₂R in which R is alkyl. Alkylsulfonyl groups employed in compounds of the present invention are typically loweralkylsulfonyl groups having from 1 to 6 carbon atoms in R. Thus, exemplary alkylsulfonyl groups employed in compounds of the present invention include, for example, methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl), propylsulfonyl (i.e., where R is propyl), and the like. The term

"arylsulfonyl" refers herein to the group -S0₂-aryl. The term "aralkylsulfonyl" refers herein to the group -S0₂-aralkyl. The term "sulfonamido" refers herein to -S0₂NH₂, or to -S0₂NRR' if substituted.

Unless otherwise stated, each radical/moiety described herein (e.g., "alkyl," "cycloalkyl,"

"heterocycloalkyl," "aryl," "heteroaryl," "alkoxy," etc.) is meant to include both substituted and unsubstituted forms.

"Optionally substituted" as used herein indicates that the particular group or groups being described may have no non-hydrogen substituents (i.e., it can be unsubstituted), or the group or groups may have one or more non-hydrogen substituents. If not otherwise specified, the total number of such substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Typically, a group will contain up to three (0- 3) substituents. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen (=0), the group takes up two available valences on the group being substituted, so the total number of substituents that may be included is reduced according to the number of available valences. Suitable substituent groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,

methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl, loweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl, alkylamino, alkylsulfonyl, aralkylamino, alkylcarbonylamino, carbonyl, piperidinyl, morpholinyl, pyrrolidinyl and the like. Deuterium, when introduced into a compound at levels at least 5x above natural abundance, can also be considered a substituent for purposes of describing the compounds herein. Note that because deuterium is an isotope of hydrogen that does not substantially change the shape of the molecule, deuterium is exempt from the typical numerical limitations placed on numbers of substituents: deuterium (D) can be included in place of hydrogen (H) in addition to other substituents and should not be counted in the numerical limitations that apply to other substituents.

A substituent group can itself be substituted by the same groups described herein for the corresponding type of structure. The group substituted onto the substituted group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, aminocarbonyl, -SR, thioamido, -SO₃H, -SO₂R, N-methylpyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, 4-chloropyrimidinyl, pyridinyl, tetrahydropyranyl, heterocycloalkyl, heteroaryl, or cycloalkyl, where R is typically hydrogen or loweralkyl.

When the substituted substituent includes a straight chain group, the substituent can occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substituents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms (N, O or S).

The term "cycloalkyl" may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom, and "cycloalkylalkyl" may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.

Similarly, "heterocyclyl" may be used to describe a non-aromatic cyclic group that contains at least one heteroatom as a ring member and that is connected to the molecule via a ring atom, which may be C or N; and "heterocyclylalkyl" may be used to describe such a group that is connected to another molecule through a linker. The sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. As used herein, these terms also include rings that contain a double bond or two, as long as the ring is not aromatic.

As used herein, "isomer" includes all stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as all conformers, rotamers, and tautomers, unless otherwise indicated. The invention includes all enantiomers of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers. For compounds disclosed as an (i?)-enantiomer, the invention also includes the (5)-enantiomer; for compounds disclosed as the (5)-enantiomer, the invention also includes the (i?)-enantiomer. The invention includes any diastereomers of the compounds referred to in the above formulas in diastereomerically pure form and in the form of mixtures in all ratios. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotamers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereomers

(including (R,R), (S,S), (R,S), and (R,S) isomers).

In all uses of the compounds of the formulas disclosed herein, the invention also includes use of any or all of the stereochemical, enantiomeric, diastereomeric, conformational, rotomeric, tautomeric, solvate, hydrate, polymorphic, crystalline form, non-crystalline form, salt, pharmaceutically acceptable salt, metabolite and prodrug variations of the compounds as described.

The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.

Additionally, the phrase "any combination thereof implies that any number of the listed functional groups and molecules may be combined to create a larger molecular architecture. For example, the terms "phenyl," "carbonyl" (or "=0"), "-0-," "-OH," and Ci_6 (i.e., -CH₃ and - CH₂CH₂CH₂-) can be combined to form a 3-methoxy-4-propoxybenzoic acid substituent. It is to be understood that when combining functional groups and molecules to create a larger molecular architecture, hydrogens can be removed or added, as required to satisfy the valence of each atom. The description of the disclosure herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substituent at any given location. Furthermore, it is to be understood that definitions of the variables (i.e., "R groups"), as well as the bond locations of the generic formulae of the invention (e.g., formulas I or II), will be consistent with the laws of chemical bonding known in the art. It is also to be understood that all of the compounds of the invention described above will further include bonds between adjacent atoms and/or hydrogens as required to satisfy the valence of each atom. That is, bonds and/or hydrogen atoms are added to provide the following number of total bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds. Preferably, the compounds do not include any oxygen-oxygen bonds. As used herein, "isomer" includes all stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as all conformers, rotamers, and tautomers, unless otherwise indicated. The invention includes all enantiomers of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers. For compounds disclosed as an (i?)-enantiomer, the invention also includes the (5)-enantiomer; for compounds disclosed as the (5 -enantiomer, the invention also includes the (i?)-enantiomer. The invention includes any diastereomers of the compounds referred to in the above formulas in diastereomerically pure form and in the form of mixtures in all ratios.

Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotamers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereomers

(including (R,R), (S,S), (R,S), and (R,S) isomers).

It will also be noted that the substituents of some of the compounds of this invention include isomeric cyclic structures. It is to be understood accordingly that constitutional isomers of particular substituents are included within the scope of this invention, unless indicated otherwise. For example, the term "tetrazole" includes tetrazole, 2H-tetrazole, 3H-tetrazole, 4H- tetrazole and 5H-tetrazole.

The compounds of the invention include compounds of Formula (I):

or a pharmaceutically acceptable salt or deuterated version thereof, wherein: Ai is N or CRs;

A₃ is N or CR₈;

Ri is -X-Rie;

X is a bond, or Ci_-4 alkylene;

Ri₆ is selected from the group consisting of Ci-₆ alkyl, C3-₆branched alkyl, C3- ₈Cycloalkyl, C3-10 heterocycloalkyl, C3-8-partially unsaturated cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C₆-io aryl- or C₅_6-heteroaryl-fused C₅-7 heterocycloalkyl, and C3-10 partially unsaturated heterocycloalkyl wherein R½ is substituted with up to three groups independently selected from halogen, Ci-₆alkyl, Ci-₆haloalkyl, C3_₆branched alkyl, C3_₆branched haloalkyl, OH, oxo, Ci-₆alkoxy, heterocycloalkyl, Ci_-2alkyl-heterocycloalkyl, Ci_-2alkyl-heteroaryl, -R₂₂-ORi_2i S(0)o-₂Ri₂, -R₂₂-S(0)o-₂Ri₂, S(0)₂NRi3Ri₄, -R₂₂-S(0)₂NRi₃Ri₄, -C(0)ORi₂, -R₂₂-C(0)ORi₂, C(0)Ri9, -R₂₂-C(0)Ri9, O-Ci-3 alkyl, OCi_-3 haloalkyl, OC(0)Ri₉, -R₂₂-OC(0)Ri₉, C(0)NRi₃Ri₄, -R₂₂-C(0)NRi₃Ri₄, NRi₅S(0)₂Ri2, -R₂₂-NRi₅S(0)₂Ri₂, -NR₁₇R₁₈, -R₂₂-NRi₇Ri₈,

NRi₅C(0)Ri9, -R₂₂-NRi₅C(0)Ri9, NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)OCH₂Ph, NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)ORi2, NRi₅C(0)NRi3Ri₄, and -R₂₂-NRi₅C(0)NRi₃Ri₄;

Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, hydroxyl, Ci_-6alkyl,

C3_-6branched alkyl, C3_8 cycloalkyl, Ci_-4-alkyl-C3.8-cycloalkyl, C3 -8 heterocycloalkyl, Ci_-4-alkyl-C3-8 heterocycloalkyl, R₂₂-ORi_2i R₂₂-S(0)o_-2Ri_2, -R₂₂- S(0)₂NRi₃Ri4, -R₂₂-C(0)ORi2, -R₂₂-C(0)Ri₉, -R₂₂-OC(0)Ri₉, -R₂₂-C(0)NRi₃Ri₄, -R22-

NRi₅S(0)₂Ri2, -R₂₂-NR₂₃R₂₄, -R₂₂-NRi₅C(0)Ri₉, .R₂₂-NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)ORi₂,

-R₂₂-NRi₅C(0)NRi3Ri₄, -R₂₂-cycloalkyl, -R₂₂-heterocycloalkyl, heteroaryl, and -R₂₂-heteroaryl; wherein each alkyl, cycloalkyl, branched alkyl, heterocycloalkyl, and heteroaryl can be substituted with up to two groups selected from R²⁰;

alternatively, Rn and Ri8 along with the nitrogen atom to which they are attached can be taken together to form a four to six or seven or eight-membered heterocyclic ring containing up to two heteroatoms selected from N, O and S as ring members and optionally fused to an optionally substituted 5-6 membered aryl or heteroaryl ring, wherein the carbon atoms of said rings are optionally substituted with R₂o, and the nitrogen atoms of said rings are optionally substituted with R₂i;

Ri9 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R₂o is selected from the group consisting of oxo (=0), halo, amino, hydroxy, Ci_6 alkoxy, Ci-6 alkyl and Ci_6 haloalkyl;

20

and where two R on the same or adjacent connected atoms can be taken together with the atoms to which they are attached to form a 3-8 membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from N, O and S as ring members and optionally substituted with up to two groups selected from halo, oxo, Me, OMe, CN, hydroxy, amino, and dimethylamino;

R₂i is selected from the group consisting of Ci-₆alkyl, Ci-₆haloalkyl, C(0)Ri₂, C(0)ORi₂, and S(0)₂Ri₂;

R₂₂ is selected from the group consisting of Ci-₆ alkylene, Ci-₆haloalkylene, C3-6 branched alkylene, C3-₆branched haloalkylene;

R₂3 and R₂₄ are each, independently, selected from the group consisting of hydrogen, Ci_-6 alkyl, Ci-₆ acyl, Ci-₆haloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl;

R₂ is selected from the group consisting of H, optionally substituted Ci-6 alkyl, optionally substituted C3-8 branched alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted C₆-io aryl, and optionally substituted C_5- 10 heteroaryl; R4a, R4 , R₅, and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C_1-4 alkyl, Ci_-4haloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, amino, NR10R11, and alkoxy;

R3, R7 and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, NR₁₀R₁₁, C(0)Ri₂,

C(0)ORi2, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(O)₀-₂NRi₃Ri₄, morpholino, tetrazolyl, and optionally substituted C3_-4 cycloalkyl;

R9 is selected from the group consisting of hydrogen, C_1-4 alkyl, alkoxy, C(0)Ri₂, C(0)ORi5_, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(O)₀-₂NRi₃Ri₄, optionally substituted C_3-4 cycloalkyl, and optionally substituted heterocycloalkyl;

Rio and Rn are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(0)R₁₂, C(0)OR₁₂, C(0)NR₁₃R₁₄, S(O)₀-₂Ri₂, and S(O)₀-₂NRi₃Ri₄; alternatively, Rio and Rn along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non- aromatic heterocyclic ring;

R₁₂ and Ri₅ are each, individually, selected from the group consisting of hydrogen, alkyl, branched alkyl, haloalkyl, branched haloalkyl, hydroxyalkyl, alkoxyalkyl, (CH₂)o-₃-cycloalkyl, (CH₂)o_-3-heterocycloalkyl, (CH₂)o_-3-aryl, and heteroaryl;

Ri₃ and Ri₄ are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, branched alkyl, haloalkyl, branched haloalkyl, alkoxy, cycloalkyl or heterocycloalkyl; and alternatively, Ri₃ and Ri₄ along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or non-aromatic heterocyclic ring. In certain embodiments of these compounds,

Ai is N or CR₅;

A₃ is N or CR₈;

A₄ is selected from a bond, S0₂, CO-NR9, -SO2-NR9-, NR₉, or O;

L is selected from a bond, optionally substituted Ci_-4alkyl, C₃-₆ cycloalkyl, C₃-₆ heterocycloalkyl, or C_2-4 alkenyl;

Ri is -X-Rie; X is a bond, or C_1-4 alkyl and;

Ri₆ is selected from the group consisting of C_1-6 alkyl, C3-₆branched alkyl, C3- ₈Cycloalkyl, heterocycloalkyl, C3-8-partially unsaturated cycloalkyl, aryl, and heteroaryl, wherein Ri₆ is substituted with up to three groups independently selected from halogen, Ci-₆alkyl, Ci_ ₆haloalkyl, C3_₆branched alkyl, C3_₆branched haloalkyl, OH, Ci-₆alkoxy, heterocycloalkyl, Ci_ ₂alkyl-heterocycloalkyl, Ci_-2alkyl-heteroaryl, .R₂₂-ORi_2i S(O)₀-₂Ri₂, -R₂₂-S(O)₀-₂Ri2_,

S(0)₂NRi₃Ri4, -R₂₂-S(0)₂NRi₃Ri₄, -C(0)ORi₂, -R₂₂-C(0)ORi₂, C(0)Ri₉, -R₂₂-C(0)Ri₉, 0-Ci_-3 alkyl, OCi_-3 haloalkyl, OC(0)Ri₉, -R₂₂-OC(0)Ri₉, C(0)NRi₃Ri₄, -R₂₂-C(0)NRi₃Ri₄,

NRi₅S(0)₂Ri₂, -R₂₂-NRi₅S(0)₂Ri₂, -NR₁₇R₁₈, -R₂₂-NRi₇Ri₈, NRi₅C(0)Ri₉, -R₂₂-NRi₅C(0)Ri₉, NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)OCH₂Ph, NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)ORi₂,

NRi₅C(0)NRi₃Ri₄, and -R₂₂-NRi₅C(0)NRi₃Ri₄;

Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, hydroxyl, Ci-₆alkyl, Ci-₆haloalkyl, C3_₆branched alkyl, C3-6 cycloalkyl, R₂₂-ORi_2i R₂₂-S(0)o_-2Ri_2, -R₂₂-S(0)₂NRi₃Ri₄, -R₂₂-C(0)ORi2, -R₂₂-C(0)Ri₉, -R₂₂-OC(0)Ri₉, -R₂₂-C(0)NRi₃Ri₄, -R₂₂- NRi₅S(0)₂Ri₂, -R₂₂-NR₂₃R₂₄, -R₂₂-NRi₅C(0)Ri₉, .R₂₂-NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)NRi₃Ri₄, cycloalkyl, -R₂₂-cycloalkyl, heterocycloalkyl, -R₂₂-heterocycloalkyl, heteroaryl, and -R₂₂ -heteroaryl; alternatively, Ri₇ and Ri₈ along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein the carbon atoms of said ring are optionally substituted with R₂o, and the nitrogen atoms of said ring are optionally substituted with R₂i;

R₂o is selected from the group consisting of oxo (=0), halo, amino, hydroxy, C_1-6 alkoxy, Ci-6 alkyl and C_1-6 haloalkyl;

R₂i is selected from the group consisting of Ci_-6alkyl,

C(0)Ri₂, C(0)ORi₂, and S(0)₂Ri₂;

R₂₂ is selected from the group consisting of C_1-6 alkyl, Ci-₆haloalkyl, C3-6 branched alkyl, C3 ^branched haloalkyl;

R₂3 and R₂₄ are each, independently, selected from the group consisting of hydrogen, C_1-6 alkyl, Ci-₆ acyl, Ci-₆haloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl; R₂ is selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C3-8 branched alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R4a, R4 , R5, and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C_1-4 alkyl, Ci_-4haloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, amino, NR10R11, and alkoxy;

R3, R7 and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, NR10R11, C(0)Ri₂, C(0)ORi₂, C(0)NRi₃Ri₄, S(O)_0-2Ri₂ , S(O)₀-₂NRi₃Ri₄, morpholino, tetrazolyl, and optionally substituted C3_-4 cycloalkyl;

R9 is selected from the group consisting of hydrogen, C_1-4 alkyl, alkoxy, C(0)Ri₂, C(0)ORi5_, C(0)NRi₃Ri₄, S(O)_0-2Ri₂ , S(O)₀-₂NRi₃Ri₄, optionally substituted C_3-4 cycloalkyl, and optionally substituted heterocycloalkyl;

Rio and Rn are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(0)R₁₂, C(0)OR₁₂, C(0)NRi₃Ri₄, S(O)_0-2Ri₂, and S(O)₀-₂NRi₃Ri₄; alternatively, Rio and Rn along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non- aromatic heterocyclic ring;

Ri3 and Ri₄ are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, branched alkyl, haloalkyl, branched haloalkyl, alkoxy, cycloalkyl or

heterocycloalkyl; and alternatively, R13 and Ri₄ along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or non-aromatic heterocyclic ring.

In compounds of Formula (I), Ai and A3 can each be a carbon group or N; preferably they are not both N. Typically, Ai is CR₆, and in many embodiments it is CH. A3 can be N, but is often CRs, where Rs is H or a small substituent such as halo (e.g., F or CI), Me, CF3, OMe, or CN. In some embodiments, CRs is C-Cl or C-F or C-H, and in specific embodiments of interest, Rs is C-Cl. In preferred embodiments, Ai is CR6 and A3 is CRs, where R6 and Rs are as set forth here.

In alternative embodiments, Ai is N and A3 is CRs; or Ai is CR6 and A3 is N.

In any of the foregoing compounds, R₅ can be selected from a range of groups as described above, and in many embodiments, R₅ is halo (e.g., F or CI), Me, CF₃, OMe, or CN, and is preferably H.

In any of the foregoing compounds, Ri can be selected from a range of groups as described above, and in many embodiments, Ri is H, Me, OMe, or halo, and is preferably H.

In any of the foregoing compounds, Rt_a can be selected from a range of groups as described above, and in many embodiments, Rt_a is H, Me, OMe, or halo, and is preferably H or halo (F or CI).

In any of the foregoing compounds, the groups R3 and R7 can be any of the options set forth above. In some embodiments, each of them is selected independently from hydrogen, hydroxyl, cyano, F, CI, C1-4 alkyl, Ci_-4 haloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, Ci_-4 alkoxy, NR10R11, C(0)Ri2, C(0)ORi₂, C(0)NRi₃Ri₄, S(O)_0-2Ri₂ , S(O)₀-₂NRi₃Ri₄, morpholino, tetrazolyl, and optionally substituted C3_-4 cycloalkyl. Rio-Ri₄ can be as defined above; in many embodiments each of Rio-Ri₄ is selected from H and Ci_-4 alkyl. In other embodiments, two of them present on one N (e.g., Rio and Rn in NRioRn, or R_i3 and Ri₄ in C(0)NRi₃Ri₄, can be taken together to form a 5-6 membered heterocyclic ring that may contain an additional heteroatom (N, O or S) in addition to the N to which the two R's are attached, and these heterocyclic rings can be substituted with up to two Ci_-4 alkyl or oxo groups. Examples of such heterocyclic groups include piperidine, morpholine, piperazine, N-methyl piperazine, pyrrolidine, pyrrolidinone, and the like. In some preferred embodiments, R3 is selected from H, halo, CN, Me, tetrazole, morpholine, CONH₂, OMe, and CF₃. In some preferred embodiments, R₇ is selected from H, halo, OMe, Me and CF₃.

In any of the foregoing compounds, A can be as set forth above, and in some embodiments it is selected from NH, O and S. In some preferred embodiments, A₄ is NH. In alternative embodiments, A₄ is O.

In any of the foregoing compounds, L can be a bond or a linker such as (CH₂)i_-4. In some embodiments, L is selected from CH₂, -CH₂CH₂-, and -CH₂CH₂CH₂-. In preferred

embodiments, -A₄-L- is a group of the formula -NH-(CH₂)-. In any of the foregoing compounds, R₂ can be any of the groups set forth above in conjunction with Formula (I). In some embodiments, R₂ is an optionally substituted cyclic group selected from C3-6 cycloalkyl, C5-6 heterocycloalkyl, C5-6 heteroaryl, and phenyl. Some suitable embodiments of R₂ include: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; piperidine, morpholine, and piperazine; pyrrolidine, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyranyl, and the like. These cyclic R₂ groups can be unsubstituted or they can be substituted, typically with up to two groups selected from halo, Cl-3 alkyl, Cl-3 alkoxy, (e.g., Me, OMe), OH, COOMe, CN, CONH₂, CONHMe, CONMe₂, C2-4 alkenyl (e.g., vinyl), C2-4 alkynyl, (e.g., ethynyl), and CF₃.

In some embodiments, six-membered rings are preferred for R₂, e.g., phenyl, piperidinyl, tetrahydropyranyl, and pyridinyl. Preferred embodiments of R₂ when -A₄-L- is a group of the formula -NH-(CH₂)- or -0-CH₂- include phenyl, pyridinyl, piperidinyl, and tetrahydropyranyl, each of which can be substituted with up to two groups selected from halo, Me, OMe, OH, CN, and CONH₂; particularly phenyl or 4-pyridinyl substituted with up to 2 halo substituents, preferably F or CI; and piperidin-4-yl or tetrahydropyran-4-yl, each of which is unsubstituted or is substituted with Me, OMe, OH, CN or CONH₂, preferably at position 4.

In other embodiments, R₂ can be a C3-C5 cyclic group, such as cyclopropyl, pyrrolidine or tetrahydrofuran. In these embodiments, R₂ can be unsubstituted, or it can be substituted with up to two groups selected from halo, OH, COOMe, CN, CONH₂, CONHMe, CONMe₂, Me, OMe, vinyl, ethynyl, and CF₃. In some of these embodiments, R₂ is preferably cyclopropyl, and may be substituted at C-l .

In specific embodiments of the compounds described above, -L-R₂ is

where each R^* is independently H, F, CI, -OCHF₂, -C(0)-Me, -OH, Me, -OMe, CF₃, ethynyl, -CN, -Ethyl, -CONH₂, or -NH-C(0)-Me.

Embodiments wherein R^* is H or halo are often utilized when R₂ is phenyl; when R₂ is -aromatic, R^* is frequently -CN, -H, F, OMe, or -OH. In preferred embodiments of the foregoing compounds, Rt_a and Ri are both H.

In the foregoing compounds of Formula (I), Ri is -X-R₁₆, where X can be as set forth above; in some embodiments, X is a bond or (CI¾)i-2. R½ can be an C_1-6 alkyl group, cyclic or branched, or a cyclic group selected from C3-8Cycloalkyl, C5-6 heterocycloalkyl, C3-8-partially unsaturated cycloalkyl, aryl, and 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S in accordance with well-known valence and aromaticity principles. Suitable examples for R½ include (CI¾)2-4; cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinone, piperazinone, phenyl, and pyridinyl.

Typically, R½ is substituted with up to three groups, frequently 1 or 2 groups, independently selected from halogen, Ci-6alkyl, Ci-6haloalkyl, C3-6branched alkyl, C3-6branched haloalkyl, OH, Ci-6alkoxy, heterocycloalkyl, Ci-2alkyl-heterocycloalkyl, Ci-2alkyl-heteroaryl, . R22-OR12, S(0)o-₂Ri2, -R22-S(0)o-₂Ri2, S(0)₂NRi₃Ri4, -R22-S(0)₂NRi3Ri4, -C(0)ORi2, -R22- C(0)ORi2, C(0)Ri9, -R₂₂-C(0)Ri9, 0-Ci_-3 alkyl, OCi_-3 haloalkyl, OC(0)Ri₉, -R₂₂-OC(0)Ri₉, C(0)NRi3Ri4, -R22-C(0)NRi₃Ri4, NRi₅S(0)₂Ri₂, -R2₂-NRi₅S(0)₂Ri2, -NRnRs, -R22-NR17R18, NRi₅C(0)Ri9, -R₂2-NRi₅C(0)Ri9, NRi₅C(0)OCH₂Ph, -R₂2-NRi₅C(0)OCH₂Ph, NRi₅C(0)ORi₂, -R₂2-NRi₅C(0)ORi2, NRi₅C(0)NRi₃Ri4, and -R₂2-NRi₅C(0)NRi3Ri4; where R2-R22 when present are as set forth above for Formula I. Where R½ is not aromatic, the optional substituents also include oxo (=0).

In some embodiments, R½ is substituted with at least one nitrogen- containing group from this set of options; particularly suitable nitrogen-containing groups for this purpose include -

NRivRis, -R22-NR17R18, NRi₅C(0)Ri9, and -R₂2-NRi₅C(0)Ri9. In preferred embodiments, R16 is substituted with at least one group of the formula -NHRis, where Ri8 is H or an optionally substituted C1-C4 alkyl group whose optional substituents include hydroxy, amino, halo, CI -4 alkoxy, CF3, CN, -NMe2, and morpholine. In other embodiments, R½ is unsubstituted.

In certain embodiments of the compounds described above, X is a bond, and R½ is C3-7 cycloalkyl, and is substituted with -NR17R18. In particular embodiments, R_½ is substituted with a group -NR17R18 of the formula

wherein each R' is H, Me, or Et. In these embodiments, R½ may be cyclohexyl, and -NR₁7R₁8 can be attached at position 3 or 4, preferably position 4, of the cyclohexyl ring..

In addition to the particular selections for each group in Formula I set forth above, each combination of these selections is a suitable embodiment for use in the invention, and each combination of groups that are among the preferred ones is a preferred embodiment of the compounds of Formula I.

In certain embodiments of the compounds of Formula (I), Ai is CRe, and A3 is CRs. In such embodiments, R₆ can be H; Rg can be selected from H, F and CI.

In certain embodiments of the compounds of Formula (I), Ai is N; and A3 is CR». In these embodiments, Rs can be selected from H, CI, F, Me or CF3.

In certain embodiments of the compounds of Formula (I), Ai is CRe, and A3 is N. In such embodiments, R₆ is often H.

In certain embodiments of the compounds of Formula (I) described above, A₄ is O or NH. In some of these embodiments, Rs is selected from halogen, hydrogen, CN, CF3, O-C₁-3- alkyl, and Ci-3-alkyl. In particular, Rg can be selected from H, CI, F, and methyl. In preferred embodiments of these compounds, Rs is CI or F.

In any of the preceding embodiments of compounds of Formula I, unless otherwise indicated, X can be a bond, -CH₂- or -(CH₂)₂-; and R½ can be selected from the group consisting of Ci-₂-alkyl, C_4-6Cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein R_½ is substituted with one to three groups independently selected from halogen, Ci-₃alkyl, C₃_₆branched alkyl, OH, Ci_-2alkoxy, R22-OR12, S(0)i_-2Ri₂, C(0)ORi₂, R₂₂-C(0)ORi₂, C(0)Ri₉, R₂₂-OC(0)Ri₉, C(0)NRi₃Ri₄, NRi₅S(0)₂Ri2, NRiyRis, R22-NR17R18, NRi₅C(0)Ri₉, R₂2-NRi₅C(0)Ri₉, and

In some such compounds, R½ is selected from the group consisting of Ci-₂-alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran; wherein R½ is substituted with one to three groups selected from amino, hydroxyl, NHCH₂-phenyl, CH₂-amino, COO-i-butyl, methoxy, NH-SCVethyl, CH₂- NHS0₂-ethyl, S0₂-ethyl, i-butyl, methyl, CH₂-COOH, CO-NHCH3, CON(CH₃)₂, NHC(CH₃)- CH₂-SO₂-CH3, NH-COO-CH₂-phenyl, hydroxy-methyl, CH₂-NH-CH₃, CH₂-NH-ethyl, NH-CH₂- CH₂-methoxy, CH₂-NH-CO-CH₃, NH-CH₂-CH₂OH, NH-CO-CH₂-N(CH₃)₂. NH-CO- methylpyrrolidine, NH-CH₂-C(CH₃)-dioxolane, NH-CO-pyridyl, NH-ethyl, pyrrolidine, CH₂- NH-CO-pyridyl, NH-tetrahydropyran, COCH₂-N(CH₃)₂, NH-CH₂-C(CH₃)-dimethyldioxolane, tetrahydropyran, CO-methylpyrrolidine, CH₂-methylpiperidine, NH-CO-CH₃, NH-S0₂-CH₃, NH-CH(CH₂-OCH₃)₂, NH-CH₂-tetrahydrofuran, NH-CH₂-oxetane, NH-tetrahydropyran, NH- CH₂-dioxane, N(CH₃)-CH₂CH₂-OCH₃, CH(OH)-CH₂-amino, NH-CH₂CH₂-OCF₃, NHCH₂- OCH₃, NH-CH₂-CH(CF₃)-OCH₃, NH-CH(CH₃)-CH₂-OH, F, NH-oxetane, CH₂-CH₂-OCH₃, CH₂-OCH₃, CH₂-tetrahydropyran, CH₂-methylpiperizine, NH₂-CH₂-CH(OH)-CF₃, piperidine, CH₂-pyrrolidine, NH-CH(CH₃)CH₂OCH₃, NH-tetrahydrofuran, (CH₂)₃-NH₂, hydroxyethyl, propyl, CH₂-pyridyl, CH₂-piperidine, morpholine, NH-chloropyrimidine, NH-CH₂CH₂-S0₂- methyl, -N(CH₃)₂, piperazine,

and CH₂-morpholine.

In some such embodiments, R½ is selected from the group consisting of Ci_-2-alkyl, C_4- ₆cycloalkyl, C_3-io heterocycloalkyl, phenyl, and heteroaryl, wherein R_i6 is substituted with one to three groups independently selected from halogen, Ci_-3alkyl, C_3-6branched alkyl, OH, Ci_ ₂alkoxy, R₂₂-ORi2_, S(0)i_-2Ri₂, C(0)ORi₂, R₂₂-C(0)ORi₂, C(0)Ri₉, R₂₂-OC(0)Ri₉,

C(0)NRi₃Ri4, NRi₅S(0)₂Ri2, NRiyRis, R₂₂-NRi₇Ri₈, NRi₅C(0)Ri₉, R₂₂-NRi₅C(0)Ri₉, and

In certain embodiments of the compounds of Formula (I) described above, R₃ is selected from H, methyl, cyano, chloro, CONH₂, amino, cyclopropyl, ethyl, and fluoro;

Ri_a and Ri are independently selected from halogen, methyl, hydrogen, and halo- methyl; Rs is H; R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃; and Rs is CI, wherein Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, Ci_-3alkyl, Ci_-4haloalkyl, C_3-6branched alkyl, R₂₂-ORi_2i R₂₂-S(0)₂Ri₂, R₂₂- NRi₅S(0)₂Ri₂, heterocycloalkyl or heteroaryl; alternatively, Ri₇ and Ri₈ along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R₂o, and the ring nitrogen atoms are optionally substituted with R21;

R 9 is selected from Ci-3-alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

R20 represents the group Ci-₃alkyl; and

R22 is selected from the group consisting of Ci-₄alkyl, and C3-6 branched alkyl.

In certain embodiments of the compounds of Formula (I) described above, A₄ is selected from NR₉, O, and a bond; L is selected from a bond, Ci_-4-alkyl, and cyclopropyl;

R2 is selected from the group consisting of C3-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R2 group is substituted with up to three substituents independently selected from cyano, CO-NH2, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, Ci-3-alkyl, C2-4 alkenyl, C2-4 alkynyl, and hydroxy; and R9 represents methyl, hydrogen, or ethyl.

In these embodiments, Rn_a and Ri can be independently selected from halogen, methyl, hydrogen, and halo-methyl;

Re is H;

R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃;

R₈ is CI;

Ri7 and Ri8 are each, independently, selected from the group consisting of hydrogen, Ci_-3alkyl, Ci_-4haloalkyl, C₃-₆branched alkyl, R22-OR12_, R₂2-S(0)₂Ri₂, R22-

NRi₅S(0)2Ri2, heterocycloalkyl or heteroaryl; alternatively, R17 and Ri8 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R20, and the ring nitrogen atoms are optionally substituted with R₂₁;

Rig is selected from Ci-3-alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

R20 represents the group Ci-₃alkyl; and

R22 is selected from the group consisting of Ci_-4alkylene, and C3-6 branched alkylene. In some embodiments of these compounds, A₄ is selected from NR₉, O, and a bond; L is selected from a bond, Ci_-4-alkyl, and cyclopropyl; R₂ is selected from the group consisting of C₃-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R₂ group is substituted with up to three substituents independently selected from cyano, CO-NH₂, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, Ci-3-alkyl, and hydroxy; and

R₉ represents methyl, hydrogen, or ethyl.

In certain embodiments of the compounds of Formula (I) as described above, X represents a bond;

Ri₆ is selected from cyclohexyl, and C_2-5-alkyl, wherein each said R½ group is substituted with 1 to 2 substituents selected from amino, methyl-amino, hydroxy, amino-ethyl, dimethyl- amino, NH-(CH₂)₂-0-ethyl, NH-S0₂-methyl, CH₂-NH-S0₂-methyl, piperidinyl, pyrrolidinyl, NH-CH₂-CF₃, NH-(CH₂)₂-0-methyl, N(CH₃)-(CH₂)i_-2-methoxy, NH-CH₂-CH(CH₃)-OH, NH- CH₂-tetrahydrofuranyl, NH-(CH₂)₂-OH, NH-CH₂-CONH₂, NH(CH₂)₂-CF₃, methylpyrrolidin-3- ol, NH-(CH₂)₂-pyrrolidinyl, NH-CH₂-COOH, NH-CH₂-dioxane, NH-oxetane, NH- tetrahydrofuranyl, morpho nyl, NH-(CH₂)₂-0-(CH₂)₂-OCH₃, NH-(CH₂)₂-CONH₂, and

N(CH₂CH₂OCH₃)₂;

R₂ is selected from CONH₂, COCH₃, S0₂-methyl, CH₂-fluorophenyl, CH₂- difluorophenyl, CH₂-chlorophenyl, -CH₂-cyclopropyl, CH₂-pyridyl, CH₂-cyclohexyl, CH₂- cyano-phenyl, CH₂-tetrahydropyran (particularly -CH₂-(tetrahydropyran-4-yl)), benzyl, CH₂- toluyl, and CH₂-methoxy-phenyl;

A₄ is selected from NR₉, CONR₉, and O;

L is a bond;

R3 is selected from H, CONH₂, hydroxyethyl, chloro, cyano, fluoro, and methoxy;

Ri_a and Ri are independently selected from H, and fluoro;

R5 represents H;

R6 represents hydrogen;

R7 is selected from H, cyano, and fluoro; and

Re is selected from hydrogen, and chloro.

In certain embodiments of the compounds of Formula (I) described above, Ai is CH; A3 is C-Cl or C-F; R₅ is H; Rt_b is H; and Ri_a is H.

In further embodiments of the compounds of Formula I: R3 is selected from H, methyl, cyano, chloro, CONH₂, amino, cyclopropyl, ethyl, and fluoro;

R4 is selected from halogen, methyl, hydrogen, and halo-methyl;

R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃;

R₈ is CI;

Ri7 and Ri8 are each, independently, selected from the group consisting of hydrogen, Ci-3alkyl, Ci-4haloalkyl, C3-6branched alkyl, R22-OR12, R22-S(0)₂Ri2, R22- NRi₅S(0)₂Ri₂, heterocycloalkyl or heteroaryl; alternatively, R17 and Ri₈ along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R₂0, and the ring nitrogen atoms are optionally substituted with R₂₁;

Ri9 is selected from Ci-3-alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R₂0 represents the group Ci-₃alkyl; and

R₂₂ is selection from the group consisting of Ci-₄alkyl, and C3-6 branched alkyl.

In additional embodiments of the compounds of Formula I:

A₄ is selected from NR₉, O, and a bond;

L is selected from a bond, Ci_-4-alkyl, and cyclopropyl;

R₂ is selected from the group consisting of C3-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R₂ group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO-NH₂, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, Ci-3-alkyl, and hydroxy; and

R9 represents methyl, hydrogen, or ethyl.

In some preferred embodiments of the compounds of Formula I as described above, the group -A₄-L-R₂ represents the group

wherein Z is selected from Me, Et, CF₃, OMe, OH, CN, C≡CH, and CONH₂,

and L is -CH₂- or -CH₂CH₂-. In still further embodiments of the compounds of Formula I, X represents a bond;

Ri6 represents cyclohexyl, wherein said cyclohexyl group is substituted with 1 to 2 substituents selected from amino, methyl-amino, hydroxy, amino-ethyl, dimethyl-amino, NH- (CH₂)₂-0-ethyl, NH-S0₂-methyl, CH₂-NH-S0₂-methyl, piperidinyl, pyrrolidinyl, NH-CH₂-CF₃, NH-(CH₂)₂-0-methyl, N(CH₃)-(CH₂)i_-2-methoxy, NH-CH₂-CH(CH₃)-OH, NH-CH₂- tetrahydrofuranyl, NH-(CH₂)₂-OH, NH-CH₂-CONH₂, NH(CH₂)₂-CF₃, methylpyrrolidin-3-ol, NH-(CH₂)₂-pyrrolidinyl, NH-CH₂-COOH, NH-CH₂-dioxane, NH-oxetane, NH- tetrahydrofuranyl, morpholinyl, NH-(CH₂)₂-0-(CH₂)₂-OCH₃, NH-(CH₂)₂-CONH₂, and

N(CH₂CH₂OCH₃)₂;

R₂ is selected from CONH₂, COCH₃, S0₂-methyl, CH₂-fluorophenyl, CH₂- difluorophenyl, CH₂-chlorophenyl, CH₂-pyridyl, CH₂-cyclopropyl, CH₂-cyclohexyl, CH₂- (cyano-phenyl), CH₂-tetrahydropyran, benzyl, CH₂-toluyl, and CH₂-(methoxy-phenyl);

A₄ is selected from NR₉, CONR₉, and O;

L is a bond;

R₃ is selected from H, CONH₂, hydroxyethyl, methyl, tetrazole, chloro, cyano, fluoro, and methoxy;

Rzt_a and R^, are independently selected from H, and fluoro;

R5 represents H;

R6 represents hydrogen;

R7 is selected from H, cyano, and fluoro; and

Re is selected from hydrogen, and chloro.

In certain embodiments of the compounds of Formula (I), the compound is any of the specific compounds of that formula that are disclosed herein, particularly such compounds that are found in Table 1 and Table IB.

In another aspect, the invention provides a compound of Formula (II):

wherein:

Ai is N or CH;

Rs is selected from F, CI and Me;

R₇ is selected from H, CI, F, CN;

R₃ is selected from H, halo, CN, Me and OMe;

X is a bond, CH₂ or (CH₂)₂;

Ri₆ is optionally substituted cyclohexyl;

A₄ is NH or O;

and R₂ is selected from optionally substituted cyclopropyl, optionally substituted tetrahydropyran, optionally substituted phenyl, and optionally substituted pyridyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments of the compounds of Formula (II), Ai is CH. In some such compounds, Rs is selected from CI, F, and methyl. Preferably in these compounds Rs is CI.

In typical embodiments of the compounds of Formula II, X is a bond; and

Ri₆ is selected from the group consisting of Ci_-2-alkyl, C_4-6Cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl,

wherein R½ is substituted with one to three groups independently selected from halogen, hydrogen, Ci-₃alkyl, C3_₆branched alkyl, OH, Ci_-2alkoxy, R₂₂-ORi_2i S(0)i_-2Ri₂, C(0)ORi2, R₂₂-C(0)ORi2, C(0)Ri₉, R₂₂-OC(0)Ri₉, C(0)NRi₃Ri_4, NRi₅S(0)₂Ri₂, NRi₇Ri8, R₂₂-NRi₇Ri8, NRi₅C(0)Ri₉, R₂₂-NRi₅C(0)Ri₉, and NRi₅C(0)OCH₂Ph.

In some of the embodiments of compounds of Formula II, R½ is selected from the group consisting of Ci_-2-alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro-2H-pyran; wherein R½ is substituted with one to three groups selected from amino, hydroxyl, NHCH₂-phenyl, CH₂-amino, COO-i-butyl, H, methoxy, NH-S0₂-ethyl, CH₂- NHS0₂-ethyl, S0₂-ethyl, i-butyl, methyl, CH₂-COOH, CO-NHCH₃, CON(CH₃)₂, NHC(CH₃)-CH₂-S0₂-CH₃, NH-COO-CH₂-phenyl, hydroxy-methyl, CH₂-NH-CH₃, CH₂- NH-ethyl, NH-CH₂-CH₂-methoxy, CH₂-NH-CO-CH₃, NH-CH₂-CH₂OH, NH-CO-CH₂- N(CH₃)₂. NH-CO-methylpyrrohdine, NH-CH₂-C(CH₃)-dioxolane, NH-CO-pyridyl, NH- ethyl, pyrrolidine, CH₂-NH-CO-pyndyl, NH-tetrahydropyran, COCH₂-N(CH₃)₂, NH- CH₂-C(CH₃)-dimethyldioxolane, tetrahydropyran, CO-methylpyrrolidine, CH₂- methylpipendine, NH-CO-CH₃, NH-S0₂-CH₃, NH-CH(CH₂-OCH₃)₂, NH-CH₂- tetrahydrofuran, NH-CH₂-oxetane, NH-tetrahydropyran, NH-CH₂-dioxane, N(CH₃)- CH₂CH₂-OCH₃, CH(OH)-CH₂-amino, NH-CH₂CH₂-OCF₃, NHCH₂-OCH₃, NH-CH₂- CH(CF₃)-OCH₃, NH-CH(CH₃)-CH₂-OH, F, NH-oxetane, CH₂-CH₂-OCH₃, CH₂-OCH₃, CH₂-tetrahydropyran, CH₂-methylpiperazine, NH₂-CH₂-CH(OH)-CF₃, piperidine, CH₂- pyrrolidine, NH-CH(CH₃)CH₂OCH₃, NH-tetrahydrofuran, (CH₂)₃-NH₂, hydroxyethyl, propyl, CH₂-pyridyl, CH₂-piperidine, morpholine, NH-chloropyrimidine, NH-CH₂CH₂- -methyl, -(CH₂)₃-N(CH₃)₂, piperazine,

and CH₂-morpholine.

In certain embodiments of the compounds of Formula (II), R₃ is selected from H, methyl, cyano, chloro, CONH₂, amino, cyclopropyl, ethyl, and fluoro;

R4a and R4 are independently selected from halogen, methyl, hydrogen, and halo- methyl;

R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃;

R₈ is CI;

Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, Ci_-3alkyl, Ci-₄haloalkyl, C_3-6branched alkyl, -R₂₂-ORi_{2 -}R₂₂-S(0)₂Ri₂, -R₂₂- NRi₅S(0)₂Ri₂, heterocycloalkyl or heteroaryl; alternatively, R₁₇ and Ri₈ along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R₂o, and the ring nitrogen atoms are optionally substituted with R₂i;

R₂o represents the group Ci-3alkyl; and

R₂₂ is selection from the group consisting of Ci-₄alkyl, and C₃-6 branched alkyl.

In certain embodiments of the compounds of Formula (II), A₄ is selected from NR₉, O, and a bond; L is selected from a bond, Ci_-4-alkyl, and cyclopropyl;

R₂ is selected from the group consisting of C₃-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R₂ group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO-NH₂, halogen, CI -3 alkoxy (e.g., methoxy), CI -3 alkyl (e.g., methyl), dihalo-methoxy, trihalo-methoxy, trihalo alkyl, Ci-3-alkyl, and hydroxy; and

R₉ represents methyl, hydrogen, or ethyl.

In certain embodiments of the compounds of Formula (II), X represents a bond;

N(CH₂CH₂OCH₃)₂;

R₂ is selected from CONH₂, COCH₃, S0₂-methyl, CH₂-fluorophenyl, CH₂- difluorophenyl, CH₂-chlorophenyl, CH₂-cyclopropyl, CH₂-pyridyl, CH₂-cyclohexyl, CH₂- (cyano-phenyl), CH₂-tetrahydropyran, benzyl, CH₂-toluyl, and CH₂-(methoxy-phenyl);

A₄ is selected from NR₉, CONR₉, and O, and is preferably O or NR⁹;

L is a bond;

R3 is selected from H, CONH₂, hydroxyethyl, methyl, tetrazole, chloro, cyano, fluoro, and methoxy;

Ri_a and Ri are independently selected from H, CI and fluoro; R₅ represents H;

Re represents hydrogen;

R7 is selected from H, cyano, and fluoro; and

Re is selected from hydrogen, and chloro.

In the compounds of Formula II, in some embodiments R₈ is CI, F or Me.

In the compounds of Formula II, in some embodiments R₈ is CI.

In some embodiments of these compounds, Ai is CH.

In certain embodiments of these compounds, X is a bond, and R½ is substituted with one to three groups independently selected from halogen, Ci-₃alkyl, C₃-₆branched alkyl, OH, Ci_ ₂alkoxy, R₂₂-ORi2_, S(0)i_-2Ri₂, C(0)ORi₂, R₂₂-C(0)ORi₂, C(0)Ri₉, R₂₂-OC(0)Ri₉,

C(0)NRi₃Ri4, NRi₅S(0)₂Ri2, NRiyRis, R₂₂-NRi₇Ri₈, NRi₅C(0)Ri₉, R₂₂-NRi₅C(0)Ri₉, and NRi₅C(0)OCH₂Ph. In some of these embodiments, R½ is of this formula:

In some embodiments of the foregoing compounds of Formula II, R3 is H and R₉ is H. In some embodiments of the foregoing compounds of Formula II, L is -CH₂- and R₂ is C5--7 heterocycloalkyl,

wherein the heterocycloalkyl contains 1 -2 heteroatoms selected from N, O and S as ring members, and is optionally substituted with up to three groups independently selected from halo, hydroxy, amino, haloalkyl, CN, C₁-4 alkyl, and Ci_-4 haloalkyl.

In some preferred embodiments, -LR₂ is -CH₂-phenyl, where the phenyl is optionally substituted with one to three groups selected from halo, hydroxy, amino, methyl CF₃, and methoxy,

or -LR₂ is a group of this formula, where the wavy line bisects the point of attachment of L to the rest of the Formula II structure:

where V is O, NR, S or S0₂, where R is H or C_1-4 alkyl, and W is selected from H, Me, CN, OH, OMe, and CONH₂. In some such embodiments, V is O or NH, and W is H or CN.

In some embodiments of the compounds of Formula II, L is a bond and R₂ is cyclopropyl, aryl or heteroaryl, each of which is optionally substituted with up to three groups independently selected from halo, hydroxy, amino, haloalkyl, CN, C_1-4 alkyl, and Ci_-4 haloalkyl. In some such embodiments, R₂ is phenyl and is optionally substituted with up to three groups independently selected from halo, hydroxy, amino, haloalkyl, CN, C_1-4 alkyl, and C_1-4 haloalkyl. In these embodiments, A₄ may be O or NH.

In some of these embodiments, R₂ is cyclopropyl, and may be substituted as just described. In some such embodiments, R₂ is cyclopropyl that is unsubstituted, or is substituted at C-l with OH, CN, CONH₂, Me, or OMe. R₉ represents methyl, hydrogen, or ethyl.

In some preferred embodiments of the compounds of Formula II as described above, -A₄-

L-R₂ represents the group

wherein Z is selected from Me, Et, CF₃, OMe, OH, CN, C≡CH, and CONH₂,

and L is -CH₂- or -CH₂CH₂-.

In some preferred embodiments of the foregoing compounds of Formula II, -X-R₁₆ is a C5-6 cycloalkyl or heterocycloalkyl substituted with an amine-containing group such as NR17R18 as described above for Formula I. For example, -X-R16 can be a group of this formula:

wherein R' is selected from C_1-6 haloalkyl, halo, hydroxy, amino, oxo, Ci_-4 aminoalkyl, -(CH₂)i. ₄OR, -NR-(CH₂)₂-₄-OR, and -0-(CH₂)_2-4-OR, wherein each R is independently Ci_-4 alkyl or H.

In certain embodiments of the compounds described above, X is a bond, and R½ is C3-7 cycloalkyl, and is substituted with -NR₁₇R₁₈. In particular embodiments, R½ is substituted with a group -NRi₇Ri₈ of the formula

wherein each R' is H, Me, or Et. In these embodiments, R½ may be cyclohexyl, and -NRnRis can be attached at position 3 or 4, preferably 4, of the cyclohexyl ring.

In other aspects, the invention includes a method of treating a disease or condition mediated by CDK9 comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the foregoing embodiments, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition mediated by CDK9 is selected from cancer, cardiac hypertrophy, HIV and inflammatory diseases. In some embodiments, the disease or condition mediated by CDK9 is cancer, including a cancer selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.

In another aspect, the invention provides a pharmaceutical composition comprising a compound according to any of the embodiments described herein, or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Preferably, the composition is sterile or consists of a compound of the invention and one or more, preferably at least two, pharmaceutically acceptable carriers, dilents or excipients. Preferably, the pharmaceutical compositions are sterile compositions, or compositions that consist essentially of or only of the above-described compounds and one or more

pharmaceutically acceptable excipients, carriers and/or diluents.

The invention also includes compounds of any of the above embodiments for use in therapy. The use can be to treat a condition selected from the group consisting of cancer, cardiac hypertrophy, HIV, and inflammatory diseases. Use to treat cancer is preferred, and the cancer can be selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.

The invention also includes use of a compound of any of the above-described

embodiments for the manufacture of a medicament for treatment of any of the conditions described herein as suitably treated by a CDK9 modulator, including cancers such as bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system,

hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small- cell lung, glioma, colorectal, and pancreatic cancer.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms (i.e., solvates). Compounds of the invention may also include hydrated forms (i.e., hydrates). In general, the solvated and hydrated forms are equivalent to unsolvated forms for purposes of biological utility and are encompassed within the scope of the present invention. The invention also includes all polymorphs, including crystalline and non-crystalline forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The present invention includes all salt forms of the compounds described herein, as well as methods of using such salts. The invention also includes all non-salt forms of any salt of a compound named herein, as well as other salts of any salt of a compound named herein. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts.

"Pharmaceutically acceptable salts" are those salts which retain the biological activity of the free compounds and which can be administered as drugs or pharmaceuticals to humans and/or animals. The desired salt of a basic functional group of a compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, hippuric, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. The desired salt of an acidic functional group of a compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, Ν,Ν'- dibenzylethylenediamine, and triethylamine salts.

Pharmaceutically acceptable metabolites and prodrugs of the compounds referred to in the formulas herein are also embraced by the invention. The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, Vol. 14 of the A.C.S.

Symposium Series, and in Edward B. Roche, ed., BIOREVERSIBLE CARRIERS IN DRUG DESIGN, American Pharmaceutical Association and Pergamon Press, 1987.

Pharmaceutically acceptable esters of the compounds referred to in the formulas herein are also embraced by the invention. As used herein, the term "pharmaceutically acceptable ester" refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety

advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The invention further provides deuterated versions of the above-described compounds. As used herein, "deuterated version" refers to a compound in which at least one hydrogen atom is enriched in the isotope deuterium beyond the natural rate of deuterium occurrence. Typically, the hydrogen atom is enriched to be at least 50% deuterium, frequently at least 75% deuterium, and preferably at least about 90% deuterium. Optionally, more than one hydrogen atom can be replaced by deuterium. For example, a methyl group can be deuterated by replacement of one hydrogen with deuterium (i.e., it can be -CI¾D), or it can have all three hydrogen atoms replaced with deuterium (i.e., it can be -CD₃). In each case, D signifies that at least 50% of the corresponding H is present as deuterium.

A substantially pure compound means that the compound is present with no more than

15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total amount of compound as impurity and/or in a different form. For instance, substantially pure S,S compound means that no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total R,R; S,R; and R,S forms are present.

As used herein, "therapeutically effective amount" indicates an amount that results in a desired pharmacological and/or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition. Therapeutically effective amounts of the compounds of the invention generally include any amount sufficient to detectably inhibit CDK or CDK9 activity by any of the assays described herein, by other CDK or CDK9 kinase activity assays known to those having ordinary skill in the art or by detecting an inhibition or alleviation of symptoms of cancer. The formulations comprising one or more compounds described herein may be administered in conjunction with one or more of the pharmaceutical agents as described herein and as known in the art, including one or more additional pharmaceutical agents to further reduce the occurrence and/or severity of symptoms and/or clinical manifestations thereof, as well as pharmaceutical agents that treat or prevent the underlying conditions, or in conjunction with (e.g., prior to, concurrently with, or after) additional treatment modalities. The formulations as described herein may be administered before, concurrently with, or after the administration of one or more of the pharmaceutical agents described herein. The compounds described herein may also be administered in conjunction with (e.g., prior to, concurrently with, or after) agents to alleviate the symptoms associated with either the condition or the treatment regimen.

The formulations described herein will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular condition being treated or prevented. The formulations may be administered therapeutically to achieve therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying condition being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying condition such that the individual reports an improvement in feeling or condition, notwithstanding that the individual may still be afflicted with the underlying condition. Therapeutic benefit also includes halting or slowing the progression of the condition, regardless of whether improvement is realized.

The amount of the formulation administered in order to administer an effective amount will depend upon a variety of factors, including, for example, the particular condition being treated, the frequency of administration, the particular formulation being administered, the severity of the condition being treated and the age, weight and general health of the individual, the adverse effects experienced by the individual being treated, etc. Determination of an effective dosage is within the capabilities of those skilled in the art, particularly in view of the teachings provided herein. Dosages may also be estimated using in vivo animal models.

The compounds of the invention may be administered enterally (e.g., orally or rectally), parenterally (e.g., sublingually, by injection, or by inhalation (e.g., as mists or sprays)), or topically, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g., via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. The compounds may be mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. In some embodiments, the route of administration is orally. In other embodiments, formulations are suitable for oral administration. The compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The route of administration may vary according to the condition to be treated. Additional methods of administration are known in the art.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such formulations may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and

metabolizable lipid capable of forming liposomes can be used. The present formulations in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Suitable lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., METHODS IN CELL BIOLOGY, Volume XIV, Academic Press, New York, N.W., p. 33 et seq (1976).

The compounds can be administered in prodrug form. Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds of the invention and esters of compounds of the inventions. Further discussion of suitable prodrugs is provided in H.

Bundgaard, DESIGN OF PRODRUGS, New York: Elsevier, 1985; in R. Silverman, THE ORGANIC CHEMISTRY OF DRUG DESIGN AND DRUG ACTION, Boston: Elsevier, 2004; in R.L. Juliano (ed.), BIOLOGICAL APPROACHES TO THE CONTROLLED DELIVERY OF DRUGS (Annals of the New York Academy of Sciences, v. 507), New York: New York Academy of Sciences, 1987; and in E.B. Roche (ed.), DESIGN OF BIOPHARMACEUTICAL PROPERTIES THROUGH PRODRUGS AND ANALOGS (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), Washington: The Academy, 1977. In some variations, the compounds are administered in a form of pharmaceutically acceptable esters.

The frequency and duration of administration of the formulation will depend on the condition being treated, the condition of the individual, and the like. The formulation may be administered to the individual one or more times, for example, 2, 3, 4, 5, 10, 15, 20, or more times. The formulation may be administered to the individual, for example, once a day, 2 times a day, 3 times a day, or more than 3 times a day. The formulation may also be administered to the individual, for example, less than once a day, for example, every other day, every third day, every week, or less frequently. The formulation may be administered over a period of days, weeks, or months.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular individual will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy. The pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

Examples of dosages which can be used are a therapeutically effective amount within the dosage range of about 0.1 μg/kg to about 300 mg/kg, or within about 1.0 μg/kg to about 40 mg/kg body weight, or within about 1.0 μg/kg to about 20 mg/kg body weight, or within about 1.0 μg/kg to about 10 mg/kg body weight, or within about 10.0 μg/kg to about 10 mg/kg body weight, or within about 100 μg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight. Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.

For topical application, the formulation may be administered, for example transdermally at about 5 mg to about 100 mg over 24 hours. For IV administration, the formulation may be administered at a dosage of, for example, from about 0.1 mg per day to about 500 mg per day, typically from about 1 to about 200 mg/day. For oral administration, the formulation may be administered at a dosage of, for example, from about 1 mg per day to about 1500 mg per day, often from about 5 to about 250 mg/day.

As used herein, the term "pharmaceutically acceptable carrier," and cognates thereof, refers to adjuvants, binders, diluents, etc., known to the skilled artisan that are suitable for administration to an individual (e.g., a mammal or non-mammal). As used herein, the term "pharmaceutically acceptable carriers, diluents or excipients" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329).

Combinations of two or more carriers or diluents are also contemplated in the present invention. In some embodiments, the pharmaceutical compositions comprise at least two pharmaceutically acceptable carriers, diluents or excipients selected from those disclosed herein.

The pharmaceutically acceptable carrier(s) and any additional components, as described herein, should be compatible for use in the intended route of administration (e.g., oral, parenteral) for a particular dosage form. Such suitability will be easily recognized by the skilled artisan, particularly in view of the teaching provided herein. Pharmaceutical compositions described herein include at least one pharmaceutically acceptable carrier or excipient; preferably, such compositions include at least one carrier or excipient other than or in addition to water.

The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, and parenteral administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

The invention further provides pharmaceutical compositions and dosage forms that may comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.

As used herein, the term "pharmaceutical agent" or "additional pharmaceutical agent," and cognates of these terms, are intended to refer to active agents other than the claimed compounds of the invention, for example, drugs, which are administered to elicit a therapeutic effect. The pharmaceutical agent(s) may be directed to a therapeutic effect related to the condition that a claimed compound is intended to treat or prevent (e.g., conditions mediated by CDK9, including, but not limited to those conditions described herein (e.g., cancer)) or, the pharmaceutical agent may be intended to treat or prevent a symptom of the underlying condition (e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc.) or to further reduce the appearance or severity of side effects of administering a claimed compound.

When used with respect to methods of treatment/prevention and the use of the compounds and formulations thereof described herein, an individual "in need thereof may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.). Typically, when a step of administering a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

In some embodiments, the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, the primate is a human. In some embodiments, the individual is human, including adults, children and premature infants. In some embodiments, the individual is a non- mammal. In some variations, the primate is a non-human primate such as chimpanzees and other apes and monkey species. In some embodiments, the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex.

In some variations, the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art (e.g., via blood tests, X-rays, CT scans, endoscopy, biopsy, etc.) and may also be suspected by the individual or others, for example, due to tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc.

In some embodiments, the individual has been identified as susceptible to one or more of the conditions as described herein. The susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the skilled artisan, including, but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), lifestyle or habits.

As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural forms, unless the context clearly dictates otherwise.

Unless defined otherwise or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

General Synthetic Methods

The compounds disclosed herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

Furthermore, the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the embodiments, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co.

(Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon

Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The various starting materials, intermediates, and compounds of the embodiments may be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses.

The disclosure herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substituent at any given location. Furthermore, it is to be understood that definitions of the variables {i.e., "R groups"), as well as the bond locations of the generic formulae of the invention {e.g., formulas I or II), will be consistent with the laws of chemical bonding known in the art. It is also to be understood that all of the compounds of the invention described above will further include bonds between adjacent atoms and/or hydrogens as required to satisfy the valence of each atom. That is, bonds and/or hydrogen atoms are added to provide the following number of total bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds.

Preferred embodiments of the compounds described herein are stable enough to be pharmaceutically useful. For example, they should be stable enough to undergo no more than 5% degradation when in contact with water for an hour at room temperature. Compounds of the embodiments may generally be prepared using a number of methods familiar to one of skill in the art, and may generally be made in accordance with the following reaction Schemes la, lb and 2, which are described in detail in the Examples below.

EXAMPLES

Referring to the examples that follow, compounds of the embodiments were synthesized using the methods described herein, or other methods known to one skilled in the art.

The compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2695 Separation Module (Milford, MA). The analytical columns were reversed phase Phenomenex Luna CI 8 5 μ, 4.6 x 50 mm, from Alltech (Deerfield, IL). A gradient elution was used (flow 2.5 mL/min), typically starting with 5 % acetonitrile/95 % water and progressing to 100 % acetonitrile over a period of 10 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA).

In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on LCMS instruments: Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8-micron, 2.1 x 50 mm; gradient: 5-95 % acetonitrile in water with 0.05 % TFA over a 1.8 min period ; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50 °C). All masses were reported as those of the protonated parent ions.

GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 μΕ; initial column temperature: 50 °C; final column temperature: 250 °C; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5 % phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m).

Nuclear magnetic resonance (NMR) analysis was performed on some of the compounds with a Vanan 300 MHz NMR (Palo Alto, CA) or Vanan 400 MHz MR NMR (Palo Alto, CA). The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (e.g., 75 °C) to promote increased sample solubility.

The purity of some of the compounds is assessed by elemental analysis (Desert Analytics, Tucson, AZ).

Melting points are determined on a Laboratory Devices Mel-Temp apparatus (Holliston,

MA).

Preparative separations are carried out using a Combiflash Rf system (Teledyne Isco, Lincoln, NE) with RediSep silica gel cartridges (Teledyne Isco, Lincoln, NE) or SiliaSep silica gel cartridges (Silicycle Inc., Quebec City, Canada) or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C-18 reversed phase column, 30X50 mm, flow 75 mL/min. Typical solvents employed for the Combiflash Rf system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, heptane, acetone, aqueous ammonia (or ammonium hydroxide), and triethyl amine. Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

The examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. Abbreviations

ACN: Acetonitrile

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

DCM: Dichloromethane

DIEA: diisopropylethylamine

DIPEA: N,N-diisopropylethylamine

DME: 1 ,2-dimethoxy ethane

DMF: N,N-dimethylformamide

DMSO dimethyl sulfoxide

DPPF 1 , 1 '-bis(diphenylphosphino)ferrocene

eq equivalent

EtOAc ethyl acetate EtOH ethanol

HATU 2- (7-aza- 1 H-benzotriazole- 1 -y 1) - 1 , 1 , 3 , 3 -tetramethy luronium

hexafluorophosphate

HPLC high performance liquid chromatography

MCPBA «¾eto-chloroperoxybenzoic acid

MeOH methanol

NBS N-bromosuccinimide

NMP N-methyl-2-pyrrolidone

Rt rentention time

THF tetrahydrofuran

Synthetic Examples

Compounds of the present invention can be synthesized by the schemes outlined below.

Scheme la.

As shown in Scheme la, synthesis can start with a functionalized pyridine or pyrimidine I wherein LG is a leaving group such as F, CI, OTf, and the like. X can be a functional group like CI, Br, I or OTf. Compound I can be converted into boronic acid or boronic ester II by:

1) PdCl₂(dppf) DCM adduct, potassium acetate, bis(pinacolato)diboron heating from 30 - 120 °C in solvents such as THF, DMF, DME, DMA, toluene and dioxane; and 2) In a solvent such as THF or diethylether, anion halogen exchange by addition of nBuLi or LDA followed by quenching the anion with triisopropyl borate. Upon hydrolysis a boronic acid can be obtained. Suzuki cross-coupling reaction between compound II and phenyl III then gives bi-heteroaryl intermediate IV. The SN_AR reaction between IV and a functionalized amine NH₂Ri' under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V. When Ri' is not identical to Ri, further functional manipulation is needed to obtain VI. When Ri' is identical to Ri, compound V will be the same as compound VI. Alternatively, VI can be obtained by following Scheme lb. In which the Suzuki cross-coupling step is carried out between I and VII. Boronic acid or ester VII is synthesized from III in the same fashion as described above.

Scheme lb.

V VI

Another alternative route is illustrated in Scheme 2. As described in Scheme la, boronic ester or acid, X, can be prepared from aminopyridine or aminopyrimidine IX. Suzuki cross- coupling reaction between compound X and substituted aryl compound XT then can give the bi- heteroaryl intermediate XII. The SNAR reaction between XII and functionalized amine HA₄LR₂ under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V. When Ri' is not identical to Ri, further functional manipulation will be needed to obtain VI. When Ri' is identical with Ri, compound V will be the same as compound VII.

Synthesis of examples

Compounds of the present invention, listed in Table I, were prepared by following the specific procedures outlined below. The procedures include synthesis of intermediates and using these intermediates to make compounds of Formula I.

Preparation of Selected Intermediates

Synthesis of tert-butyl (2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)phenyl)((tetrahvdro-2H-pyran-

4-vDmethyl^') carbamate

Step 1: Preparation of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)- phenylcarbamate

To a mixture of 5-chloro-2-fluoro-4-iodopyridine (210 mg, 0.816 mmol), 3-(tert- butoxycarbonylamino)-4-chlorophenylboronic acid (310 mg, 1.142 mmol) and PdCi₂(dppf) CH₂CI₂ adduct (66.6 mg, 0.082 mmol) in DME (3.6 mL) was added 2M aqueous sodium carbonate solution (1.2 mL). The resulting mixture was heated in a sealed tube under argon at 100 °C for 2 hrs. The mixture was cooled to room temperature, diluted with EtOAc (10 mL) and MeOH (5 mL), filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 12 g, EtO Ac/heptane = 0/100 to 15/85]. Fractions were combined and concentrated under reduced pressure providing tert-butyl 2-chloro-5-(5-chloro-2- fluoropyridin-4-yl)phenylcarbamate (243 mg) as a white solid. LCMS (m/z): 357.0/358.9

[M+H]+; Retention time = 1.23 min. Step 2: Preparation of [2-chloro-5-(5-chloro-2-fluoro-pyridin-4-yl)-phenyl]-(tetrahydro- pyran-4-ylmethyl)-carbamic acid tert-butyl ester

A mixture of sodium hydride (60 wt.% in mineral oil, 15.74 mg) in DMF (0.7 mL) was added to a solution of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (213 mg, 0.596 mmol) in DMF (0.70 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. To this stirred mixture was then added (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (161 mg, 0.596 mmol) in one portion. The mixture was warmed to 40 °C and maintained at this temperature for 16 hrs. The reaction mixture was diluted with EtOAc, washed with IN aqueous sodium hydroxide solution, water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by preparative TLC [silica gel, 1 mm; EtO Ac/heptane = 15/85] providing [2-chloro-5-(5-chloro-2-fluoro- pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (176 mg) as a colorless oil. LCMS (m/z): 355.0/356.9 [M+H, loss of t-Bu]; Retention time = 1.21 min.

Synthesis of 3-(5-chloro-2-fluoropyridin-4-yl)-5-fluoro-N-((tetrahvdro-2H-pyran-4- yl)methyl)aniline

Step 1: Preparation of 3-bromo-5-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline

A mixture of Pd(OAc)₂ (88 mg, 0.394 mmol) and BINAP (294 mg, 0.473 mmol) in dioxane (8 mL) was stirred in a sealed tube for ~5 min. To the mixture was then added l,3-dibromo-5- fluorobenzene (0.496 mL, 3.94 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine

hydrochloride (299 mg, 1.969 mmol), stirring was continued for additional ~5 min and KOtBu (486 mg, 4.33 mmol) was added. The resulting mixture was heated at 93 °C for ~18 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (-50 mL) and MeOH (-10 mL), filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 40 g, EtO Ac/heptane = 5/95 to 30/70] providing 3-bromo-5-fluoro- N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (220 mg) as a colorless liquid. LCMS (m/z): 289.9 [M+H]+; Retention time = 1.03 min.

Step 2: Preparation of 3-(5-chloro-2-fluoropyridin-4-yl)-5-fluoro-N-((tetrahydro-2H-pyran- 4-yl)methyl)aniline

A mixture of 3-bromo-5-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (220 mg, 0.763 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (268 mg, 1.527 mmol) and PdCi₂(dppf) CH₂CI₂ adduct (62.3 mg, 0.076 mmol) in DME (3.6 mL), and 2M aqueous sodium carbonate solution (1.2 mL) was heated in a sealed tube at 103 °C for about 2 hrs. The mixture was cooled to room temperature, diluted with EtO Ac (-25 mL) and MeOH (-5 mL), filtered off and concentrated under reduced pressure. The residue was purified by column chromatography

[silica gel, 12 g, EtO Ac/heptane = 10/90 to 50/50] providing 3-(5-chloro-2-fluoropyridin-4-yl)-5- fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (200 mg) as a colorless liquid. LCMS (m/z): 339.0 [M+H]+; Retention time = 1.05 min.

Synthesis of 3-(5-chloro-2-fluoropyridin-4-yl)-4-fluoro-N-((tetrahvdro-2H-pyran-4- yl)methyl)aniline

Step 1: Preparation of (3-bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester

To a solution of 3-bromo-4-fluoroaniline (1.0 g, 5.26 mmol) in DMF (10 mL) was added sodium hydride (60 wt.%, 210 mg). The suspension was stirred at ambient temperature for 5 min and BOC-anhydride (1.15 g, 5.26 mmol) was added. The reaction mixture was stirred at ambient temperature for 48 hrs and was diluted with EtOAc. The organic phase was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 12 g, EtO Ac/heptane = 0/100 to 40/60] providing (3-bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester (800 mg) as light yellow solid. LCMS (m/z): 275/277 [M+H, loss of t-Bu]; Retention time = 1.08 min.

Step 2: Preparation of (3-bromo-4-fluoro-phenyl)-(tetrahydro-pyran-4-ylmethyl)- carbamic acid tert-butyl ester

To a solution of (3-bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester (300 mg, 1.03 mmol) and toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (335 mg, 1.24 mmol) in DMF (4 mL) under argon was added sodium hydride (60 wt.%, 83 mg). The mixture was stirred at ambient temperature for 30 min and at 45 °C for 15 hrs. The reaction mixture was cooled to room temperature and was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (3-bromo-4-fluoro-phenyl)-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (320 mg) as yellow oil, which was directly used in the next step without purification. LCMS (m/z): 288/290 [M+H, loss of t-Bu]; Retention time = 1.11 min. Step 3: Preparation of 5-chloro-4-(2-fluoro-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)- phenyl)pyridin-2-amine

To a solution of (3-bromo-4-fluoro-phenyl)-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert- butyl ester (320 mg, 0.82 mmol) and 5-chloro-2-fluoro-pyridine-4-boronic acid (400 mg, 2.2 mmol) in DMF (3 mL) was added 2M aqueous sodium carbonate solution (0.8 rriL, 1.6 mmol), followed by PdCl₂(dppf) CH₂CI₂ adduct (107 mg, 0.13 mmol). The reaction mixture was heated at 95 °C for 20 hrs. The reaction mixture was cooled to room temperature and was diluted with EtOAc. The mixture was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue purified by column chromatography

[silica gel, 12 g, EtO Ac/heptane = 10/90 to 30/70] providing 5-chloro-4- {2-fluoro-5- [(tetrahydro-pyran-4-ylmethyl)-amino]-phenyl}-pyridin-2-ylamine (190 mg). LCMS (m/z): 339/341 [M+H]+; Retention time = 1.13 min. Synthesis of [3-(5-chloro-2-fluoro-pyridin-4-yl)-phenyll-(tetrahvdro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester

Stepl: Preparation of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate

To 5-chloro-2-fluoro-4-iodopyridine (1750 mg, 6.80 mmol) was added 3-(tert- butoxycarbonylamino)phenylboronic acid (3223 mg, 13.60 mmol), PdCl₂(dppf) CH₂CI₂ adduct (444 mg, 0.544 mmol), DME (28 mL) and last 2M aqueous sodium carbonate solution (13.6 mL). The reaction mixture was stirred at 100 °C for 2 hrs. The crude mixture was cooled to room temperature and diluted with EtO Ac (50 mL) and methanol (10 mL), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 120 g, EtO Ac/heptane = 0/100 to 40/60] providing tert-butyl 3-(5-chloro-2-fluoropyridin-4- yl)phenylcarbamate (1.82 g). LCMS (m/z): 323.0 [M+H]+; Retention time = 1.10 min. Step 2: Preparation of [3-(5-chloro-2-fluoro-pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4- ylmethyl)-carbamic acid tert-butyl ester

To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (270 mg, 0.837 mmol) in DMF (3 rriL) was added slowly sodium hydride (60 wt.% in mineral oil, 40.1 mg) at 0 °C. The ice bath was removed and the crude mixture was stirred for 20 min at room temperature. To the crude mixture was added (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (271 mg, 1.004 mmol) and stirring was continued at 40 °C for 40 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 mL). The mixture was washed saturated aqueous sodium bicarbonate solution (2x), water (2x) and brine (lx), dried with sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 24 g, EtO Ac/heptane = 0/100 to 30/70] providing [3-(5-chloro-2- fluoro-pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (205 mg). LCMS (m/z): 421.2 [M+H]+; Retention time = 1.19 min.

Intermediates 2

Synthesis of (R)-2-methyl-2-(trifluoromethyl)oxirane

(Reference: A. Harada, Y. Fujiwara, T. Katagiri, Tetrahedron: Asymmetry (2008) 1210-1214.)

To a solution of (R)-2-(trifluoromethyl)oxirane (0.5 g, 4.46 mmol) under argon at -100 °C was added n-BuLi (1.89 mL, 4.91 mmol) and the mixture was stirred at this temperature for 10 min. To the solution was added iodomethane (0.558 mL, 8.92 mmol) and the mixture was stirred at - 80 °C for 3 hours. The mixture was allowed to warm to 0 °C and directly usded in the next reaction. Total volumen: -24.8 mL; 0.18 M solution. To 1 mL of this solution was added triethylamine (139 μΕ, 0.997 mmol). The mixture was stirred for ~30 min and the formed precipitate was removed over a syringe filter. The clear solution was directly used. Synthesis of 2.5-difluoropyridin-4-ylboronic acid

To a solution of diisopropylamine (1.74 mL, 12.20 mmol) in anhydrous tetrahydrofuran (22 mL) under argon at -20 °C was added ft-butyllithium (7.66 mL, 1.6M in hexanes) slowly over 10 min. The newly formed LDA was then cooled to -78 °C. A solution of 2,5-difluoropyridine (1.05 mL, 11.5 mmol) in anhydrous tetrahydrofuran (3 mL) was added slowly over 30 min and the mixture was stirred at -78 °C for 4 hrs. A solution of triisopropyl borate (5.90 mL, 25.4 mmol) in anhydrous tetrahydrofuran (8.6 mL) was added dropwise. Once the addition was complete the reaction mixturre was warmed to room temperature and stirring was continued for an additional hour. The reaction mixture was diluted with aqueous sodium hydroxide solution (4 wt.%, 34 mL). The separated aqueous layer was cooled to 0 °C and then slowly acidified to pH = 4 with 6N aqueous hydrochloride solution (-10 mL). The mixture was extracted with EtOAc (3x 50 mL). The combined organic layers washed with brine (50 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was triturated with

diethylether to give 2,5-difluoropyridin-4-ylboronic acid (808 mg).

Synthesis of (l-cyanocvclopropyl)methyl methanesulfonate

Stepl: Preparation of methyl 1-cyanocyclopropanecarboxylate

In a 100 mL flask at 0 °C, 1 -cyanocyclopropanecarboxylic acid (3 g, 27.0 mmol) was dissolved in toluene (45 mL) and MeOH (5 mL). Reaction was treated dropwise with TMS-Diazomethane (27.0 mL, 27.0 mmol) and reaction stirred at 0 °C for 2 hr. Reaction was concentrated under reduced pressure providing a yellow oil, which was used without further purification (3.21 g, 25.7 mmol) GC/MS Rt = 5.0 mm, m/z = 125.

Step2: Preparation of l-(hydroxymethyl)cyclopropanecarbonitrile

In a 100 mL flask at 0 °C, methyl 1 -cyanocyclopropanecarboxylate (1 g, 7.99 mmol) was dissolved in 1,2-Dimethoxy ethane (20 ml) and MeOH (2 mL). Reaction was treated portion wise with NaBH₄ (0.605 g, 15.98 mmol) and reaction stirred at 0 °C for 2 hr and then 20 hrs overnight. Reaction was quenched with 20 mL of saturated NH₄C1 solution. Reaction was diluted with Et₂0 and stirred vigorously for 2 hrs. Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure to provide the title compound as a yellow oil which was used without further purification (755 mg) GC/MS Rt = 4.8 min, m/z = 98.

Step 3: Preparation of (l-cyanocyclopropyl)methyl methanesulfonate

In a 250 mL RBR at 0 °C, l-(hydroxymethyl)cyclopropanecarbonitrile (400 mg, 4.12 mmol) was dissolved in methylene chloride (15 mL) and triethylamine (1.148 mL, 8.24 mmol). Reaction was treated drop wise with methanesulfonyl chloride (0.353 mL, 4.53 mmol) and reaction stirred at 0 °C for 2 hr. Reaction was quenched with 20 mL of saturated aqueous Na₂CC>3 solution. Reaction mixture was diluted with Et₂0 and stirred vigorously for 30 minutes. Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure providing the title compound as a yellow oil which was used without further purification (622 mg).

Synthesis of (SVl-(tetrahvdro-2H-pyran-4-vDethanamine

Step 1: Preparation of (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane- 2-sulfinamide

A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2-methylpropane-2- sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.

Step 2: Preparation of (R)-2-methyl-N-((S)-l-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2- sulfinamide

To a solution of (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (0.93 g, 4.28 mmol) in dichloromethane (21.4 mL) at 0 °C was added slowly methylmagnesium bromide (2.0 M in tetrahydrofuran, 4.28 mL, 8.56 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hrs. The mixture was diluted with saturated aqueous ammonium chloride solution (5 mL). The separated organic layer was washed with water and brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography providing (R)-2-methyl-N-((S)-l-(tetrahydro- 2H-pyran-4-yl)ethyl)propane-2-sulfinamide (910 mg). LCMS (m/z): 234.0 [M+H]+; Retention time = 0.58 min.

Step 3: Preparation of (S)-l-(tetrahydro-2H-pyran-4-yl)ethanamine

To a solution of (R)-2-methyl-N-((S)-l-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2-sulfinamide (400 mg, 1.714 mmol) in MeOH (5 rriL) was added 4M hydrochloride in dioxane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue was diluted with diethylether (10 mL). The precipitate was collected by filtration and washed with diethylether providing crude (S)-l-(tetrahydro-2H- pyran-4-yl)ethanamine hydrochloride salt. The hydrochloride salt was dissolved in water (10 mL) and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (S)-l-(tetrahydro-2H-pyran-4- yl)ethanamine (212 mg), which was directly used in the next reaction without further purification. LCMS (m/z): 130.1 [M+H]+; Retention time = 0.34 min.

Synthesis of (R)-l-(tetrahydro-2H-pyran-4-yl) ethanamine

Step 1: Preparation of (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2- sulfinamide

A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (S)-2-methylpropane-2- sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (1.50 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.

Step 2: Preparation of (S)-2-methyl-N-((R)-l-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2- sulfinamide

To a solution of (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2- sulfinamide (1.5 g, 6.90 mmol) in dichloromethane (34.5 rriL) at 0 °C was slowly added methylmagnesium bromide (1.646 g, 13.80 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hrs. The mixture was diluted with saturated aqueous ammonium chloride solution (5 rriL). The separated organic layer was washed with water and brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatograph providing (S)-2-methyl-N-((R)-l-(tetrahydro-2H-pyran-4- yl)ethyl)propane-2-sulfinamide (1.40 g). LCMS (m/z): 234.3 [M+H]+; Retention time = 0.57 min.

Step 3: Preparation of (R)-l-(tetrahydro-2H-pyran-4-yl) ethanamine

To a solution of (S)-2-methyl-N-((R)-l-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2-sulfinamide (400 mg, 1.714 mmol) in MeOH (5 rriL) was added 4M hydrochloride in dioxane (5 rriL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue was diluted with diethylether (10 mL). The precipitate was collected by filtration and washed with diethylether providing crude (R)-l-(tetrahydro-2H- pyran-4-yl)ethanamine hydrochloride salt. The hydrochloride salt was dissolved in water (10 mL) and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2x). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (R)-l-(tetrahydro- 2H-pyran-4-yl)ethanamine (200 mg), which was directly used in the next reaction without further purification. LCMS (m/z): 130.1 [M+H]+; Retention time = 0.34 min. Synthesis of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine

Step 1: Preparation of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate

To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in dichloromethane (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The resulting mixture was stirred for 18 hrs at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and dichloromethane. The separated organic phase was washed with 0.2N aqueous hydrochloride solution (lx), IN aqueous hydrochloride solution (2x), brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 40 g, EtOAc/hexane = 0/100 to 50/50] providing (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (2.05 g) as a colorless oil. LCMS (m/z): 299.1 [M+H]+; Retention time = 0.96 min.

Step 2: Preparation of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine

Into a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (3 g, 10.05 mmol) in tetrahydrofuran (25 mL) in a steel bomb was condensed ammonia (-5.00 mL) at -78 °C. The mixture was heated in the steel bomb at 125 °C for -18 hrs. The mixture was cooled to -78 °C, the steel bomb was opened, and the mixture was allowed to warm up to room temperature under a stream of nitrogen. The mixture was concentrated under reduced pressure and the residue was partitioned between a aqueous sodium hydroxide solution (5 wt.%) and dichloromethane. The separated aqueous layer was extracted with dichloromethane (lx). The combined organic layers were washed with aqueous sodium hydroxide solution (5 wt.%), dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2,2- dimethyltetrahydro-2H-pyran-4-yl)methanamine (-2.36 g) as yellow liquid, which was directly used in the next reaction without further purification. LCMS (m/z): 144.1 [M+H]+; Retention time = 0.26 min.

Synthesis of (6,6-dimethyl-l,4-dioxan-2-yl)methanamine

Step 1: Preparation of l-(allyloxy)-2-methylpropan-2-ol

To allylic alcohol (57.4 mL, 844 mmol) was added sodium hydride (60 wt.% in mineral oil, 2.43 g, 101 mmol) at 0 °C. After stirring for 20 min 2,2-dimethyloxirane (15 mL, 169 mmol) was added and the solution was refluxed overnight. The mixture was allowed to cool to room temperature, diluted with saturated aqueous ammonium chloride solution and extracted with diethylether (3x). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure to remove diethylether. The residue was distilled providing l-(allyloxy)-2-methylpropan-2-ol (12.3 g, 42 torr, bp 58-60 °C) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ [ppm]: 5.87 - 5.96 (m, 1 H) 5.26 - 5.31 (m, 1 H) 5.18 - 5.21 (m, 1 H) 4.03 - 4.05 (m, 2 H) 3.28 (s, 2 H) 2.31 (br. s, 1H) 1.23 (s, 3 H) 1.22 (s, 3 H).

Step 2: Preparation of 6-(iodomethyl)-2,2-dimethyl-l,4-dioxane

To a solution of l-(allyloxy)-2-methylpropan-2-ol (5.0 g, 38 mmol) in acetonitrile (400 mL) was added sodium bicarbonate (19.5 g, 77 mmol) and the mixture was cooled to 0 °C. Iodine (11.7 g, 46.1 mmol) was added and the reaction mixture was allowed to warm up to room temperature and stirred overnight. To the mixture was added triethylamine (6.42 mL, 46.1 mmol) and additional iodine (7.8 g, 30.7 mmol) and stirring was continued for additional 5 hrs at 0 °C. To the mixture was added potassium carbonate (6.37 g, 46.1 mmol) and the suspension was stirred at room temperature for ~3 days. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution (200 mL) and EtOAc (300 mL). The separated aqueous layer was extracted with EtOAc (2x) and the combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtOAc/hexane = 10/100 to 10/40] providing 6-(iodomethyl)-2,2- dimethyl- 1,4-dioxane as a yellow oil (2.07 g). 1H NMR (400 MHz, chloroform-d) δ [ppm]: 4.01 (dd, J = 11.2, 2.8 Hz, 1 H) 3.81 - 3.88 (m, 1 H) 3.44 (d, J = 11.2 Hz, 1 H) 3.22 (dd, J = 11.6, 0.8 Hz, 1 H) 2.97-3.13 (m, 3 H) 1.33 (s, 3 H) 1.14 (s, 3 H). l-(Allyloxy)-2-methylpropan-2-ol (1.63 g) was recovered. Step3: Preparation of 6-(azidomethyl)-2,2-dim ethyl- 1,4-dioxane

To a solution of 6-(iodomethyl)-2,2-dimethyl- 1,4-dioxane (1.80 g, 7.03 mmol) in anhydrous DMF (9 mL) was added sodium azide (0.685 g, 10.5 mmol) and the suspension was heated at 80 °C for 2.5 hrs. The mixture was diluted with water (30 mL) and EtOAc (30 mL). The separated organic layer was washed with water (3x). The aqueous layers were combined and extracted with EtOAc (lx). The combined organic layers, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtOAc/hexane = 10/40 to 20/40] providing 6-(azidomethyl)-2,2-dimethyl- 1,4-dioxane (0.93 g) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ [ppm]: 4.00-4.06 (m, 1 H) 3.75

(ddd, J = 11.2, 2.4, 0.4 Hz, 1 H) 3.49 (d, J = 11.2 Hz, 1 H) 3.14-3.29 (m, 4 H) 1.35 (s, 3 H), 1.14 (s, 3 H).

Step 4: Preparation of (6,6-dimethyl-l,4-dioxan-2-yl)methanamine

To a solution of 6-(azidomethyl)-2,2-dimethyl- 1,4-dioxane (502 mg, 2.93 mmol) in anhydrous tetrahydrofuran (15 mL) was added slowly a solution of lithium aluminumhydride (1M in tetrahydrofuran, 3.81 mL) 0 °C and the mixture was stirred at 0 °C for 1 hr and at room temperature for 0.5 hr. The reaction mixture was cooled to 0 °C and sodium sulfate decahydrate (excess) was slowly added and the suspension was vigorously stirred overnight. The suspension was filtered through cotton and the filtrate was concentrated under reduced pressure providing crude (6,6-dimethyl-l,4-dioxan-2-yl)methanamine (410 mg) as a colorless oil, which was directly used in the next step without purification. LCMS (m/z): 146.1 [M+H]+; Retention time = 0.42 min.

Synthesis of (5,5-dimethyl-l,4-dioxan-2-yl)methanamine

Step 1: Preparation of 2-(allyloxy)-2-methylpropan-l-ol

To a solution of 2,2-dimethyloxirane (15.0 mL, 169 mmol) in allylic alcohol (57.4 mL) was added perchloric acid (70 wt.%, 7.26 mL, 84 mmol) slowly at 0°C. The solution was warmed to room temperature and stirred for 1.5 hrs. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with diethylether (3x). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure to remove diethylether. The residue was distilled providing 2-(allyloxy)-2- methylpropan-l-ol (9.70 g, 38 torr, bp 74-76 °C) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ [ppm]: 5.87 - 5.97 (m, 1 H) 5.25 - 5.31 (m, 1 H) 5.12 - 5.16 (m, 1 H) 3.92 - 3.94 (m, 2 H) 3.45 (m, 2 H) 1.19 (s, 6 H).

Step 2: Preparation of 5-(iodomethyl)-2,2-dimethyl-l,4-dioxane

To a solution of 2-(allyloxy)-2-methylpropan-l-ol (5.0 g, 38.4 mmol) in acetonitrile (350 mL) was added sodium bicarbonate (9.68 g, 115 mmol) and the mixture was cooled to 0 °C. Iodine (29.2 g, 115 mmol) was added and the reaction mixture was allowed to warm up to room temperature and stirred for 6 hrs. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution and concentrated under reduced pressure removing most of the organic solvent. The residue was extracted with EtOAc (2x) and the combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtOAc/hexane = 10/100 to 10/40] providing 6-(iodomethyl)-2,2-dimethyl-l,4-dioxane as a colorless oil (7.04 g). 1H NMR (400 MHz, chloroform-d) δ [ppm]: 3.70-3.73 (m, 1 H) 3.57 - 3.64 (m, 2 H) 3.43 - 3.50 (m, 2 H) 3.13 - 3.15 (m, 2 H) 1.32 (s, 3 H) 1.13 (s, 3 H).

Step 3: Preparation of 5-(azidomethyl)-2,2-dimethyl-l,4-dioxane

To a solution of 5-(iodomethyl)-2,2-dimethyl-l,4-dioxane (2.58 g, 10.1 mmol) in anhydrous DMF (13 mL) was added sodium azide (0.982 g, 15.1 mmol) and the suspension was heated at 80 °C for 2.5 hrs. The mixture was diluted with water (40 mL) and EtOAc (40 mL). The separated organic layer was washed with water (3x). The aqueous layers were combined and extracted with EtOAc (lx). The combined organic layers, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtOAc/hexane = 10/40 to 50/50] providing 6-(azidomethyl)-2,2-dimethyl-l,4-dioxane (1.61 g) as a colorless oil. NMR (400 MHz, chloroform-d) δ [ppm]: 3.63 - 3.72 (m, 2 H) 3.52 - 3.59 (m, 2 H) 3.42 (d, J = 11.6 Hz, 1 H) 3.29 (d, J = 4.4 Hz, 2 H) 1.33 (s, 3 H) 1.13 (s, 3 H).

Step 4: Preparation of (5,5-dimethyl-l,4-dioxan-2-yl)methanamine

To a solution of 5-(azidomethyl)-2,2-dimethyl-l,4-dioxane (810 mg, 4.73 mmol) in anhydrous tetrahydrofuran (20 mL) was added slowly a solution of lithium aluminumhydride (1.0 M tetrahydrofuran, 6.2 mL) 0 °C and the mixture was stirred at 0 °C for 1 hr and at room temperature for 0.5 hr. The reaction mixture was cooled to 0 °C and sodium sulfate decahydrate (excess) was slowly added and the suspension was vigorously stirred overnight. The suspension was filtered through cotton and the filtrate was concentrated under reduced pressure providing crude (5,5-dimethyl-l,4-dioxan-2-yl)methanamine (673 mg) as a colorless oil, which was directly used in the next step without purification. LCMS (m/z): 146.1 [M+H]+; Retention time = 0.42 min.

Synthesis of (4-methyltetrahvdro-2H-pyran-4-yf)methanamine

Step 1: Preparation of 4-methyltetrahydro-2H-pyran-4-carbonitrile

To a solution of tetrahydro-2H-pyran-4-carbonitrile (2 g, 18.00 mmol) in tetrahydrofuran (10 mL) at 0 - 5 °C was added slowly LHMDS (21.59 mL, 21.59 mmol). The mixture was stirred for 1.5 hrs at 0 °C. lodomethane (3.37 mL, 54.0 mmol) was added slowly and stirring was continued for 30 min at ~0 °C and then for ~2 hrs at room temperature. The mixture was cooled to 0 °C and carefully diluted with IN aqueous hydrochloride solution (30 mL) and EtOAc (5 mL) and concentrated under reduced pressure. The residue was taken up in diethylether and the separated organic layer was washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude 4-methyltetrahydro-2H-pyran-4-carbonitrile (1.8 g) as an orange oil, which was directly used in the next reaction without further purification. LCMS (m/z): 126.1 [M+H]+; Retention time = 0.44 min. Step 2: Preparation of (4-methyltetrahydro-2H-pyran-4-yl)methanamine

To a solution of 4-methyltetrahydro-2H-pyran-4-carbonitrile (1.8 g, 14.38 mmol) in

tetrahydrofuran (30 mL) was carefully added lithium aluminum hydride (1M solution in tetrahydrofuran, 21.57 mL, 21.57 mmol) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, allowed to warm to room temperature and stirred for additional 3 hrs at room temperature. To the reaction mixture was carefully added water (0.9 mL) [Caution: gas development!], IN aqueous sodium hydroxide solution (2.7 mL) and water (0.9 mL). The mixture was vigorously stirred for 30 min. The precipitate was filtered off and rinsed with tetrahydrofuran. The solution was concentrated under reduced pressure providing crude (4-methyltetrahydro-2H-pyran-4- yl)methanamine (1.54 g) as a yellowish solid, which was directly used in the next step without further purification. LCMS (m/z): 130.1 [M+H]+; Retention time = 0.21 min.

Synthesis of 4-(aminomethyl)tetrahvdro-2H-pyran-4-carbonitrile

Step 1: Preparation of dihydro-2H-pyran-4,4(3H)-dicarbonitrile

A mixture of malononitrile (0.991 g, 15 mmol), l-bromo-2-(2-bromoethoxy)ethane (3.83 g, 16.50 mmol) and DBU (4.97 mL, 33.0 mmol) in DMF (6 mL) was heated at 85 °C for 3 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (25 mL), washed with water (2x 10 mL), dried over sodium sulfat, filtered off and concentrated under reduced pressure and further dried in high vacuo providing crude dihydro-2H-pyran-4,4(3H)-dicarbonitrile (1.65 g) as a light brown solid, which was directly used in the next step without further purification. GCMS: 136 [M]; Retention time = 5.76 min. 1H NMR (300 MHz, chloroform-d) δ [ppm]: 2.14-2.32 (m, 4 H) 3.77-3.96 (m, 4 H).

Step 2: Preparation of 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile

To a solution of dihydro-2H-pyran-4,4(3H)-dicarbonitrile (450 mg, 3.31 mmol in EtOH (15 mL) was added sodium borohydride (375 mg, 9.92 mmol) in portions and the mixture was stirred at room temperature for 4 hrs. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with water (10 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude 4-(aminomethyl)tetrahydro- 2H-pyran-4-carbonitrile (388 mg), which was directly used in the next step without further purification. LCMS (m/z): 141.0 [M+H]+; Retention time = 0.18 min.

Synthesis of 4-(hvdroxymethyl)tetrahvdro-2H-pyran-4-carbonitrile

Step 1: Preparation of methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate

To methylcyanoacetate (7.87 ml, 101 mmol) in DMF (60 mL) at room temperature was added a solution of l-bromo-2-(2-bromoethoxy)ethane (25.7 g, 111 mmol) in 20 mL DMF. To this mixture was added a solution of DBU (33.2 mL, 222 mmol) in 20 mL DMF dropwise via an addition funnel. The brown mixture was heated to 85 °C under argon for 3 hours. The reaction mixture was allowed to cool to room temperature, poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography

[Si0₂, 120 g, EtO Ac/heptane]. Fractions were combined and concentrated under reduced pressure providing methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (11.2 g) as a nearly colorless oil.

Step 2: Preparation of 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile

To a solution of methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (11.2 g, 66.2 mmol) in DME (60 mL) and MeOH (6 mL) at 0 °C was added sodium borohydride (1.454 g, 38.4 mmol) in one portion. The reaction mixture was stirred under argon at room temperature for 16 hrs. The resulting mixture was was poured into saturated aqueous ammonium chloride solution (30mL) and extracted with EtOAc (2x 20 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure providing crude 4- (hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (7.8 g) as a nearly colorless oil, which was diectly used without further purification. 1H NMR (400 MHz, chloroform-i 3) δ ppm 1.58 - 1.70 (m, 2 H) 1.91 (dd, J=13.69, 1.96 Hz, 2 H) 2.31 (br. s., 1 H) 3.64 - 3.76 (m, 4 H) 3.94 - 4.06 (m, 2 H).

Synthesis of toluene-4-sulfonic acid 4-methoxy-tetrahvdro-pyran-4-ylmethyl ester

Step 1: Preparation of 1,6-dioxaspiro [2.5] octane

To a solution of trimethylsulfonium iodide (3.27 g, 16 mmol) in DMSO (20 mL) under nitrogen atmosphere was added dihydro-2H-pyran-4(3H)-one (1.0 g, 10 mmol). To the mixture was added slowly a solution of tert-butoxide (1.68 g, 15 mmol) in DMSO (15 mL) and the solution was stirred at room temperature overnight. The reaction mixture was diluted slowly with water (50 mL) and extracted with diethylether (3x 20 mL). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude 1,6- dioxaspiro[2.5]octane (650 mg), which was directly used without further purification. 1H NMR (300 MHz, chloroform-d) 5.[ppm]: 1.44 - 1.62 (m, 2 H) 1.76 - 1.98 (m, 2 H) 2.70 (s, 2 H) 3.70 - 3.98 (m, 4 H). Step 2: Preparation of (4-methoxytetrahydro-2H-pyran-4-yl) MeOH

To a solution of l,6-dioxaspiro[2.5]octane (600 mg, 5.26 mmol) in MeOH (10 mL) under nitrogen was added camphorsulfonic acid (50 mg, 0.21 mmol) at 0 °C and the mixture was stirred at 0 °C for 2 hrs. The mixture was concentrated under reduced pressure providing crude (4-methoxytetrahydro-2H-pyran-4-yl)methanol (707 mg) as a light yellow oil, which was directly used in the next step without further purification. 1H NMR (300 MHz, chloroform-d) δ .[ppm]: 1.89 - 2.08 (m, 4 H), 3.18 - 3.30 (m, 3 H), 3.47 - 3.59 (m, 2 H), 3.64 - 3.78 (m, 4 H). Step 3: Preparation of toluene-4-sulfonic acid 4-methoxy-tetrahydro-pyran-4-ylmethyl ester

To a solution of (4-methoxytetrahydro-2H-pyran-4-yl) MeOH (300 mg, 2.05 mmol) in pyridine (4 rriL) was added toluenesulfonic chloride (430 mg, 2.25 mmol) at room temperature and the mixture was stirred at 25 °C overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (2 mL). Purification by column

chromatography [silica gel, 12 g, EtOAc/hexane = 0/100 to 30/70] provided toluene-4-sulfonic acid 4-methoxy-tetrahydro-pyran-4-ylmethyl ester (360 mg) as a light yellow solid. ¹H NMR (300 MHz, chloroform-d) 5.[ppm]: 1.45 - 1.63 (m, 2 H) 1.61 - 1.79 (m, 2 H) 2.46 (s, 3 H), 3.16 (s, 3 H) 3.53 - 3.75 (m, 4 H) 3.93 (s, 2 H), 7.36 (d, J = 8.20 Hz, 2 H) 7.81 (d, J = 8.20 Hz, 2 H).

Synthesis of (4-methoxytetrahydro-2H-pyran-4-yl)methanamine

Step 1: Preparation of 4,4-dimethoxytetrahydro-2H-pyran

A mixture of dihydro-2H-pyran-4(3H)-one (501 mg, 5 mmol), trimethyl orthoformate (0.608 mL, 5.50 mmol) and toluenesulfonic acid monohydrate (2.85 mg, 0.015 mmol) in MeOH (1 mL) was stirred in a sealed tube at 80 °C for 30 min. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure providing crude 4,4- dimethoxytetrahydro-2H-pyran (703 mg), which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) 6.[ppm]: 1.61 - 1.90 (m, 4 H) 3.20 (s, 6 H) 3.60 - 3.78 (m, 4 H). Step 2: Preparation of 4-methoxytetrahydro-2H-pyran-4-carbonitrile

To a solution of 4,4-dimethoxytetrahydro-2H-pyran (0.703 g, 4.81 mmol) and tin(IV)chloride (0.564 mL, 4.81 mmol) in dichloromethane (15 mL) was added slowly 2-isocyano-2- methylpropane (0.400 g, 4.81 mmol) at -70 °C and the mixture was allowed to warm to room temperature over 2-3 hrs. The mixture was diluted with aqueous sodium bicarbonate solution (10 mL) and dichloromethane (20 mL). The separated organic layer was washed with water (3x 10 mL) and dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude 4-methoxytetrahydro-2H-pyran-4-carbonitrile (511 mg), which was used in the next step without further purification. GCMS: 109 [M-MeOH]; Retention time = 5.44 min. Step 3: Preparation of (4-methoxytetrahydro-2H-pyran-4-yl)methanamine

To a mixture of L1AIH₄ (275 mg, 7.24 mmol) in tetrahydrofuran (10 mL) at room temperature was slowly added a solution of 4-methoxytetrahydro-2H-pyran-4-carbonitrile (511 mg, 3.62 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hr and heated to reflux for 3 hrs. The reaction mixture was cooled to 0 °C and water (3 mL) was carefully added dropwise. The resulting mixture was stirred for additional 30 min and filtered to remove all solids. The filtrate was dried over sodium sulfate for 2 hrs, filtered off and concentrated under reduced pressure providing crude (4-methoxytetrahydro-2H-pyran-4- yl)methanamine (370 mg), which was used in the next step without further purification. LCMS (m/z): 146.1 [M+H]+, 114.0 [M-MeOH]; Retention time = 0.19 min.

Synthesis of toluene-4-sulfonic acid . -dioxo-hexahvdro-l-thiopyran-4-yl-methyl ester

A mixture of (r,l '-dioxo-hexahydro-l-thiopyran-4-yl)-methanol (2.5 g, 15.22 mmol) [Organic Process Research & Development 2008, 12, 892-895.], pyridine (25 mL) and tosyl-Cl (2.90 g, 15.22 mmol) was stirred for 18 hrs at 50 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography [silica gel,

EtOAc/hexane = 0/100 to 70/30]. Fractions were combined and concentrated under reduced pressure providing toluene-4-sulfonic acid Γ,Γ -dioxo-hexahydro-l-thiopyran-4-yl-methyl ester (3.78 g). LCMS (m/z): 319.0 [M+H]+; Retention time = 0.71 min. Synthesis of (2R,6S)-2,6-dimethyltetrahvdro-2H-pyran-4-carbaldehyde

Step 1: Preparation of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one

A solution of 2,6-dimethyl-4H-pyran-4-one (2 g, 16.1 mmol) in EtOH (20 mL) was stirred over Pd/C (10 wt.%, 0.2 g) under hydrogen (15 psi) for 16 hrs at ambient temperature. The suspension was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 mL) and treated with Dess-Martin periodinane (2.3 g) at ambient temperature for 16 hrs. To the suspension was added saturated aqueous sodium thiosulfate solution (~3 mL) and the mixture was stirred for 1 hr. The mixture was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and stirred for an additional 1 hr. The separated organic phase was washed with water and brine, dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtO Ac/heptane = 10/90]. Fractions were combined and concentrated under reduced pressure providing (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (600 mg). GCMS: 128 [M]; Retention time = 4.25 mm. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.18 (d, J=6.26 Hz, 6 H) 2.11 - 2.25 (m, 4 H) 3.58 - 3.77 (m, 2 H).

Step 2: Preparation of (2R,6S)-4-(methoxymethylene)-2,6-dimethyltetrahydro-2H-pyran

To a suspension of (methoxymethyl)triphenyl phosphine chloride (1.5 g, 4.45 mmol) in tetrahydrofuran (8 mL) was added slowly sodium bis(trimethylsilyl) amide (1M solution in tetrahydrofuran, 4.45 mL) at -10 °C. The reaction mixture was stirred for 1 hr and a solution of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (380 mg, 2.96 mmol) in tetrahydrofuran (2 mL) was added slowly. The resulting mixture was allowed to warm to ambient temperature and stirred for 3 hrs. The reaction mixture was diluted with water (15 mL) and extracted with diethylether (2x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtO Ac/heptane = 10/90] providing (2R,6S)-4- (methoxymethylene)-2,6-dimethyltetrahydro-2H-pyran (240 mg) as a colorless oil. GCMS: 156 [M]; Retention time = 5.40 mm. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.07 (t, J=6.06 Hz, 6 H) 1.18 - 1.29 (m, 1 H) 1.31 - 1.46 (m, 1 H) 1.61(t, J=12.13 Hz, 1 H) 1.93 (d, J=13.30 Hz, 1 H) 3.17 - 3.28 (m, 2 H) 3.46 (s, 3 H) 5.89 (s, 1 H).

Step 3: Preparation of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde

A mixture of (2R,6S)-4-(methoxymethylene)-2,6-dimethyltetrahydro-2H-pyran (240 mg, 1.53 mmol) and formic acid (-88 wt.% in water, 1.5 mL, 34.4 mmol) under argon was heated at 90 °C for 1 hr. The reaction mixture was cooled to 0 °C, neutralized with IN aqueous sodium hydroxide solution until pH~6 and extracted with diethylether. The organic layer were dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde (120 mg) as a yellow oil, which was directly used in the next reaction without further purification. GCMS: 142 [M]; Retention time = 5.0 mm. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.89 - 1.00 (m, 2 H) 1.09 (d, J=6.26 Hz, 6 H) 1.77 (ddd, J=12.33, 1.96, 1.76 Hz, 2 H) 3.35 (t, J=7.04 Hz, 1 H) 3.38 - 3.48 (m, 2 H) 9.51 (s, 1 H).

Synthesis of 6-bromo-N-((4-fluorotetrahvdro-2H-pyran-4-yl)methyl)pyridin-2-amine

Step 1: Preparation of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde

Step la: To a solution of DIPEA (6.12 mL, 35.0 mmol) in dichloromethane (80 mL) was added trimethylsilyl trifluoromethanesulfonate (7.79 g, 35.0 mmol) and slowly a solution of tetrahydro- 2H-pyran-4-carbaldehyde (2 g, 17.52 mmol) in dichloromethane (80 mL) at 0 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature for 2 hrs. The mixture was concentrated under reduced pressure and the residue was treated with hexane (200 mL). The precipitate was filtered off and the solution was concentrated under reduced pressure providing crude trimethylsilyl ether, which was directly used in the next step without further purification.

Step lb: To a solution of crude trimethylsilyl ether in dichloromethane (100 mL) was added dropwise a solution of N-fluorobenzenesulfonimide (5.53 g, 17.52 mmol), dissolved in dichloromethane (50 mL), at 0 °C. The mixture was stirred for 3 hrs at room temperature and the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde was directly used in the next reaction.

Step 2: Preparation of 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2- amine

To 6-bromopyridin-2-amine (3.03 g, 17.50 mmol) was added the crude solution of 4- fluorotetrahydro-2H-pyran-4-carbaldehyde in dichloromethane. To the resulting mixture was added acetic acid (1.002 mL, 17.50 mmol) and sodium triacetoxyborohydride (5.56 g, 26.3 mmol) in portions. The mixture was stirred for 2 hrs at room temperature. The mixture was diluted carefully with saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane (lx). The combined organic layers were washed with water (lx), saturated aqueous sodium bicarbonate solution (lx) and concentrated under reduced pressure. The solid residue was dissolved in dichloromethane (100 mL) and 3M aqueous hydrochloride solution (60 mL). The separated organic layer was extracted with 3M aqueous hydrochloride solution (3x 20 mL). The combined acidic layers were washed with

dichloromethane (lx). Solid sodium bicarbonate was added carefully to the acidic solution

[Caution: gas development!] until pH>~8. The aqueous mixture was extraction with

dichloromethane (2x) and EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in EtOAc. The solution was washed with 0.3M aqueous hydrochloride solution and brine, dried over sodium sulfate, filtered off and

concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 40 g, EtO Ac/heptane = 5/95 to 30/70] providing 6-bromo-N-((4-fluorotetrahydro-2H- pyran-4-yl)methyl)pyridin-2-amine (1.82 g) as a white solid. LCMS (m/z): 288.9/291.0

[M+H]+; Retention time = 0.84 min. Synthesis of N-(l,3-dimethoxypropan-2-yl)cvclohexane-trans-l,4-diamine

Step 1: Preparation of l,3-dimethoxypropan-2-yl 4-methylbenzenesulfonate

To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added l,3-dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to room temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The white cloudy mixture was stirred at room temperature for 16 hours. LC/MS showed complete conversion. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give 2 g of colorless oil. The crude mixture was purified by column chromatography (silica gel column 80 g, gradient: 0 min, 100%n-heptane; 5-12 min, 20% EtOAc in Heptane; 12-15 min. 30% EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated under reduced pressure to give 1.25 g of product as colorless oil which solidified upon standing.

Step 2: Preparation of N-(l,3-dimethoxypropan-2-yl)cyclohexane-trans-l,4-diamine

To the tosylate obtained in Step 1 (0.8g, 2.92 mmol) in DMSO (8 ml) was added 1,4-trans- cyclohexane diamine (0.999 g, 8.75 mmol). The brown mixture in a capped vial was heated to 95 °C with stirring for 2 hours. The reaction mixture was poured into 10% HC1 in water (10 mL) at 0 °C (ice cubes in HC1) and extracted with DCM (lx 20 mL). The aqueous (light pink) was basified with 6N aqueous NaOH to pH >12 and extracted with DCM (2x 20mL). The organic extracts were combined, dried with sodium sulfate and concentrated under reduced pressure to give a purple liquid. LCMS (m/z): 217 [M+H]+; Retention time = 0.32 min; no UV absorption at 214 nm wavelength. This was used in the next step without further purification. Synthesis of cis- and fram-4-(2,2-dimethylmorpholino)cvclohexanamine

Stepl: Preparation of tert-butyl cis/trans-4-(2,2-dimethylmorpholino)

cyclohexylcarbamate

To a solution of tert-butyl 4-oxocyclohexylcarbamate (350 mg, 1.641 mmol) in methylene chloride (8 mL) was added 2,2-dimethylmorpholine (189 mg, 1.641 mmol) followed by sodium triacetoxyborohydride (1.739 g, 8.21 mmol). Reaction mixture was stirred at 25 °C for 6 hr. Reaction mixture was diluted with EtOAc and washed with water. Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [Si0₂; 12 g] to provide the title compound as a yellow oil. LCMS (m/z): 313.1 [M+H]+; Retention time = 0.60 min. Step2: Preparation of cis- and fra«s-4-(2,2-dimethylmorpholino)cyclohexanamine

To a solution of tert-butyl cis/trans-4-(2,2-dimethylmorpholino)cyclohexylcarbamate (419 mg. 1.341 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (0.103 mL, 1.341 mmol). Reaction was stirred at 25 °C for 2 hr. Reaction was concentrated to provide the title compounds as trifluoroacetic acid salts as a white solid which was used without further purification. (400 mg, 1.884 mmol). LCMS (m/z): 213.1 [M+H]+; Retention time = 0.19 min LC/MS Rt = 0.19 mm, m/z (H+)= 213.1

Synthesis of trans-Nl -((R)- 1 -methoxypropan-2-yl)cvclohexane- 1 ,4-diamine

H

Step 1: Preparation of (S)-l-methoxypropan-2-yl 4-methylbenzenesulfonate

To sodium hydride (5.99 g, 150 mmol) in THF (200mL) at 0 °C was added (S)-l- methoxypropan-2-ol (13.5 g, 150 mmol) dropwise. The mixture was warmed to room temperature and stirred under argon for 1 hr. The resulting white cloudy mixture was cooled to 0 °C. To this was added 4-methylbenzene-l-sulfonyl chloride (28.6 g, 150 mmol) in THF (200 mL). The reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into water and extracted with EtOAc (3x 150 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 45 g of oil. The crude mixture was purified by column chromatography [Si0₂, 330 g, EtOAc /heptane = 0/100 for 10 min, 10/90 for 20 min, then 30/70], providing 27.33 g of (S)-l- methoxypropan-2-yl 4-methylbenzenesulfonate as colorless oil. 1H NMR (400 MHz, chloroform-^ δ ppm 1.28 (d, 3 H) 2.45 (s, 3 H) 3.25 (s, 3 H) 3.33 - 3.47 (m, 2 H) 4.72

7.34 (d, 2 H) 7.82 (d, 2 H).

Step 2: Preparation of trans-Nl-((R)-l-methoxypropan-2-yl)cyclohexane-l,4-diamine

To (S)- 1 -methoxypropan-2-yl 4-methylbenzenesulfonate (15 g, 61.4 mmol) in acetonitrile (100 mL) at room temperature was added 1,4-trans-cyclohexane-diamine (17.53 g, 153 mmol). The light brown mixture was heated to 90 °C in a sealed steel bomb for 18 hr. The resulting mixture was cloudy light brown. LC/MS showed formation of desired product and side bis-alkylated product. A second batch of the same reaction mixture was set up in a similar fashion (12.33 g of (S)-l-methoxypropan-2-yl 4-methylbenzenesulfonate, 14.41 g of 1 ,4-trans-cyclohexane-diamine) and the two reactions were cooled to room temperature, combined and worked up as below. To the cooled reaction mixture, ether (-200 mL) was added. The solid was removed by filtration. The filtrate was concentrated then heptane (80 mL) and EtOAc (15 mL) were added. The precipitates were removed by filtration. The filtrate was concentrated under reduced pressure to give brown oil and some solid. The residue was dissolved with 100 mL of water and extracted with ether (lx 100 mL) and DCM (4x 45 mL). Ether extract was discarded. The DCM extracts were combined, dried with sodium sulfate and concentrated under reduced pressure to give 10.4 g (50% yield) of brown oil. LC/MS showed this contained trans-Nl-((R)-l-methoxypropan-2- yl)cyclohexane-l,4-diamine (major) along with bis-alkylated side product (-5%). This was used in the next step without further purification. LCMS (m/z): 187.1 [M+H]+; Retention time = 0.15 mm. 1H NMR (400 MHz, chloroform-^ δ ppm 1.02 (d, 3 H) 1.05 - 1.23 (m, 4 H) 1.77 - 2.03 (m, 4 H) 2.49 (br. s., 1 H) 2.65 (d, 1 H) 2.95 - 3.06 (m, 1 H) 3.18 - 3.31 (m, 2 H) 3.34 (s, 3 H).

Synthesis of trans-Nl-(l-(trideuteromethoxy)propan-2-yl)cvclohexane-l,4-diamine

Step 1: Preparation of l-(trideuteromethoxy)propan-2-yl 4-methylbenzenesulfonate

To 2-methyloxirane (0.603 niL, 8.61 mmol) in DMF (10 mL) at room temperature was added methanol-d4 (0.310 g, 8.61 mmol) dropwise. The resulting grey cloudy mixture was stirred at room temperature under argon for 30 min followed by addition of 2-methyloxirane (0.603 mL, 8.61 mmol). The mixture was heated to 50 °C in a sealed scintillation vial for 18 hr. The resulting mixture was dark brown and cloudy. To this was added tosyl-Cl (1.641 g, 8.61 mmol) in one portion and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into aqueous saturated NaHCC solution (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extracts were combined, washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude mixture was purified by column chromatography [Si0₂, 40 g, EtO Ac/heptane = 0/100 for 4 min, 30/70 for 4-8 min, then 50/50 for 20 min] providing 0.77g of 1 -(trideuteromethoxy)propan-2-yl 4- methylbenzenesulfonate as a light yellow oil. Step 2: Preparation of trans-Nl-(l-(trideuteromethoxy)propan-2-yl)cyclohexane-l,4- diamine

To l-(trideuteromethoxy)propan-2-yl 4-methylbenzenesulfonate (0.77 g, 3.11 mmol) in acetonitrile (10 mL) at room temperature was added 1,4-trans-cyclohexane-diamine (0.711 g, 6.23 mmol). The light brown mixture was heated to 90 °C in a sealed steel bomb for 18 hr. The resulting mixture was cloudy light brown. LC/MS showed formation of desired product and side bis-alkylated product in a ratio about 2: 1. The reaction mixture was cooled to room temperature and ether was added. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to give a brown oil. The residue was dissolved with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ether (lx 10 mL) and DCM (4x 5 mL). LC/MS showed ether extract mainly contained bis-alkylated side product and little product, this was discarded. The DCM extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure to give 0.19 g of trans-Nl-(l- (trideuteromethoxy)propan-2-yl)cyclohexane-l,4-diamine as a brown oil. LC/MS showed this contained desired product (major) along with bis-alkylated side product and other impurity (with UV absorption). This was used in the next step without further purification. LCMS (m/z): 188.1 [M+H]+; Retention time = 0.17 min.

Synthesis of trans-Nl-(2-deutero-l-methoxypropan-2-vf)cvclohexane-1.4-diamine

H

Step 1: Preparation of 2-deutero-l-methoxypropan-2-ol

To l-methoxypropan-2-one (5.26 mL, 56.8 mmol) in MeOH-d4 (10 mL) and THF (50.00 mL) at 0 °C was added NaBD₄ (2.375 g, 56.8 mmol) portion wise. Vigorous off-gassing was seen. The reaction mixture was warmed to room temperature and stirred under argon for 5 hrs. The reaction mixture was worked up by pouring saturated aqueous NaHCC solution (10 mL) and stirred for 1 hr. The product was extracted with diethyl ether (100 mL), washed with brine, dried with sodium sulfate and concentrated under reduced pressure to give 3.53 g of colorless liquid. This was used in the next step without further purification.

Step 2: Preparation of 2-deutero-l-methoxypropan-2-yl 4-methylbenzenesulfonate

To NaH (1.549 g, 38.7 mmol) in THF (10 mL) was added 2-deutero-l-methoxypropan-2-ol (3.53 g, 38.7 mmol) in THF (10 mL) dropwise. The mixture was stirred at room temperature for 10 min to give a grey cloudy mixture. To this was added tosyl-Cl (7.39 g, 38.7 mmol) in one portion. The reaction mixture was stirred under argon at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 7.2 g of colorless oil. The crude mixture was purified by column chromatography [Si0₂, 120 g, EtOAc/heptane = 0/100 for 4 min, 30/70 until 12 min, then 50/50 until 20 min] providing 4.3 g of 2-deutero-l-methoxypropan-2-yl 4-methylbenzenesulfonate as a colorless oil. 1H NMR (400 MHz, chloroform-^/) δ ppm 1.27 (s, 3 H) 2.45 (s, 3 H) 3.25 (s, 3 H) 3.33 - 3.46 (m, 2 H) 7.34 (d, 2 H) 7.81 (d, 2 H).

Step 3: Preparation of trans-Nl-(2-deutero-l-methoxypropan-2-yl)cyclohexane-l,4- diamine

To 2-deutero- 1 -methoxypropan-2-yl 4-methylbenzenesulfonate (4.3g, 17.53 mmol) in acetonitrile (80 mL) at room temperature was added 1 ,4-trans-cyclohexane-diamine (4.00 g, 35.1 mmol). The light brown mixture was heated to 90 °C in a sealed steel bomb for 18 hr. The resulting mixture was cloudy light brown. LC/MS showed formation of desired product and side bis-alkylated product in a ratio of 2: 1. The reaction mixture was cooled to room temperature and ether was added. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to give a brown oil. To this was added ether (80 mL) and heptane (80 mL). A lot of precipitates formed which were removed by filtration. The filtrate was concentrated under reduced pressure to give 2.85 g of brown oil. The residue was dissolved with 20 mL of saturated aqueous sodium bicarbonate solution and extracted with ether (lx 40 mL) and DCM (4x 20 mL). LC/MS showed ether extract only contained bis-alkylated side product and little product. The DCM extracts were combined, dried with sodium sulfate and concentrated under reduced pressure to give 1.19 g of brown oil. LC/MS showed this contained desired product (major) along with bis-alkylated side product. This was used in the next step without further purification. LCMS (m/z): 188.1 [M+H]+; Retention time = 0.17 mm. 1H NMR (400 MHz, chloroform-i/) δ ppm 0.97 - 1.27 (m, 7 H) 1.81 - 2.03 (m, 4 H) 2.42 - 2.55 (m, 1 H) 2.59 - 2.71 (m, 1 H) 3.19 - 3.31 (m, 2H) 3.34 (s, 3 H).

Synthesis of trans-Nl-cvclopropyl-Nl-(2-methoxyethyl)cvclohexane-l,4-diamine

Step 1: Preparation of tert-butyl (trans-4-((2-methoxyethyl)amino)cyclohexyl)carbamate

To 2-methoxy ethyl 4-methylbenzenesulfonate (2.68 g, 11.64 mmol) in acetonitrile (50 mL) at room temperature was added N-Boc-trans-cyclohexane-l,4-diamine (4.99 g, 23.28 mmol). The off- white suspension was heated to 95 °C in a sealed glass bomb for 18 hr. The resulting mixture was light brown with white precipitate. LC/MS showed no starting materials with desired product and side product in a ratio of ~1 : 1. The reaction mixture was cooled to room

temperature and filtered. The filtrate was concentrated under reduced pressure to give 3 g of brown oil. The crude product was purified by column chromatography [silica gel, 40 g,

MeOH/DCM = 0/100 for 5 min, 5/95 for 5 min, then 1/9 for 30 min]. The pure fractions were combined and concentrated under reduced pressure to give 2.08 g of product as white foam. LC/MS showed the material was not very clean, but contains desired product as main component, showed no UV absorption. LCMS (m/z): 273.1 [M+H]+; Retention time = 0.45 min. 1H NMR showed as mono-tosylate salt. 1H NMR (400 MHz, methanol-i/4) δ ppm 1.17 - 1.51 (m, 13 H) 1.93 - 2.19 (m, 4 H) 2.37 (s, 3 H) 2.88 - 3.03 (m, 1 H) 3.10 - 3.17 (m, 2 H) 3.40(s, 3 H) 3.55 - 3.64 (m, 2 H) 7.16 - 7.27 (m, 2 H) 7.67 - 7.75 (m, 2 H).

Step 2: Preparation of tert-butyl (trans-4-(cyclopropyl(2-methoxyethyl)amino)- cyclohexyl)carbamate

BocHN

Similar to procedure as described in Gillaspy et ah, Tetrahedron Lett. 1995, 36, 7399-7402:

To tert-butyl (trans-4-((2-methoxyethyl)amino)cyclohexyl)carbamate (0.5 g, 1.836 mmol) in MeOH (10 mL) at room temperature was added acetic acid (1.051 mL, 18.36 mmol), 3 A molecular sieves (0.7 g, 1.836 mmol) (powder, dried at 150 °C in oven overnight) and (1- ethoxycyclopropoxy)trimethylsilane (1.600 mL, 9.18 mmol) sequentially. To the mixture was added sodium cyanoborohydride (0.461 g, 7.34 mmol). The reaction mixture was heated to 70 °C under argon for 16 hr. The reaction mixture was cooled and filtered through filter paper. The collected solids were washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to dryness. The residue was re-dissolved in 30 mL of 2N aqueous NaOH solution and extracted with EtOAc (3x 30 mL). The organic extracts were combined, washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give 0.34 g of while solid. This was used in the next step without further purification. LCMS (m/z): 313.1

[M+H]+; Retention time = 0.54 min.

Step 3: Preparation of trans-Nl-c clopropyl-Nl-(2-methoxyethyl)cyclohexane-l,4-diamine

To tert-butyl (trans-4-(cyclopropyl(2-methoxyethyl)amino)cyclohexyl)carbamate (0.33g, 1.056 mmol) in DCM (1 mL) was added trifluoroacetic acid (1 mL, 12.98 mmol). The homogeneous reaction mixture was stirred at room temperature for 2 hr. LC/MS showed complete conversion. Methanol was added to the reaction and the mixture was concentrated under reduced pressure to give a light brown oil. This was diluted with methanol (30 mL). To this was added PL-HC03 MR-Resin (1.87 mmol/g, 6 g) until the pH 8. The resin was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure to give 0.25 g of colorless oil. LCMS (m/z): 213.1 [M+H]+; Retention time = 0.19 min. This was used in the next step without further purification.

Synthesis of trans-4-(morpholinomethyl)cvclohexanamine

Step 1: Preparation of benzyl (trans-4-(morpholinomethyl)cyclohexyl)carbamate

To the solution of benzyl (trans-4-formylcyclohexyl)carbamate (525 mg, 2.0 mmol) and morpholine (0.175 mL, 2.0 mmol) in DCE (13 mL), was added sodium triacetoxhydroborate (596 mg, 2.81 mmol) and acetic acid (0.115 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white residue as benzyl (trans-4- (morpholinomethyl)cyclohexyl)carbamate (652 mg) without further purification. LCMS (m/z): 333.1 [M+H]+; Retention time = 0.55 min.

Step 2: Preparation of trans-4-(morpholinomethyl)cyclohexanamine

A mixture of benzyl (trans-4-(morpholinomethyl)cyclohexyl)carbamate (652 mg, 1.96 mmol) and 10% palladium on carbon (208 mg, 0.2 mmol) in a solution of EtOH (20 mL) and THF (5 mL) was stirred in a round bottom flask under hydrogen atmosphere at 25 °C for 16 hr. The reaction mixture was filtered through a pad of celite and washed with methanol (80 mL). All organic filtrate was concentrated under reduced pressure to give trans-4- (morpholinomethyl)cyclohexanamine (395 mg) as an oil, which was used without further purification. LCMS (m/z): 199.1 [M+H]+; Retention time = 0.13 min. Synthesis of Nl-((RV3.3.3-trifluoro-2-methoxypropyf)cvclohexane-trans-1.4-diamine

Step 1: Preparation of (R)-3-(benzyloxy)-l,1 -trifluoropropan-2-ol

(R)-(+)-3,3,3-Trifluoro-l,2-epoxypropane (700 μL·, 8.08 mmol) and benzyl alcohol (1.68 mL, 16.17 mmol) were dissolved in DCM (20 ml). Boron trifluoride diethyl etherate (102 μL·, 0.808 mmol) was added. The reaction mixture was stirred for about 16 hours at 60 °C in a sealed vessel. The reaction was judged to be complete by TLC (2: 1 heptanes: ethyl acetate). The reaction mixture was cooled to ambient temperature, diluted with DCM, and washed sequentially with saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography

(heptanes/ethyl acetate gradient) to give 998 mg of (R)-3-(benzyloxy)-l,l,l-trifluoropropan-2-ol as a colorless oil. Step 2: Preparation of (R)-((3,3,3-trifluoro-2-methoxypropoxy)methyl)benzene (R)-3-(benzyloxy)-l,l,l-trifluoropropan-2-ol (998 mg, 4.53 mmol) was dissolved in THF (20 ml) at ambient temperature. Sodium hydride (190 mg, 4.76 mmol) was added. The mixture was stirred for 10 minutes at ambient temperature and 20 minutes at 50 °C. Iodomethane (0.312 ml, 4.99 mmol) was added. The reaction vessel was sealed and stirred at 50 °C for about 16 hours. TLC (2: 1 heptanes: ethyl acetate) showed clean conversion to product. The cooled reaction was quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.05 g of crude (R)-((3,3,3-trifluoro-2- methoxypropoxy)methyl)benzene which was used without further purification.

Step 3: Preparation of (R)-3,3,3-trifluoro-2-methoxypropan-l-ol

(R)-((3,3,3-trifluoro-2-methoxypropoxy)methyl)benzene (1.05 g, 4.48 mmol) was dissolved in methanol (90 ml). Argon was bubbled through the solution for 5 minutes, and 20% palladium hydroxide on carbon (0.079 g, 0.112 mmol) was added. The flask was purged and flushed twice with hydrogen. The mixture was stirred for about 16 hours at ambient temperature under a hydrogen balloon. The mixture was filtered through a pad of celite. The filter cake was rinsed with additional methanol. The filtrate was concentrated at ambient temperature to give 495 mg of (R)-3,3,3-trifluoro-2-methoxypropan-l-ol as a colorless oil. This was used in the next step without further purification.

Step 4: Preparation of (R)-3,3,3-trifluoro-2-methoxypropyl 4-methylbenzenesulfonate

Sodium hydride (412 mg, 10.31 mmol) was added to a solution of (R)-3,3,3-trifluoro-2- methoxypropan-l-ol (495 mg, 3.44 mmol) in THF (10 ml) at ambient temperature. The mixture was stirred for 30 minutes. P-Toluenesulfonyl chloride (1965 mg, 10.31 mmol) was added. The white cloudy solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash chromatography (heptanes : EtOAc gradient) to give 0.51 g of (R)-3,3,3-trifluoro-2-methoxypropyl 4-methylbenzenesulfonate as a colorless crystalline solid. LCMS (m/z): 298.9 [M+H]+; Retention time = 1.01 min. Step 5: Preparation of Nl-((R)-3,3,3-trifluoro-2-methoxypropyl)cyclohexane-trans-l,4- diamine

(R)-3,3,3-trifluoro-2-methoxypropyl 4-methylbenzenesulfonate (510 mg, 1.71 mmol) and trans- 1,4-diaminocyclohexane (586 mg, 5.13 mmol) were suspended in DMSO (4 ml). The reaction mixture was stirred at 100 °C for 3 hours. The cooled reaction mixture was diluted with water (40 mL) and extracted with DCM. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 400 mg of crude N1-((R)- 3,3,3-trifluoro-2-methoxypropyl)cyclohexane-trans-l,4-diamine which was used without further purification. LCMS (m/z): 241.1 [M+H]+; Retention time = 0.33 min. 1H NMR (400 MHz, chloroform-d) δ ppm 0.93 - 1.20 (m, 4 H) 1.83 (br. s., 4 H) 2.25 - 2.41 (m, 2 H) 2.65 - 2.85 (m, 4 H) 3.52 (s, 3 H) 3.54 - 3.66 (m, 2 H).

Synthesis of 3-((trans-4-aminocvclohexynamino l.l.l-trifluoro-2-methylpropan-2-ol (racemic mixture)

Step 1: Preparation of trans-tert-butyl-4-aminocycl oh exyl carbamate

To a stirred solution of trans-cyclohexane-l,4-diamine (40.0 g, 350 mmol) in CHCI₃ (400 mL) at 0 °C was added di-tert-butyl dicarbonate (40.6 mL, 175 mmol), in one portion. The reaction mixture was allowed to warm to room temperature and stirred for -72 hrs. The solvent was removed under reduced pressure and water (150 mL) was added. The product was filtered off. Toluene was added and the water was evaporated off until material precipitated, which was filtered off. Further evaporation yielded more precipitate which was collected by filtration. The combined precipitates were stirred in ether (250 mL) and filtered, providing trans-tert-butyl-4- aminocyclohexylcarbamate (34.2 g, 160 mmol). 1H NMR (400 MHz, chloroform-d) δ ppm 1.10 - 1.34 (m, 4 H) 1.43 (s, 9 H) 1.79 - 2.03 (m, 4 H) 3.17 - 3.30 (m, 2 H). Step 2: Preparation of trans-tert-butyl-4-(dibenzylamino)cyclohexylcarbamate

To trans-tert-butyl-4-aminocyclohexylcarbamate (6 g, 28.0 mmol) in acetonitrile (40 mL) was added benzyl bromide (7.33 mL, 61.6 mmol) and potassium carbonate (15.48 g, 112 mmol). The mixture was heated at 80 °C for -20 hrs. The mixture was allowed to cool to room temperature and water (-100 mL) was added. The precipitate was filtered off and washed with water, dried under educed pressure providing crude trans-tert-butyl-4-(dibenzylamino)cyclohexylcarbamate as a white solid, which was directly used in the next step without further purification. LCMS (m/z): 395.0 [M+H]+; Retention time = 0.81 min.

Step 3: Preparation of trans-Nl,Nl-dibenzylcyclohexane-l,4-diamine

Crude trans-tert-butyl-4-(dibenzylamino)cyclohexylcarbamate (-28 mmol) was suspended in MeOH (10 mL). 4M HC1 (60 mL; solution in dioxane) was added and the mixture was stirred -lhr. Additional 4M HC1 (10 mL) were added and stirring was continued for 30 min. The mixture was concentrated under reduced pressure. The residue was suspended in diethylether, filtered off and washed with diethylether to give trans-Nl,Nl-dibenzylcyclohexane-l,4-diamine as its HCl-salt. LCMS (m/z): 295.1 [M+H]+; Retention time = 0.48 min. The HCl-salt was suspended in DCM and basified with potassium carbonate. The aqueous mixture was extracted with DCM (3x) and ethyl acetate (2x). The organic mixtures were (seperately) washed with saturated NaHCC solution and brine, filtered through celite. The organic solutions were combined and concentrated under reduced pressure providing trans-Nl,Nl-dibenzylcyclohexane- 1,4-diamine (2.46 g), which was directly used in the next step without further purification.

Step 4: Preparation of N-(trans-4-(dibenzylamino)cyclohexyl)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamide

To a solution of 2-hydroxy-2-(trifloromethyl)propionic acid (0.846 g, 5.35 mmol), HOBT (0.819 g, 5.35 mmol), and diisopropylethylamine (1.112 mL, 6.37 mmol) in DCM (45 rriL) was added trans-Nl,Nl-dibenzylcyclohexane-l,4-diamine (1.5 g, 5.09 mmol) and EDC (1.025 g, 5.35 mmol). The reaction solution was stirred at 25 °C for 5 hr. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution. It was diluted with dichloromethane (100 mL) and stirred vigorously for 15 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 40 g, EtO Ac/heptane = 0/100 to 60/40] providing N-(trans-4- (dibenzylamino)cyclohexyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (497 mg). LCMS (m/z): 435.2 [M+H]+; Retention time = 0.66 min. Step 5: Preparation of 3-((trans-4-(dibenzylamino)cyclohexyl)amino)-l,1 -trifluoro-2- methylpropan-2-ol

To a solution of N-(trans-4-(dibenzylamino)cyclohexyl)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamide (322 mg, 0.741 mmol) in THF (6 mL) was added 1M borane

tetrahydrofuran complex (7 mL, 7 mmol). The reaction mixture was stirred at 55 °C for 3 hr, but was not complete. The solution was quenched with saturated aqueous sodium bicarbonate solution and stirred vigorously overnight. It was diluted with ethyl acetate (60 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2x) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was filtered by column chromatography [silica gel, 24 g, ethyl acetate/dichloromethane = 0/100 to 35/65] providing product 3 -((trans-4-(dibenzylamino)cyclohexyl)amino)- 1,1,1 -trifluoro-2- methylpropan-2-ol (84 mg, 80% pure) with impurity N-(trans-4-(dibenzylamino)cyclohexyl)- 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg). LCMS (m/z): 421.1 [M+H]+;

Retention time = 0.53 min for the product. LCMS (m/z): 421.1 [M+H]+; Retention time = 0.69 min for the impurity. Step 6: Preparation of 3-((trans-4-aminocyclohexyl)amino)-l,1 -trifluoro-2- methylpropan-2-ol (racemic mixture)

A mixture of 50/50 3-((trans-4-(dibenzylamino)cyclohexyl)amino)-l,l,l-trifluoro-2- methylpropan-2-ol and N-(trans-4-(dibenzylamino)cyclohexyl)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamide (314 mg), and 20% by weight palladium hydroxide on carbon (115 mg, 0.164 mmol) in ethanol (7 mL) was stirred in a steel bomb under hydrogen atmosphere (60 psi) at 25 °C for 18 hr. The reaction mixture was filtered through a pad of celites and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure providing crude product mixture of 3 -((trans-4-aminocy clohexy l)amino)- 1,1,1 -trifluoro-2-methylpropan-2-ol as a solid, which was directly used in the next step without further purification. LCMS (m/z): 241.1 [M+H]+; Retention time = 0.16 min. Purity -50%. Synthesis of (S)-4-(3-methoxypyrrolidin-l-yl)cvclohexanamine

Step 1: Preparation of (S)-benzyl (4-(3-methoxypyrrolidin-l-yl)cyclohexyl)carbamate

To the solution of benzyl (4-oxocyclohexyl)carbamate (1.5 g, 6.07 mmol) and (S)-3- methoxypyrrolidine (0.876 g, 6.37 mmol) in DCE (30 mL) was added sodium

triacetoxhydroborate (1.8 g, 8.5 mmol). The reaction mixture was stirred at room temperature for 18 hr and became a brown solution. The reaction solution was diluted with ethyl acetate and sodium bicarbonate solution. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a beige color residue as (S)-benzyl (4- (3-methoxypyrrolidin-l-yl)cyclohexyl)carbamate (1.99 g) without further purification. LCMS (m/z): 333.2 [M+H]+; Retention time = 0.55 min.

Step 2: Preparation of (S)-4-(3-methoxypyrrolidin-l-yl)cyclohexanamine

A mixture of (S)-benzyl (4-(3-methoxypyrrolidin-l-yl)cyclohexyl)carbamate (1.99 g, 5.69 mmo and 10% palladium on carbon (1.21 g, 1.14 mmol) in EtOH (40 mL) was stirred in a round bottom flask under hydrogen atmosphere at 25 °C for 16 hr. The reaction mixture was filtered through a pad of celite and washed with methanol (300 mL). All organic filtrate was

concentrated under reduced pressure to give (S)-4-(3-methoxypyrrolidin-l-yl)cyclohexanamine (1.12 g) as a brown oil without further purification. LCMS (m/z): 199.1 [M+H]+_; time = 0.18 min.

Example 1 : Compound 1

3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)benzamide

Step 1. Preparation of trans-Nl-(5-chloro-4-iodopyridin-2-yl)cyclohexane-l,4-diamine:

To 5-chloro-2-fluoro-4-iodopyridine (1000 mg, 3.88 mmol) was added DMSO (7 ml) and last trans-cyclohexane-l,4-diamine (2661 mg, 23.31 mmol). The reaction was stirred at 85 °C for 2 hours followed by LCMS. To the crude reaction mixture was added 5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 1.17 grams of the title compound as a TFA salt was obtained. LCMS (m/z): 352.1 (MH+), rt = 0.50 mm. Step 2. Preparation of 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)benzamide: To trans-Nl-(5-chloro-4-iodopyridin-2-yl)cyclohexane-l,4-diamine (18 mg, 0.051 mmol) was added 3-carbamoylphenylboronic acid (21.11 mg, 0.128 mmol), PdC12(dppf).CH2C12 adduct (8.36 mg, 10.24 μιηοΐ), DME (0.5 ml) and last 2M Sodium carbonate (0.154 ml, 0.307 mmol). The reaction was stirred at 105 °C for 2 hr or until done by LCMS. The reaction was cooled, 2.5 ml of ethyl acetate and 0.5 ml of methanol was added, and the mixture was stirred, filtered and concentrated to crude solid. The solid was dissolved in DMF, refiltered and purified by prep LC.

After lyophilization, 10.9 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 345.2 (MH+), rt = 0.40 mm. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.35 - 1.69 (m, 4 H) 2.02 - 2.29 (m, 4 H) 3.15 (ddd, J=11.28, 7.62, 3.96 Hz, 1 H) 3.71 (tt, J=11.10, 3.70 Hz, 1 H) 6.74 (s, 1 H) 7.55 - 7.64 (m, 1 H) 7.64 - 7.73 (m, 1 H) 7.94 - 8.02 (m, 2 H) 8.06 (s, 1 H) Example 2: Compound 5

3-(2-(trans-4-aminocyclohexylamino)-5-chloropyrimidin-4-yl)benzamide

Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)benzamide:

To 2,4,5-trichloropyrimidine (44.0 mg, 0.240 mmol) was added 3-carbamoyl phenylboronic acid (36 mg, 0.218 mmol), PdC12(dppf).CH₂Cl₂ adduct (17.82 mg, 0.022 mmol), DME (0.75 ml) and last 2M sodium carbonate (0.240 ml, 0.480 mmol). The reaction was stirred at 80 °C for 2 hr. The reaction was cooled, 2.5 ml of ethyl acetate was added, stirred, filtered and concentrated to crude solid. The solid was dissolved in DMF refiltered and purified by prep LC. After lyophilization, 31 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 268.0 (MH+), rt = 0.66 mm. Step 2. 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyrimidin-4-yl)benzamide:

To 3-(2,5-dichloropyrimidin-4-yl)benzamide (15 mg, 0.056 mmol) add DMSO (0.4 ml) and then trans-cyclohexane-l,4-diamine (51.1 mg, 0.448 mmol). The reaction was capped and heated at 100 °C for 18 hr. The crude reaction was let cool and added 0.4ml of DMSO, filtered and purified by prep LC. After lyophilization, 14.6 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 346.2 (MH+), rt = 0.49 mm. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.33 - 1.65 (m, 4 H) 2.00 - 2.28 (m, 4 H) 3.12 (td, J=l 1.06, 3.37 Hz, 1 H) 3.83 (t, J=10.70 Hz, 1 H) 7.59 (t, J=7.77 Hz, 1 H) 7.98 (t, J=6.89 Hz, 2 H) 8.27 - 8.38 (m, 2 H)

Example 3: Compound 11

trans-Nl-(5-chloro-4-(3-(3-fluorobenzylamino)phenyl)pyridin-2-yl)cyclohexane-l,4-diamine

Step 1. Preparation of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate:

To 5-chloro-2-fluoro-4-iodopyridine (175 mg, 0.680 mmol) was added 3-(tert- butoxycarbonylamino)phenylboronic acid (322 mg, 1.360 mmol), PdC12(dppf).CH2C12 adduct (55.5 mg, 0.068 mmol), DME (2.8 ml) and last 2M sodium carbonate (1.360 ml, 2.72 mmol). The reaction was stirred at 100 °C for 2 hr. The reaction was let cool, added 5ml of ethyl acetate, 1 ml of methanol, filtered and concentrated. The crude material was purified by silica gel chromatography using 12g column and eluting with 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 188 mg of the titled compound as free base used without further purification. LCMS (m/z): 323.1 (MH+), rt = 1.14 min.

Step 2. Preparation of 3-(5-chloro-2-fluoropyridin-4-yl)-N-(3-fluorobenzyl)aniline:

To dry DMF (0.7 ml) add NaH (7.36 mg, 0.307 mmol), cool to 0 °C then add a solution of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (90 mg, 0.279 mmol) in DMF (0.7 ml). Stir at 0 °C for 25 minutes. Then at 0 °C with stirring add l-(bromomethyl)-3- fluorobenzene (52.7 mg, 0.279 mmol) and let warm to room temperature for 2 hr. The reaction was followed by LCMS. To the crude reaction was added 120 ml of ethyl acetate washed with, saturated sodium bicarbonate, water (2x), saturated salt solution, dried with sodium sulfate, filtered and concentrate the solvent off to give about 115 mg crude material used as is. To the crude material was added HCl 4M in Dioxane (4 ml, 16.00 mmol) and stirring for 90 minutes. The reaction was concentrated to constant mass, giving 115 mg of the titled compound as HCl salt used with out further purification. LCMS (m/z): 331.2 (MH+), rt = 1.15 min.

Step 3. Preparation of trans-Nl-(5-chloro-4-(3-(3-fluorobenzylamino)phenyl)pyridin-2- yl)cy clohexane- 1 ,4-diamine: To 3-(5-chloro-2-fluoropyridin-4-yl)-N-(3-fluorobenzyl)aniline (75 mg, 0.227 mmol) add DMSO (1.0 ml), TEA (0.063 ml, 0.454 mmol) and trans-cyclohexane-l,4-diamine (69.0 mg, 0.302 mmol) and TEA (0.063 ml, 0.454 mmol). The reaction was heated at 105 °C for 20 hr. The reaction was let cool 1.0 ml of DMSO was added, filtered and purify by prep LC. After lyophilization 17.8 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 425.2 (MH+), rt = 0.70 mm. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.18 - 1.56 (m, 4 H) 2.04 (t, J=14.80 Hz, 4 H) 2.94 - 3.12 (m, 1 H) 3.46 - 3.63 (m, 1 H) 4.28 (s, 2 H) 6.51 - 6.60 (m, 3 H) 6.60 - 6.69 (m, 1 H) 6.84 (td, J=8.50, 2.34 Hz, 1 H) 6.99 (d, J=9.96 Hz, 1 H) 7.04 - 7.15 (m, 2 H) 7.16 - 7.28 (m, 1 H) 7.86 (s, 1 H)

Example 4: Compound 12

N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(3-(3-fluorobenzylamino)phenyl)pyridin-2- amine

Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(3-(3-fluorobenzylamino) phenyl)pyridin-2-amine

To 3-(5-chloro-2-fluoropyridin-4-yl)-N-(3-fluorobenzyl)aniline, (Example 3 step 2), (20 mg, 0.060 mmol) add DMSO (0.4 ml), TEA (0.017 ml, 0.121 mmol) and tert-butyl (trans-4- aminocyclohexyl)methylcarbamate (69.0 mg, 0.302 mmol) flush with argon and heat at 100 °C for 20 hr. The crude material was concentrated under vacuum to remove excess amine. Then to the crude reaction mixture was added HCl 4M in Dioxane (1.0 mL, 4.00 mmol) and stirred at room temperature 90 minutes. The reaction was concentrated then dissolved in 0.75 ml of DMSO with 0.075 ml of water, filtered and purify by prep LC. After lyophilization, 11.4 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 439.3 (MH+), rt = 0.71 min. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.13 - 1.49 (m, 4 H) 1.57 - 1.77 (m, 1 H) 1.87 - 2.01 (m, 2 H) 2.06 - 2.21 (m, 2 H) 2.83 (d, J=7.03 Hz, 2 H) 3.50 - 3.66 (m, 1 H) 4.38 (s, 2 H) 6.60 - 6.71 (m, 2 H) 6.70 - 6.81 (m, 2 H) 6.87 - 7.00 (m, 1 H) 7.09 (d, J=9.96 Hz, 1 H) 7.14 - 7.25 (m, 2 H) 7.25 - 7.37 (m, 1 H) 7.94 (s, 1 H)

Example 5: Compound 22

N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(3-(3-chlorobenzyloxy)phenyl)pyridin-2- amine:

Step 1. Preparation of 3-(5-chloro-2-fluoropyridin-4-yl)phenol:

To 5-chloro-2-fluoro-4-iodopyridine (516 mg, 2.004 mmol) add 3- hydroxyphenylboronic acid (498 mg, 3.61 mmol), PdC12(dppf).CH2C12 adduct (164 mg, 0.200 mmol), DME (12.5 ml), Ethanol (1.5 ml) and last add 2M sodium carbonate (3.51 ml, 7.02 mmol). The reaction was stirred at 100 °C for 2 hr and followed by LCMS. The reaction was cooled, 200 ml of ethyl acetate was added, and washed with saturated sodium bicarbonate, water, saturated salt solution, dried sodium sulfate, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 40g column eluting with 0%-35% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 425 mg of the titled compound as free base used without further purification. LCMS (m/z): 224.1 (MH+), rt = 0.85 min. Step 2. Preparation of 5-chloro-4-(3-(3-chlorobenzyloxy)phenyl)-2-fluoropyridine

To the 3-(5-chloro-2-fluoropyridin-4-yl)phenol (80 mg, 0.358 mmol) add (3- chlorophenyl)methanol (102 mg, 0.715 mmol), THF (0.6 ml), triphenylphosphine (188 mg, 0.715 mmol) stir to dissolve and then lastly add DEAD (0.113 ml, 0.715 mmol). The reaction gives off heat. The reaction was stirred at room temperature for 1 hr and follow by LCMS. The reaction was concentrated to crude product. The crude was purified by silica gel chromatography using 12g column eluting with 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 95mg of the titled compound as free base used without further purification. LCMS (m/z): 348.1 (MH+), rt = 1.31 min.

Step 3. Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(3-(3- chlorobenzyloxy)phenyl)pyridin-2-amine:

To 5-chloro-4-(3-(3-chlorobenzyloxy)phenyl)-2-fluoropyridine (27 mg, 0.080 mmol) add DMSO (0.8 ml), TEA (0.022 ml, 0.159 mmol) and tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (36.4 mg, 0.159 mmol) flush with argon and heat at 100-105 °C for 40 hr. The crude material was concentrated under vacuum to remove excess amine. Then to the crude reaction mixture was added HC1 4M in Dioxane (1.5 ml, 6.00 mmol) and stirred at room temperature for 90 minutes. The reaction was concentrated then dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purify by prep LC. After lyophilization, 21.8 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 456.3 (MH+), rt = 0.82 mm. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.12 - 1.48 (m, 4 H) 1.57 - 1.77 (m, 1 H) 1.92 (d, J=12.31 Hz, 2 H) 2.15 (d, J=10.55 Hz, 2 H) 2.83 (d, J=7.03 Hz, 2 H) 3.55 - 3.71 (m, 1 H) 5.14 (s, 2 H) 6.72 (s, 1 H) 7.00 - 7.17 (m, 3 H) 7.28 - 7.45 (m, 4 H) 7.47 (s, 1 H) 7.99 (s, 1 H)

Example 6: Compound 26

trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cy clohexane- 1 ,4-diamine

Step 1. Preparation of 4-(3-bromophenyl)-5-chloro-2-fluoropyridine:

To 1,3-dibromobenzene (807 mg, 3.42 mmol) was added 5-chloro-2-fluoropyridin-4- ylboromc acid (300 mg, 1.711 mmol), PdC12(dppf).CH2C12 adduct (140 mg, 0.171 mmol), DME (7 ml) and then last 2M sodium carbonate (2.57 ml, 5.13 mmol). The reaction was stirred at 85-90 °C for 2 hr. The reaction was followed by LCMS. The reaction was cooled, 20 ml of ethyl acetate was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 40g column eluting with 0-15% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 252 mg of the titled compound as free base used without further purification. In addition 12 mg was further purified by prep LC and lyophilized to give 3.1 mg of title compound as TFA salt. LCMS (m/z): 286.1/288.0 (MH+), rt = 1.17 min.

Step 2. Preparation of trans-Nl-(4-(3-bromophenyl)-5-chloropyridin-2-yl)cyclohexane-l,4- diamine:

To 4-(3-bromophenyl)-5-chloro-2-fluoropyridine (240 mg, 0.838 mmol) was added trans-cyclohexane-l,4-diamine (765 mg, 6.70 mmol), DMSO (2.5 ml) and last TEA (0.140 ml, 1.005 mmol). The reaction was stirred at 100 °C for 18 hr and followed by LCMS.

The crude reaction was let cool, added 1.0 ml of DMSO, filtered, purified by prep LC. The product was free based by concentrating some of ACN off, adding 250 ml of ethyl acetate, 40 ml of saturated sodium bicarbonate, shake well and extracted. The basic water was extracted again with 120 ml of ethyl acetate. Combine organic layers were washed 3 x 25 ml of water, filter and concentrated to a constant mass to giving 268 mg of the title compound as freebase. LCMS (m/z): 380.1/382.1 (MH+), rt = 0.64 mm. Step 3. Preparation of trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-yl)cyclohexane-l,4-diamine:

To Pd(OAc)₂ (2.359 mg, 10.51 μηιοΐ) was added BINAP (8.18 mg, 0.013 mmol), trans- Nl-(4-(3-bromophenyl)-5-chloropyridin-2-yl)cyclohexane-l,4-diamine (20 mg, 0.053 mmol), and Dioxane (0.5 ml) the reaction was stirred for 5 minutes at room temperature. Then to the crude mixture was added (tetrahydro-2H-pyran-4-yl)methanamine (36.3 mg, 0.315 mmol) and stirred for 3-5 minutes and then was added potassium tert-butoxide (23.58 mg, 0.210 mmol). The reaction was stirred at 95 °C for 45 minutes and followed by LCMS. The crude reaction was cooled. Then to the crude reaction was added 3 ml of ethyl acetate, filtered, concentrated most of solvent off, dissolved with 1.0ml of DMSO and purified by prep LC. After lyophilization, 11.7 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 415.2 (MH+), rt = 0.53 min. In addition for NMR the title compound was free based by adding ethyl acetate washing with saturated sodium bicarbonate, water (3x), saturated salt solution, dried sodium sulfate, filtered and concentrate to constant mass. The sample was lyophilized from 1 : 1 ACN/water. The NMR was run on the Free Base. 1H NMR (300 MHz, METHANOW4, 25 °C) 1.19 - 1.44 (m, 6 H) 1.74 (d, J=12.89 Hz, 2 H) 1.82 - 1.91 (m, 1 H) 1.95 (d, 2 H) 2.08 (d, J=9.96 Hz, 2 H) 2.66 - 2.81 (m, 1 H) 3.01 (d, J=6.74 Hz, 2 H) 3.40 (td, J=11.72, 1.76 Hz, 2 H) 3.55 - 3.70 (m, 1 H) 3.95 (dd, J=11.14, 3.52 Hz, 2 H) 6.44 (s, 1 H) 6.57 - 6.70 (m, 3 H) 7.15 (t, J=7.77 Hz, 1 H) 7.92 (s, 1

H)

Example 7: Compound 48

N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(4-chloro-3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-amine

Step 1 : Preparation Intermediate tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)- phenylcarbamate

To a mixture of 5-chloro-2-fluoro-4-iodopyridine (210 mg, 0.816 mmol), 3-(tert- butoxycarbonylamino)-4-chlorophenylboronic acid (310 mg, 1.142 mmol), PdCl₂(dppf).CH2Ci2 adduct (66.6 mg, 0.082 mmol) in DME (3.6 mL) was added 2M Na₂C0₃ (1.2 mL). The resulting mixture was heated in a sealed tube under argon for about 2 hours at about 100 °C. The mixture was cooled to room temperature, and diluted with EtOAc (10 mL) and MeOH (5 mL), filtered and concentrated in vacuo. The residue was purified by column chromatography [Si0₂, 12g, EtO Ac/heptane = 0/100 to 15/85]. Pure fractions were combined and concentrated in vacuo to yield 243 mg of the title compound (tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4- yl)phenylcarbamate) as a white solid.

LCMS (m/z): 357.1 (MH+), Rt = 1.25 minutes. Step 2: Preparation of 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4- yl)methyl)aniline:

To dry DMF (0.7 ml) was added NaH (8.62 mg, 0.216 mmol), cool to 0 °C then added a solution of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (70 mg, 0.196 mmol) in DMF (0.7 ml). The reaction was stirred at 0 °C for 25 minutes. Then at 0 °C with stirring was added (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (53.0 mg, 0.196 mmol) and let warm to room temperature and stirred at 40 °C for 40 hr, followed by LCMS. To the crude reaction was added 90 ml of ethyl acetate washed with, 5% NaOH solution, water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate to crude solid. The crude was purified by silica gel chromatography using 12g column eluting with 0%-20% ethyl acetate with heptane. Concentrate to constant mass, giving 46 mg of crude intermediate with BOC on. The BOC was removed by adding HC1 4M in Dioxane (5 ml, 20.00 mmol) and stirring for 1 hour at room temperature. The solvent was removed under vacuum to a constant mass, to give 46 mg of product as HCL salt used with out further purification In addition 5 mg was further by prep LC, and lyophilized to TFA salt. LCMS (m/z): 355.0 (MH+), Rt = 1.16 minutes.

Step 3: Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(4-chloro-3- ((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-amine:

To 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4- yl)methyl)aniline (12 mg, 0.034 mmol) was added DMSO (0.4 ml), tert-butyl (trans-4- aminocyclohexyl)methylcarbamate (61.7 mg, 0.270 mmol) and TEA (9.42 μΐ, 0.068 mmol). The reaction was stirred at 100-105 °C for 20 hr and followed by LCMS. The BOC group was removed by adding HC1 6M aq (120 μΐ, 0.720 mmol) and heated at 90 °C for 45 minutes. The reaction was followed by LCMS. The crude material was cooled, added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 10.9 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 463.3 (MH+), rt = 0.72 min.

1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.12 - 1.51 (m, 6 H) 1.61 - 1.80 (m, 3 H) 1.84 - 2.04 (m, 3 H) 2.16 (d, J=10.55 Hz, 2 H) 2.84 (d, J=7.03 Hz, 2 H) 3.14 (d, J=6.74 Hz, 2 H) 3.34 - 3.46 (m, 2 H) 3.56 - 3.70 (m, J=l 1.03, 11.03, 3.74, 3.52 Hz, 1 H) 3.96 (dd, J=l 1.14, 3.22 Hz, 2 H) 6.66 (dd, J=8.20, 2.05 Hz, 1 H) 6.76 (d, J=1.76 Hz, 1 H) 6.79 (s, 1 H) 7.34 (d, J=8.20 Hz, 1 H) 8.01 (s, 1 H) Example 8: Compound 45

N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(4-fluoro-3-(3- fluorobenzylamino)phenyl)pyridin-2-amine

Step 1. Preparation of 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluoroaniline:

To 5-chloro-2-fluoro-4-iodopyridine (210 mg, 0.816 mmol) was added 2-fluoro-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (271 mg, 1.142 mmol),

PdC12(dppf).CH2C12 adduct (66.6 mg, 0.082 mmol), DME (3.6 ml) and then last 2M sodium carbonate (1.224 ml, 2.447 mmol). The reaction was stirred at 100 °C for 2 hr and followed by LCMS. The reaction was cooled, 8 ml of ethyl acetate and 4 ml of methanol was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 12g column eluting with 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 191 mg of the titled compound as free base used without further purification. LCMS (m/z): 241.1 (MH+), rt = 0.85 min.

Step 2. Preparation of tert-butyl 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluorophenylcarbamate:

To dry DMF (1.5 ml) add NaH (34.0 mg, 0.850 mmol), cool to 0 °C then add a solution of 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluoroaniline (186 mg, 0.773 mmol) in DMF (1.5 ml). The mixture was stirred at 0 °C for 25 minutes. Then at 0 °C with stirring add di-tert-butyl di carbonate (0.179 ml, 0.773 mmol) and let warm to room temperature for 20 hours. The reaction was followed by LCMS. More di-tert-butyl dicarbonate (0.179 ml, 0.773 mmol) was added and continue at 50 °C for an additional 24 hr. To the crude material add 120 ml of ethyl acetate wash with, saturated sodium bicarbonate, water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate the solvent off, to give crude solid. The crude product was purified additionally by prep LC. The product was free based by adding 200 ml of ethyl acetate washed with saturated sodium bicarbonate, water (3x), saturated salt solution, and dry sodium sulfate, filtered and concentrated to a constant mass, giving 36 mg of product. LCMS (m/z): 341.0 (MH+), rt = 1.14 mm.

Step 3. Preparation of 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluoro-N-(3-fluorobenzyl)aniline:

To dry DMF (0.6 ml) add NaH (4.39 mg, 0.110 mmol), cool to 0 °C then add a solution of tert-butyl 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluorophenylcarbamate (34 mg, 0.100 mmol) in DMF (0.6 ml). The mixture was stirred at 0 °C for 25 minutes. Then at 0 °C with stirring add 1- (bromomethyl)-3 -fluorobenzene (18.86 mg, 0.100 mmol) and let warm to room temperature for 3 hr. The reaction was followed by LCMS. To the crude material add 100 ml of ethyl acetate wash with, sat. sodium bicarbonate, water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate to constant mass to give about 40 mg crude intermediate with BOC on. The BOC was removed by adding HC1 4M in Dioxane (4 ml, 16.00 mmol) and stirring for 90 minutes. The crude was concentrated to solid and used as is giving 38 mg of the titled compound as HC1 salt, used without further purification. LCMS (m/z): 349.1 (MH+), rt = 1.17 min.

Step 4. Preparation of N-(trans-4-(aminomethyl)cyclohexyl)-5-chloro-4-(4-fluoro-3-(3- fluorobenzylamino)phenyl)pyridin-2-amine:

To 5-(5-chloro-2-fluoropyridin-4-yl)-2-fluoro-N-(3-fluorobenzyl)aniline (16 mg, 0.046 mmol) add DMSO (0.4 ml), tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (52.4 mg, 0.229 mmol) and TEA (12.79 μΐ, 0.092 mmol). The reaction was stirred at 100 °C for 40 hr. The reaction was followed by LCMS. The BOC was removed by adding HCL 6M aq (140 μΐ, 0.840 mmol) and heated at 90 °C for 45 minutes and followed by LCMS. The crude reaction was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 11.4 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 457.3 (MH+), rt = 0.74 min 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.12 - 1.48 (m, 4 H) 1.67 (ddd, J=10.84, 7.33, 3.81 Hz, 1 H) 1.93 (d, J=12.01 Hz, 2 H) 2.12 (d, J=9.96 Hz, 2 H) 2.83 (d, J=6.74 Hz, 2 H) 3.49 - 3.66 (m, 1 H) 4.44 (s, 2 H) 6.59 - 6.71 (m, 3 H) 6.94 (t, J=7.47 Hz, 1 H) 7.05 - 7.21 (m, 3 H) 7.26 - 7.36 (m, 1 H) 7.91 (s, 1 H) Example 9: Compound 50

trans-Nl-(5-chloro-4-(3-(3-fluorobenzylamino)-4-methylphenyl)pyridin-2-yl)cyclohexane-l,4- diamine

Step 1. Preparation of tert-butyl 5-bromo-2-methylphenylcarbamate:

To dry DMF (5 ml) add NaH (132 mg, 3.30 mmol), cool to 0 °C then add a solution of 5-bromo-2-methylaniline (558 mg, 3.00 mmol) in DMF (5 ml). Stir at 0 °C for 25 minutes. Then at 0 °C with stirring add di -tert-butyl di carbonate (0.696 ml, 3.00 mmol) and let warm to room temperature and then stir at 40 °C for 22 hr. The reaction was followed by LCMS. To the crude reaction add 200 ml of ethyl acetate, wash with 5% NaOH soln (filter solid impurities off), water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate to crude solid. The crude was purified by silica gel chromatography using 40g column eluting with 0%-15% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 320 mg of the titled compound as free base used without further purification. LCMS (m/z): 230.1/232.1

(MH+) (loss of BOC t-butyl), rt = 1.12 mm. 1H NMR (300 MHz, DMSO-i/6, 25 °C) δ ppm 1.45 (s, 9 H) 2.14 (s, 3 H) 7.07 - 7.14 (m, 1 H) 7.14 - 7.22 (m, 1 H) 7.58 (d, J=1.47 Hz, 1 H) 8.65 (s, 1 H) Step 2. Preparation of tert-butyl 5-(5-chloro-2-fluoropyridin-4-yl)-2-methylphenylcarbamate:

To tert-butyl 5-bromo-2-methylphenylcarbamate (200 mg, 0.699 mmol) was added 5- chloro-2-fluoropyridin-4-ylboronic acid (306 mg, 1.747 mmol), PdC12(dppf).CH2C12 adduct

(57.1 mg, 0.070 mmol), DME (3 ml) and last 2M sodium carbonate (1.048 ml, 2.097 mmol).

The reaction was stirred at 105 °C for 2 hr and followed by LCMS. The reaction was cooled, 8 ml of ethyl acetate and 4 ml of methanol was added, filtered and concentrated to crude product.

The crude was purified by silica gel chromatography using 40g column eluting with 0%-15% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 124 mg of the titled compound as free base used without further purification. LCMS (m/z): 337.0 (MH+), rt = 1.14 mm. Step 3. Preparation of 5-(5-chloro-2-fluoropyridin-4-yl)-N-(3-fluorobenzyl)-2-methylaniline:

To dry DMF (1 ml) add NaH (9.14 mg, 0.229 mmol), cool to 0 °C then add a solution of tert-butyl 5-(5-chloro-2-fluoropyridin-4-yl)-2-methylphenylcarbamate (70 mg, 0.208 mmol) in DMF (1 ml). Stir at 0 °C for 25 minutes. Then at 0 °C with stirring add l-(bromomethyl)-3- fluorobenzene (39.3 mg, 0.208 mmol) and let warm to room temperature for 3 hr. The reaction was followed by LCMS. To the crude reaction add 100 ml of ethyl acetate, washed with saturated sodium bicarbonate, water (2x), saturated salt solution, dry sodium sulfate, filter and concentrated the solvent off to give crude intermediate with BOC on. The BOC was removed by adding HC1 4M in Dioxane (4 ml, 16.00 mmol) and stirring for 90 minutes. The crude was concentrate to constant mass, giving 78 mg of the titled compound as HC1 salt, used without further purification. LCMS (m/z): 345.0 (MH+), rt = 1.20 min.

Step 4. Preparation of trans-Nl-(5-chloro-4-(3-(3-fluorobenzylamino)-4-methylphenyl)pyridin- 2-yl)cyclohexane-l ,4-diamine:

To 5-(5-chloro-2-fluoropyridin-4-yl)-N-(3-fluorobenzyl)-2-methylaniline (32 mg, 0.093 mmol) add DMSO (0.9 ml), trans-cyclohexane-l,4-diamine(95 mg, 0.835 mmol) and TEA (0.026 ml, 0.186 mmol). The reaction was stirred at 105 °C for 18 hr. The reaction was followed by LCMS. The crude material was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 12.9 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 439.1 (MH+), rt = 0.72 mm. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) 5 ppm l .22 - 1.59 (m, 4 H) 2.04 (t, J=11.87 Hz, 4 H) 2.19 (s, 3 H) 2.95 - 3.12 (m, 1 H) 3.51 (dddd, J=10.92, 7.18, 3.81, 3.59 Hz, 1 H) 4.37 (s, 2 H) 6.38 (s, 1 H) 6.54 (dd, J=7.62, 1.17 Hz, 1 H) 6.60 (s, 1 H) 6.82 (td, J=8.42, 2.20 Hz, 1 H) 6.96 (d, J=9.96 Hz, 1 H) 7.01 - 7.11 (m, 2 H) 7.20 (d, J=5.86 Hz, 1 H) 7.81 (s, 1 H) Example 10: Compound 66

trans-N 1 -(5 -chloro-4-(2-fluoro-3 -(3 -fluorobenzylamino)pheny l)pyridin-2-y l)cy clohexane- 1 ,4- diamine

Step 1. Preparation of 4-(3-bromo-2-fluorophenyl)-5-chloro-2-fluoropyridine:

To 5-chloro-2-fluoro-4-iodopyridine (400 mg, 1.554 mmol) was added 3-bromo-2- fluorophenylboromc acid (340 mg, 1.554 mmol), PdCl₂(dppf).CH2C12 adduct (127 mg, 0.155 mmol), DME (6.8 ml) and last 2M sodium carbonate (2.331 ml, 4.66 mmol). The reaction was stirred at 85 °C for 3 hr. The reaction was followed by LCMS. The reaction was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 40g column eluting with 0%-10% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 250 mg of the titled compound as free base used without further purification. LCMS (m/z): 304.0/306.0 (MH+), rt = 1.07 mm.

Step 2. Preparation of trans-Nl-(4-(3-bromo-2-fluorophenyl)-5-chloropyridin-2-yl)cyclohexane- 1,4-diamine:

To 4-(3-bromo-2-fluorophenyl)-5-chloro-2-fluoropyridine (240 mg, 0.788 mmol) add DMSO (3 ml) and trans-cy clohexane- 1 ,4-diamine (810 mg, 7.09 mmol). The reaction was stirred at 100 °C for 18 hr. The reaction was followed by LCMS. The crude material was let cool, added 1.0 ml of DMSO, filtered, purified by prep LC and lyophilized to TFA salt. The product was free based by adding 250 ml of ethyl acetate washed with saturated sodium bicarbonate, water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate to constant mass giving 132 mg of the titled compound as free base used without further purification. LCMS (m/z): 398.0/400.0(MH+), rt = 0.66 mm. Step 3. Preparation oftrans-Nl-(5-chloro-4-(2-fluoro-3-(3-fluorobenzylamino)phenyl)pyridin-2- yl)cy clohexane- 1 ,4-diamine:

To Pd(OAc)₂ (3.55 mg, 0.016 mmol) was added BINAP (11.48 mg, 0.018 mmol) and Dioxane (0.5 ml) the reaction was stirred for 5 minutes at room temperature. Then to the crude mixture was added trans-Nl-(4-(3-bromo-2-fluorophenyl)-5-chloropyridin-2-yl)cyclohexane-l,4-diamine (21 mg, 0.053 mmol), (3-fluorophenyl)methanamine (39.5 mg, 0.316 mmol) and stirred for 3-5 minutes. To the crude mixture was added potassium tert-butoxide (23.64 mg, 0.211 mmol) and was stirred at 105 °C for 2 hr. The reaction was followed by LCMS. The reaction was let cool, 3 ml of ethyl acetate and 0.5 ml of methanol was added, filtered and concentrated the solvent off. The crude was dissolved with 1.0 ml of DMSO, filtered and purified by prep LC. After lyophilization 5.5 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 443.3 (MH+), rt = 0.76 mm. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.13 - 1.58 (m, 4 H) 1.92 - 2.16 (m, 4 H) 3.04 (ddd, J=l 1.65, 7.84, 3.96 Hz, 1 H) 3.60 (tt, J=l 1.14, 3.81 Hz, 1 H) 4.35 (s, 2 H) 6.33 - 6.42 (m, 1 H) 6.50 (s, 1 H) 6.52 - 6.62 (m, 1 H) 6.86 (t, J=7.91 Hz, 2 H) 7.01 (d, J=9.96 Hz, 1 H) 7.06 - 7.14 (m, 1 H) 7.18 - 7.29 (m, 1 H) 7.90 (s, 1 H)

Example 11 : Compound 69

trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)-N4-(2- methoxyethyl)cyclohexane- 1 ,4-diamine

Preparation of trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin- 2-yl)-N4-(2-methoxyethyl)cy clohexane- 1,4-diamine:

To trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cy clohexane- 1,4-diamine (18 mg, 0.043 mmol) add DMSO (0.5 ml) and l-bromo-2- methoxyethane (8.44 mg, 0.061 mmol) stir at 70-80 °C for 6 hr. or until done by LCMS. The crude material was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization 6.8 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 473.3 (MH+), rt = 0.59 mm. NMR on Free Base 1.18 - 1.42 (m, 6 H) 1.74 (d, J=13.19 Hz, 2 H) 1.80 - 1.97 (m, 1 H) 1.96 - 2.17 (m, 4 H) 2.52 (br. s., 1 H) 2.80 (t, J=5.13 Hz, 2 H) 3.01 (d, J=6.74 Hz, 2 H) 3.35 (s, 3 H) 3.38 - 3.46 (m, 2 H) 3.50 (t, J=5.27 Hz, 2 H) 3.63 (br. s., 1 H) 3.95 (dd, J=11.14, 2.93 Hz, 2 H) 6.43 (s, 1 H) 6.55 - 6.70 (m, 3 H) 7.15 (t, J=7.77 Hz, 1 H) 7.92 (s, 1 H)

Example 12: Compound 71

trans-Nl-(5-chloro-4-(3-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)pyridin-2-yl)- N4,N4-dimethy Icy clohexane- 1 ,4-diamine

Preparation of trans-Nl -(5-chloro-4-(3-(methyl((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)pyridin-2-yl)-N4,N4-dimethylcyclohexane-l,4-diamine:

To trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cyclohexane-l,4-diamine (18 mg, 0.043 mmol) add MeOH (0.5 ml), acetic acid (9.93 μΐ, 0.174 mmol) and formaldehyde 37% in water (0.035 ml, 0.434 mmol) stir at room temperature for 20 minutes then add sodium triacetoxyborohydride (55.2 mg, 0.260 mmol) and stir at room temperature for 18 hr. The reaction is followed by LCMS. The reaction was let cool, concentrated the solvent off, added 0.8 ml of DMSO, filtered and purified by prep LC. After lyophilization 16.3 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 457.2 (MH+), rt = 0.61 mm. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.24 - 1.81 (m, 8 H) 1.93 - 2.11 (m, 1 H) 2.11 - 2.38 (m, 4 H) 2.88 (s, 6 H) 3.03 (s, 3 H) 3.28 - 3.33 (dMeOH, 3H App.) 3.34 - 3.44 (m, 2 H) 3.61 - 3.76 (m, J=11.36, 7.62, 3.70, 3.70 Hz, 1 H) 3.94 (dd, J=11.14, 3.52 Hz, 2 H) 6.71 - 6.86 (m, 3 H) 6.90 (dd, J=8.35, 2.20 Hz, 1 H) 7.33 (t, J=7.91 Hz, 1 H) 8.05 (s, 1 H) Example 13 : Compound 75

N-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- ylamino)cyclohexyl)methanesulfonamide

Preparation of N-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl) pyridin-2-ylamino) cyclohexyl)methanesulfonamide:

To trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cyclohexane-l,4-diamine (15 mg, 0.036 mmol) add DCM (1 ml) and with stirring was added methanesulfonyl chloride (3.94 μΐ, 0.051 mmol). The reaction was stirred at room temperature for 30 min. The reaction was followed by LCMS. The crude material was concentrated to remove solvent, dissolved in 1.0 ml of DMSO, filtered and purified by prep LC. After lyophilization 10.7 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 493.2 (MH+), rt = 0.66 mm. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.24 - 1.42 (m, J=12.49, 12.49, 12.23, 4.40 Hz, 2 H) 1.42 - 1.59 (m, 4 H) 1.75 (d, J=12.89 Hz, 2 H) 1.82 - 1.98 (m, 1 H) 2.12 (d, J=7.91 Hz, 4 H) 2.97 (s, 3 H) 3.05 (d, J=6.74 Hz, 2 H) 3.29-3.32 ((dMeOH, 1H App.) 3.35 - 3.48 (m, 2 H) 3.50 - 3.64 (m, 1 H) 3.96 (dd, J=11.28, 3.37 Hz, 2 H) 6.68 - 6.78 (m, 2 H) 6.78 - 6.87 (m, 1 H) 6.90 (s, 1 H) 7.26 (t, J=7.91 Hz, 1 H) 8.00 (s, 1 H) Example 14: Compound 84

trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)-N4- (((R)-tetrahydrofuran-2-yl)methyl)cyclohexane- 1 ,4-diamine

To 5-chloro-2-fluoro-4-iodopyridine (2.00 g, 7.77 mmol) was added 3-(tert- butoxycarbonylamino)phenylboronic acid (3.13 g, 13.21 mmol), PdC12(dppf).CH2C12 adduct (0.508 g, 0.622 mmol), DME (40 ml) and last 2M sodium carbonate (15.54 ml, 31.1 mmol). The reaction was stirred at 100 °C for 2 hr and followed by LCMS. The crude reaction was let cool, 30ml of ethyl acetate and 10 ml of methanol was added, filtered and concentrated to crude residue. The crude material was purified by silica gel chromatography using 120 g column and eluting with 0%-40% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 1.8 grams of the titled compound as free base used without further purification. LCMS (m/z): 323.0 (MH+), rt = 1.03 min.

Step 2. Preparation of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenyl((tetrahydro-2H-pyran- 4-yl)methyl)carbamate:

To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (2.3 g, 7.13 mmol) was added DMF (18 ml) cooled to 0 °C and added sodium hydride 60% (0.342 g, 8.55 mmol). The ice bath was removed and the crude mixture was stirred for 20 minutes at room temperature. Then to the crude mixture was added (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (2.312 g, 8.55 mmol) and the reaction was stirred at 45 °C for 26 hr. The reaction was followed by LCMS. (Note the BOC parent MS is weak by LCMS) The reaction was let cool, added 450 ml of ethyl acetated, washed with saturated sodium bicarbonate (2x), water (2x) and saturated salt solution, dry with sodium sulfate, filter and concentrate to crude residue. The crude was purified by silica gel chromatography using 120g column eluting with 0%-30 ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 2.48 grams of the titled compound as free base used without further purification. LCMS (m/z): 421.1 (MH+), rt = 1.17 mm. Step 3. Preparation of tert-butyl 3-(5-chloro-2-((ls,4s)-4-hydroxycyclohexylamino)pyridin-4- yl)phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate (440 mg, 1.045 mmol) was added DMSO (4 ml), TEA (0.729 ml, 5.23 mmol), and (ls,4s)-4-aminocyclohexanol hydrochloride (476 mg, 3.14 mmol) . The reaction was stirred at 95-100 °C for 40 hr. The reaction was followed by LCMS. The reaction was let cool, added 250 ml of ethyl acetate, washed with saturated sodium bicarbonate, water (2x), filtered and concentrated to constant mass. The crude was purified by silica gel chromatography using 12g column eluting with 30-85% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 363 mg of the titled compound as free base used without further purification. LCMS (m/z): 516.2 (MH+), rt = 0.80 min.

Step 4. Preparation of (ls,4s)-4-(4-(3-(tert-butoxycarbonyl((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)-5-chloropyridin-2-ylamino)cyclohexyl methanesulfonate

To tert-butyl 3-(5-chloro-2-((l s,4s)-4-hydroxycyclohexylamino)pyridin-4- yl)phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate (360 mg, 0.698 mmol) was added DCM (8 mL), and TEA (0.146 mL, 1.046 mmol) then cooled to 0 °C. Then with stirring was added methanesulfonyl chloride (0.065 mL, 0.837 mmol). The reaction was stirred at room

temperature for 2 hr and was followed by LCMS. To the crude reaction was added 150 ml of ethyl acetate, washed with saturated sodium bicarbonate, water (2x), saturated salt solution, dry sodium sulfate, filtered and concentrated to constant mass, giving 420 mg of the titled compound as free base used without further purification. LCMS (m/z): 594.3 (MH+), rt = 0.90 min. Step 5. Preparation of trans-Nl -(5-chloro-4-(3-((tetrahy dro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-yl)-N4-(((R)-tetrahydrofuran-2-yl)methyl)cyclohexane-l,4- diamine:

To (1 s,4s)-4-(4-(3-(tert-butoxycarbonyl((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)-5-chloropyridin-2-ylamino)cyclohexyl methanesulfonate (50 mg, 0.084 mmol) add DMSO (0.4 ml), (Note: t-butanol may be used as alternative solvent ) and (R)- (tetrahydrofuran-2-yl)methanamine (213 mg, 2.104 mmol). The reaction was stirred at 95-100 °C for 2 hr or until done by LCMS. The reaction was cooled, 12 ml of ethyl acetate was added then washed with saturated sodium bicarbonate, water (2x), filtered and concentrated to crude residue. The crude material was dissolved in 1 ml of DMSO, filtered and purified by prep LC, and lyophilized to TFA salt giving the BOC intermediate. The BOC intermediate was de- protected by adding 4M HCL in Dioxane (1 rriL, 4.00 mmol) and stirred at room temperature for 1 hour. The solvent was removed and concentrated to constant mass, dissolved in 5ml of 1 : 1 ACN/water, filtered and lyophilized, giving 3.1 mg of titled compound as HCL salt. LCMS (m/z): 499.3 (MH+), rt = 0.60 mm. 1H NMR (400 MHz, METHANOL-i/4, 25 °C) δ ppm 1.41 (qd, J=12.19, 4.11 Hz, 2 H) 1.48 - 1.83 (m, 7 H) 1.90 - 2.09 (m, 3 H) 2.15 (td, J=13.01, 7.24 Hz, 1 H) 2.25 (d, J=10.56 Hz, 4 H) 2.96 - 3.07 (m, 1 H) 3.21 (d, J=l 1.35 Hz, 2 H) 3.27 (d, J=7.04 Hz, 2 H) 3.42 (t, J=11.35 Hz, 2 H) 3.74 - 3.86 (m, 2 H) 3.88 - 4.02 (m, 3 H) 4.16 (q, J=6.78 Hz, 1 H) 7.08 (s, 1 H) 7.28 - 7.44 (m, 3 H) 7.57 (t, J=7.63 Hz, 1 H) 8.09 (s, 1 H)

Example 15: Compound 102

trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)-N4,N4- bis(2-methoxy ethyl)cyclohexane- 1 ,4-diamine

Step 1. Preparation of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenyl((tetrahydro-2H-pyran- 4-yl)methyl)carbamate:

To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (Example 3, Step g, 17.66 mmol) was added dry DMF (40 ml) then under argon with a room temperature water bath add Sodium Hydride 60% (0.848 g, 21.19 mmol). The reaction was stirred at room temperature for 20 minutes. Then add (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (5.73 g, 21.19 mmol) and the reaction was stirred at 45-48 °C for 20 hr. The reaction was followed by LCMS (Note the BOC parent MS is weak by LCMS). The reaction was let cool, added 100 ml of ethyl acetate, washed with saturated sodium bicarbonate, water (3x), filtered and concentrated to solid. The crude material was purified by silica gel chromatography using 330g column and eluting with 0%-20% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 5.88 grams of the titled compound as free base used without further purification. LCMS (m/z): 421.1 (MH+), rt = 1.14 min.

Step 2. Preparation of tert-butyl 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4- yl)phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate:

To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate (500 mg, 1.188 mmol) add DMSO (4.5 ml) and trans-cyclohexane- 1 ,4- diamine (1221 mg, 10.69 mmol). The reaction was stirred at 95-100 °C for 18 hr. The reaction was followed by LCMS. The crude reaction was cooled, 250 ml of ethyl acetate was added, washed with saturated sodium bicarbonate, water (3x) and the solvent was removed and concentrated to constant mass, giving 625 mg of titled compound as free base used without further purification. LCMS (m/z): 515.2 (MH+), rt = 0.71 min.

Step 3. Preparation of trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-yl)-N4,N4-bis(2-methoxyethyl)cyclohexane-l,4-diamine:

To tert-butyl 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4- yl)phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate (31 mg, 0.060 mmol) add potassium carbonate (33.3 mg, 0.241 mmol), DMSO (0.5 ml) and 1 -bromo-2-methoxy ethane (25.10 mg, 0.181 mmol). The reaction was stirred at 80 °C for 6 hr. The reaction was followed by LCMS. The crude reaction was cooled and the BOC intermediate was purified by prep LC and lyophilized to TFA salt. Then HC1 4M in Dioxane (1 ml, 4.00 mmol) was added and stirred at room temperature for 1 hour. The solvent was removed and concentrated to constant mass, dissolved in 5ml of 1 : 1 ACN/water, filtered and lyophilized, giving 4.5 mg of titled compound as HCL salt. LCMS (m/z): 531.3 (MH+), rt = 0.59 min. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.42 (qd, J=12.26, 4.25 Hz, 2 H) 1.58 (d, J=l 1.72 Hz, 2 H) 1.70 - 1.95 (m, 4 H) 1.96 - 2.15 (m, 1 H) 2.22 (d, J=14.94 Hz, 4 H) 3.27 - 3.32 (dMeOH, 2H App.) 3.37 - 3.49 (m, 10 H) 3.49 - 3.62 (m, 3 H) 3.74 (t, J=4.54 Hz, 4 H) 3.78 - 3.87 (m, 1 H) 3.98 (dd, J=l 1.28, 3.37 Hz, 2 H) 7.09 (s, 1 H) 7.31 - 7.48 (m, 3 H) 7.59 (t, J=7.77 Hz, 1 H) 8.11 (s, 1 H) Example 16: Compound 101

3-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- ylamino)cyclohexylamino)propanamide

Step 1. Preparation of 3-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-ylamino)cyclohexylamino)propanamide:

To trans-Nl-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cyclohexane-l,4-diamine (Example 6) (50 mg, 0.120 mmol) add potassium carbonate (50.0 mg, 0.361 mmol), DMSO (0.5 ml) and 3-bromopropanamide (27.5 mg, 0.181 mmol). The reaction was stirred at 80 °C for 3 hr or until done by LCMS. The starting material, product and di-addition side-product co eluted. To the crude reaction was added di-tert-butyl dicarbonate (0.056 ml, 0.241 mmol) and stirred at room temperature for 2 hr. The BOC intermediate was purified by prep. LC and lyophilized to TFA salt. Then HC1 4M in Dioxane (1 ml, 4.00 mmol) was added and stirred at room temperature for 1 hour. The solvent was concentrated off, dissolved in 1.0 ml of DMSO and purified by prep LC. After lyophilization 7.5 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 486.1 (MH+), rt = 0.53 min. 1H NMR (300 MHz, METHANOL-i 4, 25 °C) δ ppm 1.25 - 1.81 (m, 8 H) 1.82 - 2.00 (m, 1 H) 2.14 - 2.31 (m, 4 H) 2.67 (t, J=6.45 Hz, 2 H) 3.05 (d, J=6.74 Hz, 2 H) 3.19 (t, J=11.57 Hz, 1 H) 3.28 - 3.34 (dMeOH, 2H App.) 3.35 - 3.48 (m, 2 H) 3.61 - 3.77 (m, 1 H) 3.96 (dd, J=l 1.28, 3.37 Hz, 2 H) 6.66 - 6.85 (m, 4 H) 7.25 (t, J=7.77 Hz, 1 H) 8.02 (s, 1 H)

Example 17: Compound 49

4-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-2-(3- fluorobenzylamino)benzonitrile

Preparation of 4-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-2-(3- fluorobenzylamino)benzonitrile:

To 4-(5-chloro-2-fluoropyridin-4-yl)-2-(3-fluorobenzylamino)benzonitrile (made by Example 9) (50 mg, 0.141 mmol) add DMSO (1.5 ml), trans-cyclohexane-l,4-diamine (144 mg, 1.265 mmol) and TEA (0.039 ml, 0.281 mmol). The reaction was stirred at 105 °C for 18 hr. The reaction was followed by LCMS. The crude material was let cool, added 1.0 ml of DMSO, filtered, purified by prep LC. After, lyophilization 30 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 450.1 (MH+), rt = 0.70 mm. 1H NMR (300 MHz, METHANOL- d4, 25 °C) 5 ppm l .27 - 1.68 (m, 4 H) 2.12 (t, J=13.63 Hz, 4 H) 3.05 - 3.21 (m, 1 H) 3.65 (t,

J=11.28 Hz, 1 H) 4.52 (s, 2 H) 6.56 (s, 1 H) 6.61 (s, 1 H) 6.69 (d, J=7.91 Hz, 1 H) 6.96 (t, J=8.20 Hz, 1 H) 7.07 (d, J=9.96 Hz, 1 H) 7.17 (d, J=7.62 Hz, 1 H) 7.28 - 7.39 (m, 1 H) 7.55 (d, J=7.91 Hz, 1 H) 7.95 (s, 1 H) Example 18: Compound 57

trans-Nl -(5 -chloro-4-(3 -(3 -fluorobenzylamino)-4-( 1 H-tetrazol-5 -yl)phenyl)pyridin-2- yl)cy clohexane- 1 ,4-diamine

Preparation of trans-Nl -(5-chloro-4-(3-(3-fluorobenzylamino)-4-(lH-tetrazol-5- yl)pheny l)pyridin-2-yl)cy clohexane- 1 ,4-diamine:

To 4-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-2-(3- fluorobenzylamino)benzonitrile (20 mg, 0.044 mmol) add DMF (0.6 ml), zinc chloride (42.4 mg, 0.311 mmol) and sodium azide (43.3 mg, 0.667 mmol). The reaction was microwaved at 195 °C for 800 seconds (1^st). The reaction was followed by LCMS. The reaction was not done and was microwaved again at 195 °C for 800 seconds (2^nd). The reaction was microwaved again at 195 °C for 800 seconds (3^rd). The crude material was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization 2.1 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 493.2 (MH+), rt = 0.67 min.

Example 19: Compound 82

trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)-N4-(2- (methylsulfonyl)ethyl)cy clohexane- 1 ,4-diamine

Step 1. Preparation of 2-(methylsulfonyl)ethyl methanesulfonate:

To a round-bottom flask containing 2-(methylsulfonyl)ethanol (2000 mg,16.11 mmol) was added DCM (80 ml) and triethylamine (2.69 ml, 19.33 mmol) cooled to at 0 °C and followed by dropwise addition of methanesulfonyl chloride (2030 mg, 17.72 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, saturated salt solution, dried with sodium sulfate, filtered and concentrated to give 2.9 grams of the title compound as a free base, used without further purification. LCMS (m/z): 203.0 (MH+), rt = 0.22 mm. 1H NMR (400 MHz, CHLOROFORM-d, 25 °C) δ ppm 3.04 (s, 3 H) 3.10 (s, 3 H)

3.45 (t, J=5.48 Hz, 2 H) 4.66 (t, J=5.48 Hz, 2 H) Step 2. Preparation of trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-yl)-N4-(2-(methylsulfonyl)ethyl)cyclohexane-l,4-diamine:

To trans-Nl -(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cyclohexane-l,4-diamine (Example 6) (38 mg, 0.092 mmol) add DMSO (0.4 ml), potassium carbonate (31.6 mg, 0.229 mmol) and 2-(methylsulfonyl)ethyl methanesulfonate (27.8 mg, 0.137 mmol). The reaction was stirred at 95-100 °C and followed by LCMS. At 4 hours 2- (methylsulfonyl)ethyl methanesulfonate (27.8 mg, 0.137 mmol) was added and continued stirring at 95-100 °C for 4 hours more, for total of 8 hr. The crude material was let cool, added 0.5 ml of DMSO, filtered, purified by prep LC. After lyophilization 16.2 mg of the title compound as a TFA salt was obtained. LCMS (m/z): 521.2 (MH+), rt = 0.57 min. 1H NMR (300 MHz, METHANOL-i/4, 25 °C) δ ppm 1.26 - 1.80 (m, 8 H) 1.90 (dddd, J=14.87, 11.28, 3.59, 3.37 Hz, 1 H) 2.17 - 2.34 (m, 4 H) 3.06 (d, J=6.74 Hz, 2 H) 3.12 (s, 3 H) 3.22 - 3.32 (dMeOH, 1H App.) 3.41 (td, J=11.72, 1.76 Hz, 2 H) 3.58 (s, 4 H) 3.70 (ddd, J=10.92, 7.55, 3.81 Hz, 1 H) 3.96 (dd, J=11.28, 3.37 Hz, 2 H) 6.72 - 6.80 (m, 2 H) 6.81 - 6.88 (m, 2 H) 7.27 (t, J=7.77 Hz, 1 H) 8.04 (s, 1 H)

Example 20: Compound 103

2-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- ylamino)cyclohexylamino)acetic acid

Preparation of 2-(trans-4-(5-chloro-4-(3-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-ylamino)cyclohexylamino)acetic acid:

To tert-butyl 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4- yl)phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate (Example 15, step 2) (31 mg, 0.060 mmol) add potassium carbonate (33.3 mg, 0.241 mmol), DMSO (0.5 ml) and tert-butyl 2- bromoacetate (17.61 mg, 0.090 mmol). The reaction was stirred at room temperature for 3 hours and followed by LCMS. The crude reaction was cooled and the BOC intermediate was purified by prep LC and lyophilized to TFA salt. Then HC1 4M in Dioxane (1 ml, 4.00 mmol) was added and stirred at room temperature for 1 hour. The solvent was removed and concentrated to constant mass, dissolved in 5ml of 1 : 1 ACN/water, filtered and lyophilized, giving 7.5 mg of titled compound as HCL salt. LCMS (m/z): 473.2 (MH+), rt = 0.53 min.

Example 21 trans-Nl-(5-chloro-4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2- yl)cy clohexane- 1 ,4-diamine

Step 1 : Preparation Intermediate tert-butyl 3-bromo-4-fluorophenylcarbamate To a solution of 3-bromo-4-fluoroaniline (1 g, 5.26 mmol) in DMF (10 mL) was added sodium hydride (0.21 g, 5.26 mmol). The resulting mixture was stirred at ambient temperature for 5 min, and di-tert-butyl dicarbonate (1.15 g, 5.26 mmol) was added to. Mixture was stirred at ambient temperature for 48 hours. The mixture was diluted with EtOAc (100 mL) and was washed with water, brine, dried over sodium sulfate and concentrated to remove solvent. The residue was purified by column chromatography [Si0₂, 40g, EtO Ac/heptane = 0/100 to 20/80]. Pure fractions were combined and concentrated in vacuo to yield 800 mg of compound tert-butyl 3-bromo-4-fluorophenylcarbamate as a yellow solid. LCMS (m/z): 275/277 [M-tBu+ACN]+; Rt = 1.08 minutes.

Step 2: Preparation of Intermediate tert-butyl 3-bromo-4-fluorophenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate

To a solution of tert-butyl 3-bromo-4-fluorophenylcarbamate (300 mg, 1.03 mmol),

(tertrahydropyran-4-yl)methyl tosylate (335 mg, 1.24 mmol) in DMF (4 mL) at ambient temperature under Argon was added sodium hydride (83 mg, 2 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes, then was heated to 45 °C for about 17 hours. The reaction mixture was diluted with EtOAc, washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 320 mg of compound tert-butyl 3-bromo-4- fluorophenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate as yellow oil.

LCMS (m/z): 332.0/334.0 [M-tBu] 288.0/290.0 (loss of boc-group); Rt = 1.13 minutes.

Step 3 : Preparation of Intermediate tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)-4- fluorophenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a mixture of tert-butyl 3-bromo-4-fluorophenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate (320 mg, 0.82 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (400 mg, 2.2 mmol) in DME (3 mL) was added 2M sodium carbonate aqueous solution (0.8 mL), followed by the addition of PdCl₂(dppf).CH₂Ci₂ adduct (107 mg, 0.13 mmol). The reaction mixture was heated to 95 °C in an oil bath for about 20 hours. Suspension was diluted with ethyl acetate, and was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Crude product was purified by column chromatography [Si0₂, 12g, EtO Ac/heptane = 0/100 to 20/80]. Pure fractions were combined and concentrated in vacuo to yield 190 mg of compound tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)-4-fluorophenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate as yellow oil. LCMS (m/z): 382.9 [M-tBu], 339.0/341.0 (loss of boc- group); Rt = 1.13 minutes

Step 4: Preparation of trans-Nl-(5-chloro-4-(2-fluoro-5-((tetrahydro-2H-pyran-4- yl)methyl)aminophenyl)pyridin-2-yl)cyclohexane-l,4-diamine

The mixture of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)-4-fluorophenyl((tetrahydro-

2H-pyran-4-yl)methyl)carbamate (40 mg, 0.09 mmol) and trans- 1,4-cyclohexanediamine (52 mg, 0.45 mmol) in DMSO (1 mL) was heated to 95 °C in a sealed tube for about 15 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc (10 mL), washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was treated with 10 mL 30% TFA in DCM for 15 min. Solution was concentrated in vacuo and residue purified by HPLC to give 17 mg desired compound trans-Nl-(5-chloro-4-(2-fluoro-5- ((tetrahydro-2H-pyran-4-y l)methyl)aminophenyl)pyridin-2-y l)cy clohexane- 1 ,4-diamine as TFA salt. LCMS (m/z): 433.2/435.1 [M+H]+; Rt = 0.55 minutes.

Example 22

trans-Nl-(5-chloro-4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)- N4-(2-methoxyethyl)cy clohexane- 1 4-diamine

Step 1 : Preparation of Intermediate tert-butyl 3-(2-(trans-4-aminocyclohexylamino)-5- chloropyridin-4-yl)-4-fluorophenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate

The mixture of tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)-4-fluorophenyl((tetrahydro- 2H-pyran-4-yl)methyl)carbamate (Example 21, Step 3, 380 mg, 0.6 mmol), trans-1,4- cyclohexanediamine (346 mg, 3.0 mmol) and triethylamine (184 mg, 1.8 mmol) in DMSO (6.0 mL) was heated to 95 °C in a sealed tube for about 20 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc (50 mL), washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography [Si0₂, 24g, EtOAc/methanol = 60/40 containing 10% TEA]. Pure fractions were combined and concentrated in vacuo to yield 260 mg compound tert-butyl 3-(2-(trans-4- aminocyclohexylamino)-5-chloropyridin-4-yl)-4-fluorophenyl((tetrahydro-2H-pyran-4- yl)methyl)carbamate as white solid. LCMS (m/z): 533.2/535.3 [M+H]+; Rt = 0.74 minutes.

Step2: Preparation of trans-Nl-(5-chloro-4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)

methylamino)phenyl)pyridin-2-yl)-N4-(2-methoxyethyl)cyclohexane- 1 ,4-diamine

The mixture of tert-butyl 3-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-4- fluorophenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamate (60 mg, 0.11 mmol), p- toluenesulfonic acid 2-methoxyethyl ester (26 mg, 0.11 mmol) and solid sodium carbonate (24 mg, 2.0 mmol) in DMSO (2.0 mL) was heated to 85 °C in an oil bath for about 16 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc (15 mL), washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Residue was treated with 10 mL 30% TFA in DCM for about 15 minutes. Solution was concentrated in vacuo and crude product was purified by HPLC to give 14.8 mg desired product trans-Nl-(5-chloro-4-(2- fluoro-5-((tetrahydro-2H-pyran-4-yl)methyl)aminophenyl)pyridin-2-yl)-N4-(2- methoxyethyl)cyclohexane-l,4-diamine as TFA salt. LCMS (m/z): 491.3/493.3 [M+H]+; Rt = 0.59 minutes.

Example 23: Compound 68:

Synthesis of trans-Nl-(4-(3-((3,5-difluorobenzyl)amino)phenyl)-5-methoxypyridin-2- vDcyclohexane- 1 ,4-diamine

Step 1: Preparation of N-(3,5-difluorobenzyl)-3-iodoaniline

To a stirred solution of 3-iodoaniline (1 g, 4.57 mmol) in CH2CI2 (20 mL) was added 3,5- difluorobenzaldehyde (0.649 g, 4.57 mmol) and sodium triacetoxyborohydride (1.161 g, 5.48 mmol) followed by acetic acid (0.261 mL, 4.57 mmol). The mixture was stirred for 16 hrs. The mixture was concentrated under reduced pressure, then dissolved in EtOAc and washed with 1M aqueous NaOH solution (2x), water (2x), brine (lx), dried over sodium sulfate, filtered and concentrated under reduced pressure providing N-(3,5-difluorobenzyl)-3-iodoaniline.

Step 2: Preparation of 3-(2-chloro-5-methoxypyridin-4-yl)-N-(3,5-difluorobenzyl)aniline

To a solution of N-(3,5-difluorobenzyl)-3-iodoaniline (466 mg, 1.350 mmol) and 2-chloro-5- methoxypyridin-4-ylboronic acid (354 mg, 1.890 mmol) in DME (4 mL) and 2M aqueous Na₂C0₃ solution (2.0 mL) was added PdCl₂(dppf) CH₂C1₂ adduct (55.1 mg, 0.068 mmol). The mixture was heated at 110 °C. The mixture was allowed to cool to room temperature, concentrated under reduced pressure. The residue was extracted with EtOAc and then dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, EtOAc/hexane] to give 3-(2-chloro-5-methoxypyridin-4-yl)-N-(3,5- difluorobenzyl)aniline. Step 3: Preparation of trans-Nl-(4-(3-((3,5-difluorobenzyl)amino)phenyl)-5- methoxypyridin-2-yl)cyclohexane-l,4-diamine

To a 4 mLvial was added 3-(2-chloro-5-methoxypyridin-4-yl)-N-(3,5-difluorobenzyl)aniline (101 mg, 0.280 mmol), trans-cyclohexane-l,4-diamine (144 mg, 1.260 mmol), l,3-bis(2,6-di- isopropylphenyl)imidazol-2-ylidene(l,4-naphthoquinone)palladium(0) (18.28 mg, 0.014 mmol) and finally KOH (141 mg, 2.52 mmol). The vial was purged with Argon, then dioxane (1 mL) was added. The vial was sealed and heated at 100 °C for 16 hrs. The mixture was concentrated under reduced pressure, diluted with EtOAc and washed with brine (2x). The organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. Fractions were lyophilized providing trans-Nl -(4- (3-((3,5-difluorobenzyl)amino)phenyl)-5-methoxypyridin-2-yl)cyclohexane-l,4-diamine (1.8 mg) as its trifluoroacetic acid salt. LCMS (m/z): 439.3 [M+H]+; Retention time = 0.68 min.

Example 24: Compound 78

Synthesis of trans-Nl -(5-chloro-4-(5-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclohexane-l A- diamine

Step 1: Preparation of 5-chloro-2-fluoro-4-(5-fluoro-2-methoxyphenyl)pyridine

A mixture of 5-chloro-2-fluoro-4-iodopyridine (325 mg, 1.262 mmol), (5-fluoro-2- methoxyphenyl)boronic acid (300 mg, 1.767 mmol), PdCl₂(dppf) CH₂C1₂ adduct (82 mg, 0.101 mmol) in DME (4.5 mL) and 2M aqueous Na₂CC>3 solution (1.894 rriL, 3.79 mmol) in a sealed tube was heated at 85 °C for 2 hr. The mixture was allowed to cool to room temperature and was diluted with EtOAc (-25 mL), washed with water (2x), brine (lx) and concentrated under reduced pressure. The residue was purified by column chromatography [Si0₂, 12g,

EtO Ac/heptane = 0/100 to 15/85]. Pure/enriched fractions were combined and concentrated under reduced pressure providing 5-chloro-2-fluoro-4-(5-fluoro-2-methoxyphenyl)pyridine as a white solid. Yield: 330 mg. LCMS (m/z): 255.9 [M+H]+; Retention time = 1.05 min.

Step 2: Preparation of trans-Nl-(5-chloro-4-(5-fluoro-2-methoxyphenyl)pyridin-2- yl)cyclohexane-l,4-diamine

A mixture of 5-chloro-2-fluoro-4-(5-fluoro-2-methoxyphenyl)pyridine as a white solid (25 mg, 0.098 mmol), trans-cyclohexane-l,4-diamine (89 mg, 0.782 mmol), diisopropylethylamine

(0.027 mL, 0.196 mmol) in DMSO (0.25 mL) was heated at 105 °C for 16 hr. The mixture was diluted with EtO Ac and 1/2 saturated aqueous NaHCC solution. The separated organic layer was washed with water (2x), 1/2 saturated aqueous NaHCC solution, dried over Na₂S0₄, filtered off and concentrated under reduced pressure. Purification by preparative HPLC provided trans-Nl-(5-chloro-4-(5-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclohexane-l,4-diamine as its trifluoroacetic acid salt as a white solid. Yield: 21.6 mg. LCMS (m/z): 350.1 [M+H]+;

Retention time = 0.61 min.

Example 25: Compound 7

Synthesis of N-(3-(2-(trans-4-aminocvclohexylaminoV5-chloropyrimidin-4- yl)phenyl)methanesulfonamide

Step 1: Preparation of N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)methanesulfonamide

To 2,4,5-trichloropyrimidine (44.1 mg, 0.240 mmol) was added 3-

(methylsulfonamido)phenylboronic acid (47 mg, 0.219 mmol), PdCi₂(dppf) CH₂CI₂ adduct (17.9 mg, 0.022 mmol), DME (0.75 mL) and last 2M aqueous sodium carbonate solution (0.240 mL, 0.481 mmol). The reaction mixture was stirred at 80 °C for 2 hrs. The reaction mixture was cooled to room temperature, 2.5 mL of ethyl acetate was added, stirred, filtered and concentrated under reduced pressure. The residue was dissolved in 2 mL of DMF filtered and purified by HPLC. After lypohilization, 36 mg of the title compound, as a trifluoroacetic acid salt was obtained. LCMS (m/z): 318.0 [M+H]+; Retention time = 0.82 min.

Step 2: Preparation of N-(3-(2-(trans-4-aminocyclohexylamino)-5-chloropyrimidin-4- yl)phenyl)methanesulfonamide

To N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)methanesulfonamide (15 mg, 0.047 mmol) was added DMSO (0.4 mL) and trans-cyclohexane-l,4-diamine (43.1 mg, 0.377 mmol). The reaction mixture was stirred at 100 °C for 20 hrs. The reaction mixture was allowed to cool to room temperature, 0.4 mL of DMSO was added, filtered and purified by HPLC. After lypohilization, 19.4 mg of the title compound, as a trifluoroacetic acid salt was obtained. LCMS (m/z): 396.2 [M+H]+; Retention time = 0.57 min. 1H NMR (400 MHz, chloroform d3) δ ppm 1.33 - 1.61 (m, 4 H) 2.07 (d, J=12.13 Hz, 2 H) 2.18 (d, J=11.35 Hz, 2 H) 2.98 (s, 3 H) 3.05 - 3.17 (m, 1 H) 3.74 - 3.84 (m, 1 H) 7.30 (dd, J=7.83, 1.17 Hz, 1 H) 7.43 (t, J=7.83 Hz, 1 H) 7.56 (d, J=7.04 Hz, 1 H) 7.74 (br. s., 1 H) 8.30 (s, 1 H).

The following synthetic examples describe synthesis of bi-aryl compounds and illustrate additional methods that can be adapted for making compounds of the invention. Example of synthesis of a racemic product followed by chiral separation:

Synthesis of 1 -(((5'-fluoro-2'-(Ytrans-4-((YRV 1 -methoxypropan-2-vf)amino')cvclohexyf)aminoV [2,4'-bipyridinl-6-yl)amino)methyl)cvclopropanecarbonitrile and l-(((5'-fluoro-2'-((trans-4-(((S)- l-methoxypropan-2-yl)amino)cvclohexyl)amino)-[2,4'-bipyridinl-6- yl)amino)methyl)cvclopropanecarbonitrile

Step 1: Preparation of l-(((5'-fluoro-2'-((trans-4-((l-methoxypropan-2- yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)cyclopropanecarbonitrile

To the reaction mixture of l-(((2'-((trans-4-aminocyclohexyl)amino)-5'-fluoro-[2,4'-bipyridin]-6- yl)amino)methyl)cyclopropanecarbonitrile (497 mg, 1.306 mmol), 1 -methoxypropan-2-one (0.156 rriL, 1.698 mmol) and acetic acid (0.15 mL, 2.61 mmol) in DCE (6 mL), sodium triacetoxyhydroborate (388 mg, 1.829 mmol) was added. The reaction mixture was stirred at 24.5 °C for 1 day. The reaction solution was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution for 2 hrs. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 40 g, methanol/dichoromethane = 0/100 to 10/90] providing l-(((5'- fluoro-2'-((trans-4-((l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6- yl)amino)methyl)cyclopropanecarbonitrile (508 mg) as yellow solid. LCMS (m/z): 453.3

[M+H]+; Retention time = 0.56 min. Step 2: Chiral resolution - l-(((5'-fluoro-2'-((trans-4-(((R)-l-methoxypropan-2- yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)cyclopropanecarbonitrile and 1 -

(((5'-fluoro-2'-((trans-4-(((S)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-

6-yl)amino)methyl)cyclopropanecarbonitrile The racemate (250 mg, 0.55 mmol) was purified by chiral column chromatography [silica gel, AD-H, ethanol/heptane = 10/90] providing l-(((5'-fluoro-2'-((trans-4-((l-methoxypropan-2- yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)cyclopropanecarbonitrile (69 mg) [Fraction 1; LCMS (m/z): 453.1 [M+H]+; Retention time = 0.57 min] as yellow solid and 1- (((5'-fluoro-2'-((trans-4-(((S)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]- 6-yl)amino)methyl)cyclopropanecarbonitrile (81 mg) [Fraction 2; LCMS (m/z): 453.1 [M+H]+; Retention time = 0.56 min] as yellow solid.

Chiral separation of 250 mg, 14 mg/mL in EtOH

Analytical separation:

Column: CHIRALPAK AD-H (5 urn) 100 x 4.6 mm (Daicel Chemical Industries, LTD.).

Solvent: n-heptane : ethyl alcohol = 90 : 10

Flow rate: 1.0 mL/min; detection: UV = 220 nm.

Fraction 1 : Retention time: 10.951 min.

Fraction 2: Retention time: 12.690 min.

Preparative separation:

Column: CHIRALPAK AD-prep (10 urn) 2 x 25 cm.

Solvent: n n-heptane : ethyl alcohol = 90 : 10

Flow rate: 20 mL/min injection: 250 mg / 180 mL detection: UV = 210 nm.

Fraction 1 : white powder. Yield: 69 mg; ee = 99% (UV, 220 nm).

Fraction 2: white powder. Yield: 81 mg; ee = 94% (UV, 220 nm). Synthesis of trans-Nl -(6-(6-(((tetrahvdro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)pyrimidin-

4-vf)cvclohexane-l .4-diamine

Step 1: Preparation of tert-butyl (trans-4-((6-chloropyrimidin-4- yl)amino)cyclohexyl)carbamate

Dissolved 4,6-dichloropyrimidine (3.0 g, 20.14 mmol) in MeOH (30 mL), added tert-butyl (trans-4-aminocyclohexyl)carbamate (4.32 g, 20.14 mmol) and N,N-diisopropylethylamine (7.03 mL, 40.3 mmol). Stired overnight at reflux, allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column

chromatography [silica gel; 120 g]. Pure fractions were combined and concentrated under reduced pressure providing tert-butyl (trans-4-((6-chloropyrimidin-4- yl)amino)cyclohexyl)carbamate (3.5 g) as a white solid. LCMS (m/z): 327.0 [M+H]+; Retention time = 0.77 min.

Synthesis of trans-Nl -(5'-chloro-5-(3-fluorobenzyloxy)-3,4'-bipyridin-2'-yl)cvclohexane- 1,4- diamine

Step 1: Preparation of 3-bromo-5-(3-fluorobenzyloxy)pyridine

To 5-bromopyridin-3-ol (125 mg, 0.718 mmol) was added (3-fluorophenyl)methanol (181 mg, 1.437 mmol), THF (1.0 mL), triphenylphosphine (377 mg, 1.437 mmol) and stirred to dissolve. Then DEAD (0.227 mL, 1.437 mmol) was added. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 12g column eluting with 0%-30% ethyl acetate in hexane. The desired fractions were concentrated under reduced pressure giving 150 mg of titled compound. LCMS (m/z): 282.0/284.0 [M+H]+; Retention time = 0.99 min. Step 2: Preparation of 5'-chloro-2'-fluoro-5-(3-fluorobenzyloxy)-3,4'-bipyridine

To 3-bromo-5-(3-fluorobenzyloxy)pyridine (144 mg, 0.510 mmol) was added 5-chloro-2- fluoropyridin-4-ylboronic acid (134 mg, 0.766 mmol), PdCl₂(dppf) CH₂CI₂ adduct (50.0 mg, 0.061 mmol), DME (3 mL) and last 2M aqueous sodium carbonate solution (1.02 mL, 2.042 mmol). The reaction mixture was stirred at 100 °C for 2 hrs. The reaction mixture was cooled to room temperature, 10 mL of ethyl acetate was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 12g column eluting with 0%-35% ethyl acetate in hexane. The desired fractions were concentrated under reduced pressure, giving 108 mg of titled compound. LCMS (m/z): 333.1 [M+H]+; Retention time = 0.94 min. Step 3: Preparation of trans-Nl-(5'-chloro-5-(3-fluorobenzyloxy)-3,4'-bipyridin-2'- yl)cyclohexane-l,4-diamine

To 5'-chloro-2'-fluoro-5-(3-fluorobenzyloxy)-3,4'-bipyridine (33 mg, 0.099 mmol) was added DMSO (0.8 mL), trans-cyclohexane-l,4-diamine (79 mg, 0.694 mmol) and TEA (0.028 mL, 0.198 mmol). The reaction mixture was stirred at 105 °C for 20 hrs. The reaction mixture was allowed to cool to room temperature, 0.25 mL of DMSO was added, filtered and purified by HPLC. After lypohilization, 37.8 mg of the title compound, as a trifluoroacetic acid salt was obtained.

LCMS (m/z): 427.3 [M+H]+; Retention time = 0.63 min. 1H NMR (400 MHz, chloroform-d3) δ ppm 1.29 - 1.43 (m, 2 H) 1.55 (qd, J=12.65, 3.13 Hz, 2 H) 2.08 (d, J=12.13 Hz, 2 H) 2.17 (d, J=11.35 Hz, 2 H) 3.05 - 3.17 (m, 1 H) 3.71 (tt, J=11.35, 3.72 Hz, 1 H) 5.25 (s, 2 H) 6.57 (s, 1 H) 7.06 (td, J=8.51, 2.15 Hz, 1 H) 7.22 (d, J=9.78 Hz, 1 H) 7.27 (d, J=7.83 Hz, 1 H) 7.40 (td, J=7.83, 5.87 Hz, 1 H) 7.59 - 7.64 (m, 1 H) 8.03 (s, 1 H) 8.22 (d, J=1.57 Hz, 1 H) 8.41 (d, J=2.74 Hz, 1 H).

Synthesis of trans-Nl -(6-(2-(3-fluorobenzylamino)pyridin-4-yl)pyrimidin-4-yl)cvclohexane- 1 ,4- diamine

Step 1: Preparation of trans-Nl-(6-chloropyrimidin-4-yl)cyclohexane-l,4-diamine

To 4,6-dichloropyrimidine (300 mg, 2.014 mmol) was added DMSO (3 mL), TEA (0.337 mL, 2.416 mmol) and trans-cyclohexane-l,4-diamine (345 mg, 3.02 mmol). The reaction mixture was stirred at 80 °C for 1 hr. To the reaction mixture was added 1.5 mL of DMSO, the mixture was filtered and purified by HPLC. After lypohilization, 216 mg of the title compound, as a trifluoroacetic acid salt was obtained. LCMS (m/z): 227.1 [M+H]+; Retention time = 0.33 min.

Step 2: Preparation of trans-Nl-(6-(2-fluoropyridin-4-yl)pyrimidin-4-yl)cyclohexane-l,4- diamine

To trans-Nl -(6-chloropyrimidin-4-yl)cyclohexane-l,4-diamine (105 mg, 0.463 mmol) was added 2-fluoropyridin-4-ylboronic acid (117 mg, 0.834 mmol), PdCl₂(dppf) CH₂C1₂ adduct (45.4 mg, 0.056 mmol), DME (2.5 mL), ethanol (0.5 mL) and then 2M aqueous sodium carbonate solution (0.926 mL, 1.853 mmol). The reaction mixture was heated at 90 °C for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, 10 mL of ethyl acetate and 5 mL of methanol were added, the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in 4 mL of DMSO, filtered and purified by HPLC. After lypohilization, 23 mg of the title compound, as a trifluoroacetic acid salt was obtained. LCMS (m/z): 288.2 [M+H]+;

Retention time = 0.32 min. Step 3: Preparation of trans-Nl-(6-(2-(3-fluorobenzylamino)pyridin-4-yl)pyrimidin-4- yl)cyclohexane-l,4-diamine

To trans-Nl-(6-(2-fluoropyridin-4-yl)pyrimidin-4-yl)cyclohexane-l,4-diamine (19 mg, 0.066 mmol) was added DMSO (0.6 mL) and (3-fluorophenyl)methanamine (83 mg, 0.661 mmol). The reaction mixture was heated at 105 °C for 24 hrs. Some of the excess amine was remove under reduced pressure. To the mixture was added 0.5 mL of DMSO, the mixture was filtered and purified by HPLC. After lypohilization, 7.7 mg of the title compound, as a trifluoroacetic acid salt was obtained. LCMS (m/z): 393.2 [M+H]+; Retention time = 0.43 min.

1H NMR (400 MHz, methanol-d4) δ ppm 1.34 - 1.50 (m, 2 H) 1.50 - 1.67 (m, 2 H) 2.02 - 2.24 (m, 4 H) 3.14 (ddd, J=l 1.54, 7.83, 3.72 Hz, 1 H) 3.99 (br. s., 1 H) 4.65 (s, 2 H) 6.97 (br. s., 1 H) 7.05 (td, J=8.51, 2.15 Hz, 1 H) 7.15 (d, J=9.78 Hz, 1 H) 7.22 (d, J=7.43 Hz, 1 H) 7.27 (d, J=5.87 Hz, 1 H) 7.40 (td, J=7.92, 6.06 Hz, 1 H) 7.52 (s, 1 H) 7.98 (d, J=6.26 Hz, 1 H) 8.57 (s, 1 H).

Synthesis of 4-(((5'-chloro-2'-((trans-4-(((RV3.3.3-trifluoro-2-hvdroxy-2- methylpropyl)amino)cvclohexyl)amino)-[2,4'-bipyridinl-6-yl)amino)methyl)tetrahvdro-2H- pyran-4-carbonitrile

To a mixture of 4-(((2'-((trans-4-aminocyclohexyl)amino)-5'-chloro-[2,4'-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (26 mg, 0.059 mmol) in EtOH (0.3 mL) was added a solution of (R)-2-methyl-2-(trifluoromethyl)oxirane (360 μΐ_^, 0.065 mmol). The mixture was heated in as sealed tube for 30 min at 45 °C. Additional solution of (R)-2-methyl-2- (trifluoromethyl)oxirane (0.3 mL) was added and stirring was continued at 65 °C for -2.5 hrs. LCMS indicated -50% conversion. The reaction was stopped at this point. The mixture was concentrated under reduced pressure, the residue was diluted with DMSO, filtered through a syringe filter and purified by auto-preparative HPLC. Pure fraction was lyophilized providing 4- (((5'-chloro-2'-((trans-4-(((R)-3,3,3-trifluoro-2-hydroxy-2- methylpropyl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H- pyran-4-carbonitrile as its trifluoroacetic acid salt. Yield: 7.9 mg. LCMS (m/z): 567.1 [M+H]+; Retention time = 0.59 min.

The trifluoroacetic acid salt was dissolved in DCM (~2 mL) and stirred with 150 mg of carbonate based silica gel [Silicycle; particle size: 40-63 mikroM; loading: 0.8 mmol/g; lot#: 37446; cat#: R66030B] in ~1 mL of DCM for -30 min. The mixture was filtered and the clear solution concentrated under reduced pressure. Enantiomeric excess determination:

AD-column, 5 mL/min; IPA+0.1 % DEA=25%;

Column: CHIRALPAK AD (5 urn) 100 x 4.6 mm (Daicel Chemical Industries, LTD.).

Solvent: C0₂ : isopropyl alcohol+0.1%DEA = 75: 25

Flow rate: 5.0 mL/min; detection: UV = 220 nm.

Fraction 1 : Retention time: 2.12 min; 95.7% ee.

Fraction 2: Retention time: 2.61 min.

Synthesis of 4-(((6-(5-chloro-2-((trans-4-((2-hvdroxy-2- methylpropyl)amino)cvclohexyl)amino)pyridin-4-yl)pyrazin-2-yl)oxy)methyl)tetrahvdro-2H- pyran-4-carbonitrile

4-(((6-(2-((trans-4-aminocyclohexyl)amino)-5-chloropyridin-4-yl)pyrazin-2- yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile was dissolved in acetonitrile (2 mL), added lithium perchlorate (13.37 mg, 0.126 mmol), 2,2-dimethyloxirane (9.06 mg, 0.126 mmol).

Heated under argon in a sealed tube for -2.5 hrs (T-50 °C). The mixture was concentrated under reduced pressure, the residue was dissolved in DMSO and water, filtered through a syringe filter, purified py autoprep HPLC. Fractions were collected and lyophilized providing 4-(((6-(5- chloro-2-((trans-4-((2-hydroxy-2-methylpropyl)amino)cyclohexyl)amino)pyridin-4-yl)pyrazin-2- yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile as its trifluoroacetic acid salt as a yellowish solid. Yield: 4.1 mg. LCMS (m/z): 515.1 [M+H]+; Retention time = 0.57 min.

Examples in Table 1 were prepared using methods analogous to those described above. The 'method' column in Table 1 indicates the synthetic procedure, from a specific example, that was used to synthesize certain of the compounds. Thus for example, Compound 7 is synthesized by the procedure outlined in Example 2, while compound 25 is synthesized by the procedure outlined in Example 6, and the like. These methods can be adapted by the person of ordinary skill to synthesize additional compounds in the scope of the invention, such as compounds depicted in Table IB. Where the word 'chiral' appears with the structure in Table 1, it indicates that the compound was tested as one isomer having the stereochemistry shown. Where the structure illustrates absolute stereochemistry but the word 'chiral' is not present with the structure, the structure depicts relative stereochemistry of the chiral centers but the tested compound was not optically active.

Table 1.

Cmpd

Structure Method M+H RT No.

7 Example 2 396.2 0.57

8 Example 2 390.2 0.49

0

9 Example 2 346.2 0.47

10 Example 1 426.3 0.76

Cmpd

Structure Method M+H RT No.

11 Example 3 425.2 0.7

12 Example 4 439.3 0.71

13 Example 5 444.3 0.78

F

14 Example 5 409.3 0.44

Cmpd

Structure Method M+H RT No.

19 Example 5 423.3 0.45

20 Example 5 428.3 0.89

21 Example 5 447.3 0.71

22 Example 5 456.3 0.82

Cmpd

Structure Method M+H RT No.

23 Example 6 380.1 0.64

24 Example 6 443.3 0.71

25 Example 6 408.3 0.4

26 Example 6 415.2 0.53

Cmpd

Structure Method M+H RT No.

27 Example 6 407.2 0.66

28 Example 6 443.2 0.7

29 Example 6 441.2 0.73

30 Example 6 443.2 0.71

Cmpd

Structure Method M+H RT No.

31 Example 6 421.2 0.71

32 Example 6 437.3 0.66

33 Example 6 425.2 0.68

34 Example 6 439.2 0.74

Cmpd

Structure Method M+H RT No.

52 Example 9 440.1 0.82

53 Example 9 453.2 0.73

54 Example 8 455.3 0.7

H₃C

55 Example 8 456.3 0.79

Cmpd

Structure Method M+H RT No.

60 Example 6 433.2 0.63

61 Example 6 426.2 0.44

61 Example 6 443.2 0.74

63 Example 6 461.2 0.75

F

Cmpd

Structure Method M+H RT No.

80 1 H 1 F Example 11 497.3 0.58

81 1 H Example 14 487.3 0.6

82 Example 19 521 0.57

ti ^Chiral

83 Example 14 473.3 0.56

Cmpd

Structure Method M+H RT No.

t! ^chiral

84 Example 14 499.3 0.6

85 1 H Example 14 526.3 0.57

86 i^Nr^Mn Example 14 487.3 0.58

t! ^Chiral

87 Example 14 473.3 0.56

Cmpd

Structure Method M+H RT No.

t! ^Chiral

88 Example 14 499.3 0.6

89 1 H Example 14 459.3 0.55

90 Example 14 472.2 0.54

Η

91 1 Η Example 11 511.2 0.62

Cmpd

Structure Method M+H RT No.

t! ^Chiral

96 1 H Example 14 473.2 0.54

97 Example 14 485.2 0.54

98 Example 14 515.1 0.56

99 Example 14 517.2 0.57

Cmpd

Structure Method M+H RT No.

l_l AND Enantiomer

108

Using the synthetic methods described herein along with conventional methods in the art and available starting materials, the following additional compounds in Table IB can be prepared. These compounds contain combinations of features that are considered to be preferred based on the compounds and activities disclosed herein and in related CDK9 inhibitors.

Table IB

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd.

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

ı92 Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Table IB, cont'd

Biological Methods

Cdk9/cvclinTl IMAP Protocol

The biological activity of the compounds of the invention can be determined using the assay described below.

Cdk9/cyclinTl is purchased from Millipore, cat #14-685. The final total protein concentration in the assay 4nM. The 5TAMRA-cdk7tide peptide substrate, 5TAMRA- YSPTSPSYSPTSPSYSTPSPS-COOH, is purchased from Molecular Devices, cat#R7352. The final concentration of peptide substrate is ΙΟΟηΜ. The ATP substrate (Adenosine-5'- triphosphate) is purchased from Roche Diagnostics, cat#l 140965. The final concentration of ATP substrate is 6uM. IMAP (Immobilized Metal Assay for Phosphochemicals) Progressive Binding reagent is purchased from Molecular Devices, cat#R8139. Fluorescence polarization (FP) is used for detection. The 5TAMRA-cdk7tide peptide is phosphorylated by Cdk9/cyclinTl kinase using the ATP substrate. The Phospho-5TAMRA-cdk7tide peptide substrate is bound to the IMAP Progressive Binding Reagent. The binding of the IMAP Progressive Binding Reagent changes the fluorescence polarization of the 5TAMRA-cdk7tide peptide which is measured at an excitation of 531nm and FP emission of 595nm. Assays are carried out in lOOmM Tris, pH=7.2, 10mM MgC12, 0.05% NaN3, 0.01% Tween-20, lmM dithiothreitol and 2.5% dimethyl sulfoxide. IMAP Progressive Binding Reagent is diluted 1 :800 in 100% IX Solution A from Molecular Devices, cat#R7285.

General protocol is as follows: To lOul of cdk9/cyclinTl, 0.5ul of test compound in dimethyl sulfoxide is added. 5TAMRA-cdk7tide and ATP are mixed. lOul of the 5TAMRA- cdk7tide /ATP mix is added to start the reaction. The reaction is allowed to proceed for 4.5 hrs. 60uL of IMAP Progressive Binding Reagent is added. After >1 hr of incubation, plates are read on the Envision 2101 from Perkin-Elmer. The assay is run in a 384-well format using black Corning plates, cat#3573.

Cdk9/cyclinTl Alpha Screen Protocol

Full length wild type Cdk9/cyclin Tl is purchased from Invitrogen, cat#PV4131. The final total protein concentration in the assay InM. The cdk7tide peptide substrate, biotin- GGGGYSPTSPSYSPTSPSYSPTSPS-OH, is a custom synthesis purchased from the Tufts University Core Facility. The final concentration of cdk7tide peptide substrate is 200nM. The ATP substrate (Adenosine-5' -triphosphate) is purchased from Roche Diagnostics. The final concentration of ATP substrate is 6uM. Phospho-Rpbl CTD (ser2/5) substrate antibody is purchased from Cell Signaling Technology. The final concentration of antibody is 0.67ug/ml. The Alpha Screen Protein A detection kit containing donor and acceptor beads is purchased from PerkinElmer Life Sciences. The final concentration of both donor and acceptor beads is 15ug/ml. Alpha Screen is used for detection. The biotinylated-cdk7tide peptide is

phosphorylated by cdk9/cyclinTl using the ATP substrate. The biotinylated-cdk7tide peptide substrate is bound to the streptavidin coated donor bead. The antibody is bound to the protein A coated acceptor bead. The antibody will bind to the phosphorylated form of the biotinylated- cdk7tide peptide substrate, bringing the donor and acceptor beads into close proximity. Laser irradiation of the donor bead at 680nm generates a flow of short-lived singlet oxygen molecules. When the donor and acceptor beads are in close proximity, the reactive oxygen generated by the irradiation of the donor beads initiates a luminescence/fluorescence cascade in the acceptor beads. This process leads to a highly amplified signal with output in the 530-620nm range. Assays are carried out in 50mM Hepes, pH=7.5, 1 OmM MgC12, 0.1% Bovine Serum Albumin, 0.01% Tween-20, ImM Dithiolthreitol, 2.5% Dimethyl Sulfoxide. Stop and detection steps are combined using 50mM Hepes, pH=7.5, 18mM EDTA, 0.1% Bovine Serum Albumin, 0.01% Tween-20.

General protocol is as follows: To 5ul of cdk9/cyclinTl, 0.25ul of test compound in dimethyl sulfoxide is added. Cdk7tide peptide and ATP are mixed. 5ul of the cdk7tide peptide/ATP mix is added to start the reaction. The reaction is allowed to proceed for 5hrs. I OUL of Ab/ Alpha Screen beads/S top-detection buffer is added. Care is taken to keep Alpha Screen beads in the dark at all times. Plates are incubated at room temperature overnight, in the dark, to allow for detection development before being read. The assay is run is a 384- well format using white polypropylene Greiner plates.

The data shown in Table 2 provides IC-50's on CDK9, which were generated using the IMAP assay described above. That assay as used has a lower limit readout of 0.007946: where that value is reported in Table 2, the actual IC-50 may be lower. The upper limit of the readout is 25 micromolar. Table 2

10 0.007946

11 0.007946

12 0.007946

13 0.007946

14 0.007946

15 0.178446

16 0.007946

17 0.007946

18 0.012295

19 0.007946

20 0.504088

21 0.007946

22 0.039262

23 0.068197

24 0.007946

25 0.007946

26 0.008832

27 0.007946

28 0.01 1847

29 0.007946

30 0.007946

31 0.007946

32 0.016373

33 0.007946

34 0.01057

35 0.007946

36 0.028897

37 0.007946

38 0.019564

39 0.007946 40 0.007946

41 0.249184

42 0.007946

43 0.007946

44 0.007946

45 0.007946

46 0.007946

47 0.007946

48 0.007946

49 0.007946

50 0.007946

51

52

53

54 0.007946

55 0.012465

56 0.014617

57 0.007946

58 0.007946

59 0.007946

60 0.007946

61 0.007946

62 0.007946

63 0.007946

64 0.007946

65 0.304713

66 0.053559

67 0.007946

68 0.007946

69 0.007946 70 0.023503

71 0.009527

72 0.007946

73 0.012804

74 0.015904

75 0.04225

76 0.009614

77 0.007946

78 0.007946

79 0.015674

80 0.105615

81 0.024567

82 0.01 1543

83 0.01057

84 0.008687

85 0.022708

86 0.012306

87 0.014233

88 0.007946

89 0.008916

90 0.014858

91 0.027465

92 0.007946

93 0.034267

94 0.023095

95 0.016486

96 0.020673

97 0.027903

98 0.008557

99 0.018667 100 0.010893

101 0.009314

102 0.026035

103 0.024087

104 0.053173

105 0.015444

106 0.007946

107 0.007946

108 0.041

Claims

A compound of Formula (I):

A₃ is N or CR₈;

Ri is -X-Rie;

X is a bond, or Ci_-4 alkylene;

Ri₆ is selected from the group consisting of Ci-₆ alkyl, C3-₆branched alkyl, C3- ₈Cycloalkyl, C3-10 heterocycloalkyl, C3-8-partially unsaturated cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C₆-io aryl- or C₅_6-heteroaryl-fused C₅-7 heterocycloalkyl, and C3-10 partially unsaturated heterocycloalkyl wherein R½ is substituted with up to three groups independently selected from halogen, Ci-₆alkyl, Ci-₆haloalkyl, C3_₆branched alkyl, C3_₆branched haloalkyl, OH, oxo, Ci-₆alkoxy, heterocycloalkyl, Ci_-2alkyl-heterocycloalkyl, Ci_-2alkyl-heteroaryl, -R₂₂-ORi_2i S(0)o-₂Ri₂, -R₂₂-S(0)o-₂Ri₂, S(0)₂NRi3Ri₄, -R₂₂-S(0)₂NRi₃Ri₄, -C(0)ORi₂, -R₂₂-C(0)ORi₂, C(0)Ri9, -R₂₂-C(0)Ri9, O-Ci-3 alkyl, OCi_-3 haloalkyl, OC(0)Ri₉, -R₂₂-OC(0)Ri₉, C(0)NRi₃Ri₄, -R₂₂-C(0)NR₁₃Ri₄, NR₁₅S(0)₂R₁₂, -R₂₂-NR₁₅S(0)₂R₁₂, -NR₁₇R₁₈, -R₂₂-NR₁₇R₁₈, NRi₅C(0)Ri9, -R₂₂-NRi₅C(0)Ri9, NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)OCH₂Ph, NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)ORi₂, NRi₅C(0)NRi₃Ri4, and -R₂₂-NRi₅C(0)NRi₃Ri₄;

Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, hydroxyl, Ci-₆alkyl, Ci-₆haloalkyl, C3-₆branched alkyl, C3-8 cycloalkyl, Ci_-4-alkyl-C3-8-cycloalkyl, C3-8 heterocycloalkyl, Ci_-4-alkyl-C3-8 heterocycloalkyl, R₂₂-ORi_2i R₂₂-S(0)o_-2Ri_2, -R₂₂- S(0)₂NRi₃Ri4, -R₂₂-C(0)ORi2, -R₂₂-C(0)Ri₉, -R₂₂-OC(0)Ri₉, -R₂₂-C(0)NRi₃Ri₄, -R₂₂- NRi₅S(0)₂Ri2, -R₂₂-NR₂₃R₂₄, -R₂₂-NRi₅C(0)Ri₉, .R₂₂-NRi₅C(0)OCH₂Ph, -R₂₂-NRi₅C(0)ORi₂, -R₂₂-NRi₅C(0)NRi₃Ri₄, -R₂₂-cycloalkyl, -R₂₂-heterocycloalkyl, heteroaryl, and -R₂₂-heteroaryl; wherein each alkyl, cycloalkyl, branched alkyl, heterocycloalkyl, and heteroaryl can be

20

substituted with up to two groups selected from R ;

alternatively, R17 and Ri₈ along with the nitrogen atom to which they are attached can be taken together to form a four to six or seven or eight-membered heterocyclic ring containing up to two heteroatoms selected from N, O and S as ring members and optionally fused to an optionally substituted 5-6 membered aryl or heteroaryl ring, wherein the carbon atoms of said rings are optionally substituted with R₂o, and the nitrogen atoms of said rings are optionally substituted with R₂i;

R₂o is selected from the group consisting of oxo (=0), halo, amino, hydroxy, Ci-6 alkoxy,

Ci-6 alkyl and Ci-6 haloalkyl;

R₂₂ is selected from the group consisting of Ci-₆ alkylene, Ci-₆haloalkylene, C3-6 branched alkylene, C3_₆branched haloalkylene; R23 and R24 are each, independently, selected from the group consisting of hydrogen, C_1-6 alkyl, Ci-₆ acyl, Ci-₆haloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl;

R₂ is selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C3-8 branched alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted C₆-io aryl, and optionally substituted C_5- 10 heteroaryl;

Ri_a, Ri , R5, and Re are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C_1-4 alkyl, Ci_-4haloalkyl, C_2-4 alkenyl, C_2-4 alkynyl, amino, NR10R11, and alkoxy;

R3, R7 and Rs are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, NR10R11, C(0)Ri₂, C(0)ORi2, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(0)o-₂NRi₃Ri₄, morpholino, tetrazolyl, and optionally substituted C3_-4 cycloalkyl;

R9 is selected from the group consisting of hydrogen, C_1-4 alkyl, alkoxy, C(0)Ri₂, C(0)ORi5_, C(0)NRi₃Ri₄, S(O)₀-₂Ri₂ , S(0)o-₂NRi₃Ri₄, optionally substituted C_3-4 cycloalkyl, and optionally substituted heterocycloalkyl;

Rio and Rn are each, independently, selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C(0)Ri₂, C(0)ORi_2, C(0)NRi₃Ri₄, S(O)_0-2Ri₂, and S(O)_0-2NRi3Ri₄; alternatively, Rio and Rn along with the nitrogen atom to which they are attached to can be taken together to form an optionally substituted four to six membered heteroaromatic, or a non- aromatic heterocyclic ring;

2. The compound of Claim 1, wherein:

Ai is CRe, and

A₃ is CR₈. 3. The compound of Claim 1, wherein:

Ai is N; and

A₃ is CR₈.

4. The compound of Claim 1, wherein:

Ai is CRe; and

A₃ is N.

5. The compound of any of claims 1-4, wherein A₄ is O or NH. 6. The compound of any of claims 1-5, wherein R₂ is selected from C3-6 cycloalkyl, C5-6 heterocycloalkyl, phenyl, and pyridyl, each of which is substituted with one to three groups selected from Me, OMe, CN, OH, CF₃, ethynyl, ethenyl, CONH₂, COOH, COOMe, halo, NH₂, and NMe₂. 7. The compound of any of claims 1 -6, wherein -L-R₂ is

where each R^* is independently H, F, CI, -OCHF₂, -C(0)-Me, -OH, Me, -OMe, CF₃, ethynyl, vinyl, -CN, -Ethyl, -CONH₂, or -NH-C(0)-Me.

8. The compound of any of claims 1 -7, wherein Rn_a and Ri are both H.

9. The compound of any of claims 1-8, wherein X is a bond, and R½ is C₃-₇ cycloalkyl, and is substituted with -NR₁₇R₁₈.

10. The compound of any of claims 1-9, wherein R½ is substituted with a group -NRi₇Ri₈ of the formula

wherein each R' is H, Me, or Et.

11. The compound of any of claims 1-10, wherein:

Rs is selected from halogen, hydrogen, CN, CF₃, O-Ci-₃-alkyl, and Ci-₃-alkyl.

12. The compound of claim 11, wherein:

Rs is selected from H, CI, F, and methyl.

13. The compound of claim 12, wherein:

Rs is CI or F.

14. The compound of any of claims 1-13, wherein:

X is a bond, -CH₂- or -(CH₂)₂-;

Ri₆ is selected from the group consisting of Ci_-2-alkyl, C4-₆Cycloalkyl, C₃-10 heterocycloalkyl, phenyl, and heteroaryl, wherein R_½ is substituted with one to three groups independently selected from halogen, Ci-₃alkyl, C₃_₆branched alkyl, OH, Ci_ 2alkoxy, R₂₂-ORi2_, S(0)i_-2Ri₂, C(0)ORi₂, R₂₂-C(0)ORi₂, C(0)Ri₉, R₂₂-OC(0)Ri₉, C(0)NRi₃Ri4, NRi₅S(0)₂Ri2, NR₁₇R₁₈, R₂₂-NRi₇Ri₈, NRI₅C(0)RI₉, R₂₂-NRI₅C(0)RI₉,

15. The compound of Claim 1 or claim 14, wherein:

Ri6 is selected from the group consisting of Ci-2-alkyl, cyclopentyl, cyclohexyl, piperidine, piperazine, morpholine, pyridine, pyrrolidine, cyclohexenyl, and tetrahydro- 2H-pyran; wherein R½ is substituted with one to three groups selected from amino, hydroxyl, NHCH₂-phenyl, CH₂-amino, COO-i-butyl, methoxy, NH-S0₂-ethyl, CH₂- NHS0₂-ethyl, S0₂-ethyl, i-butyl, methyl, CH₂-COOH, CO-NHCH₃, CON(CH₃)₂, NHC(CH₃)-CH₂-S0₂-CH₃, NH-COO-CH₂-phenyl, hydroxy-methyl, CH₂-NH-CH₃, CH₂- NH-ethyl, NH-CH₂-CH₂-methoxy, CH₂-NH-CO-CH₃, NH-CH₂-CH₂OH, NH-CO-CH₂- N(CH₃)₂, NH-CO-methylpyrro dine, NH-CH₂-C(CH₃)-dioxolane, NH-CO-pyridyl, NH- ethyl, pyrrolidine, CH₂-NH-CO-pyndyl, NH-tetrahydropyran, COCH₂-N(CH₃)₂, NH- CH₂-C(CH₃)-dimethyldioxolane, tetrahydropyran, CO-methylpyrrolidine, CH₂- methylpipendine, NH-CO-CH₃, NH-S0₂-CH₃, NH-CH(CH₂-OCH₃)₂, NH-CH₂- tetrahydrofuran, NH-CH₂-oxetane, NH-tetrahydropyran, NH-CH₂-dioxane, N(CH₃)- CH₂CH₂-OCH₃, CH(OH)-CH₂-amino, NH-CH₂CH₂-OCF₃, NHCH₂-OCH₃, NH-CH₂- CH(CF₃)-OCH₃, NH-CH(CH₃)-CH₂-OH, F, NH-oxetane, CH₂-CH₂-OCH₃, CH₂-OCH₃, CH₂-tetrahydropyran, CH₂-methylpiperizine, NH₂-CH₂-CH(OH)-CF₃, piperidine, CH₂- pyrrolidine, NH-CH(CH₃)CH₂OCH₃, NH-tetrahydrofuran, (CH₂)₃-NH₂, hydroxyethyl, propyl, CH₂-pyridyl, CH₂-piperidine, morpholine, NH-chloropyrimidine, NH-CH₂CH₂- -methyl, (CH₃)₃-N(CH₃)₂, piperizine,

and CH₂-morpholine.

16. The compound of any one of claims 1-15, wherein:

R₃ is selected from H, methyl, cyano, chloro, CONH₂, amino, cyclopropyl, ethyl, and fluoro;

Re is H; R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃;

R₈ is CI;

Ri₇ and Ri₈ are each, independently, selected from the group consisting of hydrogen, Ci-3alkyl, Ci-4haloalkyl, C3-6branched alkyl, R22-OR12_, R22-S(0)₂Ri2, R22- NRi₅S(0)₂Ri₂, heterocycloalkyl or heteroaryl; alternatively, R17 and Ri₈ along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R₂₀, and the ring nitrogen atoms are optionally substituted with R₂₁;

Ri₉ is selected from Ci-3-alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

R₂₀ represents the group Ci-3alkyl; and

R₂₂ is selected from the group consisting of Ci-₄alkylene, and C₃-6 branched alkylene.

17. The compound of claim 1 or claim 16, wherein:

A₄ is selected from NR₉, O, and a bond;

L is selected from a bond, Ci_-4-alkyl, and cyclopropyl;

R₂ is selected from the group consisting of C₃-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R₂ group is substituted with up to three substituents independently selected from cyano, CO-NH₂, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalo alkyl, Ci-3-alkyl, and hydroxy; and

R9 represents methyl, hydrogen, or ethyl.

18. The compound of Claim 1, wherein:

X represents a bond;

Ri6 is selected from cyclohexyl, and C₂-₅-alkyl, wherein each said R½ group is substituted with 1 to 2 substituents selected from amino, methyl-amino, hydroxy, amino-ethyl, dimethyl- amino, NH-(CH₂)₂-0-ethyl, NH-S0₂-methyl, CH₂-NH-S0₂-methyl, piperidinyl, pyrrolidinyl, NH-CH₂-CF₃, NH-(CH₂)₂-0-methyl, N(CH₃)-(CH₂)i-₂-methoxy, NH-CH₂-CH(CH₃)-OH, NH- CH₂-tetrahydrofuranyl, NH-(CH₂)₂-OH, NH-CH₂-CONH₂, NH(CH₂)₂-CF₃, methylpyrrolidin-3- ol, NH-(CH₂)₂-pyrrolidinyl, NH-CH₂-COOH, NH-CH₂-dioxane, NH-oxetane, NH- tetrahydrofuranyl, morpholinyl, NH-(CH₂)2-0-(CH₂)2-OCH3, NH-(CH₂)₂-CONH₂, and

R₂ is selected from CONH₂, COCH₃, S0₂-methyl, CH₂-fluorophenyl, CH₂- difluorophenyl, CH2-chlorophenyl, CH2-pyridyl, CH2-cyclopropyl, CH2-cyclohexyl, CF^-cyano- phenyl, CH2-tetrahydropyran, benzyl, CH2-toluyl, and CH2-methoxy-phenyl;

A₄ is selected from NR₉, CONR₉, and O;

L is a bond;

R3 is selected from H, CONH2, hydroxyethyl, chloro, cyano, fluoro, and methoxy;

Rzta and R^, are independently selected from H, and fluoro;

R5 represents H;

R6 represents hydrogen;

R7 is selected from H, cyano, and fluoro; and

Re is selected from hydrogen, and chloro. 19. The compound of claim 1, wherein A 1 is CH;

A₃ is C-Cl or C-F;

R₅ is H;

20. The compound of claim 1, which is a compound selected from the compounds disclosed in Table 1 or Table IB.

21. The compound of Claim 1, which is a compound of Formula (II):

wherein:

Ai is N or CH;

Rs is selected from F, CI and Me;

R₇ is selected from H, CI, F, CN;

R₃ is selected from H, halo, CN, Me and OMe;

X is a bond, CH₂ or (CH₂)₂;

Ri6 is optionally substituted cyclohexyl;

A₄ is NH or O;

and R₂ is selected from optionally substituted cyclopropyl, optionally substituted tetrahydropyran, optionally substituted phenyl, and optionally substituted pyridyl; or a pharmaceutically acceptable salt thereof.

The compound of Claim 21, wherein:

Ai is CH.

The compound of Claim 21 or 22, wherein:

Re is selected from CI, F, and methyl.

The compound of Claim 23, wherein:

Rs is CI.

The compound of Claim 21, wherein:

X is a bond; Ri6 is substituted with one to three groups independently selected from halogen, Ci_-3alkyl, C₃-₆branched alkyl, OH, Ci_-2alkoxy, R₂₂-ORi_2, S(0)i_-2Ri₂, C(0)ORi₂, R₂₂- C(0)ORi2, C(0)Ri9, R₂₂-OC(0)Ri9, C(0)NRi₃Ri₄, NRi₅S(0)₂Ri₂, NRi₇Ri₈, R₂₂- NRi₇Ri8, NRi₅C(0)Ri9, R₂₂-NRi₅C(0)Ri9, and NRi₅C(0)OCH₂Ph.

The compound of Claim 21 or 25, wherein:

Ri6 is

27. The compound of Claim 1, wherein:

R4 is selected from halogen, methyl, hydrogen, and halo-methyl;

R₇ is selected from H, COOH, CI, F, CONH₂, CN, and CF₃;

R₈ is Cl;

Ri₇ and Ri8 are each, independently, selected from the group consisting of hydrogen, Ci_-3alkyl, Ci_-4haloalkyl, C_3-6branched alkyl, R₂₂-ORi_2i R₂₂-S(0)₂Ri₂, R₂₂- NRi₅S(0)₂Ri₂, heterocycloalkyl or heteroaryl; alternatively, Ri₇ and Ri8 along with the nitrogen atom to which they are attached to can be taken together to form a four to six membered heterocyclic ring wherein said ring carbon atoms are optionally substituted with R₂o, and the ring nitrogen atoms are optionally substituted with R₂₁;

Ri9 is selected from Ci_-3-alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R₂o represents the group Ci_-3alkyl; and

R₂₂ is selection from the group consisting of Ci_-4alkyl, and C₃-₆ branched alkyl.

28. The compound of Claim 1, wherein: A₄ is selected from NR₉, O, and a bond;

L is selected from a bond, Ci_-4-alkyl, and cyclopropyl;

R₂ is selected from the group consisting of C3-7 cycloalkyl, a five to seven membered heterocycloalkyl, phenyl, and pyridyl, wherein each said R₂ group is substituted with one, two, or three substituents independently selected from hydrogen, cyano, CO-NH₂, -C≡CH, halogen, methoxy, dihalo-methoxy, trihalo-methoxy, trihalomethyl, Ci-3-alkyl, and hydroxy; and

R₉ represents methyl, hydrogen, or ethyl.

29. The compound of Claim 1, wherein the group -A₄-L-R₂ represents the group

wherein Z is selected from Me, Et, CF₃, OMe, OH, CN, vinyl, -C≡CH, and CONH₂, and L is -CH₂- or -CH₂CH₂-.

30. The compound of Claim 1, wherein:

X represents a bond;

Ri6 represents cyclohexyl, wherein said cyclohexyl group is substituted with 1 to 2 substituents selected from amino, methyl-amino, hydroxy, amino-ethyl, dimethyl-amino, NH- (CH₂)₂-0-ethyl, NH-S0₂-methyl, CH₂-NH-S0₂-methyl, piperidinyl, pyrrolidinyl, NH-CH₂-CF₃, NH-(CH₂)₂-0-methyl, N(CH₃)-(CH₂)_1-2-methoxy, NH-CH₂-CH(CH₃)-OH, NH-CH₂- tetrahydrofuranyl, NH-(CH₂)₂-OH, NH-CH₂-CONH₂, NH(CH₂)₂-CF₃, methylpyrrolidin-3-ol, NH-(CH₂)₂-pyrrolidinyl, NH-CH₂-COOH, NH-CH₂-dioxane, NH-oxetane, NH- tetrahydrofuranyl, morpholinyl, NH-(CH₂)₂-0-(CH₂)₂-OCH₃, NH-(CH₂)₂-CONH₂, and

N(CH₂CH₂OCH₃)₂;

A₄ is selected from NR₉, CONR₉, and O;

L is a bond; R3 is selected from H, CONH₂, hydroxyethyl, methyl, tetrazole, chloro, cyano, fluoro, and methoxy;

Ri_a and Ri are independently selected from H, and fluoro;

R₅ represents H;

R6 represents hydrogen;

R7 is selected from H, cyano, and fluoro; and

Re is selected from hydrogen, and chloro.

31. A method of treating a disease or condition mediated by CDK9 comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Claims 1-30, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the disease or condition mediated by CDK9 is selected from cancer, cardiac hypertrophy, HIV and inflammatory diseases

33. The method of Claim 32 wherein the disease or condition mediated by CDK9 is cancer

34. The method of Claim 33 wherein the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.

35. A pharmaceutical composition comprising a compound according to any one of claims 1- 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

36. The pharmaceutical composition of claim 35, comprising at least two pharmaceutically acceptable excipients.

A compound according to any one of claims 1-30 for use in therapy.

38. The compound of claim 37 wherein the therapy is to treat a condition selected from the group consisting of cancer, cardiac hypertrophy, HIV, and inflammatory diseases.

39. The compound of claim 38, for use to treat cancer.

40. The compound of claim 39, wherein the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.

41. Use of a compound of any of claims 1-30 for the manufacture of a medicament.

42. The use of claim 40, wherein the medicament is a medicament for the treatment of cancer.