Piperidine derivatives as inhibitors of nicotinamide n-methyl transferase

Abstract

There are disclosed certain piperidine derivatives of Formula (I), and pharmaceutically acceptable salts thereof, together with compositions containing them and their use in therapy. The compounds are inhibitors of the and nicotinamide N-methyl transferase (NNMT) are thereby particularly useful in the treatment or prophylaxis of, for example chronic kidney disease, acute kidney injury or heart failure.

Description

[0001] PIPERIDINE DERIVATIVES AS INHIBITORS OF NICOTINAMIDE N-METHYL

[0002] TRANSFERASE

[0003] TECHNICAL FIELD

[0004] The technical field relates to certain piperidine derivatives of Formula (I), to their use in the treatment of a nicotinamide N-methyl transferase related disease or condition, for example chronic kidney disease, acute kidney injury or heart failure.

[0005] BACKGROUND

[0006] Nicotinamide N-methyl transferase (NNMT) is a cytosolic methyl transferase expressed in many tissues with highest expression in liver, adipose tissue and blood vessels. In healthy kidney tissue, expression is very low, but increases markedly in chronic kidney disease (CKD).

[0007] NNMT catalyzes the transfer of a methyl group from S -adenosyl L-methionine (SAM) to nicotinamide producing 1-methyl nicotinamide (1-MNA) and S-adenosyl L-homocysteine (SAH) which can be further metabolized to homocysteine. Metabolism of nicotinamide to 1- MNA by NNMT and further to N-methyl-2-pyridone-5-carboxamide (N-Me-2Py) and N- methyl-4-pyridone-3 -carboxamide (N-Me-4Py) via aldehyde oxidase leads to its excretion (Trends Endocrinol Metab., 2017, 28(5), 340-353). N-Me-2Py has been reported to be a uremic toxin (Toxins 2016, 8, 339). High NNMT-activity may affect cellular homeostasis of nicotinamide adenine dinucleotide (NAD+) by preventing nicotinamide from entering NAD+salvage pathway (Int J Mol Sci., 2023, 24, 137).

[0008] The heart and the kidneys are the most energy demanding organs in the body. Large amounts of ATP is required in kidney tubules to support solute transport. NAD+is required for the metabolism of glucose, pyruvate and fatty acids to acetyl-CoA and for metabolism of the latter in the Krebs cycle. The NADH generated in these processes is then used for ATP production in the electron transport chain. NAD+is a also an important co-factor for the NAD+-dependent enzymes: sirtuins, PARPs and CD38 (Mol Sci., 2023, 24, 137).

[0009] Increase in cellular NNMT activity may also shift the ratio of SAM / SAH and thereby affect additional SAM-dependent methyl transferases, possibly leading to epigenetic changes. High NNMT activity will also lead to increased production of homocysteine (Atherosclerosis, 2009, 204(2), 412-7). Transcriptomic analysis has demonstrated that NNMT is highly increased in human CKD of different etiologies including diabetic kidney disease (DKD) and highest NNMT expression in the tubulointerstitial compartment, particularly in proximal tubule cells (Int. J. Gen. Med., 2023, 3331-3344). Sci. Rep., 2022, 12, 6398) also report that NNMT localizes to atrophic tubular cells in fibrotic lesions in human CKD.

[0010] In serum from CKD patients, N-Me-2Py and N-Me-4Py increase and nicotinamide decrease with increasing CKD-stage (Sci. Rep., 2022, 12, 6398). Doke, T et al (Nat. Metab., 2023, Mar. 5, 414-430) report decreased nicotinamide and NAD+levels in kidney biopsies from CKD-patients.

[0011] Current standard of care for chronic kidney disease, that is, inhibitors of the renin-angiotensin- aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) and more recently, inhibitors of the sodium / glucose cotransporter 2 (SGLT2), slow down progression of CKD. Despite this treatment, many patients still continue to loose kidney function and progress towards end-stage kidney disease (ESKD) requiring kidney-replacement therapy - dialysis or kidney transplantation (N. Engl. J. Med., 2020, 383, 1436; Cardiovasc Diabetol., 2021, 20, 36).

[0012] Pharmacological inhibition of NNMT activity could stop the progression of tubular and glomerular injury and thereby the decline in kidney function in different forms of CKD, including diabetic kidney disease, DKD (Int. J. Gen. Med., 2023, 16, 3331-3344).

[0013] Acute kidney injury (AKI) is associated with decreased kidney NAD+levels. Different approaches aimed at increasing kidney NAD+levels by supplementation with nicotinamide (NAM), nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) have shown protective effect in preclinical models of AKI (Clin Kidney J, 2021, 14(12), 2453-2462). Since inhibition of NNMT is expected to increase NAD+, NNMT -inhibitors may also be beneficial in AKI.

[0014] In heart failure with preserved ejection fraction (HFpEF), cardiac levels of NAD+are decreased and in preclinical models of HFpEF, nicotinamide supplementation improved cardiac function, suggesting that NNMT -inhibition may also be beneficial in HFpEF (Sci. Trans. Med, 2021, 13, 580).

[0015] Molecules 2021, 26, 991 disclose small molecule inhibitors of NNMT.

[0016] J. Med. Chem. 2022, 65 (21), 14642 disclose azaindole carboxamide inhibitors of NNMT. WO2021163583 and WO2023129513 disclose NNMT inhibitors and methods of inhibiting tumor growth.

[0017] J. Med. Chem. 2019, 62 (21), 9837 disclose alkynyl inhibitors of NNMT.

[0018] WO2023129512 disclose NNMT inhibitors and methods of inhibiting tumor growth.

[0019] Bioorg. Med. Chem. Lett. 2018, 28, 922 and WO2021025975 disclose nicotinamides that inhibits NNMT.

[0020] US 10,087,449 B2 discloses a therapeutic agent for treating chronic kidney disease comprising a substance which inhibits the enzymatic activity of NNMT.

[0021] WO2018183668 disclose quinoline derived small molecule inhibitors of NNMT.

[0022] WO2012068463 discloses methods of inhibiting NNMT production or activity in a cell, and methods of treating or preventing obesity or a related metabolic condition, comprising administering a NNMT antagonist.

[0023] An object is to provide compounds that are inhibitors of nicotinamide N-methyl transferase (NNMT), their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.

[0024] SUMMARY

[0025] There is provided a compound of Formula (I) wherein

[0026] R! is selected from a 8-, 9- or 10-membered heteroaryl substituted by R^, R10 and 0, 1 or 2 substituents independently selected from R^;

[0027] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3; is selected from a 5- or 6-membered heteroaryl substituted by 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from RIS or a 8-, 9- or 10-membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from R13;

[0028] R^ is selected from H, OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0029] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3;

[0030] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0031] R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC3. 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0032] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0033] R^ is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC3. 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O (oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0034] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0035] R11is independently selected from H, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CH2cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3; R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0036] RIS is selected from a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0037] The compounds of Formula (I) are NNMT inhibitors. Thus, the compounds of Formula (I) may be used as a medicament, in particular for disorders, diseases or conditions responsive to inhibition of NNMT, and more specifically chronic kidney disease or kidney conditions or disorders in mammals including man. Further, the disclosed compounds are particularly indicated for use in the treatment of acute kidney injury (AKI), diabetic kidney disease (DKD), heart failure (HF), cardiorenal syndrome (CRS), metabolic dysfunction-associated steatohepatitis (MASH) and arrhythmia conditions or disorders in mammals including man. Conditions or disorders that may be specifically mentioned include diabetic kidney disease, hypertensive nephropathy, rapidly progressive glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, focal segmental glomerulosclerosis and acute kidney injury, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, in which NNMT plays a role.

[0038] DETAILED DESCRIPTION

[0039] This detailed description and its specific examples, while indicating embodiments, are intended for purposes of illustration only. Therefore, there is no limitation to the illustrative embodiments described in this specification. In addition, it is to be appreciated that various features that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

[0040] Listed below are definitions of various terms used in the specification and claims.

[0041] It is to be understood that where in this specification a group is qualified by “defined above” said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.

[0042] It is to be understood that in this specification “€4.3” means a carbon group having 1, 2 or 3 carbon atoms.

[0043] It is to be understood that in this specification “C^” means a carbon group having 1 or 2 carbon atoms.

[0044] It is to be understood that in this specification “cyPr” means cyclopropyl.

[0045] It is to be understood that in this specification “cyBu” means cyclobutyl.

[0046] In this specification, unless stated otherwise, the term “alkyl” includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n- propyl or z-propyl.

[0047] It is to be understood that in this specification “8-, 9- or 10-membered heteroaryl” means a bicyclic aromatic or partially aromatic ring with 8, 9 or 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.

[0048] It is to be understood that in this specification “5- or 6-membered heteroaryl” means an aromatic ring with 5 or 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.

[0049] It is to be understood that in this specification “6-membered heterocycloalkyl” means a partially or completely saturated ring system with 6 atoms and wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulphur.

[0050] It is to be understood that in this specification a “heterocycloalkyl” substituent may be attached via a nitrogen atom having the appropriate valences, or via any ring carbon atom.

[0051] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g. a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0052] In one embodiment, there are provided compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein R!-R13 and m are as defined in Formula (I).

[0053] In one embodiment R1 is selected from a 8-, 9- or 10-membered heteroaryl substituted by R^, R10 and 0, 1 or 2 substituents independently selected from R^.

[0054] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0055] R^ is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl.

[0056] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or

[0057] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0058]

[0059]

[0060] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl. is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl.

[0061] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or

[0062] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3. n is 0, 1 or 2.

[0063]

[0064] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or Cl.

[0065] R^ is independently selected from C^.2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCi_2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl.

[0066] R10is selected from H, CH3, CH2F, CHF2, CF3or CH2CH3. n is 0, 1 or 2.

[0067]

[0068] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl. is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl. n is 0, 1 or 2.

[0069]

[0070] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl. is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl. n is 0, 1 or 2.

[0071] In still a further embodiment, R* is selected from

[0072] R8is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl. is independently selected from C^.2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCj_2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl. n is 0, 1 or 2.

[0073] In still a further embodiment, R* is selected from

[0074] R8is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or Cl. is independently selected from C^.2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCi_2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl. n is 0, 1 or 2.

[0075] In one embodiment, is independently selected from H, CH3, CH2F, CHF2and CF3. In a further embodiment, is independently selected from H and CH3.

[0076] In still a further embodiment, is H.

[0077] In one embodiment, R^ is selected from a 5- or 6-membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from R13 or a 8-, 9- or 10- membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from R11, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from R13.

[0078] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0079] R11is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0080] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0081] R13 is selected from a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S orN wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -O(6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3.

[0082] In a further embodiment, R^ is selected from

[0083]

[0084] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3. R11is independently selected from H, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3. R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3,

[0085] CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0086] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3. p is 0, 1 or 2. q is 0, 1 or 2.

[0087] In still a further embodiment, R^ is selected from

[0088]

[0089] R8 is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or Cl.

[0090] R10is selected from H, CH3, CH2F, CHF2, CF3or CH2CH3.

[0091] Rll is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0092] R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3,

[0093] CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH.

[0094] p is 0, 1 or 2. q is 0, 1 or 2.

[0095] In still a further embodiment, is selected from

[0096] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or

[0097] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0098] R11is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5

[0099] F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0100] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0101] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from

[0102] O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or (CO)CH3. p is 0, 1 or 2. q is 0, 1 or 2.

[0103] In still a further embodiment, R^ is selected from

[0104] R10is selected from H, CH3, CH2F, CHF2, CF3or CH2CH3.

[0105] Rll is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0106] R12 is independently selected from H, OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH. p is 0, 1 or 2. q is 0, 1 or 2.

[0107] In still a further embodiment, is selected from R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0108] R11is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3. p is 0, 1 or 2.

[0109] In still a further embodiment, R^ is selected from

[0110] R10is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0111] Rll is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu. p is 0, 1 or 2.

[0112] In one embodiment, R^ is selected from H, OH, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl.

[0113] In a further embodiment, R^ is selected from H, OH, OC | _3alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, CN, F.

[0114] In still a further embodiment, R^ is selected from OH, OCH3, OCH2F, OCHF2, OCF3, - CH2OH, CN, F.

[0115] In still a further embodiment, R^ is OH.

[0116] In still a further embodiment, R^ is OCH3.

[0117] In one embodiment, R^ is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3. In a further embodiment, R$ is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3.

[0118] In still a further embodiment, R$ is independently selected from H, F, OH, OCH3 or CH3.

[0119] In still a further embodiment, R^ is independently selected from H, F or OH.

[0120] In still a further embodiment, R$ is independently selected from H or OH.

[0121] In one embodiment, R^ is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3 or F.

[0122] In a further embodiment, R^ is independently selected from H, CH3, CH2F, CHF2 or CF3.

[0123] In still a further embodiment, R^ is independently selected from H or CH3.

[0124] In one embodiment, R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu.

[0125] In a further embodiment, R^ is selected from H, F, Cl, CN or C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F.

[0126] In still a further embodiment, R^ is selected from H, F, CH3 or CN.

[0127] In still a further embodiment, R^ is H.

[0128] In one embodiment, R& is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0129] In a further embodiment, R^ is selected from H, CH3, CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0130] In still a further embodiment, R^ is selected from H, CH3 or OCH3.

[0131] In still a further embodiment, R& is CH3.

[0132] In one embodiment, R^ is independently selected from H, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl. In a further embodiment, is independently selected from H, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, - CH(CH3)2, CN, F or Cl.

[0133] In still a further embodiment, is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CN, F or Cl.

[0134] In still a further embodiment, R^ is independently selected from H, CH3, OCH3, CN, F or Cl.

[0135] In one embodiment, R^® is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0136] In a further embodiment, R^® is selected from H or CH3.

[0137] In one embodiment, R11is independently selected from H, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CH2cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0138] In a further embodiment, R11is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0139] In still a further embodiment, R11is independently selected from H, CH3, CH2CH3, OCH3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0140] In still a further embodiment, R11is independently selected from H, CH3 or OCH3.

[0141] In one embodiment, Rl^ is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0142] In a further embodiment, R!2 is independently selected from H, CH3, OCH3, CN, Cl or

[0143] CH2OH.

[0144] In still a further embodiment, R!2 is independently selected from H, CH3, OCH3, CN or Cl.

[0145] In one embodiment, Rl^ is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -O(6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or (CO)CH3.

[0146] In a further embodiment, Rl^ is selected from H,

[0147] In one embodiment, m is 0, 1 or 2.

[0148] In a further embodiment, m is 0 or 1.

[0149] In still a further embodiment, m is 2.

[0150] In still a further embodiment, m is 1.

[0151] In still a further embodiment, m is 0.

[0152] In one embodiment, n is 0, 1 or 2.

[0153] In a further embodiment, n is 0 or 1.

[0154] In still a further embodiment, n is 2.

[0155] In still a further embodiment, n is 1.

[0156] In still a further embodiment, n is 0.

[0157] In one embodiment, p is 0, 1 or 2.

[0158] In a further embodiment, p is 0 or 1.

[0159] In still a further embodiment, p is 2.

[0160] In still a further embodiment, p is 1.

[0161] In still a further embodiment, p is 0.

[0162] In one embodiment, q is 0, 1 or 2.

[0163] In a further embodiment, q is 0 or 1.

[0164] In still a further embodiment, q is 2.

[0165] In still a further embodiment, q is 1.

[0166] In still a further embodiment, q is 0. In one embodiment, there are provided compounds of Formula (I) wherein

[0167] R! is selected from a 8-, 9- or 10-membered heteroaryl substituted by R8, R10 and 0, 1 or 2 substituents independently selected from R^;

[0168] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0169] R^ is selected from a 5- or 6-membered heteroaryl substituted by R*^, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from RIS or a 8-, 9- or 10-membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from R13;

[0170] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0171] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3;

[0172] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0173] R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0174] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0175] R^ is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O (oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0176] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3; R11is independently selected from H, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or

[0177] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0178] R12 is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0179] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or

[0180] 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0181] In a further embodiment, there are provided compounds of Formula (I) wherein R1 is selected from

[0182] endently selected from H, CH3, CH2F, CHF2 and CF3;

[0183]

[0184] R4 is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl; R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3;

[0185] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0186] R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu; R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0187] R^ is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O (oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl; R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0188] R11is independently selected from H, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or

[0189] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0190] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0191] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or

[0192] 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0193] In a further embodiment, there are provided compounds of Formula (I) wherein

[0194]

[0195] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0196] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0197] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0198] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCp 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0199] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl; is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0200] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0201] R11is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0202] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0203] R13 is selected from a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0204] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0205]

[0206] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0207] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0208] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0209] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCp 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0210] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl; is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC4 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0211] R10is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3;

[0212] R11is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu;

[0213] R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0214] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0215]

[0216] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0217] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0218] R5is independently selected from F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0219] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0220] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl; is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC4 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0221] R10is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3;

[0222] R11is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu;

[0223] R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0224] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0225]

[0226] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0227] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F,

[0228] CHF2or CF3; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0229] R^ is selected from H, F, CH3 or CN;

[0230] R8 is independently selected from H, CH3 or OCH3;

[0231] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0232] R10 is selected from H or CH3; R11is independently selected from CH3 or OCH3; R12 is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0233] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0234] R1 is selected from

[0235] R2is H;

[0236] R^ is selected from

[0237] R^ is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0238] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F,

[0239] CHF2or CF3; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0240] R7 is selected from H, F, CH3 or CN;

[0241] R8 is selected from H, CH3 or OCH3;

[0242] R^ is independently selected from CH3, OCH3, CN, F or Cl; R1® is selected from H or CH3;

[0243] R11is independently selected from CH3 or OCH3;

[0244] R12 is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In still a further embodiment, there are provided compounds of Formula (I) wherein

[0245] R4 is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;

[0246] R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F,

[0247] CHF2or CF3;

[0248] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F; R7 is selected from H, F, CH3 or CN;

[0249] R8 is independently selected from H, CH3 or OCH3;

[0250] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0251] R10 is selected from H or CH3;

[0252] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0253] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0254] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0255] R$ is independently selected from H, F or OH; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0256] R^ is selected from H, F, CH3 or CN;

[0257] R8 is selected from H, CH3 or OCH3;

[0258] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0259] R10 is selected from H or CH3; R11is independently selected from CH3 or OCH3;

[0260] R42is independently selected from CH3, OCH3, CN or Cl;

[0261] P 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0262] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0263] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0264] R$ is independently selected from H, F or OH; R” is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0265] R^ is selected from H, F, CH3 or CN;

[0266] R8 is independently selected from H, CH3 or OCH3;

[0267] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0268] R10 is selected from H or CH3;

[0269] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0270] In still a further embodiment, there are provided compounds of Formula (I) wherein

[0271] R1 is selected from

[0272] R2is H;

[0273] R^ is selected from

[0274] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0275] R$ is independently selected from H, F or OH;

[0276] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0277] R^ is selected from H, F, CH3 or CN;

[0278] R8 is selected from H, CH3 or OCH3;

[0279] R^ is independently selected from CH3, OCH3, CN, F or Cl; R10 is selected from H or CH3;

[0280] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0281] In one embodiment, there are provided compounds of Formula (IA) wherein

[0282] R1 is selected from a 8-, 9- or 10-membered heteroaryl substituted by R^, R10 and 0, 1 or 2 substituents independently selected from R^;

[0283] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0284] R^ is selected from a 5- or 6-membered heteroaryl substituted by 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R4^ and 0 or 1 substituents independently selected from RIS or a 8-, 9- or 10-membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R4^ and 0 or 1 substituents independently selected from R13;

[0285] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0286] R5 is selected from F or OH;

[0287] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0288] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu; R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl; is independently selected from C^.2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0289] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3;

[0290] R11is independently selected from H, C^.2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OCj_2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CH2cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3or cyBu substituted by 0 or

[0291] 1 substituent selected from F, CH3, CH2F, CHF2or CF3;

[0292] R12 is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3or CH2OH;

[0293] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or

[0294] 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or (CO)CH3; m is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0295] In a further embodiment, there are provided compounds of Formula (IA) wherein R1 is selected from endently selected from H, CH3, CH2F, CHF2 and CF3;

[0296]

[0297] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0298] R5 is selected from F or OH; R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0299] R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0300] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl; R^ is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O (oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl; R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3; R11is independently selected from H, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or

[0301] 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0302] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0303] R13 is selected from H, a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or

[0304] 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0305] In a further embodiment, there are provided compounds of Formula (IA) wherein

[0306]

[0307] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0308] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0309] R5 is selected from F or OH;

[0310] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3or F;

[0311] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0312] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F,

[0313] OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0314] R^ is independently selected from C^^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0315] R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0316] R11is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^. 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0317] R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0318] R13 is selected from a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0319] In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0320]

[0321] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0322] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0323] R5 is selected from F or OH;

[0324] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3or F;

[0325] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0326] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F,

[0327] OCHF2, OCF3or Cl;

[0328] R^ is independently selected from C^^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0329] R10is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3;

[0330] R11is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu;

[0331] R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0332]

[0333] R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;

[0334] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0335] R5 is selected from F or OH;

[0336] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3or F;

[0337] R^ is selected from H, F, Cl, CN, C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;

[0338] R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F,

[0339] OCHF2, OCF3or Cl;

[0340] R^ is independently selected from C^^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;

[0341] R10is selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3;

[0342] R11is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu;

[0343] R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0344]

[0345] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0346] R5 is selected from F or OH;

[0347] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0348] R^ is selected from H, F, CH3 or CN; R8 is independently selected from H, CH3 or OCH3;

[0349] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0350] R10 is selected from H or CH3;

[0351] R11is independently selected from CH3 or OCH3;

[0352] R42is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0353] In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0354] R1 is selected from

[0355] R2is H;

[0356] R^ is selected from

[0357] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0358] R5 is selected from F or OH;

[0359] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0360] R^ is selected from H, F, CH3 or CN;

[0361] Ro is selected from H, CH3 or OCH3; is independently selected from CH3, OCH3, CN, F or Cl;

[0362] R10 is selected from H or CH3;

[0363] R11is independently selected from CH3 or OCH3;

[0364] R12 is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0365] In still a further embodiment, there are provided compounds of Formula (IA) wherein R^ is H;

[0366] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0367] R5 is selected from F or OH;

[0368] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F; R^ is selected from H, F, CH3 or CN;

[0369] R8 is independently selected from H, CH3 or OCH3;

[0370] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0371] R10 is selected from H or CH3;

[0372] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0373] In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0374] R! is selected from

[0375] R2is H;

[0376] R^ is selected from R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0377] R5 is selected from F or OH;

[0378] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0379] R^ is selected from H, F, CH3 or CN; R8 is selected from H, CH3 or OCH3;

[0380] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0381] R10 is selected from H or CH3;

[0382] R11is independently selected from CH3 or OCH3;

[0383] R12 is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0384] In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0385] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0386] R5 is selected from F or OH;

[0387] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0388] R7 is selected from H, F, CH3 or CN;

[0389] R8 is independently selected from H, CH3 or OCH3; R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0390] R10 is selected from H or CH3;

[0391] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In still a further embodiment, there are provided compounds of Formula (IA) wherein

[0392] R! is selected from R2is H;

[0393] R^ is selected from

[0394] R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0395] R5 is selected from F or OH;

[0396] R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;

[0397] R^ is selected from H, F, CH3 or CN;

[0398] R8 is selected from H, CH3 or OCH3;

[0399] R^ is independently selected from CH3, OCH3, CN, F or Cl;

[0400] R10 is selected from H or CH3;

[0401] R11is independently selected from CH3 or OCH3; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0402] In one embodiment the compound of Formula (I) is selected from: 2-((4-(5-(4-methylpyridin-3-yl)-U7-pyrazol-3-yl)piperidin-l-yl)methyl)quinoline, 2-((4-(5-(4-i sopropylpyrimidin-5-yl)- I / / -pyrazol -3 -yl)piperidin- 1 -yl)methyl)-4- methylpyrido[2,3-t / ]pyrimidine, 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-d]pyrimidine,

[0403] 6-chloro-2-((4-(5-(pyridin-3-yl)-l#-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline,

[0404] 8-fluoro-4-methyl-2-((4-(5-(pyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline, 8-fluoro-4-methyl-2-((4-(5-(pyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline, 6-methoxy-4-rnethyl-2-((4-(T,3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l - yl)methyl)quinazoline,

[0405] 4-methyl-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)pyrido[2,3- d]pyrimidine,

[0406] 2-((4-(5-(4-chloropyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine,

[0407] 4-methyl-2-((4-(5-(4-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine,

[0408] 4-methyl-2-((4-(5-(5-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine,

[0409] 4-methyl-2-((4-(5-(2-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine,

[0410] (3-(3-(l-((4-methylpyrido[2,3-J]pyrimidin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5- yl)pyridin-4-yl)methanol,

[0411] 2-((4-(5-(2-ethylpyridin-3-yl)-IT / -pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine,

[0412] 2-((4-(5-(2,4-di ethyl pyri di n-3 -yl )- l / / -pyrazol -3 -yl )pi peri di n-1 -yl )methyl )-4- methylpyrido[2,3-t / ]pyrimidine,

[0413] 3 -((4-(5-(2,4-dimethylpyri din-3 -yl)- 1 JT-pyrazol -3 -yl)piperidin- 1 -yl)methyl)-8- methylbenzofe] [ 1 ,2,4]triazine,

[0414] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylpyrido[2,3-J]pyrimidine,

[0415] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-J]pyrimidine,

[0416] 2-((4-(5'-methoxy-r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-J]pyrimidine, 5-methyl-2-((4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-l,8- naphthyridine,

[0417] 4,7-dii'nethyl-2-((4-( r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)pyrido[2,3-d]pyrimidine,

[0418] 6-chloro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0419] 5-chloro-2-((4-(5-(pyridin-3-yl)-l#-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline,

[0420] 4,6-dimethyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0421] 4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline-6-carbonitrile,

[0422] 6-methoxy-4-methyl-2-((4-(T,3',5'-trimethyl-l' / / ,2 / / -[3,4Lbipyrazol]-5-yl)piperidin-l - yl)methyl)pyrido[3,4-d]pyrimidine,

[0423] 8-fluoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0424] 6-fluoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0425] 5-fluoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0426] 7-fluoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0427] 6-methoxy-4-methyl-2-((4-(T,3',5'-trimethyl-l' / / ,2 / / -[3,4Lbipyrazol]-5-yl)piperidin-l - yl)methyl)pyrido[3,2-d]pyrimidine,

[0428] 2-((4-(2',4'-dimethyl-2 / / ,2' / / -[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-d]pyrimidine,

[0429] 2-((4-(2\4'-dimethyl-2J7,277-[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine,

[0430] 4-(methoxy-t / 3)-2-((4-(5-(pyridin-3-yl)-l / / -pyrazol-3-yl)piperidin-l-yl)rnethyl)thieno[3,2- d]pyrimidine,

[0431] 4-methyl-2-((4-(5-(pyridin-3-yl)-l#-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline, 2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7-dimethyl-7JH- pyrrol o [2, 3 -d\ py rimi dine, 6-((4-(5-(4-methylpyridin-3-yl)-IT / -pyrazol-3-yl)piperidin-l-yl)rnethyl)-l7 / -pyrrolo[2,3-

[0432] Z>]pyridine,

[0433] 1-ethyl-2-((4-CI\3\5'-trimethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l -yl)methyl)-IT / - b enzo [d\ imi dazol e, rac-(R)-4-methyl-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)-3 ,4-dihydro-2Z / -benzo[Z>] [ 1 ,4]oxazine,

[0434] 4-methyl-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-5J7-pyrano[4,3-J]pyrimidine,

[0435] 2-((4-(2\4'-dimethyl-2J7,277-[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4-methyl-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrirnidine,

[0436] 4-chloro-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-6J7-pyrano[3,2-J]pyrimidine,

[0437] 4-methyl-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-6J7-pyrano[3,2-J]pyrimidine, rac-4-methyl-2-(((27?,47?)-2-methyl-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)-6,7-dihydro-5Z / -pyrano[2,3-J]pyrimidine,

[0438] 4-ethyl-2-((4-(5'-methoxy-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrirnidine,

[0439] 4-methyl-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-5,8- dihydro-67 / -pyrano[3,4-d]pyrirnidine,

[0440] 4-ethyl-2-((4-(5'-methoxy-l\3'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)- 6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine,

[0441] 2-((4-(5'-cyclopropyl-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methyl-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine,

[0442] 4-methyl-2-((4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrirnidine,

[0443] 2-((4-(5'-methoxy-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4-m ethyl- 6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine,

[0444] 2-((4-( l',5'-dirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4-rnethyl-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrirnidine,

[0445] 2-((4-(5'-methoxy-l',3'-dirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4- methyl-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine, 4-ethyl-2-((4-( l',3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l -yl)methyl)-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrimidine, 2-((4-(r,5'-dimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4-ethyl-6,7-dihydro-

[0446] 5H-pyrano[2,3-d]pyrimidine,

[0447] 4-methyl-2-((4-(r-methyl-5'-(trifluoromethyl)-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine,

[0448] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methyl-6,7- dihydro-57 / -pyrano[2,3-t / ]pyrimidine,

[0449] 4-(2',4'-dimethyl-27 / ,2'7 / -[3,3'-bipyrazol]-5-yl)-l -((4-methylquinazolin-2-yl)methyl)piperidin- 4-ol,

[0450] (3 / ?,4 / ?)-l-((4-methylquinazolin-2-yl)rnethyl)-4-(l',3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5- yl)piperi din-3 -ol,

[0451] 4-( l',5'-dirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l -((4-methylquinazolin-2-yl)methyl)piperidin- 4-ol,

[0452] (3A>,4A’)-4-(T,5'-dimethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2- yl)methyl)piperi din-3 -ol,

[0453] 2-((4-fluoro-4-(T,3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4- methylquinazoline,

[0454] 1-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidine-4-carbonitrile,

[0455] 2-((4-methoxy-4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0456] Z-^d-methoxy-d-^'-methoxy-r^'-dimethyl-lT^ZZZ-l^d'-bipyrazolJ-S-y^piperidin-l- yl)methyl)-4-methylquinazoline, rac-4-methyl-2-(((27?,45)-2-methyl-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)quinazoline,

[0457] (l-((4-Methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidin-4-yl)methanol, l-((4-Methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidin-4-ol,

[0458] (37?,47?)-4-(5-(l-Methyl-2,3-dihydro-l / / -imidazo[l,2-Z>]pyrazol-7-yl)-lJ7-pyrazol-3-yl)-l-((4- methylquinazolin-2-yl)methyl)piperidin-3-ol, (37?,47?)-4-(5'-Methoxy-l\3'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin- 2-yl)methyl)piperidin-3-ol,

[0459] 3 / ?,4 / ?)-4-(5'-cyclopropyl-l'-rnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l -((4-methylquinazolin-2- yl)methyl)piperi din-3 -ol,

[0460] (3£,45)-4-(5'-cyclopropyl-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2- yl)methyl)piperi din-3 -ol, 2-((4-(l\5'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)-4-methoxypiperidin-l -yl)methyl)-4- methylquinazoline,

[0461] 2-((4-methoxy-4-(5'-methoxy-r-methyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)- 4-methylquinazoline,

[0462] (37?,4S)-4-methoxy-4-(r-methyl-5'-(trifluoromethyl)-177,2JH-[3,4'-bipyrazol]-5-yl)-l-((4- methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0463] (37?,4S)-4-(5'-(difluoromethyl)-r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)-4-methoxy-l-((4- methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0464] (3 / ?,4b)-4-methoxy-4-(5'-rnethoxy-l',3'-dirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0465] (3 / ?,4b)-4-methoxy-4-(5'-rnethoxy-l'-rnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0466] (37?,4S)-4-(l\5'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)-4-methoxy-l-((4-methylquinazolin-2- yl)methyl)piperi din-3 -ol,

[0467] (37?,4S)-4-methoxy-4-(5-(l-methyl-2,3-dihydro-17 / -imidazo[l,2-b]pyrazol-7-yl)-lJH-pyrazol-

[0468] 3-yl)-l-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0469] (37?,4S)-l-((5-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl-

[0470] IT^ZZZ-l^d'-bipyrazolJ-S-y^piperidin-S-ol,

[0471] (37?,4S)-l-((5-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r / / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol,

[0472] (37?,4S)-l-((6-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r / / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol,

[0473] (37?,4S)-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4l- bipyrazol]-5-yl)piperidin-3-ol,

[0474] (35',47?)-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4l- bipyrazol]-5-yl)piperidin-3-ol, (37?,4S)-4-methoxy-4-(5-(4-methylpyridin-3-yl)-lJ7-pyrazol-3-yl)-l-((4-methylquinazolin-2- yl)methyl)piperi din-3 -ol,

[0475] (3A>,4,S')-4-(3',5'-dirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-4-rnethoxy-l -((4-rnethylquinazolin-2- yl)methyl)piperi din-3 -ol,

[0476] (37?, 4S)-4-m ethoxy- 1 -((4-methylquinazolin-2-yl)methyl)-4-(5-(pyridin-3-yl)-17 / -pyrazol-3- yl)piperi din-3 -ol,

[0477] (37?,4S)-l-((8-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol,

[0478] (37?,4S)-l-((6-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol, rac-(37?,45)-3-fluoro-l-((4-methylquinazolin-2-yl)methyl)-4-(l(3(5'-trimethyl-r7 / ,27 / -[3,4'- bipyrazol]-5-yl)piperidin-4-ol, rac-(37?,47?)-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-r7 / ,277- [3,4'-bipyrazol]-5-yl)piperidin-3-ol,

[0479] 4-methyl-2-((4-( l',3',4,5'-tetramethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline, r,3',5'-trimethyl-5-( l-((4-methylqiiinazolin-2-yl)methyl)piperidin-4-yl)-l'7 / ,27 / -[3,4'- bipyrazole]-4-carbonitrile,

[0480] 7V-methyl-5-(3-(l -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-17 / -pyrazol-5-yl)pyridin-

[0481] 3 -amine,

[0482] 4-methyl-2-((4-(5-(l-methyl-177-pyrrolo[2,3-Z>]pyridin-2-yl)-177-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline,

[0483] 4-methyl-2-((4-(5-(l-methyl-177-indazol-7-yl)-177-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline,

[0484] 4-methyl-2-((4-(5-(5-((tetrahydro-27 / -pyran-4-yl)oxy)pyridin-3-yl)-IT / -pyrazol-3- yl)piperidin-l-yl)methyl)quinazoline,

[0485] 4-methyl-2-((4-(5-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-3-yl)-17 / -pyrazol-3-yl)piperidin-

[0486] 1 -yl)methyl)quinazoline, l-(4-(5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-177-pyrazol-5-yl)pyridin-3- yl)piperazin- 1 -yl)ethan- 1 -one,

[0487] 4-methyl-5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5- yl)nicotinonitrile, 4-(5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l / / -pyrazol-5-yl)pyri din-3- yl)morpholine, 2-((4-(5-(5-methoxypyridin-3-yl)-l / / -pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline, 2-((4-(5-(5-chloropyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylquinazoline,

[0488] 4-methyl-2-((4-(5-(5-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline,

[0489] 4-methyl-2-((4-(5-(4-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline, 4-methyl-2-((4-(5-(pyridin-3-yl)-lZ / -pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline, 4-methyl-2-((4-(5-(2-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline,

[0490] 4-methyl-2-((4-(5-(2-(trifluoromethyl)pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline.

[0491] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0492] 2-((4-(5-(4-(methoxymethyl)-2-methylpyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)- 4-methylquinazoline, 2-({4-[3-(4-ethyl-2-methylpyridin-3-yl)-U7-pyrazol-5-yl]piperidin-l-yl}methyl)-4- methylquinazoline, 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0493] 2-((4-(5-(l,4-dimethyl-lJ7-imidazol-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0494] 4-methyl-2-((4-(5-(l -methyl -2, 3-dihy dro-l / / -imidazo[l,2-Z>]pyrazol -7-yl)-l / / -pyrazol-3 - yl)piperidin-l-yl)methyl)quinazoline,

[0495] 3-(3-( l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-IT / -pyrazol-5-yl)-5,6-dihydro-87 / - imidazo[2, 1 -c] [ 1 ,4]oxazine,

[0496] 3-(3-( l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-IT / -pyrazol-5-yl)-6,7-dihydro-47 / - py razol o [ 5 , 1 -c] [ 1 , 4] oxazine,

[0497] 2-((4-(5-(5,6-dihydro-477-pyrrolo[l,2-Z>]pyrazol-3-yl)-lJH-pyrazol-3-yl)piperidin-l- yl)methyl)-4-methylquinazoline,

[0498] 3-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5-yl)-6,7-dihydro-5Z / - py razol o [ 5 , 1 -b\ [ 1 , 3 ] oxazine, 7-(3-( l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-IT / -pyrazol-5-yl)-2,3- dihydropyrazolo[5, 1-Z>]oxazole,

[0499] 3 , 5 -dimethyl-4-(3 -( 1 -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)- 17 / -py razol -5 - yl)isoxazole,

[0500] 4-methyl-2-((4-(5-(l,2,4-trimethyl-lJH-imidazol-5-yl)-lJH-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline,

[0501] 2-((4-(5-(l,2-dimethyl-lJ7-imidazol-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0502] 2.4-dimethyl-5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5- yl)thi azole,

[0503] 5-methyl-2-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5-yl)-4-

[0504] (trifluoromethyl)thi azole,

[0505] 3 , 5 -dimethyl-4-(3 -( 1 -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)- 17 / -py razol -5 - yl)isothi azole,

[0506] 2-((4-(5-(4-ethyl-5-methyl-4Z / -l,2,4-triazol-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0507] 3.4-dimethyl-5-(5-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-3- yl)isoxazole,

[0508] 2-((4-(l\5'-dimethyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0509] 2-((4-(3',5’-dimethyl-l'7 / ,27 / -[3,4Lbipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0510] 4-methyl-2-((4-(r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)quinazoline,

[0511] 4-methyl-2-((4-(T,3',5'-trirnethyl-l'7 / ,27 / -[3,4Lbipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline,

[0512] 2-((4-(5'-cyclobutyl-r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0513] 2-((4-(5'-(difluoromethyl)-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0514] 4-methyl-2-((4-(r-methyl-5'-(trifluoromethyl)-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline, 2-((4-(5Amethoxymethyl)- l '-methyl - I '7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin- l -yl)methyl)-4- methylquinazoline, 2-((4-(5'-cyclopropyl-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0515] 2-((4-(5'-methoxy-l\3'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0516] 4-methyl-2-((4-(2',4',5'-trimethyl-27 / ,2'7 / -[3,3'-bipyrazol]-5-yl)piperidin- l - yl)methyl)quinazoline, 2-((4-(4',5'-dimethyl-2JH,277-[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0517] 2-((4-(l\3'-dimethyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0518] 2-((4-(2',4'-dimethyl-2JH,277-[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline, 2-((4-(5'-ethyl-l\3'-dimethyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline,

[0519] 2-((4-(5'-methoxy-r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline, rac-(3A,45)-4-Ethyl-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-177,2JH-[3,4'- bipyrazol]-5-yl)piperidin-3-ol, rac-(3A,45)-4-Methyl-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-177,2JH-[3,4'- bipyrazol]-5-yl)piperidin-3-ol and pharmaceutically acceptable salts thereof.

[0520] It shall be noted that any one of these specific compounds may be disclaimed from any of the herein mentioned embodiments.

[0521] In one embodiment there is provided a process for the preparation of compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I), and the intermediates used in the preparation thereof.

[0522] Another embodiment is a product obtainable by any of the processes or examples disclosed herein. MEDICAL AND PHARMACEUTICAL USE

[0523] The compounds of Formula (I) and their pharmaceutically acceptable salts are useful because they possess pharmacological activity as inhibitors of the enzyme NNMT.

[0524] The compounds of Formula (I) and their pharmaceutically acceptable salts are indicated for use in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme nicotinamide N-methyl transferase (NNMT) is desirable. In particular, linkage of NNMT activity to disease has been implicated in chronic kidney disease. Therefore the disclosed compounds are particularly indicated for use in the treatment of chronic kidney disease or kidney conditions or disorders in mammals including man. Further, the disclosed compounds are particularly indicated for use in the treatment of acute kidney injury (AKI), diabetic kidney disease (DKD), heart failure (HF), cardiorenal syndrome (CRS), metabolic dysfunction-associated steatohepatitis (MASH) and arrhythmia conditions or disorders in mammals including man.

[0525] Conditions or disorders that may be specifically mentioned include diabetic kidney disease, hypertensive nephropathy, rapidly progressive glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, focal segmental glomerulosclerosis and acute kidney injury, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

[0526] Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening or identified through specific biomarker pattern to be particularly susceptible to developing the disease or condition.

[0527] For the above-mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. The compounds of Formula (I), and pharmaceutically acceptable derivatives thereof, may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Thus, another aspect concerns a pharmaceutical composition comprising a novel compound of Formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0528] In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of chronic kidney disease or kidney conditions or disorders in a mammal, particularly a human.

[0529] In a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of a condition where inhibition of NNMT would be beneficial.

[0530] In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of chronic kidney disease in a mammal, particularly a human. In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of acute kidney injury in a mammal, particularly a human. In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of diabetic kidney disease in a mammal, particularly a human. In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of cardiorenal syndrome in a mammal, particularly a human. In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of heart failure in a mammal, particularly a human.

[0531] In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human.

[0532] In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.

[0533] In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of MASH in a mammal, particularly a human.

[0534] In still a further embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), for use in therapy, especially in the prevention or treatment of arrhythmia in a mammal, particularly a human.

[0535] In one embodiment there is provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of the enzyme NNMT is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0536] In a further embodiment there is provided a method of treating, or reducing the risk of, chronic kidney disease or kidney conditions or disorders, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0537] In still a further embodiment there is provided a method of treating, or reducing the risk of, chronic kidney disease, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0538] In still a further embodiment there is provided a method of treating, or reducing the risk of, acute kidney injury, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In still a further embodiment there is provided a method of treating, or reducing the risk of, diabetic kidney disease, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0539] In still a further embodiment there is provided a method of treating, or reducing the risk of, cardiorenal syndrome, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0540] In still a further embodiment there is provided a method of treating, or reducing the risk of, heart failure, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0541] In still a further embodiment there is provided a method of treating, or reducing the risk of, heart failure with reduced ejection fraction, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0542] In still a further embodiment there is provided a method of treating, or reducing the risk of, heart failure with preserved ejection fraction, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0543] In still a further embodiment there is provided a method of treating, or reducing the risk of, MASH, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0544] In still a further embodiment there is provided a method of treating, or reducing the risk of, arrhythmia, in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0545] In one embodiment there is provided a pharmaceutical formulation comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), and a pharmaceutically acceptable diluent, excipient and / or inert carrier.

[0546] In a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of a condition where inhibition of NNMT would be beneficial.

[0547] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of chronic kidney disease in a mammal, particularly a human.

[0548] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of acute kidney injury in a mammal, particularly a human.

[0549] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of diabetic kidney disease in a mammal, particularly a human.

[0550] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of heart failure in a mammal, particularly a human.

[0551] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of heart failure with reduced ejection fraction in a mammal, particularly a human. In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of heart failure with preserved ejection fraction in a mammal, particularly a human.

[0552] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of MASH in a mammal, particularly a human.

[0553] In still a further embodiment there is provided a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in therapy, especially in the prevention or treatment of arrhythmia in a mammal, particularly a human.

[0554] There is also provided a process for the preparation of such a pharmaceutical composition which comprises mixing the ingredients.

[0555] The compounds of Formula (I) herein exemplified, when tested in an NNMT cellular assay, for example Test A described below, preferably with an IC50 less than 50 pM. The compounds of Formula (I) also display a promising pharmacological profiles by separating desired and undesired effects in vivo.

[0556] These and other embodiments are described in greater detail herein below, where further aspects will be apparent to one skilled in the art from reading this specification.

[0557] PHARMACOLOGICAL PROPERTIES

[0558] The compounds of Formula (I) or pharmaceutically acceptable salts thereof are believed to be useful in the prevention or treatment of chronic kidney disease or kidney conditions or disorders, acute kidney injury, heart failure, heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, cardiorenal syndrome, metabolic dysfunction-associated steatohepatitis and arrhythmia conditions or disorders in a mammal, particularly a human. For the avoidance of doubt, as used herein, the term “treatment” includes therapeutic and / or prophylactic treatment.

[0559] When a compound or salt described herein is administered as therapy for treating a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse.

[0560] The compounds described herein are thus indicated both in the therapeutic and / or prophylactic treatment of these conditions.

[0561] The compounds described herein have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance), than compounds known in the prior art.

[0562] COMBINATION THERAPY

[0563] The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in conjunction with other compounds used for the treatment of the above conditions.

[0564] In another embodiment, there is a combination therapy wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above. Such a combination may be used in combination with one or more further active ingredients.

[0565] Compounds described herein may be of use in treating cardiovascular, metabolic and renal disease in combination with agents that are angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, glucagon-like peptide-1 modulators or endothelin receptor antagonists.

[0566] When used in a combination therapy, it is contemplated that the compounds of Formula (I) or pharmaceutically acceptable salts thereof and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately. The particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.

[0567] PHARMACEUTICAL COMPOSITIONS

[0568] There is provided a method of treatment of a condition where inhibition of NNMT is required, which method comprises administration of a therapeutically effective amount of a compound of Formula (I) to a person suffering from, or susceptible to, such a condition.

[0569] The compounds of Formula (I) will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0570] Suitable daily doses of the compounds of Formula (I) in therapeutical treatment of humans are about 0.0001-100 mg / kg body weight.

[0571] Oral formulations are preferred, particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.007 mg to 700 mg.

[0572] The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain / body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art. According to a further aspect there is thus provided a pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0573] The compounds of Formula (I) may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation.

[0574] PREPARATION OF THE COMPOUNDS

[0575] It will be appreciated by those skilled in the art that in the processes certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of Formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

[0576] The protection and deprotection of functional groups is described in Protective Groups in Organic Synthesis, 4^ Ed, T.W. Greene and P.G.M. Wuts, Wiley -Interscience (2006) and Protecting Groups, 3r^ Ed, P. J. Kocienski, Georg Thieme Verlag (2005).

[0577] The skilled person will recognize that at any stage of the preparation of the compounds of Formula (I), mixtures of isomers (e.g. racemates) of compounds may be utilized. At any stage of the preparation, a single stereoisomer may be obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation.

[0578] A further embodiment encompasses pharmaceutically acceptable salts of the compounds of Formula (I).

[0579] A salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly where the salt is intended for administration to an animal, e.g. a human, or is a reagent for use in making a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable.

[0580] The term “pharmaceutically acceptable” is used to characterize a moiety (e.g. a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0581] Where the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0582] For reviews on suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 ox Handbook of Pharmaceutical Salts: Properties, selection and use, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002.

[0583] Where an acid co-former is a solid at r.t. and there is no or only partial proton transfer between the compound of Formula (I) and such an acid co-former, a co-crystal of the coformer and compound of Formula (I) may result rather than a salt. All such co-crystal forms of the compound of Formula (I) are encompassed herein.

[0584] It is also to be understood that certain compounds of Formula (I) may exist in solvated form, e.g. hydrates, including solvates of a pharmaceutically acceptable salt of a compound of Formula (I).

[0585] In a further embodiment, certain compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Certain compounds of Formula (I) may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring bond or double bond. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis.

[0586] In a further embodiment, the compounds of Formula (I) encompass any isotopically-labelled (or “radio-labelled”) derivatives of a compound of Formula (I). Such a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be incorporated include (also written as “D” for deuterium).

[0587] In a further embodiment, the compounds of Formula (I) may also contain various tautomeric forms. It is to be understood that all such tautomeric forms are encompassed.

[0588] In a further embodiment, the compounds of Formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula (I). Various forms of prodrugs are known in the art. For examples of prodrug derivatives, see: Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein.

[0589] Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.

[0590] PHARMACOLOGICAL ACTIVITY

[0591] The pharmacological activity of compounds disclosed herein was tested in the following screen (Test A).

[0592] Test A - Cellular assay of human NNMT in RPTEC / TERT1 cells

[0593] Cryopreserved RPTEC / TERT1 cells (CRL-4031 from ATCC) endogenously expressing human NNMT were thawed, centrifuged and diluted into cell media (DMEM / F-12 + GlutaMAX-I (Gibco 31331-028), containing 0.1 mg / ml Genectin (Gibco, 10131027)). The cell suspension was dispensed to 384-well microplates (Corning 3764) containing compounds dissolved in DMSO, using a Multidrop Combi (ThermoFisher; 8000 cells per well, final assay volume 30 pl, 0.3% final DMSO). The microplates were incubated in a cell incubator (37 °C in humidified 5% CO2 / air atmosphere). After 24 h the cell media was removed and cells were washed with PBS using a BlueWasher (BlueCatBio GmbH, Germany), followed by addition of 20 pl water (Multidrop Combi) and freezing on dry ice. Plates were stored at -20 °C until sample preparation for the LC-MS analysis. Cellular NNMT activity was determined measuring 1-MNA (1 -methylnicotinamide) levels using a LC-MS detection system. Frozen cell lysates were thawed and diluted into methanol / acetonitrile (50 / 50) containing 1-MNA-D3 (M323237, TRC, Toronto, Canada) and centrifuged at 2600 g for 30 minutes prior to sampling in the API 5000 LC / MS / MS system with Qjet (Applied biosystems; sample volume of 10 pl, Phase A: 5mM acetic acid / 0.2% formic acid, Phase B: acetonitrile; Column: Xbridge amide 3.5 mm 2.1 x 50 mm column, Waters / Bridge 186004859). 1-MNA levels were quantified as the area under the curve of the 1-MNA peak and normalized using 1- MNA-D3. Data processing, assay quality control and concentration response curve fitting was analyzed using Genedata Screener (Basel, Switzerland). Compound potencies were determined from 10-point concentration response curves using 3 -fold dilution steps, with a final assay concentration ranging from 30 mM down to 15 nM. The Z’ -factor was between 0.5-0.8. The IC50 values (NNMT) for the Example compounds are set forth in Table 1 herein below.

[0594] Table 1

[0595] EXAMPLES

[0596] The following examples are non-limiting examples.

[0597] GENERAL CONDITIONS

[0598] (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 25 °C and under an atmosphere of an inert gas such as N?(g) unless otherwise stated; optionally reactions were carried out using a MBRAUN UNILab Plus ECO or a MBRAUN UNILab SP Eco glovebox workstation or a KitAlysis™ Benchtop Inertion Box from Sigma-Aldrich, in which case it is indicated;

[0599] (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g)); (iii) where reactions refer to the use of a microwave reactor, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer;

[0600] (iv) where reactions refer to the use of irradiation with LED a commercial, standardized EvoluChem™ PhotoRedOx Box Photoreactor from HepatoChem equipped with a Kessil Hl 50 blue LED (456 nm, 34W) or a commercial standardized Photoreactor m2 from Penn Photon Devices equipped with a LED module (365 nm) were used, photochemistry

[0601] (v) where reactions refer to the use of flow chemistry it was performed by administering the components using syringe pumps into a 6.8 mL PFA coil reactor (o.d. 3.2 mm) at rt, unless otherwise stated, and at a flow rate of the components as indicated in the description

[0602] (vi) in general, the course of reactions was followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS).

[0603] (vii) when necessary, organic solutions were dried over anhydrous MgSCh or ISfeSCU, or by using ISOLUTE® Phase Separator, and work-up procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4 or Na2SO4 is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer.

[0604] (viii) It is understood that washing solutions used in the work-up procedures or reagent used for acidifying such as e.g. Brine, NaHCOs, NH4CI , HC1, NaH2PO4 are presumed to be aqueous solutions unless otherwise stated

[0605] (ix), evaporations were carried out either by rotary evaporation in vacuo or in a Genevac HT- 4 / EZ-2 or Biotage VI 0;

[0606] (x) unless otherwise stated, flash column chromatography was performed on straight phase silica, using either Merck Silica Gel (Art. 9385) or prep-packed cartridges such as Biotage® SNAP cartridges (40-63 pm silica, 4-330 g), Biotage® Sfar Silica HC D cartridges (20 pm, 10-100 g), Interchim puriFlash™ cartridges (25 pm, 4-120 g), Interchim puriFlash™ cartridges (50 pm, 25-330 g), Grace™ GraceResolv™ Silica Flash Cartridges (4-120 g) or Agela Flash Colum Silica-CS cartridges (80-330 g), or on reversed phase silica using Agela Technologies C-18, spherical cartridges (20-35 pm, 100 A, 80-330g), manually or automated using a Grace Reveleris® X2 Flash system or similar system; (xi) preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and / or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section, and one of the following methods as described below; PrepMethod A; The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250^20 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as mobile phase; PrepMethod B; The compound was purified by preparative HPLC-MS on a XB ridge™ Cl 8 ODB column (5 pm, 100x 10 mm ID) using a gradient of MeCN in NH3 / H2O (0.2%, pHlO) as mobile phase; PrepMethod C; The compound was purified by preparative SFC on a Waters™ BEH, (5 pm, 250x30 mm ID) using MeOH / H2O (NH350 mM) (97 / 3) in CO2 as mobile phase; PrepMethod D; The compound was purified by preparative HPLC on a XBridge™ C18 column (10 pm, 250x 19 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as mobile phase; PrepMethod E; The compound was purified by preparative HPLC on a XBridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O / / NH4HCO3 (10 mM) as mobile phase; PrepMethod F; The compound was purified by preparative HPLC on a XBridge™ C18 column (10 pm, 250x50 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as mobile phase; PrepMethod G; The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250x50 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as mobile phase; PrepMethod H; The compound was purified by preparative HPLC on a Waters™ Sunfire™ Cl 8 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O / FA (0.1%) as mobile phase; PrepMethod I; The compound was purified by preparative HPLC on a Xbridge™ C18 ODB column (5 pm, 150x 19 mm ID) using a gradient of MeCN in a H2O / NH3 (0.2%, pH 10) buffer system as mobile phase; PrepMethod J; The compound was purified by preparative HPLC on a Waters™ Sunfire™ Cl 8 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O / FA (0.1 M) as mobile phase; PrepMethod K; The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 ODB column (5 pm, 150x 19 mm ID) using a gradient of MeCN in H2O / FA (0.1 M) as mobile phase; PrepMethod L; The compound was purified by preparative SFC on a Phenom enex Luna® HILIC column (5 pm, 250x30 mm ID) using MeOH / NH3(20 mM) in CO2 as mobile phase; PrepMethod N; The compound was purified by preparative HPLC on a XBridge™ Cl 8 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq) buffer system as mobile phase; PrepMethod O; The compound was purified by preparative SFC on a Waters™ BEH 2-EP, (5 pm, 250x30 mm ID) using MeOH / NH3(20 mM) in CO2as mobile phase; PrepMethod P; The compound was purified by preparative HPLC on a XBridge™ Shield C18 column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O / NH4CO3 (10 mM) / NH3(0.1%, aq) buffer system as mobile phase; PrepMethod Q; The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O / NH4HCO3(10 mM) as mobile phase; PrepMethod R; The compound was purified by preparative HPLC on a XBridge™ Cl 8 OBD column (5 pm, 150x19 mm ID) using a gradient of MeCN in H2O / NH4HCO3(0.1 M) as mobile phase; PrepMethod T; The compound was purified by preparative HPLC on a XBridge™ C18 column (5 pm, 150x25 mm ID) using a gradient of MeCN in H2O / NH4HCO3(0.01 M) as mobile phase; PrepMethod U; The compound was purified by preparative SFC on a Waters™ Acquity UPC2 BEH, (3.5 pm, 100x3 mm ID) using MeOH / H2O / NH397 / 3 / 50 mM in CO2 as mobile phase; PrepMethod V;The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP column (5 pm, 250x30) using MeOH / NH3(100 / 20 mM) in CO2 as mobile phase; PrepMethod W; The compound was purified by preparative HPLC on a Water Atlantis T3 C18 ODB column (5 pm, 150x19 mm ID) using a gradient of MeCN in H2O / FA (0.1 M) as mobile phase; PrepMethod X; The compound was purified by preparative HPLC on a XBridge™ C18 OBD column (5 pm, 150x19 mm ID) using a gradient of MeCN in a H2O / NH4HCO3(0.01 M) buffer system as mobile phase; PrepMethod Y; The compound was purified by preparative SFC on a Waters™ BEH, (5 pm, 250x30 mm ID) using MeOH / NH3(20 mM) in CO2 as mobile phase; PrepMethod Z; The compound was purified by preparative SFC on a Kromasil DIOL, (5 pM, 50 x 30 mm ID) using EtOH / NH3(100 / 20 mM) in CO2 as mobile phase; PrepMethod CC; The compound was purified by preparative HPLC on a XBridge™ C18 column (10 pm, 250x19 mm ID) using a gradient of MeCN in a H2O / MeCN / NH4HCO3(95 / 5 / 10 mM) buffer system as mobile phase.

[0607] PrepMethod DD; The compound was purified by preparative SFC on a Kromasil CN, (5 pM, 250 x 30 mm ID) using EtOH / DEA (100 / 20 mM) in CO2 as mobile phase. PrepMethod EE; The compound was purified by preparative HPLC on a Waters Atlantis T3 C18 ODB column (5 pm, 150x19 mm ID) using a gradient of MeCN in H2O / TFA (0.15 M) as mobile phase. PrepMethod FF; The compound was purified by preparative HPLC on a XBridge™ Cl 8 OBD column (5 pm, 150x19 mm ID) using a gradient of MeCN in a H2O / MeCN / TFA (95 / 5 / 150 mM) buffer system as mobile phase. PrepMethod GG; The compound was purified by preparative HPLC on a Waters XSelect CSH Fluoro Phenyl OBD column (5 pm, 150x 19 mm ID) using a gradient of MeCN in H2O / TFA (0.15 M) as mobile phase;

[0608] PrepMethod HH; The compound was purified by preparative HPLC on a XB ridge™ Cl 8 OBD column (5 pm, 150x 19 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq) buffer system as mobile phase. PrepMethod II; The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq) buffer system as mobile phase. PrepMethod JJ; The compound was purified by preparative HPLC on a XBridge™ C18 column (10 pm, 250x50 mm ID) using a gradient of MeCN in H2O / MeCN / NH4HCO3 (95 / 5 / 10 mM) as mobile phase; PrepMethod NN; The compound was purified by preparative SFC on a Kromasil XT, (10 pM, 250 x 50 mm ID) using MeOH / NHs (100 / 20 mM) in CO2 as mobile phase. PrepMethod OO; The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250x50 mm ID) using a gradient of MeCN in a H2O / MeCN / AcOH (95 / 5 / 0.2) buffer buffer system as mobile phase. PrepMethod PP; The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250x20 mm ID) using a gradient of MeCN in a H2O / MeCN / AcOH (95 / 5 / 0.2) buffer system as mobile phase.

[0609] PrepMethod QQ; The compound was purified by preparative HPLC on a Xbridge BEH Cl 8 column (5 pm, 100x 10 mm ID) using a gradient of MeCN in a H2O as mobile phase. Relevant fractions were collected, combined and freeze-dried to give the purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried either over Na2SO4 or by using a phase-separator, and then concentrated at reduced pressure to give the purified compound,

[0610] (xii) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instruments, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section;

[0611] (xiii) yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required;

[0612] (xiv) where certain compounds were obtained as an acid-addition salt, for example a monohydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data;

[0613] (xv) in general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating atJH frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25 °C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, ddd, doublet of doublet of doublets, dt, doublet of triplets, dq, doublet of quartet etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet; h, heptet. It is understood, where the NMR spectra contains residual impurities and / or residual solvent(s), this is not reported unless it coincides or partially coincides with peaks of Intermediates and / or structures of Formula (I), in which case they are reported as multiplets, partially overlapping with said solvent or impurity and the integral is omitted. In some cases, the structures of the endproducts of the Formula (I) might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported. In some cases, the structures of the end-products of Formula (I) might appear as rotamers in more equal portions, in such instances the peaks of such rotamers are either reported as multiplets, if the signals of said rotamers are partially overlapping, or as individual peaks, if the signals of said rotamers are well separated. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported

[0614] (xvi) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xvii) unless stated otherwise compounds containing an asymmetric carbon and / or sulfur atom were not resolved;

[0615] (xviii) in general Examples and Intermediate compounds are named using ChemDraw Professional version 22.2.0 from PerkinElmer. ChemDraw Professional version 22.2.0 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules.

[0616] ChemDraw is optionally using labels in the graphical representation of stereocenters such as '&' and 'or' to describe the configuration of the stereochemical centers present in the structure.

[0617] A number following the '&' and 'or' flag is assigned to each stereocenter present in the structure. The numbers are incremented automatically to indicate that stereocenters may vary independently to each other.

[0618] In general, for chemical structures of Examples and Intermediates where more than one stereocenter is present and said stereocenters have a fixed relative configuration, the same number is used after the label '&' and 'or' to indicate that said stereocenters forms a group. A third stereocenter present in the same chemical structure, that varies independently to the former stereocenters, is designated with a unique new number following the label '&' and 'or'. In general, chemical structures of Examples and Intermediates containing the label '&' at a stereocenter, means the configuration of such Example or Intermediate at that stereocenter is a mixture of both (R) and (A); and a label 'or' means the configuration of such Example or Intermediate at that stereocenter is either (5) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure.

[0619] In general, for structures of Examples and Intermediates, where all of the stereocenters are designated as '&', the structure is named with a “rac-” prefix. For structures of Examples and Intermediates, where all of the stereocenters are designated as 'or', the structure is named with a “rel-” prefix.

[0620] In general Examples and Intermediate compounds are named using the descriptors (RS) and (SR) to denote general '&' centers for chemical structures with multiple chiral centers where only some are designated as '&'. The descriptors (R*) and (5*) are used to denote the general 'or' centers for chemical structures with multiple chiral centers where only some are designated as 'or'.

[0621] In general Examples and Intermediate compounds containing stereocenters having a relationship that is either cis or trans, are named using the descriptors (RS, SR) or (RS, RS), to denote chemical structures with multiple chiral centers where only some are designated as '&'.

[0622] In general, for structures of Examples and Intermediates where all stereocenters present are racemic, no flag is designated to the stereocenter(s) and the structure is drawn with straight bond(s) at each stereocenter.

[0623] In general, for structures of Examples and Intermediates where two or more stereocenters are present in a ring and fixed to each other and do not vary independently of each other, e.g. are cis or trans to each other, said stereocenters are drawn with stereobonds representing their internal relationship. Said stereocenters are labelled with an “&1” flag representing a mixture of cis-configuration or a mixture of trans-configuration, or an “orl” flag representing a single cis-isomer or a single trans-isomer with unknown absolute stereochemistry. In general, should the structure of said Example or Intermediate further contain one or more stereocenters that are racemic and not fixed in relation to the former stereocenters, said stereocenter(s) is drawn with straight bond(s) at said stereocenters.

[0624] In general the descriptors (r) and (s) are used to describe the absolute configuration of any pseudoasymmetric centers in the structures of Examples and Intermediates.

[0625] In general the label “Isomer 1” corresponds to the first eluted isomer, and “Isomer 2” corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration;

[0626] (xix) in addition to the ones mentioned above, the following abbreviations and units have been used:

[0627] Intermediate 1

[0628] Piperidine-4-carboxylic acid

[0629] TFA (6 mL) was added to a solution of l-(terLbutoxycarbonyl)piperidine-4-carboxylic acid in DCM (20 mL) and stirred at rt for 30 min. The reaction mixture was concentrated to dryness to grant the TFA salt of the title compound (2.69 g, 100%).

[0630] Intermediate 2

[0631] 1 -(1 -(Ouinazolin-2-ylmethyl)piperidin-4-yl)ethan- 1 -one Piperidine-4-carboxylic acid, TFA Intermediate 1 (2.69 g, 11.15 mmol) and sodium triacetoxyhydroborate (4.73 g, 22.3 mmol) were added to a solution of quinoline-2- carbaldehyde (2.63 g, 16.73 mmol) in DCM (30 mL) and the resulting mixture was stirred at rt for 42 h. 8% NaHCCL (aq) was added and the stirring continued for 20 min. The phases were separated using a phase separator and the organic layer was concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient 0-100% EtOAc in heptane (1% TEA)) to grant the title compound (2.25 g, 75%) as a brown oil. MS (ESI) m / z [M+H]+269.3. Intermediate 3

[0632] 1-(4-Methylpyri din-3 -yl)-3-(l-(quinolin-2-ylmethyl)piperidin-4-yl)propane-L 3-dione A solution containing 4-methylnicotinic acid (73 mg, 0.53 mmol) and CDI (86 mg, 0.53 mmol) in THF (1.5 mL) was stirred at rt for 1 h. 1 M LiHMDS in THF (0.533 mL, 0.53 mmol) was added to a stirred solution of l-(l-(quinazolin-2-ylmethyl)piperidin-4-yl)ethan-l- one, TFA Intermediate 2 (110 mg, 0.41 mmol) in THF (1.5 mL) at -78 °C, under an atmosphere of N2 (g), and the reaction mixture was stirred for 30 min. The CDI-activated acid solution was added dropwise, and the reaction mixture was stirred at -78 °C for 30 min, and then allowed to warm to rt over 18 h. The mixture was diluted with EtOAc, washed with sat NaHCCh (aq), brine and concentrated. The residue was purified by preparative HPLC, PrepMethod D, (gradient: 10-55%) to yield the title compound (5 mg, 3%) as an off white solid. MS (ESI) m / z [M+H]+388.3.

[0633] Intermediate 4 terLButyl 4-(5-(pyrimidin-5-yl)-lZ / -pyrazol-3-yl)piperidine-l-carboxylate 4-Methylbenzenesulfonohydrazide (1.72 g, 9.24 mmol) was added to a solution of pyrimidine-5-carbaldehyde (1 g, 9.25 mmol) in toluene (10 mL) and the reaction mixture was stirred at 20 °C for 3 h under an atmosphere of N2 (g). The mixture was allowed to cool to 0 °C and 5 M NaOH (aq, 1.85 mL, 9.25 mmol) was added to the suspension and stirred at 0 °C for 20 min. / c / V-Butyl 4-ethynylpiperidine-l -carboxylate (5.81 g, 27.75 mmol) was added and the reaction mixture was stirred at 50 °C for 48 h. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by reversed phase flash chromatography on a Cl 8 column (gradient: 0-100% MeCN in water) to grant the title compound (1.5 g, 49%) as a yellow solid. MS (ESI) m / z [M+H]+330.1.

[0634] Intermediate 5 terLButyl 4-(5-(4-isopropylpyrimidin-5-yl)-U / -pyrazol-3-yl)piperidine-l -carboxylate

[0635] 2 -Hydroxyisoindoline-1, 3-dione (44.6 mg, 0.27 mmol) and DMAP (1.11 mg, 9.10 pmol) were added to isobutyric acid (29.9 0.33 m μLm,ol) in a microwave vial. DMSO (0.86 mL) was added, followed by DIC (42.3 0.27 μL m,mol) and the reaction mixture was stirred at rt for 24 h. A solution of tert-butyl 4-(5-(pyrimidin-5-yl)- IT / -pyrazol-3-yl)piperidine- l - carboxylate Intermediate 4 (60.0 mg, 0.18 mmol) in DMSO (0.75 mL) and TFA (27.9 μL, 0.36 mmol) in DMSO (0.5 mL) was added to the reaction, followed by 4-CzIPN (1.437 mg, 1.82 pmol). The mixture was evacuated and filled with N?(g) three times and then degassed vigorously for 10 min. The vial was irradiated with a 34 W LED (Xmax 456 nm) for 3 h. The solution was filtered and the filtrate was purified by preparative HPLC, PrepMethod D, (gradient: 20-65%), to grant the title compound (27 mg, 40%) as a white solid. MS (ESI) m / z [M+H]+372.3.

[0636] Intermediate 6

[0637] 2-((3-Acetylpyri din-2 -yl)amino)-2-oxoethyl acetate

[0638] TEA (0.77 mL, 5.52 mmol) was added to a solution of l-(2-aminopyridin-3-yl)ethan-l-one (500 mg, 3.67 mmol) in DCM (17.2 mL) followed by 2-chloro-2-oxoethyl acetate (0.40 mL, 3.67 mmol) and the reaction mixture was stirred at rt for 5 h. Additional 2-chloro-2-oxoethyl acetate (0.08 mL, 0.734 mmol) was added and the reaction mixture was stirred for a further 1 h. The reaction was quenched with sat NaHCCh (aq) and stirred overnight. The mixture was passed through a phase separator and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 50-100% EtOAc in heptane) to grant the title compound (720 mg, 83%) as a white solid. MS (ESI) m / z [M+H]+237.1.

[0639] Intermediate 7

[0640] (4-Methylpyridor2.3-J]pyrimidin-2-yl)methyl acetate

[0641] NELOAc (34.3 g, 444.49 mmol) was added in small portions to a solution of 2-((3- acetylpyridin-2-yl)amino)-2-oxoethyl acetate Intermediate 6 (21 g, 88.90 mmol) in AcOH (200 mL). The reaction mixture was equally separated into 7 batches and each batch was stirred at 130 °C in a microwave reactor for 1 h. The batches were combined and concentrated. The concentrate was diluted with EtOAc and washed three times with sat NaHCOs (aq) solution. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica, (gradient: 0-15% MeOH in DCM), to grant the title compound (14.0 g, 73%) as an orange solid. MS (ESI) m / z [M+H]+218.3. Intermediate 8

[0642] (4-Methylpyridor2,3-J|pyrimidin-2-yl)methanol

[0643] NaOMe in MeOH (3.94 g, 21.88 mmol) was added slowly to a solution of (4- methylpyrido[2,3-d]pyrimidin-2-yl)methyl acetate Intermediate 7 (12 g, 55.24 mmol) in MeOH (120 mL) under an atmosphere of N2 (g), The reaction mixture was stirred at 25 °C for 45 min. The mixture was poured into brine and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 0-100% EtOH in DCM), to grant the title compound (8.70 g, 90%) as a pale-yellow solid. MS (ESI) m / z [M+H]+176.3.

[0644] Intermediate 9

[0645] (4-Methylpyridor2,3-J|pyrimidin-2-yl)methyl methanesulfonate

[0646] DIPEA (418 μL 2,.40 mmol) was added to a suspension of (4-methylpyrido[2,3-J]pyrimidin- 2-yl)methanol Intermediate 8 (210 mg, 1.20 mmol) in DCM (5.58 mL) followed by MsCl (313 mg, 1.80 mmol). The reaction mixture was stirred for 1 h and then concentrated. The crude product was purified by straight phase flash chromatography on silica (isocratic EtOAc) to grant the title compound (0.28 g, 91%) as a slightly yellow oil. MS (ESI) m / z [M+H]+254.1.

[0647] Intermediate 10 tert-Butyl 4-(5-(4.6-dimethylpyrimidin-5-yl)-lJ7-pyrazol-3-yl)piperidine-l -carboxylate / c / V-Butyl 4-ethynylpiperidine-l -carboxylate (1.83 g, 9.83 mmol) was added to 4- methylpyrimidine-5-carbaldehyde (1.2 g, 9.83 mmol) in toluene (15 mL) and the reactioin mixture was stirred for 3 h at 10 °C. 5 M NaOH (aq, 1.97 mL, 9.85 mmol) was added to the mixture and stirred at 0 °C for 30 min. 4-Methylbenzenesulfonohydrazide (6.17 g, 29.48 mmol) was added to the reaction mixture at 10 °C and then stirred at 50 °C for 50 h. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed phase flash chromatography on a Cl 8 column, (gradient: 0-100% MeCN in water), to grant the title compound (1.00 g, 30%) as a yellow solid. MS (ESI) m / z [M+H]+344.4.

[0648] Intermediate 11 4,6-Dimethyl-5-(3-(piperidin-4-yl)-l / / -pyrazol-5-yl)pyrimidine

[0649] A microwave vial was charged with, tert-butyl 4-(5-(4,6-dimethylpyrimidin-5-yl)-l / / - pyrazol-3-yl)piperidine-l -carboxylate Intermediate 10 (71.8 mg, 0.21 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PFe (4.69 mg, 4.18 pmol). The vial was sealed, evacuated, and filled with N2 (g). MeCN (0.95 mL) and TFA (0.95 mL) were added. The reaction mixture was cooled in an ice bath and degassed with N2 (g) for 2 min, followed by addition of tert-butyl ethaneperoxoate (200 0.6 μ3L m, mol). The mixture was degassed for an additional 5 min and then irradiated with a 34 W LED (A.max456 nm) for 1.5 h. The mixture was concentrated, and the residue was treated with water and MTBE. The layers were separated, and the MTBE layer was extracted with water. The combined aqueous layers were concentrated, and the resulting crude material was purified by preparative HPLC, PrepMethod D, (gradient-40%), to grant the title compound (11 mg, 21%) as a clear oil. MS (ESI) m / z [M+H]+258.2.

[0650] Intermediate 12

[0651] 2-((3-Acetyl-6-methylpyri din-2 -yl)amino)-2-oxoethyl acetate

[0652] TEA (19.31 mL, 138.5 mmol) was added to l-(2-amino-6-methylpyridin-3-yl)ethan-l-one (10.4 g, 69.25 mmol) and 2-chloro-2-oxoethyl acetate (9.45 g, 69.25 mmol) in DCM (200 mL) at 0°C over a period of 5 min. The reaction mixture was stirred at 15 °C for 16 h. The solvent was removed under reduced pressure. The crude solid was triturated with 20% EtOAc in petroleum ether and filtered. The precipitate was washed with 20% EtOAc in petroleum ether and dried under vacuum to grant the title compound (17.2 g, 99%) as a brown solid. MS (ESI) m / z [M+H]+372.3.

[0653] Intermediate 13

[0654] (4.7-Dimethylpyridor2.3-d1pyrimidin-2-yl)methyl acetate

[0655] A solution of 2-((3-acetyl-6-m ethylpyri din-2 -yl)amino)-2-oxoethyl acetate Intermediate 12 (247 mg, 0.99 mmol) and NFLOAc (380 mg, 4.93 mmol) in AcOH (2.47 mL) was heated in a microwave reactor at 130 °C for 40 min. The solution was concentrated and the residue was purified using straight phase flash chromatography on silica (gradient: 50-100% EtOAc in heptane) to grant the title compound (89 mg, 39%) as a yellow oil. MS (ESI) m / z [M+H]+232.2. Intermediate 14

[0656] (4,7-Dimethylpyridor2,3-J|pyrimidin-2-yl)methanol

[0657] NaOMe (30 wt.% in MeOH, 397 2. μ14L, mmol) was added to a solution of (4,7- dimethylpyrido[2,3-J]pyrimidin-2-yl)methyl acetate Intermediate 13 (495 mg, 2.14 mmol) in MeOH (6.62 mL). The reaction mixture was stirred at rt for 10 min followed by addition of AcOH (123 μL 2,.14 mmol) and then concentrated. The residue was dissolved in DCM (and a drop of MeOH), filtered using a syringe filter and purified by straight phase chromatography on silica (gradient: 0-20% MeOH in EtOAc) to grant the title compound (306 mg, 75%) as a slightly yellow solid. MS (ESI) m / z [M+H]+190.2.

[0658] Intermediate 15

[0659] (4,7-Dimethylpyridor2,3-J|pyrimidin-2-yl)methyl methanesulfonate

[0660] A solution of methanesulfonic anhydride (337 mg, 1.93 mmol) in DCM (2 mL) was added to a solution of (4,7-dimethylpyrido[2,3-J]pyrimidin-2-yl)methanol Intermediate 14 (305 mg, 1.61 mmol) and DIPEA (421 2. μ4L2, mmol) in DCM (6 mL) at 0 °C. The reaction mixture was stirred for 15 min and then quenched with sat NaHCOs (aq) and diluted with DCM. The aqueous layer was extracted with DCM and the combined organic layer was washed once with water and once with brine before drying over MgSCL. The organic layer was filtered and concentrated to afford the title compound (424 mg, 98%) as a yellow solid. MS (ESI) m / z [M+H]+268.1.

[0661] Intermediate 16 terLButyl 4-(3-oxo-3-(pyri din-3 -yllpropanoyllpiperi dine- 1 -carboxylate

[0662] CDI (3.89 g, 24.0 mmol) was added to l-(terLbutoxycarbonyl)piperidine-4-carboxylic acid (5.00 g, 21.8 mmol) in THF (42 mL) and the mixture was stirred at rt for 1 h. In a separate flask, 1 M LiHMDS in toluene (43.6 mL, 43.6 mmol) was added dropwise to a solution of 3- acetylpyridine (4.79 mL, 43.6 mmol) in THF (42 mL) at -78 °C and stirred for 30 min. The solution containing CDI-activated carboxylic acid was added dropwise to the acetylpyridine solution and the reaction mixture was allowed to warm to rt. The reaction mixture was diluted with EtOAc and washed sequentially with 10% citric acid (aq), NaHCOs (aq) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient 35-65% EtOAc in heptane) to give the title compound (5.91 g). The product contained 3 -acetylpyridine. MS (ESI) m / z [M+H]+333.3.

[0663] Intermediate 17 tert-Butyl 4-(5-(pyri din-3 -yl)-lrt-pyrazol-3-yl)piperi dine- 1 -carboxylate

[0664] 35% Hydrazine hydrate (aq, 2.63 mL, 29.0 mmol)) was added to a solution of tert-butyl 4-(3- oxo-3 -(pyri din-3 -yl)propanoyl)piperi dine- 1 -carboxylate Intermediate 16 (8.12 g, 22.0 mmol) in EtOH (85 mL). The reaction mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SC>4 , filtered and concentrated. 1.2 g of the crude product was purified by preparative HPLC, PrepMethod F, (gradient:25-85%), and the remainder of the crude material was purified by washing with EtOAc. The two batches were combined to grant the title compound (5.4 g, 70%) as a white solid. MS (ESI) m / z [M+H]+329.3.

[0665] Intermediate 18

[0666] 3 -(3 -(Piperidin-4-yl)- I rt-py razol -5 -y 1 )py ri di ne

[0667] TFA (5 mL, 64.9 mmol) was added to a solution of tert-butyl 4-(5-(pyridin-3-yl)-lrt-pyrazol- 3 -yl)piperidine-l -carboxylate Intermediate 17 (1g, 3.04 mmol) in DCM (30 mL) and the reaction mixture was stirred at 20 °C for 2 h. The solvent was removed under reduced pressure. The crude product was purified by reversed phase flash chromatography on a Cl 8 column (gradient: 9-90% MeCN in water), to give the TFA salt of the title compound (0.70 g) as a pale yellow oil. MS (ESI) m / z [M+H]+229.1.

[0668] Intermediate 19

[0669] 2-((4-Chloro-2-formylphenyl)amino)-2-oxoethyl acetate

[0670] 2-Chloro-2-oxoethyl acetate (1.54 mL, 14.32 mmol) was added to a solution of 2-amino-5- chlorobenzaldehyde (2.13 g, 13.69 mmol) and TEA (2.86 mL, 20.49 mmol) in DCM (63.9 mL) at rt. The reaction mixture was stirred at rt for 1.5 h and then additional 2-chl oro-2 - oxoethyl acetate was added (0.5 mL, 3.59 mmol). The reaction mixture was stirred for an additional 1.5 h and then diluted with water (50 mL). The layers were separated, and the organic layer was passed through a phase separator and concentrated. The residue was washed with EtOAc and the product was collected as a white solid by filtration. The mother liquor was concentrated and purified by straight phase flash chromatography on silica (gradient: EtOAc in heptane). The product containing fractions were collected, evaporated and combined with the precipitate to grant the title compound (2.25 g, 64%) as a white solid. MS (ESI) m / z [M+H]+254.1 and 256.1.

[0671] Intermediate 20

[0672] (6-Chloroquinazolin-2-yl)methyl acetate

[0673] AcOH (16.7 mL) was added to a mixture of 2-((4-chloro-2-formylphenyl)amino)-2-oxoethyl acetate Intermediate 19 (1.71g, 6.69 mmol) and NEUOAc (1.55 g, 20.01 mmol) in a microwave vial. The vial was sealed, heated to 130 °C and stirred for 5 min. The mixture was concentrated, redissolved in DCM, and treated with sat NaHCCE (aq). The aqeous layer was extracted and the combined organic layers were concentrated to afford the crude title compound (2.03 g). MS (ESI) m / z [M+H]+237.2 and 239.2.

[0674] Intermediate 21

[0675] (6-Chloroquinazolin-2-yl)methanol

[0676] 1 M LiOH (aq, 12.87 mL, 12.87 mmol) was added to a solution of (6-chloroquinazolin-2- yl)methyl acetate Intermediate 20 (2.03 g, 8.58 mmol) in THF (40 mL) and MeOH (20 mL) and the reaction mixture was stirred at rt for 30 min. The mixture was diluted with DCM and sat NaHCCL (aq), then passed through a phase separator. The filtrate was concentrated to grant the title compound (1.595 g, 96%). MS (ESI) m / z [M+H]+195.1 and 197.1.

[0677] Intermediate 22

[0678] (6-Chloroquinazolin-2-yl)methyl methanesulfonate

[0679] DCM (35 mL) was added to a mixture of methanesulfonic anhydride (1.948 g, 11.18 mmol) and (6-chloroquinazolin-2-yl)methanol Intermediate 21. TEA (2.08 mL, 14.92 mmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with water, extracted with EtOAc and concentrated. The crude residue was purified by straight phase chromatography on silica (gradient: 20-50% EtOAc in heptane) to grant the title compound (1.2 g, 59%) as a light-yellow solid. MS (ESI) m / z [M+H]+273.2 and 275.2.

[0680] Intermediate 23 2-((2-Acetyl-6-fluorophenyl)amino)-2-oxoethyl acetate

[0681] 1-(2-Amino-3-fluorophenyl)ethan-l-one (0.936 g, 5.81 mmol) was dissolved in DCM (20 mL) and cooled in an ice-bath. 4-Methylmorpholine (1.28 mL, 11.64 mmol) was added followed by a dropwise addition of 2-chloro-2-oxoethyl acetate (0.77 mL, 7.16 mmol). After 15 min the cooling bath was removed, and the reaction mixture was stirred at rt overnight. The solution was diluted with DCM and washed with 10% citric acid (aq), sat NaHCCL (aq), brine. The organic layer was dried over Na2SO4, filtered and concentrated to grant the crude title compound as a brown oil (1.714 g). MS (ESI) m / z [M+H]+254.0.

[0682] Intermediate 24

[0683] (8-Fluoro-4-methylquinazolin-2-yl)methanol

[0684] A solution containing 2-((2-acetyl-6-fluorophenyl)amino)-2-oxoethyl acetate Intermediate 23 (1.47 g, 5.81 mmol) in 4 M NH3 in MeOH (15.96 mL, 63.86 mmol) was heated under microwave irradiation at 80 °C and stirred for 2 h. The solution was concentrated under reduced pressure and the crude residue was redissolved in EtOAc, washed with NaHCCL and the organic layer was concentrated to afford the title compound (1.047 g, 94%). MS (ESI) m / z [M+H]+193.0.

[0685] Intermediate 25

[0686] 2-(Chloromethyl)-6-methoxy-4-methylquinazoline l-(2-Amino-5-methoxyphenyl)ethan-l-one (190 mg, 1.15 mmol) was dissolved in dioxane (0.5 mL) and cooled to 0 °C. 4 M HC1 in dioxane (1.73 mL, 6.90 mmol) was added dropwise and the reaction mixture was stirred to rt overnight. The mixture was cooled to 0 °C and a solution of 2-chloroacetonitrile (109 1.73 m μLm, ol) in dioxane (0.1 mL) was added dropwise and the reaction mixture was stirred at rt over the weekend. 2-Chloroacetonitrile (109 μL, 1.73 mmol) was added and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was added dropwise to 2 M NaOH (aq, 6.90 mL, 13.80 mmol) at rt, stirred for 15 min, and then extracted with DCM. The organic layers were filtered through a phase separator and concentrated. The residue was purified by straight phase flash chromatography on silica (gradient: 10-50% EtOAc in heptane) to grant the title compound (33 mg, 13%) as a tan solid. MS (ESI) m / z [M+H]+222.9 and 224.8. Intermediate 26 terZ-Butyl 4-(3-oxo-3-(L3,5-trimethyl-U / -pyrazol-4-yl)propanoyl)piperidine-l-carboxylate l -( l ,3,5-Trimethyl- IT / -pyrazol-4-yl)ethan- l -one (21.6 g, 0.14 mol) was dissolved in THF (600 mL) under an atmosphere of Ar (g) . The turbid solution was cooled in an ice bath to 3 °C. 1 M KHMDS in THF (250 mL, 0.25 mol) and 1 M NaHMDS in THF (34 mL, 0.03 mol) were added dropwise, within 15 min, maintaining the temperature below 5 °C. The reaction mixture was stirred for 30 min and then l-(terLbutyl) 4-methyl piperidine-l,4-dicarboxylate (69.1 g, 0.28 mol) was added in 5 portions over 10 min. The reaction mixture was heated to 60 °C for 16 h. The mixture was cooled to rt and brine (200 mL) was added. The organic solvent was removed in vacuo and the residue was extracted with EtOAc (4^ 150 mL). The combined organic layers were dried over Na2SO4, filtered and then concentrated in vacuo. The crude residue was dissolved in MeOH (200 mL). A solution of LiOH hydrate (6.30 g, 0.15 mol) in water (200 mL) was added, and the reaction mixture was rapidly stirred for 2 h at rt. The formed precipitate was isolated by filtration. The filtrate was concentrated under reduced pressure to approximately half volume, and a second crop of precipitate was isolated by filtration after standing for 2 h. The solids were combined, washed with a small amount of water, and dried in vacuo to afford (39.02 g, 76%) of colorless solid. MS (ESI) m / z [M+H]+364.4.

[0687] Intermediate 27 tert-Butyl 4-(l 3'.5'-trimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)piperidine-l -carboxylate

[0688] / c / V-Butyl 4-(3-oxo-3-(l,3,5-trimethyl-U / -pyrazol-4-yl)propanoyl)piperidine-l-carboxylate Intermediate 26 (39.0 g, 107.30 mmol) was suspended in 99.5% EtOH (350 mL) and 64% hydrazine hydrate (aq, 16.31 mL, 215 mmol) was added. The reaction mixture was stirred at rt for 16 h followed by heating to 70 °C for 20 h. The mixture was concentrated in vacuo followed by the addition of DMF (100 mL). More 64% hydrazine hydrate (aq, 8.15 mL, 168.01 mmol) was added and the mixture was heated for 18 h to 70 °C. H3PO4 (2.372 mL, 36 mmol) was added and stirring was continued at 70 °C for 16 h. The mixture was concentrated in vacuo. The residue was taken up in EtOAc (350 mL), filtered, and the filtrate was washed with brine (*4), dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred for 12 h in a mixture of EtOAc (40mL) and heptane (160 mL). The solid was isolated by filtration and dried in vacuo to yield the title compound (30.26 g, 78%) as a colorless solid. 1H NMR (500 MHz, DMSO-t / 6) 1.38 - 1.42 (9H, m), 1.49 (2H, qd), 1.86 - 1.92 (2H, m), 2.15 - 2.2 (3H, m), 2.30 (3H, s), 2.81 (3H, bs), 3.66 (3H, s), 4.00 (2H, d), 6.06 (1H, s), 12.2 - 12.49 (1H, m). MS (ESI) m / z [M+H]+360.4.

[0689] Intermediate 28 l\3\5'-Trimethyl-5-(piperidin-4-yl)-17L2rt-3,4'-bipyrazole tert-Butyl 4-(l', 3', 5'-trimethyl-l'J / ,2J / -[3,4'-bipyrazol]-5-yl)piperidine-l -carboxylate Intermediate 27 (30.25 g, 84.15 mmol) was dissolved in a mixture of water (50 mL) and 37% HC1 (aq, 50 mL) and the reaction mixture was stirred for 20 min. The mixture was concentrated in vacuo and dried overnight under vacuum. IPA (120 mL) was added to the solids and the mixture was stirred for 6 h. Solid precipitate formed was isolated by filtration and washed with small amounts of IPA, IPA / MTBE (1 : 1) and MTBE. The precipitate was dried under vacuum to give the HCl-salt of the title compound (26.733 g, 96%) as colourless solid 1H NMR (500 MHz, D2O, 25°C) δ 1.88-2.00 (2H, m), 2.24-2.30 (2H, m), 2.35 (6H, d), 3.11-3.26 (3H, m), 3.52 (2H, dt), 3.88 (3H, s), 6.49-6.53 (1H, m). MS (ESI) m / z [M+H]+260.4.

[0690] Intermediate 29 tert-Butyl 4-(5-(pyridin-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-U / -pyrazol-3- yl)piperidine-l -carboxylate and tert-butyl 4-(3-(pyridin-3-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-U / -pyrazol-5-yl)piperidine-l-carboxylate (1 : 1 mixture) NaH (60 wt.% in mineral oil) (102 mg, 2.55 mmol) was added to a mixture of tert-butyl 4-(5- (pyridin-3-yl)-U / -pyrazol-3-yl)piperidine-l-carboxylate Intermediate 17 (558 mg, 1.70 mmol) and SEM-C1 (331 1. μ8L7, mmol) in THF (8.16 mL) at 0 °C. The reaction mixture was stirred for 1 h and then quenched by addition of sat NaHCCh (aq). The mixture was diluted with DCM, filtered through a phase separator, and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient: EtOAc in heptane 33- 66%) to grant the title compounds (0.486 g, 62%) as a yellow oil. The two regioisomers were formed in a 1 : 1 ratio. MS (ESI) m / z [M+H]+459.5.

[0691] Intermediate 30 (3-(3-(l-(tert-Butoxycarbonyl)piperidin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lJT- pyrazol-5-yl)pyridin-4-yl)diphenyl(6-(trifluoromethyl)pyridin-3-yl)phosphonium trifluoromethanesulfonate and (3-(5-(l-(tert-Butoxycarbonyl)piperidin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-17 / -pyrazol-3-yl)pyridin-4-yl)diphenyl(6- (trifluorom ethyDpyri din-3 -yDphosphonium trifluoromethanesulfonate (1 : 1 mixture) 1 M Methanesulfonic anhydride in DCM (598 0.60 m μLm,ol) was added dropwise to a solution of tert-butyl 4-(5-(pyridin-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-U / -pyrazol-3- yl)piperidine-l -carboxylate and tert-butyl 4-(3-(pyridin-3-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-U / -pyrazol-5-yl)piperidine-l-carboxylate (1 : 1 mixture) Intermediate 29 (218 mg, 0.66 mmol) in DCM (5.30 mL) at -46 °C. The reaction mixture was stirred for 2 h and then cooled to -78 °C, and DBU (89 0.60 mmol μ)L w, as added. The mixture was warmed to rt and stirred for 30 min, then diluted with DCM and washed with water. The organic layer was passed through a phase separator and concentrated to grant the title compound (542.8 mg, 97%) as a (1: 1) mixture of regioisomers. MS (ESI) m / z [M+H]+788.7.

[0692] Intermediate 31

[0693] 4-Chl oro-3 -(3 -(piperidin-4-yl)- I rt-pyrazol -5 -yDpyridine

[0694] A vial containing (3-(3-(l-(tert-butoxycarbonyl)piperidin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-17 / -pyrazol-5-yl)pyridin-4-yl)diphenyl(6- (trifluoromethyl)pyridin-3-yl)phosphonium trifluoromethanesulfonate and (3-(5-(l-(tert- butoxycarbonyl)piperidin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-U / -pyrazol-3-yl)pyridin- 4-yl)diphenyl(6-(trifluorom ethyl)pyri din-3 -yl)phosphonium trifluoromethanesulfonate (1: 1 mixture) Intermediate 30 (0.563 g, 0.6 mmol) was transferred into a glovebox. Anhydrous LiCl (0.102 g, 2.40 mmol) was added followed by dioxane (3 mL). The vial was removed from the glove box, heated to 80 °C and stirred over the weekend. The mixture was cooled to rt and concentrated. The crude residue was dissolved in DCM (4 mL) and treated with TFA (4 mL, 0.60 mmol). The reaction mixture was stirred overnight and concentrated. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to grant the title compound (33 mg, 21%) as a colourless film. MS (ESI) m / z [M+H]+263.1 and 265.1.

[0695] Intermediate 32 tert-Butyl 4-(3-(4-methylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate The reaction to synthesise this intermediate was conducted in a flow reactor. \ -(lerl- Butoxycarbonyl)piperidine-4-carboxylic acid (10.08 g, 43.95 mmol) was added to CDI (6.80 g, 41.95 mmol) in THF (400 mL) at 25°C and stirred for 1 h. l-(4-Methylpyri din-3 -yl)ethan- 1-one (5.40 g, 39.95 mmol) was added to the mixture. A second solution containing 1 M LiHMDS in THF was prepared and the two solutions were mixed in flow reactor so that the pumping of 1 mL / min 1 M LiHMDS in THF was mixed with 2 mL / min of the CDI activated acid solution. The eluted solution was stirred under an atmosphere of N2 (g) for 10 min and then concentrated. The concentrate was diluted with EtOAc and washed sequentially with 0.5 M citric acid (aq), water and brine. The organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (12.8 g, 92%) as a yellow oil. MS (ESI) m / z [M+H]+347.1.

[0696] Intermediate 33 tert-Butyl 4-(5-(4-methylpyri din-3 -yl)-U / -pyrazol -3 -yllpiperi dine- 1 -carboxylate Hydrazine monohydrate (5.06 g, 101.03 mmol) was added dropwise to tert-butyl 4-(3-(4- m ethylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate Intermediate 32 (7.00 g, 20.21 mmol) in EtOH (150 mL) and the reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated, and the crude residue was purified by reverse phase flash chromatography on a C18 column (gradient: 5-40% MeCN in water) to give the title compound (4.90 g, 71%) as a white solid. MS (ESI) m / z [M+H]+343.1.

[0697] Intermediate 34

[0698] 4-Methyl-3-(3-(piperidin-4-yl)-lrt-pyrazol-5-yl)pyridine

[0699] TFA (3 mL, 3.02 mmol) was added to a solution of tert-butyl 4-(5-(4-methylpyridin-3-yl)-UT- pyrazol-3-yl)piperidine-l -carboxylate Intermediate 33 (1.03 g, 3.01 mmol) in DCM (9 mL) and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated and redissolved in MeOH (10 mL). Et2O (50 mL) was added, and the solution was stirred, white precipitate formed which was filtered off and washed with MTBE. The precipitate was dried under vacuum to grant the TFA salt of the title compound (1.33 g, 93%) as a white solid. MS (ESI) m / z [M+H]+243.2. Intermediate 35 tert-Butyl 4-(3-(5-chloropyridin-3-yl)-3-oxopropanoyl)piperidine-l-carboxylate

[0700] CDI (2.78 g, 17.15 mmol) was added to a solution of l-(tert-butoxycarbonyl)piperidine-4- carboxylic acid (3.98 g, 17.36 mmol) in THF (31.2 mL) and stirred at rt for 1 h. In a separate flask, 1 M LiHMDS (18.01 mL, 18.01 mmol) was added dropwise to a solution of l-(5- chloropyridin-3-yl)ethan-l-one (2.67g, 17.15 mmol) in THF (36.5 mL) at -78 °C and stirred for 30 min. The solution containing CDI-activated carboxylic acid was added dropwise and the reaction mixture was warmed to rt. The reaction mixture was diluted with EtOAc and washed sequentially with 10% citric acid (aq), sat NaHCCh (aq) and brine. The organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient 20-35% EtOAc in heptane) and then further purified by preparative HPLC, PrepMethod G, (gradient 20-80%), to grant the title compound (2.88g, 46%) as a white solid. MS (ESI) m / z [M+H]+365.2.

[0701] Intermediate 36 tert-Butyl 4-(5-(5-chloropyridin-3-yl)-U / -pyrazol-3-yl)piperidine-l-carboxylate Hydrazine hydrate (aq, 0.796 mL, 16.36 mmol) was added to a solution of tert-butyl 4-(3-(5- chl oropyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate Intermediate 35 (3.0 g, 8.18 mmol) in EtOH (26.5 mL). The reaction mixture was heated to 50 °C and stirred overnight. The solvent was concentrated, and the residue was purified by straight phase flash chromatography on silica (gradient; 5-50% EtOAc in heptane) to give the title compound as a white solid. MS (ESI) m / z [M+H]+363.3.

[0702] Intermediate 37

[0703] 3 -Chi oro-5 -(3 -(piperidin-4-yl)- I rt-pyrazol -5 -yllpyridine

[0704] TFA (8 mL) was added to a suspension of tert-butyl 4-(5-(5-chloropyridin-3-yl)-lrt-pyrazol- 3 -yl)piperidine-l -carboxylate Intermediate 36 (2.86 g, 7.88 mmol) in DCM (30 mL). The reaction mixture was stirred for 1 h at rt and then concentrated to afford a yellow oil which was treated with Et2O. The product precipitated and was collected by filtration and washed with additional Et2O to afford the TFA salt of the title compound as an off white solid (3.72 g, 96%). MS (ESI) m / z [M+H]+263.3. Intermediate 38

[0705] 2-((4-(5-(5-Chloropyridin-3-yl)-lrt-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylpyridor2,3- Jlpyrimidine

[0706] (4-Methylpyrido[2,3-d]pyrimidin-2-yl)methyl methanesulfonate Intermediate 9 (71.4 mg, 0.28 mmol) and DIPEA (196 pl, 1.13 mmol) was added to a solution of 3-chloro-5-(3- (piperidin-4-yl)-U / -pyrazol-5-yl)pyridine, 2 TFA Intermediate 37 (160 mg, 0.33 mmol) in DMSO (1 mL). The reaction mixture was stirred at rt for 3 h, and then filtered using a syringe filter. The resulting solution was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (0.067 g, 57%) as a slightly yellow solid. MS (ESI) m / z [M+H]+220.3.

[0707] Intermediate 39 tert-Butyl 4-(3 -(2 -methylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate The reaction to synthesise this intermediate was conducted in a flow reactor. l-(tert- Butoxycarbonyl)piperidine-4-carboxylic acid (10.08 g, 43.95 mmol) was added to CDI (6.80 g, 41.95 mmol) in THF (400 mL) and stirred at 20 °C for 1 h. l-(2-Methylpyridin-3-yl)ethan- 1-one (5.40 g, 39.95 mmol) was added to the solution. A second solution containing 1 M LiHMDS in THF was prepared and the two solutions were mixed in flow so that the pumping of 1 mL / min 1 M LiHMDS in THF was mixed with 2 mL / min of the solution of CDI activated acid with no cooling. The eluted solution was stirred under an atmosphere of N2 (g) for 10 min before concentrating under vacuum. The concentrate was diluted with EtOAc and washed sequentially with 0.5 M citric acid (aq), water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (12.1 g, 87%) as a yellow oil. MS (ESI) m / z [M+H]+347.1.

[0708] Intermediate 40 tert-Butyl 4-(5 -(2 -methylpyri din-3 -yl)-U / -pyrazol -3 -yllpiperi dine- 1 -carboxylate Hydrazine monohydrate (4.34 g, 86.60 mmol) was added dropwise to a solution containing tert-butyl 4-(3 -(2 -methylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate Intermediate 39 (6.00 g, 17.32 mmol) in EtOH (150 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h and then concentrated under reduced pressure. The crude product was purified by reversed phase flash chromatography on a Cl 8 column (gradient: 5-40% MeCN in water) to give the title compound (4.30 g, 73%) as a white solid. MS (ESI) m / z [M+H] 343.2.

[0709] Intermediate 41

[0710] 2 -Methyl -3-(3-(piperidin-4-yl)-lrt-pyrazol-5-yl)pyridine

[0711] TFA (3 mL, 3.12 mmol) was added to a solution of 2-methyl-3-(3-(piperidin-4-yl)-lrt- pyrazol-5-yl)pyridine Intermediate 40 (1.07 g, 3.12 mmol) in DCM (9 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated and redissolved in MeOH (10 mL). Et2O (50 mL) was added, and the solution was stirred. The precipitate formed was collected by filtration, washed with MTBE and dried under vacuum to grant the TFA salt of the title compound (1.376 g, 94%) as a white solid. MS (ESI) m / z [M+H]+243.2.

[0712] Intermediate 42

[0713] 3-('3- (7c / 7-Butoxycarbonyl )piperidin-4-yl )- pyrazol-5-yl)-4-('hydroxymethyl (pyridine 1- oxide

[0714] 70% mCPBA (aq, 91 mg, 0.37 mmol) was added to a solution of tert-butyl 4-(5-(4- methylpyridin-3-yl)-U / -pyrazol-3-yl)piperidine-l-carboxylate Intermediate 33 (106 mg, 0.31 mmol) in DCM (1.55 mL) and stirred at rt for 1 h. The mixture was purified by straight phase flash chromatography on silica (gradient: 0-20% MeOH in EtOAc) to grant the title compound (96 mg, 87%) as a white solid. MS (ESI) m / z [M+H]+359.3.

[0715] Intermediate 43 tert-Butyl 4-(5-(4-(hydroxymethyl)pyridin-3-yl)-U / -pyrazol-3-yl)piperidine-l-carboxylate A solution of 3-(3-(l-(tert-butoxycarbonyl)piperidin-4-yl)-U / -pyrazol-5-yl)-4- (hydroxymethyl)pyridine 1-oxide Intermediate 41 (42.0 mg, 0.12 mmol) in AC2O (0.7 mL, 0.12 mmol) was heated to 80 °C and stirred for 6 h. The solvent was concentrated and MeOH (1 mL) was added. 2 M NaOH (aq, 0.293 mL, 0.59 mmol) was added and the mixture was stirred at rt for 1 h and then concentrated. The residue was treated with DMSO and filtered using a syringe filter. The filtrate was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to grant the title compound (20 mg, 48%) as a clear oil. MS (ESI) m / z [M+H]+359.3. I l l

[0716] Intermediate 44 tert-Butyl 4-(5-(2-ethylpyridin-3-yl)-17 / -pyrazol-3-yl)piperidine-l-carboxylate Propionic acid (68.1 0 μ.9L1, mmol) and DIC (106 0.69 m μmLo,l) were added to a solution of 2-hydroxyisoindoline-l, 3-dione (149 mg, 0.91 mmol) and DMAP (5.58 mg, 0.05 mmol) in DMSO (2.197 mL). The reaction mixture was stirred at rt for 24 h. A solution of tert-butyl 4- (5-(pyridin-3-yl)-177-pyrazol-3-yl)piperidine-l-carboxylate Intermediate 17 (150 mg, 0.46 mmol) and (lA)-(-)-CSA (212 mg, 0.91 mmol) in DMSO (2.2 mL) was added to the reaction mixture, followed by 4-CzIPN (3.60 mg, 4.57 pmol). The reaction mixture was evacuated and filled with N2 (g) three times and then degassed with N2 (g) vigorously for 10 min. The vial was irradiated with a 34 W LED (A.max456 nm) for 24 h and then purified by preparative HPLC, PrepMethod OO, (gradient: 30-70%), to grant the title compound (10.0 mg, 6%). MS (ESI) m / z [M+H]+287.4.

[0717] Intermediate 45 tert-Butyl 4-(5-(2.4-diethylpyridin-3-yl)-lZ / -pyrazol-3-yl)piperidine-l -carboxylate Step, a) .1 , 3 -Di oxoi soindolin-27y 1.propi onate

[0718] DIC (0.313 mL, 2.00 mmol) was added to a solution of propionic acid (148 mg, 2 mmol), DMAP (12 mg, 0.10 mmol) and 2-hydroxyisoindoline-l, 3-dione (0.326 g, 2.00 mmol) in anhydrous DMSO (5.67 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was filtered to grant a 0.3 M solution of the title compound. The solution was used in the next step.

[0719] Step. b). tert-Butyl .^(S-Q^-diethylpy ri din-37yl) -l.^pyrazol -3 ryljpiperidine: 1 -carboxylate A microwave vial was charged with tert-butyl 4-(5-(4-methylpyridin-3-yl)- IT / -pyrazol-3- yl)piperidine-l -carboxylate Intermediate 33 (66 mg, 0.20 mmol), 4CzIPN (3.17 mg, 4.02 pmol) and CSA (93 mg, 0.40 mmol) followed by DMSO (1.1 mL) and l,3-dioxoisoindolin-2- yl propionate Intermediate 45 Step a) (0.3 M in DMSO, 1.34 mL, 0.40 mmol). The vial was sealed, evacuated and refilled with N2 (g) three times. The reaction mixture was irradiated with a 34 W LED (A.max456 nm) for 2.5 h. The mixture was filtered and purified by preparative HPLC, PrepMethod D, (gradient: 25-75%), to grant the title compound (4.6 mg, 6%). MS (ESI) m / z [M+H]+385.5.

[0720] Intermediate 46 terLButyl 4-(3-(2,4-dimethylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate The reaction to synthesise this intermediate was conducted in a flow reactor. \ -(lerl- Butoxycarbonyl)piperidine-4-carboxylic acid (3.38 g, 14.75 mmol) was added to CDI (2.28 g, 14.08 mmol) in THF (400 mL) at 20°C. The resulting solution was stirred at 55 °C for 1 h. 1- (2,4-Dimethylpyridin-3-yl)ethan-l-one (2.00 g, 13.41 mmol) was added to the solution. A second solution containing 1 M LiHMDS in THF was prepared and the two solutions were mixed in flow so that the pumping of 1 mL / min 1 M LiHMDS in THF was mixed with 2 mL / min of the CDI activated acid solution. The eluted solution was stirred under an atmosphere of N2 (g) for 10 min before quenching with brine. The mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by reversed phase flash chromatography on a Cl 8 column (gradient: 0-100% MeCN in water) to grant the title compound (2.00 g, 41%) as a brown oil. MS (ESI) m / z [M+H]+361.1.

[0721] Intermediate 47 terLButyl 4-(5-(2.4-dimethylpyridin-3-yl)-lrt-pyrazol-3-yl)piperidine-l-carboxylate Hydrazine hydrate (aq, 3.12 g, 62.42 mmol) was added to tert-butyl 4-(3-(2,4- dimethylpyri din-3 -yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate Intermediate 46 (4.5 g, 12.48 mmol) in EtOH (50 mL) at 20°C under an atmosphere of N2 (g) and stirred at 80 °C for 3 h. The solvent was removed under reduced pressure. The crude product was purified by reversed phase flash chromatography on a Cl 8 column (gradient: 0-100% MeCN in water) to grant the title compound (3.75 g, 84%) as a white solid. MS (ESI) m / z [M+H]+357.2.

[0722] Intermediate 48

[0723] Ethyl (Z)-2-chloro-2-(2-(2-methyl-6-nitrophenyl)hydrazineylidene)acetate

[0724] 12.5 M HC1 (aq, 5.26 mL, 65.72 mmol) was added to 2-methyl-6-nitroaniline (2 g, 13.14 mmol) in MeOH (12.6 mL) at 0 °C and the reaction mixture was stirred for 15 min under an atmosphere of N2 (g). A solution of NaNCL (0.998 g, 14.46 mmol) in water (2.40 mL) was added and the reaction mixture was stirred at 0 °C for 2 h. The mixture was filtered through a pad of CELITE and ethyl 2-chl oro-3 -oxobutanoate (2.81 g, 17.09 mmol) was added to the filtrate. The reaction mixture was stirred at 20 °C for 2 h. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to afford the title compound (3.50 g, 93%) as a yellow solid. MS (ESI) m / z [M+H]+286.0.

[0725] Intermediate 49

[0726] Ethyl 8-methylbenzoIel I L2,41triazine-3 -carboxylate

[0727] Under an atmosphere of N2 (g), 12.5 M HC1 (aq, 1.80 mL, 22.53 mmol) was added to ethyl (Z)-2-chloro-2-(2-(2-methyl-6-nitrophenyl)hydrazineylidene)acetate Intermediate 48 (3 g, 11.27 mmol) in AcOH (17.8 mL) at 20 °C. The solution was added dropwise to a solution of Fe(s) (3.15 g, 56.34 mmol) in water (4.3 mL) and the reaction mixture was stirred for 16 h. The mixture was poured into brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-50% EtOAc in heptane) to grant the title compound (2 g, 82%) as a yellow solid. MS (ESI) m / z [M+H]+218.1.

[0728] Intermediate 50

[0729] (8-Methylbenzo[e1 [ 1 ,2.41tri azin-3 -yllmethanol

[0730] Under an atmosphere of N2 (g), 2 M LiAlELin THF (9.21 mL, 18.41 mmol) was added dropwise over 30 min to ethyl 8-methylbenzo[e][l, 2, 4]triazine-3 -carboxylate Intermediate 49 (2 g, 9.21 mmol) in THF (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then the reaction was quenched by the addition of 2 M NaOH (aq). The mixture was filtered through CELITE and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod N, (gradient: 5-30%), to grant the title compound (1 g, 62%) as a yellow solid. MS (ESI) m / z [M+H]+176.1.

[0731] Intermediate 51

[0732] (8-Methylbenzo[e1 [ 1 ,2.41tri azin-3 -yl (methyl methanesulfonate

[0733] DIPEA (253 μL 1,.45 mmol) was added to a solution of (8-methylbenzo[e][l,2,4]triazin-3- yl)methanol Intermediate 50 (212 mg, 1.21 mmol) in DCM (6 mL) and the mixture was cooled to 0 °C. A solution of methanesulfonic anhydride (232 mg, 1.33 mmol) in DCM (1 mL) was added and the reaction mixture was stirred for 1 h at rt. Further methanesulfonic anhydride (200 mg, 1.96 mmol) was added, and the reaction mixture was stirred for 5 min. The mixture was concentrated and purified by straight phase flash chromatography on silica (gradient: 25-50% EtOAc in heptane) to grant the title compound (0.266 g, 87%) as a yellow solid. MS (ESI) m / z [M+H]+254.2.

[0734] Intermediate 52

[0735] 2,4-Dimethyl-3-(3-(piperidin-4-yl)-lJ7-pyrazol-5-yl)pyridine

[0736] 4 M HC1 in dioxane (3.51 mL, 14.03 mmol) was added to tert-butyl 4-(5-(2,4- dimethylpyridin-3-yl)-U / -pyrazol-3-yl)piperidine-l-carboxylate Intermediate 47 (500 mg, 1.40 mmol) in dioxane (5 mL) under an atmosphere of N2 (g). The reaction mixture was stirred at 20 °C for 1 h. The solvent was removed under reduced pressure, to afford the TFA salt of the title compound (500 mg) as a yellow solid. 1H NMR (300 MHz, DMSO) δ 8.67 (1H, d), 7.89 (1H, d), 6.36 (1H, s), 3.37 - 3.25 (2H, m), 3.13 - 2.93 (3H, m), 2.59 (s, 3H), 2.42 (s, 3H), 2.17 (2H, m), 1.88 (2H, m).

[0737] Intermediate 53

[0738] 5-Methoxy- l -methyl- pyrazole-4-carbonyl chloride 5-Methoxy-l-methyl-lrt-pyrazole-4-carboxylic acid (0.131 g, 0.8 mmol) was suspended in DCM (2.2 mL). Oxalyl chloride (0.143 mL, 1.60 mmol) was added, and the mixture was cooled in an ice-bath. DMF (6.19 0.08 μL m,mol) was added and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and co-evaporated with DCM to afford the title compound (0.137 g, 98%).1H NMR (500 MHz, DMSO-t / 6) 3.60 (3H, s), 4.06 (3H, s), 7.63 (1H, s).

[0739] Intermediate 54 tert-Butyl 4-(3 -(5 -methoxy- 1 -methyl - 17 / -py razol -4-yl)-3 -oxoprop- 1 -yn- 1 -yllpiperidine- 1 - carboxylate

[0740] Pd(PPh3)2Cl2(0.017 g, 0.02 mmol) was added to a solution of tert-butyl 4-ethynylpiperidine- 1-carboxylate (0.103 g, 0.493 mmol), 5-methoxy-l-methyl-lrt-pyrazole-4-carbonyl chloride Intermediate 53 (0.129 g, 0.74 mmol), Cui (4.7 mg, 0.02 mmol) and TEA (0.412 mL, 2.96 mmol) in THF (0.85 mL) and toluene (0.85 mL). The reaction mixture was stirred under an atmosphere of N2 (g) at rt for 3 h. DCM (7 mL) and sat NaHCCL (aq, 7 mL) were added. The mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 0-40% (EtOAc / 4M NH3 in MeOH (9 / 1)) in DCM) to give the title compound (0.038 g, 22%). MS (ESI) m / z [(M-Boc)+H]+248.1. 1H NMR (500 MHz, CDCI3) 1.46 (9H, s), 1.64 - 1.75 (2H, m), 1.86 - 1.94 (2H, m), 2.76 - 2.87 (1H, m), 3.22 (2H, ddd), 3.67 (3H, s), 3.70 - 3.80 (2H, m), 4.21 (3H, s), 7.86 (1H, s).

[0741] Intermediate 55 terLButyl 4-(5'-methoxy-l '-methyl-1 '77,277-13, 4'-bipyrazol]-5-yl)piperidine-l -carboxylate / crt-Buty 1 4-(3 -(5 -methoxy- 1 -methyl - 1 H-pyrazol -4-yl)-3 -oxoprop- 1 -yn- 1 -yl)piperidine- 1 - carboxylate Intermediate 54 (0.037 g, 0.11 mmol) was dissolved in 99.5% EtOH (0.7 mL). 64% Hydrazine hydrate (aq, 0.026 mL, 0.53 mmol) was added, and the reaction mixture was stirred at rt overnight. DCM and NaHCCf (aq) were added, the mixture was stirred, filtered through a phase separator, and concentrated to yield the title compound (0.039 g). Used as such in the next step.

[0742] MS (ESI) m / z [M+H]+362.3.

[0743] Intermediate 56

[0744] 5'-Methoxy-l '-methyl-5-(piperidin-4-yl)-l '77,277-3, 4'-bipyrazole

[0745] TFA (15.77 mg, 0.14 mmol) was added to a solution of tert-butyl 4-(5 ’-methoxy- l’-methyl- r77,277-[3,4’-bipyrazol]-5-yl)piperidine-l-carboxylate Intermediate 55 (50 mg, 0.14 mmol) in DCM (1 mL) at 10 °C and the reaction mixture was stirred for 2 h. The mixture was concentrated to grant the TFA salt of the title compound (40 mg). MS (ESI) m / z [M+H]+262.1.

[0746] Intermediate 57

[0747] 5-Methyl-l,8-naphthyridine-2-carboxylic acid

[0748] Under an atmosphere of N2 (g), NaOH (1.175 g, 29.38 mmol) was added to 2-amino-4- methylnicotinaldehyde (1 g, 7.34 mmol) and methyl 2-oxopropanoate (1.5 g, 14.69 mmol) in IPA (50 mL) and water (50 mL). The reaction mixture was stirred at 20 °C for 16 h. The mixture was filtered and the solvent was removed under reduced pressure to grant the title compound (1.3 g, 94%) as a yellow solid. MS (ESI) m / z [M+H]+188.8.

[0749] Intermediate 58 Methyl 5-methyl-L8-naphthyridine-2-carboxylate

[0750] SOCh (0.465 mL, 6.38 mmol) was added to 5-methyl-l,8-naphthyridine-2-carboxylic acid Intermediate 57 (1.2 g, 6.38 mmol) in MeOH (10 mL) at 0 °C. The reaction mixture was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure to afford crude product which was purified by straight phase flash chromatography on silica (gradient: 30- 50% EtOAc in petroleum ether) to grant the title compound 0.750 g, 58%) as a yellow solid. MS (ESI) m / z [M+H]+203.2.

[0751] Intermediate 59

[0752] (5-Methyl-L8-naphthyridin-2-yl)methanol

[0753] NaBH4 (374 mg, 9.89 mmol) was added to methyl 5-methyl-l,8-naphthyridine-2-carboxylate Intermediate 58 (500 mg, 2.47 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude product. The crude product was purified by preparative HPLC, PrepMethod Q, (gradient: 10-25%), to grant the title compound (265 mg, 62%) as a white solid. MS (ESI) m / z [M+H]+175.3.

[0754] Intermediate 60

[0755] 2-((2-Acetyl-4-chlorophenyl)amino)-2-oxoethyl acetate 2-Chloro-2-oxoethyl acetate (310 2.79 μ mLm, ol) was added dropwise to a solution of l-(2- amino-5-chlorophenyl)ethan-l-one (395 mg, 2.33 mmol) and NMM (512 4.66 mmol) μ iLn, DCM (9 mL) at 0 °C and stirred for 15 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. The solution was diluted with DCM and washed with 10% citric acid (aq), sat NaHCCL (aq) and brine. The organic layers were dried over Na2SO4, filtered and concentrated to grant the title compound (769 mg) as a brown oil. MS (ESI) m / z [M+H]+270.2.

[0756] Intermediate 61

[0757] (6-Chloro-4-methylquinazolin-2-yl)methanol 2-((2-Acetyl-4-chlorophenyl)amino)-2-oxoethyl acetate Intermediate 60 (628 mg, 2.33 mmol) was dissolved in 4 M NH3 in MeOH (6.4 mL, 25.6 mmol) and stirred at 85 °C for 10 h in a microwave reactor. The mixture was concentrated, redissolved in EtOAc and washed with sat NaHCCh (aq). The organic layers were concentrated to afford the title compound (449 mg, 92%) as a beige solid. MS (ESI) m / z [M+H]+209.1.

[0758] Intermediate 62

[0759] 6-Chloro-2-(chloromethyl)-4-methylquinazoline

[0760] NCS (316 mg, 2.37 mmol) was added to a solution of (6-chloro-4-methylquinazolin-2- yl)methanol Intermediate 61 (449 mg, 2.15 mmol) and PPhs (621 mg, 2.37 mmol) in DCM (7 mL) at 0 °C and stirred for 3 h. The reaction mixture was concentrated and purified by straight phase flash chromatography on silica (gradient: 5-40%), to grant the title compound (217 mg, 44%) as a white solid. 1H NMR (500 MHz, CDC13, 25°C) δ 2.95 (3H, s), 4.84 (2H, s), 7.83 (1H, m), 7.98 (1H, m), 8.07 (1H, m).

[0761] Intermediate 63

[0762] 2-((3 -Chi oro-2 -formylphenyl)amino)-2-oxoethyl acetate

[0763] 2-Chloro-2-oxoethyl acetate (3.7 mL, 34.4 mmol) was added dropwise to a solution of 2- amino-6-chlorobenzaldehyde (4.46 g, 28.67 mmol) and DIPEA (7.49 mL, 43.0 mmol) in DCM (60 mL) at 0 °C and stirred for 2 h. Further 2-chloro-2-oxoethyl acetate (0.616 mL, 5.73 mmol) was added and the reaction mixture was stirred for 45 min. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to grant the title compound (6.46 g, 88%) as a brown solid. MS (ESI) m / z [M-H]' 253.9.

[0764] Intermediate 64

[0765] (5-Chloroquinazolin-2-yl)methyl acetate

[0766] 2-((3-Chloro-2-formylphenyl)amino)-2-oxoethyl acetate Intermediate 63 (6.97 g, 27.26 mmol) and NH4OAC (6.30 g, 81.79 mmol) were suspended in AcOH (91 mL). The mixture was divided into 7 microwave vials and each of the vials were stirred at 130 °C for 3 min under microwave irradiation and then all the mixtures were combined, and solvent was removed under reduced pressure. The residue was diluted with toluene and washed with water, sat NaHCCL (aq) and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to grant the title compound (5.46 g, 85%) as a brown solid. MS (ESI) m / z [M+H]+209.1.

[0767] Intermediate 65

[0768] (5-Chloroquinazolin-2-yl)methanol

[0769] LiOH (0.112 g, 4.67 mmol) was added to a solution of (5-chloroquinazolin-2-yl)methyl acetate Intermediate 64 (0.85 g, 3.59 mmol) in THF (9 mL), MeOH (6 mL) and water (5 mL) and stirred at rt for 0.5 h. The mixture was diluted water and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated to afford the title compound (0.640 g, 92%) as a yellow solid.

[0770] Intermediate 66

[0771] ('5-Chloroquinazolin-2-yl (methyl methanesulfonate

[0772] Methanesulfonyl chloride (258 3.33 μL m,mol) was added to a solution of (5- chloroquinazolin-2-yl)methanol Intermediate 65 (499 mg, 2.56 mmol) and DIPEA (672 μL, 3.85 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred for 90 min and then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to grant the title compound (689.6 mg, 99%) as a brown oil. MS (ESI) m / z [M+H]+273.0.

[0773] Intermediate 67

[0774] 2-((2-Acetyl-4-bromophenyl)amino)-2-oxoethyl acetate

[0775] 2-Chloro-2-oxoethyl acetate (0.616 mL, 5.56 mmol) was added dropwise to a solution of 1- (2-amino-5-bromophenyl)ethan-l-one (0.992 g, 4.63 mmol) and NMM (1.019 mL, 9.27 mmol) in DCM (16 mL) at 0 °C. The reaction mixture was stirred for 15 min and then the cooling bath was removed and the reaction mixture was allowed to warm to rt overnight. The mixture was diluted with DCM and washed with 10% citric acid (aq), sat NaHCCL (aq) and brine. The organic layers were dried over Na2SO4, filtered and concentrated to grant the title compound (1.623 g) as a brown solid. MS (ESI) m / z [M-H]‘ 312.0 and 314.0.

[0776] Intermediate 68

[0777] (6-Bromo-4-methylquinazolin-2-yl)methanol 2-((2-Acetyl-4-bromophenyl)amino)-2-oxoethyl acetate Intermediate 67 (1.456 g, 4.63 mmol) was dissolved in 4 M NH3 in MeOH (12.75 mL, 50.98 mmol) and heated in a microwave reactor for 8 h at 85°C. The solution was concentrated in vacuo, redissolved in EtOAc and washed with sat NaHCCL (aq). The organic layers were concentrated to afford the title compound (1.112 g, 95%) as a beige solid. MS (ESI) m / z [M+H]+252.9 and 254.9.

[0778] Intermediate 69

[0779] 6-Bromo-2-(chloromethyl)-4-methylquinazoline

[0780] PPI13 (1.268 g, 4.83 mmol) was added to a solution of (6-bromo-4-methylquinazolin-2- yl)methanol Intermediate 68 (1.112 g, 4.39 mmol) in DCM (15 mL). The mixture was cooled to 0 °C and NCS (0.645 g, 4.83 mmol) was added and the reaction mixture was stirred for 3 h. The mixture was concentrated and purified by straight phase flash chromatography on silica (gradient: 10-40% EtOAc in heptane), to grant the title compound (0.581 g, 49%) as white solid. MS (ESI) m / z [M-H]' 269.0 and 271.0.

[0781] Intermediate 70

[0782] 6-Bromo-4-methyl-2-((4-(rj'A'-trimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)piperidin-l- yllmethyllquinoline

[0783] A solution of l',3',5'-trimethyl-5-(piperidin-4-yl)-17 / ,2JH-3,4'-bipyrazole, HC1 Intermediate 28 (156 mg, 0.60 mmol), 6-bromo-2-(chloromethyl)-4-methylquinazoline Intermediate 69 (158 mg, 0.58 mmol) and K2CO3 (663 mg, 4.80 mmol) in MeCN (9 mL) was stirred at 42 °C overnight. After cooling to rt, precipitated solids were filtered off and washed with MeCN. The filtrate was concentrated and purified by reversed phase flash chromatography on a Cl 8 column (gradient: 5-95% MeCN in 0.1% NH4OH (aq)) to grant the title compound (217 mg, 73%) as a beige solid. MS (ESI) m / z [M+H]+494.2 and 496.1.

[0784] Intermediate 71 tert-Butyl (4-acetyl-6-methoxypyridin-2-yl)carbamate

[0785] A solution of tert-butyl (4-acetyl-6-methoxypyri din-2 -yl)carbamate (5.25 g, 23.41 mmol) and TMEDA (10.9 mL, 23.41 mmol) in dry Et2O (100 mL) was cooled under an atmosphere of Ar (g) to -70 °C, and 1.6 M nBuLi in heptane (43.9 mL, 70.24 mmol) was added slowly. After complete addition the reaction mixture was stirred for 2 h at -15 °C. The mixture was cooled to -70 °C, and A-methoxy-A-methylacetamide (5 mL, 52.37 mmol) was added dropwise over 10 min. The cooling bath was removed and the reaction mixture was allowed to warm to rt overnight. The mixture was poured into a solution of NH4CI (aq) and ice. The layers were separated, the aqeous layer was extracted with MTBE, and the combined organic layers were washed with 5% citric acid (aq) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by straight phase flash chromatography on silica (15% EtOAc in heptane) to give 1.48 g of the title compound as a yellow solid. MS (ESI) m / z [M+H]+267.1.

[0786] Intermediate 72

[0787] 1-(5-Amino-2-methoxypyridin-4-yl)ethan-l-one

[0788] TFA (5.79 mL, 75.10 mmol) was added to a solution of tert-butyl (4-acetyl-6- m ethoxypyri din-3 -yl)carbamate Intermediate 71 (1 g, 3.76 mmol) in DCM (12.4 mL) and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with sat NaHCCh (aq) and extracted with DCM. The organic layers were combined, filtered through a hydrophobic frit and concentrated to grant the title compound (0.616 g, 99%) as a yellow solid. MS (ESI) m / z [M+H]+167.1.

[0789] Intermediate 73

[0790] 2-((4-Acetyl-6-m ethoxypyri din-3 -yl)amino)-2-oxoethyl acetate

[0791] 2-Chloro-2-oxoethyl acetate (0.427 mL, 3.97 mmol) was added to a solution containing TEA (2.52 mL, 18.05 mmol) and l-(5-amino-2-methoxypyridin-4-yl)ethan-l-one Intermediate 72 (600 mg, 3.61 mmol) in DCM (20 mL) at 0 °C and stirred for 3 h. The mixture was diluted with sat NaHCCL (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSCU, filtered, and concentrated. The crude residue was purified by straight phase flash chromatography on silica (0-50% EtOAc in heptane) to grant the title compound (869 mg, 90%) as a yellow solid. 1H NMR (500 MHz, CDCI3, 25°C) δ 2.18 (3H, s), 2.55 (3H, s), 3.88 (4H, s), 4.64 (2H, s), 7.23 (1H, ds, 8.62 (1H, s).

[0792] Intermediate 74

[0793] (6-Methoxy-4-methylpyridor3.4-t / ]pyrimidin-2-yl)methanol 2-((4-Acetyl -6-methoxypyri din-3 -yl)amino)-2-oxoethyl acetate Intermediate 73 (869 mg, 3.26 mmol) in 4 M NH3 in MeOH (10 mL) was heated under microwave irradiation at 80 °C for 4 h. The mixture was diluted with sat NaHCCh (aq) and extracted with DCM. The combined organic layers were washed with brine, filtered through a hydrophobic frit and concentrated. The residue was redissolved in 4 M NH3 in MeOH (10 mL) and heated under microwave irradiation at 80 °C for 3 h. The mixture was diluted with sat NaHCOs (aq) and extracted with DCM. The combined organic layers were washed with brine, filtered through a hydrophobic frit and concentrated to grant the title compound (547 mg, 82%). MS (ESI) m / z [M+H]+206.0.

[0794] Intermediate 75

[0795] 2-(Chloromethyl)-8-fluoro-4-methylquinazoline (8-Fluoro-4-methylquinazolin-2-yl)methanol Intermediate 24 (111 mg, 0.58 mmol) was dissolved in DCM (2 mL) and PPI13 (166 mg, 0.63 mmol) was added. The reaction mixture was cooled in an ice-bath and NCS (85 mg, 0.63 mmol) was added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 25-50% EtOAc in heptane) to give the title compound (0.093 g, 77%) as white solid. MS (ESI) m / z [M+H]+211.0. 1H NMR (500 MHz, CDCI3) 3.00 (3H, s), 4.89 (2H, s), 7.57 - 7.64 (2H, m), 7.87 - 7.94 (1H, m).

[0796] Intermediate 76

[0797] 2-((2-Acetyl-4-fluorophenyl)amino)-2-oxoethyl acetate l-(2-Amino-5-fluorophenyl)ethan-l-one (4.95 g, 31.35 mmol) was dissolved in DCM (90 mL) and cooled in an ice-bath. NMM (6.89 mL, 62.70 mmol) was added followed by a dropwise addition of acetoxyacetyl chloride (4.17 mL, 37.62 mmol). After 15 min the cooling bath was removed, and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM, washed with 10% citric acid (aq), sat NaHCCh (aq) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (8.72 g) as brown oil. MS (ESI) m / z [M+H]+254.0. (500 1H NMR MHz, CDCI3, 25 °C) δ 2.36 (3H, s), 2.65 (3H, s), 4.72 (2H, s), 7.29 (1H, ddd), 7.58 (1H, dd), 8.80 (1H, dd), 12.10 (1H, s).19F NMR (471 MHz, CDCI3) δ -117.68. Intermediate 77

[0798] (6-Fluoro-4-methylquinazolin-2-yl)methanol 2-((2-Acetyl-4-fluorophenyl)amino)-2-oxoethyl acetate Intermediate 76 (1.498 g, 5.92 mmol) was suspended in 4 M NH3 in MeOH (16.27 mL, 65.07 mmol) and heated in a microwave reactor for 8 h at 85 °C. The mixture was concentrated in vacuo, redissolved in EtOAc and washed with sat NaHCCL (aq). The organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (1.00 g, 88%) as a beige solid. MS (ESI) m / z [M+H]+193.0. 1H NMR (500 MHz, CDCI3, 25 °C) δ 2.92 (3H, s), 3.90 - 4.00 (1H, m), 4.91-4.96 (2H, m), 7.62 - 7.73 (2H, m), 8.00 - 8.04 (1H, m).19F NMR (471 MHz, CDCI3) δ -110.22.

[0799] Intermediate 78

[0800] 2-('Chloromethyl )-6-fluoro-4-methylquinazoline (6-Fluoro-4-methylquinazolin-2-yl)methanol Intermediate 77 (0.111 g, 0.58 mmol) was dissolved in DCM (2 mL) and PPI13 (0.167 g, 0.64 mmol) was added. The reaction mixture was cooled in an ice-bath and NCS (0.085 g, 0.64 mmol) was added. The reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 15-50% EtOAc in heptane) to give the title compound (0.085 g, 70%) as white solid.1H NMR (500 MHz, CDCI3, 25 °C) 6 2.94 (3H, s), 4.85 (2H, s), 7.64-7.72 (2H, m), 8.03 - 8.09 (1H, m).19F NMR (470 MHz, CDCI3) 6 -109.02.

[0801] Intermediate 79

[0802] 2-((2-Acetyl-3 -fl uorophenyl )ami no )-2-oxoethyl acetate l-(2-Amino-6-fluorophenyl)ethan-l-one (0.998 g, 6.52 mmol) was dissolved in DCM (21 mL) and cooled in an ice-bath. NMM (1.433 mL, 13.03 mmol) was added followed by a dropwise addition of acetoxyacetyl chloride (0.867 mL, 7.82 mmol). After 15 min the cooling bath was removed, and the reaction mixture was stirred at rt overnight. The mixture was diluted with DCM and washed with 10% citric acid (aq), sat NaHCCL (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.895 g) as brown oil. MS (ESI) m / z [M+H]+254.1 1H NMR (500 MHz, CDCh, 25 °C) δ 2.36 (3H, s), 2.67 (3H, d), 4.71 (2H, s), 6.90 (1H, ddd), 7.49 (1H, td), 8.47 - 8.52 (1H, m), 11.86 (1H, s).19F NMR (471 MHz, CDCh) δ -103.84.

[0803] Intermediate 80

[0804] (5-Fluoro-4-methylquinazolin-2-yl)methanol

[0805] 2-((2-Acetyl-3-fluorophenyl)amino)-2-oxoethyl acetate Intermediate 79 (1.650 g, 6.52 mmol) was suspended in 4 M NH3 in MeOH (17.92 mL, 71.67 mmol) and heated in a microwave reactor at 85 °C for 8 h. The mixture was concentrated in vacuo. The residue was redissolved in EtOAc and washed with sat NaHCCh (aq). The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (1.164 g, 93%) as brown solid. MS (ESI) m / z [M+H]+193.0. 1H NMR (500 MHz, CDCh, 25 °C) 6 3.08 (3H, d), 3.86-4.21 (1H, m), 4.95 (2H, s), 7.78-7.86 (2H, m).19F NMR (471 MHz, CDCh) 6 -107.38.

[0806] Intermediate 81

[0807] 2-('Chloromethyl )-5-fluoro-4-methylquinazoline (5-Fluoro-4-methylquinazolin-2-yl)methanol Intermediate 80 (0.222 g, 1.16 mmol) was dissolved in DCM (4 mL) and PPI13 (0.333 g, 1.27 mmol) was added. The mixture was cooled in an ice-bath and NCS (0.170 g, 1.27 mmol) was added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 15-45% EtOAc in heptane) to give the title compound (0.106 g, 44%) as beige-white solid. MS (ESI) m / z [M+H]+211.0. (500 1H NMR MHz, CDCh, 25 °C) 6 3.09 (3H, d), 4.84 (2H, s), 7.30 (1H, ddd), 7.79-7.89 (2H, m).19F NMR (471 MHz, CDCh) 6 -107.43.

[0808] Intermediate 82

[0809] 2-((2-Acetyl-5-fluorophenyl)amino)-2-oxoethyl acetate l-(2-Amino-4-fluorophenyl)ethan-l-one (1.041 g, 6.80 mmol) was dissolved in DCM (21 mL) and cooled in an ice-bath. NMM (1.495 mL, 13.59 mmol) was added followed by a dropwise addition of acetoxyacetyl chloride (0.904 mL, 8.16 mmol). After 15 min the cooling bath was removed, and the reaction mixture was stirred at rt over the weekend. The mixture was diluted with DCM and washed with 10% citric acid (aq), sat NaHCCh (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.940 g) as a brown solid. 1H NMR (500 MHz, CDCh, 25 °C) δ 2.37 (3H, s), 2.65 (3H, s), 4.73 (2H, s), 6.85 (1H, ddd), 7.93 (1H, dd), 8.59 (1H, dd), 12.50 (1H, s).

[0810] Intermediate 83

[0811] (7-Fluoro-4-methylquinazolin-2-yl)methanol 2-((2-Acetyl-5-fluorophenyl)amino)-2-oxoethyl acetate Intermediate 82 (1.719 g, 6.79 mmol) was suspended in 4 M NH3 in MeOH (18.67 mL, 74.67 mmol) and heated in a microwave reactor at 85 °C for 9 h. The mixture was concentrated in vacuo, redissolved in EtOAc and washed with sat NaHCCh (aq). The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (1.218 g, 93%) as a light brown solid. MS (ESI) m / z [M+H]+193.0. 1H NMR (500 MHz, CDCh, 25 °C) δ 2.93 (3H, s), 3.93-4.11 (1H, m), 4.91 (2H, s), 7.38 (1H, ddd), 7.60 (1H, dd), 8.12 (1H, dd).19F NMR (470 MHz, CDCh) δ - 101.96.

[0812] Intermediate 84

[0813] 2-('Chloromethyl )-7-fluoro-4-methylquinazoline (7-Fluoro-4-methylquinazolin-2-yl)methanol Intermediate 83 (0.266 g, 1.38 mmol) was dissolved in DCM (4.7 mL) and PPI13 (0.399 g, 1.52 mmol) was added. The mixture was cooled in an ice-bath and NCS (0.203 g, 1.52 mmol) was added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 15-50% EtOAc in heptane) to give the title compound (0.178 g, 61%) as a light -yellow solid. MS (ESI) m / z [M+H]+210.9. 'H NMR (500 MHz, CDCh, 25 °C) δ 2.97 (3H, s), 4.83 (2H, s), 7.42 (1H, ddd), 7.65 (1H, ddd), 8.14 (1H, ddd).19F NMR (471 MHZ, CDCh) 6 -101.90.

[0814] Intermediate 85

[0815] 2-(Chloromethyl)-6-methoxypyridor3.2-Jlpyrimidin-4 -one

[0816] Methyl 3 -amino-6-m ethoxypicolinate (0.225 g, 1.2 mmol) and 2-chloroacetonitrile (0.379 mL, 6.00 mmol) were dissolved in 4 M HC1 in 1,4-dioxane (4.50 mL, 18.00 mmol). The reaction mixture was heated at 60 °C overnight. The mixture was cooled to rt and Et2O was added. The mixture was stirred, and the formed precipitate was collected by filtration, washed with Et20, and dried under vacuum to yield the title compound (0.322 g) as HCl-salt. MS (ESI) m / z [M+H]+226.1. 1H NMR (500 MHz, DMSO-t / 6, 25 °C) δ 3.96 (3H, s), 4.55 (2H, s), 7.29 (1H, d), 8.01 (1H, d).

[0817] Intermediate 86

[0818] 6-Methoxy-2-((4-(l\3',5'-trimethyl-l '77,277-13, 4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)pyridor3,2-<7|pyrimidin-4-ol l',3',5'-Trimethyl-5-(piperidin-4-yl)-l'77,277-3,4'-bipyrazole, HCl-salt Intermediate 28 (0.164 g, 0.63 mmol), 2-(chloromethyl)-6-methoxypyrido[3,2-J]pyrimidin-4(377)-one, HCl-salt Intermediate 85 (0.191 g, 0.64 mmol) and DIPEA (0.884 mL, 5.06 mmol) were mixed in DMSO (4.0 mL) and stirred at rt overnight. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous phase was sublimated. EtOAc was added to the freeze-dried material and the solid material was filtered off to afford the title compound (0.226 g, 80%). MS (ESI) m / z [M+H]+449.2.

[0819] Intermediate 87

[0820] 4-Chloro-6-methoxy-2-((4-(l'.3'.5'-trimethyl-l'77.277-r3.4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)pyridor3.2-J]pyrimidine

[0821] A suspension of 6-methoxy-2-((4-(l',3',5'-trimethyl-l'77,277-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)pyrido[3,2-t / ]pyrimidin-4-ol Intermediate 86 (0.226 g, 0.50 mmol) and DIPEA (0.176 mL, 1.01 mmol) in POCI3 (0.892 mL, 9.57 mmol) was heated at 100 °C for 3 h. The mixture was concentrated under reduced pressure, and EtOAc was added followed by icewater. The organic layer was separated and washed with sat NaHCOs (aq), filtered through a phase separator, and concentrated to yield the title compound (0.095 g, 40%). MS (ESI) m / z [M+H]+467.2

[0822] Intermediate 88 tert-Butyl 4-(3-(L4-dimethyl-777-pyrazol-5-yl)-3-oxopropanoyl)piperi dine- 1 -carboxylate Step a) 1 , 4-Dimethy 1 - ITApy razol _e-5 -carbonyl . chloride l,4-Dimethyl-177-pyrazole-5-carboxylic acid, HCl-salt (200 mg, 1.13 mmol) was treated with 1 M NaOH (aq, 1.132 mL, 1.13 mmol) and MeOH (a few mL) and stirred until everything had dissolved, and then concentrated under reduced pressure. The residue was treated with THF / MeOH (1 : 1) and filtered using a syringe filter. The resulting solution was concentrated and then treated with SOCh (3 mL, 1.13 mmol) and stirred at 70 °C for 2 h and then concentrated under reduced pressure to give the sub -title compound.

[0823] Step b) tert-Butyl carboxylate

[0824] / c / V-Butyl 4-acetylpiperi dine- 1 -carboxylate (309 mg, 1.36 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. A solution of 2 M LDA in THF / heptane / ethylbenzene (0.736 mL, 1.47 mmol) was added dropwise. The mixture was stirred for 1 h followed by dropwise addition of l,4-dimethyl-U7-pyrazole-5-carbonyl chloride Intermediate 88 Step a) dissolved in THF (3 mL). The cooling bath was removed, and the reaction mixture warmed to rt and the reaction was quenched with water and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 20-35% EtOAc in heptane) to give the title compound (0.052 g, 13%) as a clear oil. MS (ESI) m / z [M-H]’ 348.5. 1H NMR (500 MHz, CDC13) δ 7.28 (s, 1H), 5.80 (s, 1H), 4.12 - 4.26 (m, 2H), 4.07 (s, 3H), 2.71 - 2.82 (m, 2H), 2.41 (tt, 1H), 2.22 (s, 3H), 1.84 - 1.90 (m, 2H), 1.60 (qd, 2H), 1.45 (s, 9H).

[0825] Intermediate 89 tert-Butyl 4-(2'.4'-dimethyl-2 / L277-r3.3'-bipyrazol]-5-yl)piperidine-l -carboxylate Zc / V-Butyl 4-(3-(l,4-dimethyl-lH-pyrazol-5-yl)-3-oxopropanoyl)piperidine-l-carboxylate Intermediate 88 (52 mg, 0.15 mmol) was dissolved in EtOH (2 mL) and 64% hydrazine hydrate (aq, 100 2 μ.2L0, mmol) was added at rt. The reaction mixture was heated to 65 °C and stirred for 1 h and then cooled to rt and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 30-100% EtOAc in heptane) to give the title compound (0.038 g, 74%) as white solid. MS (ESI) m / z [M+H]+346.4. 1H NMR (500 MHz, CDCI3) 6 7.32 (s, 1H), 6.16 (s, 1H), 4.00 - 4.29 (m, 2H), 3.89 (s, 3H), 2.64 - 2.88 (m, 3H), 2.07 (s, 3H), 1.95 - 1.85 (m, 2H), 1.59 (qd, 2H), 1.45 (s, 9H).

[0826] Intermediate 90

[0827] 2A-Dimethyl-5'-(piperidin-4-yl)-2 / L277-3.3'-bipyrazole Zc / V-Butyl 4-(2',4'-dimethyl -2H, 27 / -[3,3'-bipyrazol]-5-yl)piperidine-l -carboxylate Intermediate 89 (37.9 mg, 0.11 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL, 0.11 mmol) was added. The reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure to afford the TFA salt of the title compound (40 mg). MS (ESI) m / z [M+H]+246.3. ‘HNMR (500 MHz, Methanol-^) δ 7.41 (s, 1H), 6.41 (s, 1H), 3.88 (s, 3H), 3.54 - 3.47 (m, 2H), 3.23 - 3.10 (m, 3H), 2.36 - 2.24 (m, 2H), 2.09 (s, 3H), 2.02 - 1.91 (m, 2H).

[0828] Intermediate 91

[0829] 2-((4-(5-(Pyridin-3-yl)-17 / -pyrazol-3-yl)piperidin-l-yl)methyl)thienor3,2-J|pyrimidin-4(3JT)- one

[0830] DIPEA (695 μL 3,.99 mmol) was added to a solution of 3-(3-(piperidin-4-yl)-U / -pyrazol-5- yl)pyridine, TFA Intermediate 18 (500 mg, 1.10 mmol) and 2-(chloromethyl)thieno[3,2- d]pyrimidin-4(3J7)-one (200 mg, 1.00 mmol) in DMSO (4.29 mL) and the reaction mixture was stirred at rt overnight. The mixture was filtered and the filtrate purified by preparative HPLC, PrepMethod D, (gradient: 10-55%), to grant the title compound as a white solid. MS (ESI) m / z [M+H]+393.4.

[0831] Intermediate 92

[0832] 4-Chloro-2-((4-(5-(pyridin-3-yl)-lJ / -pyrazol-3-yl)piperidin-l-yl)methyl)thienor3.2- Jlpyrimidine

[0833] A suspension of 2-((4-(5-(pyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)thieno[3,2- t / ]pyrimidin-4(3J7)-one Intermediate 91 (26.0 mg, 0.07 mmol) in POCI3 (0.5 mL, 0.07 mmol) was heated to 100 °C for 1 h. The reaction mixture was cooled to rt and poured into a stirred solution of sat NaHCCL (aq). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSCL, filtered and concentrated to afford the title compound (25 mg, 87%) as a yellow residue. MS (ESI) m / z [M+H]+411.4.

[0834] Intermediate 93

[0835] 2-(Chloromethyl)-4-methyl-5.6.7.8-tetrahydroquinazoline

[0836] MeCN (6 mL) and 2-acetylcyclohexan-l-one (879 6.74 m μmLo,l) were added to a vial charged with 2-chloroacetimidamide, HC1 (956 mg, 7.41 mmol). The reaction mixture was heated to 140 °C in a microwave reactor for 4 h. The solvent was evaporated, and the residue was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSCL, filtered and concentrated. The crude material was purified by straight phase flash chromatography on silica (gradient: 18-25% EtOAc in heptane) to afford the title compound (0.192 g, 15%) as a pale-yellow oil. MS (ESI) m / z [M+H]+197.2.

[0837] Intermediate 94

[0838] A-(4-Cyano-l-methyl-17 / -pyrrol-3-yl)-2-(4-(5-(2,4-dimethylpyridin-3-yl)-17 / -pyrazol-3- yl)piperidin-l-yl)acetamide

[0839] Step a) 2,4-D)methyl-

[0840] TFA (2 mL, 1.25 mmol) was added to a solution of tert-butyl 4-(5-(2,4-dimethylpyridin-3-yl)- l / / -pyrazol-3-yl)piperidine- l -carboxylate Intermediate 47 (447 mg, 1.25 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h and then concentrated to dryness and redissolved in DMSO (5 mL).

[0841] Step b) 2-Chloroacetyl chloride (0.110 mL, 1.38 mmol) was added to a solution of 2-amino-l- methyl - I / / -pyrrol e-3 -carbonitrile (152 mg, 1.25 mmol) in dioxane (5 mL) and stirred at rt for 6 h. The DMSO solution of Intermediate 94 Step a) was added followed by DIPEA (2.7 mL, 15.50 mmol) and the reaction mixture was stirred for 2 d. The mixture was concentrated to remove the dioxane and the resulting dark solution was purified by preparative HPLC, PrepMethod F, (gradient: 10-55%) to grant the title compound (0.137 g, 26%) as a red-brown solid. MS (ESI) m / z [M+H]+417.0.

[0842] Intermediate 95

[0843] 2-((4-(5-(2.4-Dimethylpyridin-3-yl)-17 / -pyrazol-3-yl)piperidin-l-yl)methyl)-7-methyl-3.7- dihydro-4 / / -pyrrolor2,3-6 / ]pyrimidin-4-one

[0844] 12 M HC1 (aq, 1 mL, 0.27 mmol) was added to a stirred solution of A-(4-cyano-l-methyl-l / T- pyrrol-3-yl)-2-(4-(5-(2,4-dimethylpyridin-3-yl)-l / 7-pyrazol-3-yl)piperidin-l-yl)acetamide Intermediate 94 (113 mg, 0.27 mmol) in AcOH (3 mL) and heated to 80 °C for 1 h. The mixture was concentrated to dryness and redissolved in 2 M NaOH (aq, 2 mL, 4.00 mmol) and MeOH (4 mL) and stirred at 65 °C for 2 h. The mixture was concentrated and the residue was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSCL, filtered and concentrated to afford the title compound (57 mg, 50%) as a pink-purple film. MS (ESI) m / z [M+H]+418.4.

[0845] Intermediate 96

[0846] 4-Chloro-2-((4-(5-(2,4-dimethylpyridin-3-yl)-l / / -pyrazol-3-yl)piperidin-l-yl)methyl)-7- methyl-

[0847] A suspension of 2-((4-(5-(2,4-dimethylpyridin-3-yl)-l / / -pyrazol-3-yl)piperidin-l-yl)methyl)- 7-methyl-3,7-dihydro-4Z / -pyrrolo[2,3-J]pyrimidin-4-one Intermediate 95 (57.0 mg, 0.14 mmol) in POCI3 (2 mL, 0.14 mmol) was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to rt and added dropwise to a stirred solution of sat NaHCCL (aq). The mixture was extracted with DCM and the combined organic layers were washed with brine, dried over MgSCU, filtered, and concentrated to afford the title compound (50 mg, 84%) as a clear film. MS (ESI) m / z [M+H]+436.4 and 438.2.

[0848] Intermediate 97 (3 ,4-Di hydro-27 / -benzo[A1 [ 1 ,41oxazin-2-yl)methanol rac-(3,4-Dihydro-2J7-benzo[Z>][l,4]oxazin-2-yl)methanol, HC1 (1 g, 4.96 mmol) was dissolved in MeOH (10 mL). Carbonate on solid support (3.5 mmol / g, 2 g, 16.79 mmol) was added and the reaction mixture was stirred at rt for Ih. The polymer was filtered off and the filtrate was concentrated to grant the title compound (0.65 g, 79%) as a dark oil. MS (ESI) m / z [M+H]+166.0.

[0849] Intermediate 98 rac-tert Butyl 2-('hydroxymethyl )-2.3-dihydro-47 / - 4-carboxylate rac-(3,4-Dihydro-2J7-benzo[Z>][l,4]oxazin-2-yl)methanol Intermediate 97 (0.65 g, 3.93 mmol) was dissolved in THF (12 mL) in a microwave vial and flushed with N2 (g). A solution of BOC2O (3.65 mL, 15.74 mmol) in THF (3 mL) was added dropwise, and the vial was sealed and stirred at 60 °C for 19 h. The solvent was removed in vacuo, and the remaining mixture was diluted with DCM. The organic layers were washed with water, filtered through a phase separator and concentrated. The crude residue was purified by straight phase flash chromatography on silica, (gradient: 0-50% EtOAc in heptane) to grant the title compound (250 mg, 24%) as a tan semi-solid. MS (ESI) m / z [M-H]’ 264.1.

[0850] Intermediate 99 rac-te / 7-Butyl 2-((tosyloxy)methyl)-2,3-dihydro-4J / -benzorZ>irL41oxazine-4-carboxylate TsCl (287 mg, 1.51 mmol) was added to a mixture of rac-tert-butyl 2-(hydroxymethyl)-2,3- dihydro-4J / -benzo[Z>][l,4]oxazine-4-carboxylate Intermediate 98 (250 mg, 0.94 mmol) in pyridine (5 mL) and stirred at rt overnight. DCM and 10% citric acid (aq) were added, and the mixture was stirred, filtered through a phase separator and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-25% EtOAc in heptane) to grant the title compound (320 mg, 81%) as a tan foam.JH NMR (500 MHz, CDC13) 1.52 (9H, s), 2.45 (3H, s), 3.49 (1H, d), 4.03 - 4.14 (1H, m), 4.14 - 4.23 (2H, m), 4.35 (1H, m), 6.77 (1H, m), 6.87 (1H, m), 6.95 (1H, m), 7.35 (2H, d), 7.69 (1H, s), 7.76 - 7.85 (2H, m).

[0851] Intermediate 100

[0852] / z / c'43.4-Dihydro-27 / -benzo|A11 l .41oxazin-2-yl)rnethyl 4-methylbenzenesulfonate 6 M HC1 in IPA (0.397 mL, 2.38 mmol) was added to a solution of rac-tert-butyl 2- ((tosyloxy)methyl)-2,3-dihydro-4J / -benzo[Z>][l,4]oxazine-4-carboxylate Intermediate 99 (200 mg, 0.48 mmol) in DCM (4 mL) and the reaction mixture was stirred at rt overnight. 6 M HC1 in IPA (0.397 mL, 2,38 mmol) was added and the reaction mixture was stirred at 30 °C overnight. The mixture was concentrated and redissolved in MeOH (5 mL). Carbonate on solid support (3.5 mmol / g, 1 g, 8.39 mmol) was added and the mixture was stirred at rt for 2 h. The solids were filtered off and the filtrate concentrated to grant the title compound (144 mg, 95%) as a tan oil. MS (ESI) m / z [M+H]+320.0.

[0853] Intermediate 101

[0854] / z / c-tA-Methyl -3, 4-dihydro-27 / -benzo|A11L41oxazin-2-yl (methyl 4-methylbenzenesulfonate In a microwave vial, a solution of rac-(3,4-dihydro-2J / -benzo[Z>][l,4]oxazin-2-yl)methyl 4- methylbenzenesulfonate Intermediate 100 (145 mg, 0.45 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMF (2.5 mL) was stirred at rt for 20 min. The mixture was cooled to 0°C and Mel (0.043 mL, 0.68 mmol) was added. The vial was sealed and stirred at 50°C for 3 h. Mel (0.043 mL, 0.68 mmol) was added and the reaction mixture was stirred at 50°C overnight. The mixture was diluted with sat NaHCCL (aq) and DCM and stirred, filtered through a phase separator and concentrated. Another batch was prepared as described above starting with rac- (3,4-dihydro-2Z / -benzo[Z>][l,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate Intermediate 100 (55 mg, 0.17 mmol). The batches were combined after the workup stage and purified by straight phase flash column chromatography (gradient: 0-40% EtOAc in heptane) to grant the title compound (73 mg, 35%) as a colourless oil. MS (ESI) m / z [M+H]+334.1.

[0855] Intermediate 102

[0856] 2-((4-(l',3',5'-Trimethyl-l'Z / ,2Z / -r3,4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-3,5,7,8- tetrahydro- 4-one 2-(Chloromethyl)-3,5,7,8-tetrahydro-4H-pyrano[4,3-J]pyrimidin-4-one (87 mg, 0.43 mmol) was added to a mixture of l',3',5'-trimethyl-5-(piperidin-4-yl)-177,2JH-3,4'-bipyrazole, HC1- salt Intermediate 28 (109 mg, 0.42 mmol) and DIPEA (0.732 mL, 4.20 mmol) in DMF (1.368 mL) and the reaction mixture was stirred at rt for 3 h and then at 70 °C for 8 h. The mixture was cooled to rt and water was added, and the mixture was extracted with EtOAc (x2). The aqueous layer was concentrated, and the residue was purified by preparative HPLC, PrepMethod D, (gradient: 0-30%), to yield the title compound (0.106 g, 60%) as beige solid. MS (ESI) m / z [M+H]+424.2._1H NMR (500 MHz, DMSO-t / 6, 25 °C) δ 1.69 (2H, qd), 1.84- 1.92 (2H, m), 2.1-2.38 (8H, m), 2.55-2.66 (3H, m), 2.85-2.93 (2H, m), 3.37 (2H, s), 3.66 (3H, s), 3.84 (2H, t), 4.33-4.38 (2H, m), 6.04 (1H, s), 11.74-12.53 (2H, m).

[0857] Intermediate 103

[0858] 4-Chloro-2-((4-(l'.3'.5'-trimethyl-l'Z / .2Z / -r3.4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-5Z / -pyranor4,3-J]pyrimidine 2-((4-(l',3',5'-Trimethyl-l'Z / ,2Z / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-3,5,7,8- tetrahydro-4Z / -pyrano[4,3-J]pyrimidin-4-one Intermediate 102 (105.9 mg, 0.25 mmol) was dissolved in POOL (4 mL, 42.92 mmol) and stirred at 110 °C for 2 h. The mixture was cooled to rt and 10% NaHCCf (aq) solution was added. The mixture was basified with IN NaOH (aq) solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (0.096 g, 87%) as brown solid. MS (ESI) m / z [M+H]+442.3. Intermediate 104

[0859] 3-Acetyltetrahydro-2J7-pyran-2-one

[0860] Tetrahydro-27 / -pyran-2-one (1.446 g, 14.44 mmol) was dissolved in THF (37 mL) and cooled to -78 °C. 1 M LiHMDS in THF (28.9 mL, 28.88 mmol) was added and the reaction mixture was stirred for 10 min and then AC2O (1.362 mL, 14.44 mmol) was added. The reaction mixture was stirred for 10 min and then warmed to rt and stirred for 1 h. HO Ac (6 mL) was added followed by MTBE (40 mL). The precipitate was filtered off and washed with MTBE. The filtrate was concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 0-30% EtOAc in heptane) to give the title compound (0.886 g, 43%). 1H NMR (500 MHz, CDCI3, 25 °C) δ 1.89-1.95 (2H, m), 2.01 (3H, s), 2.41 (2H, t), 4.26-4.32 (2H, m), 13.70 (1H, s).

[0861] Intermediate 105

[0862] 2-(Chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol

[0863] 3-Acetyltetrahydro-2J7-pyran-2-one Intermediate 104 (97 mg, 0.68 mmol) was dissolved in and MeOH (1 mL) in a microwave vial. 2-Chloroacetimidamide, HCl-salt (152 mg, 1.18 mmol) and K2CO3 (229 mg, 1.66 mmol) were added. The vial was sealed and heated to 50 °C for 30 min. The suspension was filtered using a syringe filter and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-20% MeOH in EtOAc) to give the title compound (0.065 g, 44%) as an orange solid. MS (ESI) m / z [M+H]+217.1. 1H NMR (500 MHz, Methanol-d4, 25 °C) δ 1.67-1.74 (2H, m), 2.34 (3H, s), 2.55-2.62 (2H, m), 3.57 (2H, t), 4.41 (2H, s).

[0864] Intermediate 106

[0865] 2-((4-Ethynylpiperidin-l-yl)methyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol

[0866] 4-Ethynylpiperidine, TFA-salt (670 mg, 3.00 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)- 6-methylpyrimidin-4-ol Intermediate 5 (650 mg, 3.00 mmol) and DIPEA (2.62 mL, 15.00 mmol) were stirred in DMSO (6 mL) at rt overnight. The material was purified by preparative HPLC, PrepMethod D, (gradient: 10-50%), to give the title compound (622 mg, 72%) as tan solid. MS (ESI) m / z [M+H]+290.4. 1H NMR (500 MHz, Methanol -d4, 25 °C) δ 1.64-1.76 (4H, m), 1.84-1.93 (2H, m), 2.29-2.37 (5H, m), 2.38 (1H, d), 2.4-2.5 (1H, m), 2.55-2.61 (2H, m), 2.72-2.81 (2H, m), 3.42 (2H, s), 3.57 (2H, t).

[0867] Intermediate 107

[0868] 2-((4-Ethynylpiperidin-l-yl)methyl)-4-methyl-6,7-dihydro- 2-((4-Ethynylpiperidin-l-yl)methyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol Intermediate 1 (460 mg, 1.59 mmol) and PPh} (625 mg, 2.38 mmol) were dissolved in THF (25 mL) and cooled in an ice-bath. DIAD (0.469 mL, 2.38 mmol) was added dropwise. The reaction mixture was stirred for 10 min and then warmed to rt and stirred for 1 h. The mixture was concentrated under reduced pressure and the crude product was purified by straight phase flash chromatography on silica (gradient: 0-10% MeOH (2 M NH3) in DCM) and then by preparative HPLC, PrepMethod G, (gradient: 5-50%), to give the formate-salt of the title compound (327 mg, 76%) as tan solid. Part of the salt (264 mg, 0.83 mmol) was dissolved in DCM (5 mL) and sat (aq) NaHCCE (3 mL). The mixture was stirred for 5 min, then filtered through a phase separator and concentrated under reduced pressure to give the free base of the title compound (223 mg, 99%) of as tan solid. 1H NMR. (500 MHz, Methanol -t / 4, 25 °C) 5 1.61-1.71 (2H, m), 1.82-1.89 (2H, m), 2.01-2.1 (2H, m), 2.27-2.4 (3H, m), 2.41 (3H, s), 2.74 (2H, t), 2.77-2.85 (2H, m), 3.53 (2H, s), 4.36-4.41 (2H, m), 5.49 (1H, s).

[0869] Intermediate 108

[0870] 1-(L4-Dimethyl-17 / -pyrazol-5-yl)-3-(l-((4-methyl-6.7-dihydro-5J / -pyranor2.3-Jlpyrimidin-

[0871] 2-yl)methyl)piperidin-4-yl)prop-2-yn-l-one 2-((4-Ethynylpiperidin-l-yl)methyl)-4-methyl-6,7-dihydro-5J / -pyrano[2,3-d]pyrimidine Intermediate 107 (70 mg, 0.26 mmol) was dissolved in THF (0.5 mL) and toluene (0.5 mL). l,4-Dimethyl-U / -pyrazole-5-carbonyl chloride (61.4 mg, 0.39 mmol), Cui (2.5 mg, 0.01 mmol) and TEA (0.216 mL, 1.55 mmol) were added followed by Pd(PPh3)2Ch (9.1 mg, 0.01 mmol) and the reaction mixture was stirred under an atmosphere of N2 (g) at rt for 2.5 h. DCM (5 mL) and sat NaHCCL (aq, 5 mL) were added. The mixture was stirred, filtered through a phase separator and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 1-10% MeOH (2M NH3)) in DCM) to give the title compound (80 mg, 79%). MS (ESI) m / z [M+H]+394.6.1H NMR (500 MHz, CDCI3, 25 °C) δ 1.66-1.76 (1H, m), 1.79-1.88 (2H, m), 1.89-2.09 (4H, m), 2.24- 2.32 (2H, m), 2.33-2.4 (5H, m), 2.61-2.68 (2H, m), 2.78-3.00 (2H, m), 3.58 (2H, d), 4.07 (3H, d), 4.27-4.35 (2H, m), 7.24-7.28 (1H, m).

[0872] Intermediate 109

[0873] 2-(Chloromethyl)-7,8-dihydro- 4-ol

[0874] Ethyl 3-oxotetrahydro-2J / -pyran-2-carboxylate (0.740 g, 4.30 mmol) was dissolved in MeOH (6 mL) under an atmosphere of N2 (g). 2-Chloroacetimidamide, HCl-salt (0.642 g, 4.73 mmol) was added followed by a dropwise addition of 30% NaOMe in MeOH (0.959 mL, 5.16 mmol) over a few min. The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated under reduced pressure to yield the title compound (1.140 g). MS (ESI) m / z [M+H]+201.1.

[0875] Intermediate 110

[0876] 2-((4-(l'.3'.5'-Trimethyl-l'J / .2J / -r3.4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-7.8-dihydro-6JT- pyranor3,2-J]pyrimidin-4-ol

[0877] A mixture of l',3',5'-trimethyl-5-(piperidin-4-yl)-17 / ,2J / -3,4'-bipyrazole, HCl-salt Intermediate 28 (0.197 g, 0.53 mmol), 2-(chloromethyl)-7,8-dihydro-6J / -pyrano[3,2- t / ]pyrimidin-4-ol Intermediate 109 (0.107 g, 0.53 mmol) and DIPEA (0.553 mL, 3.17 mmol) in DMSO (4.0 mL) was stirred at rt overnight. The mixture was diluted with EtOAc and water. The aqueous layer was sublimated, EtOAc was added and the solids were filtered off to afford the title compound (0.206 g, 92%). MS (ESI) m / z [M+H]+424.2.

[0878] Intermediate 111 rac-te / 7-Butyl (2A.4A)-2-methyl-4-(3-oxo-3-(L3.5-trimethyl-U / -pyrazol-4- yl)propanoyl)piperidine-l -carboxylate

[0879] A mixture of rac-(2A,4A)-l-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (823 mg, 3.38 mmol) and CDI (680 mg, 4.19 mmol) in THF (14 mL) was stirred at rt for 2 h. A solution of l-(l,3,5-trimethyl-U / -pyrazol-4-yl)ethan-l-one (669 mg, 4.40 mmol) in THF (14 mL) was prepared in a separate flask, cooled to -78 °C and 1 M LiHMDS in THF (4.57 mL, 4.57 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h and then the CDL activated carboxylic acid was added. The cooling bath was removed after 10 min and the reaction mixture was allowed to reach rt and stirred for 1 h. The reaction was quenched with sat NaHCCh (aq) and the mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (1.276 g). MS (ESI) m / z [M+H]+378.2.

[0880] Intermediate 112 rac-te / 7-Butyl (2A,4A)-2 -methyl-4-(l', 3', 5'-trimethyl-l 77,2 / 7-13, 4'-bipyrazol]-5-yl)piperidine- 1 -carboxylate rac-tert-Butyl (2A>,4A>)-2-methyl-4-(3-oxo-3-( l ,3,5-trimethyl- l / / -pyrazol-4- yl)propanoyl)piperidine-l -carboxylate Intermediate 111 (1.276 g, 3.38 mmol) was dissolved in EtOH (2 mL) and 64%hydrazine hydrate (aq, 200 4. 11 mm μoLl), was added. The reaction mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 25-65%), to give the title compound (90 mg, 7%) as a white solid. MS (ESI) m / z [M+H]+374.2. 1H NMR (500 MHz, CDC13, 25 °C) δ 1.06 (3H, d), 1.44 (9H, s), 1.67-1.77 (1H, m), 1.8-1.9 (1H, m), 2.01- 2.14 (2H, m), 2.23 (6H, s), 2.88-3.00 (1H, m), 3.14-3.26 (1H, m), 3.70 (3H, s), 3.80 (1H, ddd), 3.97-4.09 (1H, m), 6.02 (1H, s).

[0881] Intermediate 113 rac-5-(3-Hydroxypropyl)-6-methyl-2-(((2A.4A)-2-methyl-4-(l\3\5Mrimethyl-17 / .27 / -r3.4'- bipyrazol]-5-yl)piperidin-l-yl)methyl)pyrimidin-4-ol rac-tert-Butyl (27?,47?)-2-methyl-4-(l',3',5'-trimethyl-17 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidine- 1 -carboxylate Intermediate 112 (90 mg, 0.24 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL) and 2-(chloromethyl)-5- (3-hydroxypropyl)-6-methylpyrimidin-4-ol Intermediate 5 (59 mg, 0.27 mmol) and K2CO3 (165 mg, 1.19 mmol) were added. The reaction mixture was stirred at rt overnight, filtered using a syringe filter and purified by preparative HPLC, PrepMethod D, (gradient: 10-50%), to give the title compound (78 mg, 71%) as a white solid. MS (ESI) m / z [M+H]+454.4.

[0882] Intermediate 114

[0883] 3 -Propi ony 1 tetrahy dro-2 / / -py ran -2 -one Tetrahydro-27 / -pyran-2-one (2.54 g, 25.37 mmol) was dissolved in THF (51 mL) and cooled at -78 °C. 1 M LiHMDS in THF (50.7 mL, 50.74 mmol) was added and and the reaction mixture was stirred for 10 min. Propionic anhydride (3.25 mL, 25.37 mmol) was added and the reaction mixture was stirred for 10 min and then allowed to warm to rt and stirred for 1 h. HO Ac (8 mL) was added followed by MTBE. The precipitate formed was filtered off and washed with MTBE. The filtrate was concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-30% EtOAc in heptane) to give the title compound (1.458 g, 37%). MS (ESI) m / z [M+H]+157.1.

[0884] Intermediate 115

[0885] 2-(Chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol

[0886] 3-Propionyltetrahydro-2J / -pyran-2-one Intermediate 114 (1.455 g, 9.32 mmol) was dissolved in MeOH (10 mL) under an atmosphere of N2 (g). 2-Chloroacetimidamide, HCl-salt (1.391 g, 10.25 mmol) was added followed by a dropwise addition of 30% NaOMe in MeOH (2.080 mL, 11.18 mmol) over a few min. The reaction mixture was stirred at rt overnight, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-50% (EtOAc / MeOH (4 / 1)) in heptane) to give the title compound (0.649 g, 30%) as solid. MS (ESI) m / z [M+H]+ZSl.l.jHNMR (500 MHz, CDCI3, 25 °C) δ 1.24 (3H, t), 1.73-1.82 (2H, m), 2.65 (2H, q), 2.72 (2H, t), 3.56 (2H, t), 4.53 (2H, s).

[0887] Intermediate 116

[0888] 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(5'-methoxy-l'-methyl-17L2J / -r3.4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)pyrimidin-4-ol

[0889] A mixture of 5'-methoxy-l'-methyl-5-(piperidin-4-yl)-U / ,17 / -3,4'-bipyrazole, TFA-salt Intermediate 56 (0.041 g, 0.11 mmol), 2-(chloromethyl)-6-ethyl-5-(3- hydroxypropyl)pyrimidin-4-ol Intermediate 115 (0.024 g, 0.105 mmol) and DIPEA (0.110 mL, 0.63 mmol) in DMSO (1 mL) was stirred at rt overnight. The product was purified by preparative HPLC, PrepMethod CC, (gradient: 15 45%), to yield the title compound (0.030 g, 63%). MS (ESI) m / z [M+H]+456.4. 1H NMR (500 MHz, DMSO-t / 6, 25 °C) δ 1.12 (3H, t), 1.50-1.58 (2H, m), 1.67 (2H, qd), 1.83-1.89 (2H, m), 2.15-2.25 (2H, m), 2.38-2.45 (2H, m), 2.85-2.92 (2H, m), 3.31 (1H, s), 3.34 (2H, s), 3.37-3.41 (2H, m), 3.64 (3H, s), 3.89 (3H, s), 4.47 (1H, t), 6.14 (1H, s), 7.54 (1H, s), 11.86 (1H, s), 12.41 (1H, s).

[0890] Intermediate 117

[0891] 2-(Chloromethyl)-5,8-dihydro- 4-ol

[0892] Ethyl 5-hydroxy-3,6-dihydro-2J / -pyran-4-carboxylate (0.917 g, 5.33 mmol) was dissolved in MeOH (7 mL) under an atmosphere of N2 (g). 2-Chloroacetimidamide, HCl-salt (0.795 g, 5.86 mmol) was added followed by a dropwise addition of 30% NaOMe in MeOH (1.189 mL, 6.39 mmol) over a few min. The reaction mixture was stirred at rt overnight, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethodG, (gradient: 0-30%), to yield the title compound (0.431 g, 40%) as solid. MS (ESI) m / z [M-H]- 199.1. 1H NMR (500 MHz, DMSO-t / 6, 25 °C) δ 2.37-2.44 (2H, m), 3.81 (2H, t), 4.31-4.36 (2H, m), 4.43 (2H, s), 12.74 (1H, s)

[0893] Intermediate 118

[0894] 2-((4-(l'.3'.5'-Trimethyl-l'J / .2J / -r3.4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-5.8-dihydro-6JT- pyranor3,4-J]pyrimidin-4-ol

[0895] A mixture of l',3',5'-trimethyl-5-(piperidin-4-yl)-17 / ,2J / -3,4'-bipyrazole, HCl-salt Intermediate 28 (0.093 g, 0.25 mmol), 2-(chloromethyl)-5,8-dihydro-6J / -pyrano[3,4- t / ]pyrimidin-4-ol Intermediate 117 (0.048 g, 0.238 mmol) and DIPEA (0.249 mL, 1.43 mmol) in DMSO (1.5 mL) was stirred at rt overnight. The product was purified by preparative HPLC, PrepMethod CC, (gradient: 15-55%), to yield the title compound (0.057 g, 57%) as beige solid. MS (ESI) m / z [M+H]+424.2. ‘HNMR (500 MHz, DMSO-t / 6, 25 °C) δ 1.68 (2H, qd), 1.82-1.91 (2H, m), 2.12-2.24 (5H, m), 2.30 (3H, s), 2.37-2.42 (2H, m), 2.55-2f.65 (1H, m), 2.85-2.92 (2H, m), 3.33 (2H, s), 3.66 (3H, s), 3.81 (2H, t), 4.3-4.38 (2H, m), 6.04 (1H, s), 12.07 (1H, s), 12.40 (1H, s).

[0896] Intermediate 119

[0897] 4-Chloro-2-((4-(l'.3'.5'-trimethyl-l'J / .2J / -r3.4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-5.8- dihydro-67 / -pyranor3,4-6 / ]pyrimidine 2-((4-(l',3',5'-Trimethyl-l'J / ,2J / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-5,8-dihydro-6JT- pyrano[3,4-t / ]pyrimidin-4-ol Intermediate 118 (0.055 g, 0.13 mmol)) was suspended in POCh (1.440 mL, 15.45 mmol) and heated to 106 °C for 90 min. The reaction mixture was cooled and concentrated in vacuo. The residue was mixed with toluene (10 mL) and concentrated again. The remaining oil was partitioned between DCM and sat NaHCCL (aq). The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, filtered through a phase separator and concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod CC, (gradient: 30-70%), to yield the title compound (0.034 g, 59%). MS (ESI) m / z [M+H]+442.2.1H NMR (500 MHz, DMSO-t / e, 25 °C) δ 1.59-1.71 (2H, m), 1.82-1.9 (2H, m), 2.12-2.24 (5H, m), 2.30 (3H, s), 2.55-2.63 (1H, m), 2.77 (2H, t), 2.87-2.98 (2H, m), 3.61-3.68 (5H, m), 3.97 (2H, t), 4.66 (2H, s), 6.04 (1H, s), 12.34 (1H, s).

[0898] Intermediate 120 tert-Butyl 4-(3-(5-methoxy-L3-dimethyl-lZ / -pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carboxylate

[0899] CDI (0.175 g, 1.08 mmol) was added to a solution of l-(tert-butoxycarbonyl)piperidine-4- carboxylic acid (0.243 g, 1.06 mmol) in THF (3 mL) and the reaction mixture was stirred at rt for 2 h. In a separated flask, a solution of l-(5-methoxy-l,3-dimethyl-lJ7-pyrazol-4-yl)ethan- 1-one (0.173 g, 1.03 mmol) in THF (6 mL) was cooled to -78 °C. 1 M LiHMDS in THF (2.57 mL, 2.57 mmol) was added and the reaction mixture was stirred for 30 min at -78 °C followed by a dropwise addition over 10 min of the CDI-activated acid. The cold bath was removed, and the reaction mixture was stirred at rt overnight. 10% citric acid (aq, 3 mL) was added, and the mixture extracted with EtOAc. The organic layer was washed with brine, filtered through a phase separator, and concentrated under reduced pressure to afford the title compound. (0.430 g). MS (ESI) m / z [M+H]+380.3.

[0900] Intermediate 121 tert-Butyl 4-(5'-methoxy-l'.3'-dimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)piperidine-l -carboxylate / c / V-Butyl 4-(3-(5-methoxy-l,3-dimethyl-lH-pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carboxylate Intermediate 120 (0.390 g, 1.03 mmol) was dissolved in 99.5% EtOH (3.5 mL) and 64% hydrazine hydrate (aq, 0.150 mL, 3.08 mmol) was added. The reaction mixture was stirred at rt overnight and then co-evaporated with toluene under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 10-100% (EtOAc / MeOH (9 / 1)) in heptane) to give the title compound (0.242 g, 63%) as yellow solid.

[0901] MS (ESI) m / z [M+H]+376.1.

[0902] Intermediate 122

[0903] 5'-Methoxy-l',3'-dimethyl-5-(piperidin-4-yl)-17L2J / -3,4'-bipyrazole

[0904] Zc / V-Butyl 4-(5'-rnethoxy-l',3'-dimethyl-177,2J / -[3,4'-bipyrazol]-5-yl)piperidine-l -carboxylate Intermediate 121 (0.242 g, 0.64 mmol) was dissolved in DCM (4.5 mL) and TFA (0.745 mL, 9.67 mmol) was added. The reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure to yield TFA-salt of the title compound (0.250 g, 100%). MS (ESI) m / z [M+H]+276.2.

[0905] Intermediate 123

[0906] 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(5'-methoxy-l'.3'-dimethyl-17L2J / -r3.4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)pyrimidin-4-ol

[0907] A mixture of 5'-methoxy-l',3'-dimethyl-5-(piperidin-4-yl)-17 / ,2J / -3,4'-bipyrazole, TFA-salt Intermediate 122 (0.250 g, 0.64 mmol), 2-(chloromethyl)-6-ethyl-5-(3- hydroxypropyl)pyrimidin-4-ol Intermediate 115 (0.148 g, 0.64 mmol) and DIPEA (0.672 mL, 3.85 mmol) in DMSO (5.5 mL) was stirred at rt overnight. The product was purified by preparative HPLC, PrepMethod CC, (gradient: 15 40%), to yield the title compound (0.544 g). MS (ESI) m / z [M+H]+470.2.

[0908] Intermediate 124 terLButyl 4-(3-(5-cyclopropyl-l-methyl- pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carb oxy late

[0909] 5-Cyclopropyl-l-methyl-U / -pyrazole-4-carboxylic acid (0.133 g, 0.80 mmol) was suspended in THF (2.5 mL) and CDI (0.131 g, 0.81 mmol) was added. The suspension was stirred at rt for 4 h. In a separate flask, a solution of terLbutyl 4-acetylpiperi dine- 1 -carboxylate (0.175 g, 0.77 mmol) in THF (5 mL) was cooled to -78 °C and 1 M LiHMDS in THF (1.925 mL, 1.93 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, followed by a dropwise addition of the solution of the CDI-activated acid. The reaction mixture was stirred at -78 °C for 5 min then at rt overnight. The reaction was quenched by addition of sat NaHCCL (aq) and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to afford the title compound (0.323 g). MS (ESI) m / z [M+H]+376.3.

[0910] Intermediate 125 tert-Butyl 4-(5'-cy cl opropyl-l'-methyl-l '77,277-13, 4'-bipyrazol]-5-yl)piperidine-l -carboxylate te / 7-Butyl 4-(3-(5-cyclopropyl-l-methyl-177-pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carboxylate Intermediate 124 (0.289 g, 0.77 mmol) was dissolved in 99.5% EtOH (7.5 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.056 mL, 1.16 mmol) was added, followed by HOAc (0.075 mL), and the reaction mixture was stirred at rt overnight. The mixture was poured into water (5mL) and sat NaHCCf (aq, 0.5 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 10-100% (EtOAc / MeOH (9 / 1)) in heptane) to give the title compound (0.156 g, 55%). MS (ESI) m / z [M+H]+372.2. 1H NMR (500 MHz, DMSO, 25 °C) δ 0.53 (2H, s), 1.01 (2H, d), 1.41 (9H, s), 1.43-1.52 (2H, m), 1.8-1.93 (3H, m), 2.74-2.93 (3H, m), 3.83 (3H, s), 3.93-4.02 (2H, m), 6.19 (1H, s), 7.54 (1H, s), 12.42 (1H, s).

[0911] Intermediate 126

[0912] 5'-Cy cl opropyl-l'-methyl-5-(piperidin-4-yl)-l '77,277-3, 4'-bipyrazole te / 7-Butyl 4-(5'-cy cl opropyl-l'-methyl-l '77, 277-[3,4'-bipyrazol]-5-yl)piperidine-l -carboxylate Intermediate 125 (0.154 g, 0.41 mmol) was dissolved in DCM (4 mL) and cooled in an icebath. TFA (0.592 mL, 7.69 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with Et2O (5 mL). The solvent was decanted, and the resulting precipitate was dried under vacuum to yield the TFA-salt of the title compound (0.160 g, 100%) as. MS (ESI) m / z [M+H]+272.1.

[0913] Intermediate 127

[0914] 2-((4-(5'-Cyclopropyl-l'-methyl-l'H.2H-r3.4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-5-(3- hydroxypropyl)-6-methylpyrimidin-4-ol A mixture of 5'-cyclopropyl-l'-methyl-5-(piperidin-4-yl)-17T, 2H-3, 4'-bipyrazole, TFA-salt Intermediate 126 (0.160 g, 0.42 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)-6- methylpyrimidin-4-ol Intermediate 5 (0.090 g, 0.415 mmol) and DIPEA (0.435 mL, 2.49 mmol) in DMSO (4 mL) was stirred at rt overnight. EtOAc and sat NaHCCh (aq) were added and the mixture was filtered through a phase separator and concentrated under reduced pressure to afford the title compound (0.162 g, 86%). MS (ESI) m / z [M+H]+452.5.

[0915] Intermediate 128

[0916] Ethyl 3-(2-amino-4-hydroxy-6-methylpyrimidin-5-yl)propanoate

[0917] Diethyl 2-acetylpentanedioate (13.51 g, 58.67 mmol) was dissolved in 99.5% EtOH (dried over 3 A molecular sieves, 100 mL). Guanidinium carbonate (12.1 g, 67.16 mmol) was added and the reaction mixture was heated to reflux for 12 h. The mixture was concentrated in vacuo. Water (40 mL) and concentrated HC1 (aq, 5.8 mL) were added, and the mixture was shaken. The precipitate formed was collected by filtration, washed with water, and dried in vacuo to give (12.6 g) of a colorless solid. The product was resolidified from 95% EtOH (approx. 150 mL) to give the title compound (7.396 g, 49%) as colorless solid. MS (ESI) m / z [M+H]+226.3. 1H NMR (500 MHz, DMSO-t / 6, 25 °C) δ 1.16 (3H, t), 2.05 (3H, s), 2.32-2.38 (2H, m), 2.48-2.54 (zm), 4.03 (2H, q), 6.30 (2H, s), 10.80 (1H, s).

[0918] Intermediate 129

[0919] Ethyl 3-(2.4-dihydroxy-6-methylpyrimidin-5-yl)propanoate

[0920] A concentrated solution of NaNO? (3.38 g, 48.99 mmol) in water (4.5 mL) was added dropwise to a mixture of ethyl 3-(2-amino-4-hydroxy-6-methylpyrimidin-5-yl)propanoate Intermediate 128 (7.37 g, 32.72 mmol) in HOAc (60 mL) and water (20 mL). The reaction mixture was stirred at rt for 2 h and then slowly heated to 60 °C and stirred for 2 h. The mixture was concentrated in vacuo to half the volume and acidified to pH3 by addition of HC1. The precipitate formed was collected by filtration, washed with water, and dried in vacuo to yield the title compound (2.45 g, 33%). MS (ESI) m / z [M+H]+227.3. 1H NMR (500 MHz, DMSO-t / e, 25 °C) δ 1.16 (3H, t), 2.06 (3H, s), 2.31-2.48 (4H, m), 4.03 (2H, q), 10.67 (1H, s), 10.96 (1H, s).

[0921] Intermediate 130 Ethyl 3-(2A-dichloro-6-methylpyrimidin-5-yl)propanoate

[0922] POCI3 (20 mL) was added to ethyl 3-(2,4-dihydroxy-6-methylpyrimidin-5-yl)propanoate Intermediate 129 (2.45 g, 10.83 mmol), followed by of 7V,7V-dimethylaniline (20 drops, 10.83 mmol) and the reaction mixture was heated to approximately 100 °C for 2 h. The mixture was cooled and concentrated in vacuo. The residue was mixed with toluene and concentrated again. The residue was partitioned between ice water and EtOAc. The organic layer was washed with water (x2) and brine. The organic layer was dried over NaSCh, and filtered through silica. The filtrate was concentrated in vacuo to yield the title compound (2.48 g, 87%) as orange oil. 1H NM (5R00 MHz, CDCI3) 1.26 (3H, t), 2.56 - 2.6 (2H, m), 2.61 (3H, s), 3.05 - 3.09 (2H, m), 4.16 (2H, q).13C NMR (126 MHz, CDCI3) δ 171.67, 170.54, 163.31, 157.86, 131.70, 55.02, 32.66, 25.54, 22.53, 15.63.

[0923] Intermediate 131

[0924] 3-(2.4-Dichloro-6-methylpyrimidin-5-yl)propan-l-ol

[0925] Ethyl 3-(2,4-dichloro-6-methylpyrimidin-5-yl)propanoate Intermediate 130 (2.48 g, 9.43 mmol) was dissolved in THF (85 mL) and cooled to -78 °C. 1 M DIBAL-H in heptane (28.4 mL, 28.40 mmol) was added dropwise over 30 min. After complete addition and additional stirring for 30 min the cooling bath was removed and stirring was continued at rt for 19 h. The reaction mixture was poured into a solution of Rochelle salt (52 g) in water (200 mL). After the gas evolution had ceased the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO4, filtered and concentrated in vacuo to yield the title compound (2.010 g, 96%) as dark orange oil. 1H NMR (500 MHz, CDCI3, 25 °C) δ 1.62 (1H, s), 1.77-1.85 (2H, m), 2.59 (3H, s), 2.83-2.91 (2H, m), 3.74 (2H, t).13C NMR (126 MHz, CDCI3) δ 170.38, 161.95, 156.96, 130.56, 61.84, 30.61, 25.21, 22.42.

[0926] Intermediate 132

[0927] 2-Chloro-4-methyl-6.7-dihydro-5J / -pyranor2.3-J]pyrimidine

[0928] NaH (60 wt% in mineral oil, 0.367 g, 9.17 mmol) was washed oil free with heptane and suspended in THF (15 mL). 3-(2,4-Dichloro-6-methylpyrimidin-5-yl)propan-l-ol Intermediate 131 (2.01 g, 8.73 mmol) was dissolved in THF (30 mL) and added dropwise under an atmosphere of Ar (g) over 20 min to the NaH suspension. The reaction mixture was stirred at rt overnight, filtered through CELITE and the filtrate was concentrated in vacuo to give the title compound (1.601 g, 99%) as pale-yellow solid. MS (ESI) m / z [M+H]+185.2.JH NMR (500 MHz, CDC13, 25 °C) δ 2.04-2.11 (2H, m), 2.40 (3H, s), 2.68 (2H, t), 4.35-4.41 (2H, m).

[0929] Intermediate 133

[0930] 4-Methyl-6,7-dihydro- 2-carbonitrile

[0931] 3-Quinoclidinol (0.13 g, 1.02 mmol) was added to a mixture of 2-chloro-4-methyl-6,7- dihydro-5J / -pyrano[2,3-J]pyrimidine Intermediate 132 (1.599 g, 8.66 mmol) and KCN (0.80 g, 12.29 mmol) in DMSO (15 mL) and water (0.2 mL), and the reaction mixture stirred at 60 °C for 24 h. The mixture was cooled to rt and partitioned between iPrOAc and water. The aqueous layer was extracted with iPrOAc. The combined organic layers were washed with water and brine, dried overNa2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.402 g, 92%) as red solid. 1H NMR (500 MHz, CDCI3, 25 °C) 5 2.07-2.16 (2H, m), 2.45 (3H, s), 2.76 (2H, t), 4.39-4.45 (2H, m).13C NMR (126 MHz, CDC13) δ 167.65, 167.08, 141.83, 116.75, 115.64, 67.95, 21.52, 21.09, 20.82.

[0932] Intermediate 134

[0933] Methyl 4-methyl-6,7-dihydro-57 / -pyranor2,3-6 / ]pyrimidine-2-carboxylate

[0934] 4-Methyl-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine-2-carbonitrile Intermediate 133 (1.398 g, 7.98 mmol) was dissolved in MeOH (80 mL). 4.37 M NaOMe in MeOH (5.3 mL, 23.16 mmol) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was poured into water (80 mL) containing H3PO4 (2.5 mL) and the mixture was stirred for 1 h. The MeOH was removed by concentration in vacuo. The remaining liquid was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4 and filtered, and concentrated in vacuo to yield the title compound (1.486 g, 89%) as pale orange solid. MS (ESI) m / z [M+H]+209.3. 1H NMR (500 MHz, CDCI3, 25 °C) δ 2.07-2.15 (2H, m), 2.51 (3H, s), 2.76 (2H, t), 3.99 (3H, s), 4.37-4.42 (2H, m).13C NMR (126 MHz, CDCI3) δ 167.35, 167.20, 163.92, 153.72, 115.63, 67.60, 53.35, 21.56, 21.31, 21.06.

[0935] Intermediate 135

[0936] (4-Methyl-6.7-dihydro-5J / -pyranor2.3-J]pyrimidin-2-yl)methanol Methyl 4-methyl-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine-2-carboxylate Intermediate 134 (104 mg, 0.50 mmol) was dissolved in MeOH (5 mL) and cooled in an ice-bath. NaBH4(56.7 mg, 1.5 mmol) was added, and the reaction mixture was stirred for 2 h. Additional NaBH4(28 mg, 0.75 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. Sat NH4CI (aq, 5 mL) was added, and the mixture was stirred for 10 min at rt and then concentrated in vacuo. The residue was extracted with EtOAc, and the organic layer was concentrated in vacuo to afford the title compound (85 mg, 94%) as light-yellow solid. MS (ESI) m / z [M+H]+181.2.13C NMR (126 MHz, Methanol-d4) δ 167.17, 166.49, 165.62, 111.69, 67.63, 63.74, 20.97, 20.51, 19.27.

[0937] Intermediate 136

[0938] 1-(5-Methoxy-l-methyl-lZ / -pyrazol-4-yl)-3-(l-((4-methyl-6,7-dihydro-5J / -pyranor2,3- J]pyrimidin-2-yl)methyl)piperidin-4-yl)prop-2-yn- 1 -one

[0939] 2-((4-Ethynylpiperidin-l-yl)methyl)-4-methyl-6,7-dihydro-5J / -pyrano[2,3-J]pyrimidine Intermediate 107 (45 mg, 0.17 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). 5 -Methoxy -l-methyl-U7-pyrazole-4 -carbonyl chloride Intermediate 53 (43.4 mg, 0.25 mmol), Cui (3.2 mg, 0.02 mmol) and TEA (0.139 mL, 0.99 mmol) were added followed by Pd(PPh3)2Cl2(11.6 mg, 0.02 mmol) and the reaction mixture was stirred under an atmosphere of N2(g) at rt for 2 h. DCM (5 mL) and sat NaHCCL (aq, 5 mL) were added, and the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0-10% MeOH in DCM) to give the title compound (36 mg, 53%). MS (ESI) m / z [M+H]+410.4.

[0940] Intermediate 137

[0941] 1-(L5-Dimethyl-U / -pyrazol-4-yl)-3-(l-((4-methyl-6.7-dihydro-5J / -pyranor2.3-J]pyrimidin-

[0942] 2-yl)methyl)piperidin-4-yl)prop-2-yn-l-one 2-((4-Ethynylpiperidin-l-yl)methyl)-4-methyl-6,7-dihydro-5J / -pyrano[2,3-d]pyrimidine Intermediate 107 (60 mg, 0.22 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). l,5-Dimethyl-U / -pyrazole-4-carbonyl chloride (52.6 mg, 0.33 mmol), Cui (2.1 mg, 0.01 mmol) and TEA (0.185 mL, 1.33 mmol), were added followed by Pd(PPh3)2Cl2(7.8 mg, 0.01 mmol) and the reaction mixture was stirred under an atmosphere of N2(g) at rt overnight. DCM (5 mL) and sat NaHCCL (aq, 5 mL) were added, and the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 1-10% MeOH (2 M NH3) in DCM) to give the title compound (47 mg, 54%). MS (ESI) m / z [M+H]+394.5.JH NMR (500 MHz, CDCI3, 25 °C) δ 1.8-1.9 (2H, m), 1.92-2.01 (2H, m), 2.01-2.07 (2H, m), 2.31- 2.44 (5H, m), 2.54 (3H, s), 2.59-2.7 (3H, m), 2.82-2.95 (2H, m), 3.63 (2H, s), 3.77 (3H, s), 4.29-4.34 (2H, m), 7.85 (1H, s).

[0943] Intermediate 138

[0944] 5-Methoxy-L3-dimethyl-lZ / -pyrazole-4-carbonyl chloride 5-Methoxy-l,3-dimethyl-U7-pyrazole-4-carboxylic acid (0.324 g, 1.90 mmol) was suspended in DCM (6.7 mL) and oxalyl chloride (0.340 mL, 3.81 mmol) was added. The reaction mixture was cooled to 0 °C and DMF (0.015 mL, 0.19 mmol) was added. The reaction mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was concentrated twice more from DCM to afford the title compound (0.359 g, 100%). 'H NMR (500 MHz, CDCI3, 25 °C) δ 2.44 (3H, s), 3.68 (3H, s), 4.07 (3H, s).

[0945] Intermediate 139

[0946] 1 -(5 -Methoxy- 1.3 -dimethyl - 17 / -py razol -4-yl)-3 -( 1 -((4-methyl -6,7 -dihy dro-5Z / -pyranor2, 3 - J]pyrimidin-2-yl)methyl)piperidin-4-yl)prop-2-yn- 1 -one 2-((4-Ethynylpiperidin-l-yl)methyl)-4-methyl-6,7-dihydro-5Z / -pyrano[2,3-d]pyrimidine Intermediate 107 (60 mg, 0.22 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). 5-Methoxy-l,3-dimethyl-U7-pyrazole-4-carbonyl chloride Intermediate 138 (63 mg, 0.33 mmol), Cui (2.1 mg, 0.01 mmol) and TEA (0.185 mL, 1.33 mmol), were added to the mixture, followed by PdfPPhs^Ch (7.8 mg, 0.01 mmol). The reaction mixture was stirred under an atmosphere of N2 (g) at rt for 3 h. DCM (5 mL) and sat NaHCCL (aq, 5 mL) were added, and the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 1-10% MeOH (2% NH3) in DCM) to give the title compound (37 mg, 40%). MS (ESI) m / z [M+H]+424.3.

[0947] Intermediate 140 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(l\3\5'-trimethyl-l 7 / 2 / 7-13, 4'-bipyrazol]-5-yl)piperidin- 1 -yl)methyl)pyrimidin-4-ol

[0948] A mixture of l',3',5'-trimethyl-5-(piperidin-4-yl)-17 / ,2 / 7-3,4'-bipyrazole, HCl-salt Intermediate 28 (0.093 g, 0.25 mmol), 2-(chloromethyl)-6-ethyl-5-(3- hydroxypropyl)pyrimidin-4-ol Intermediate 115 (0.055 g, 0.238 mmol) and DIPEA (0.249 mL, 1.43 mmol) in DMSO (1.5 mL) was stirred at rt overnight. The crude product was purified by preparative HPLC, PrepMethod CC, (gradient: of 20-55%), to yield the title compound (0.125 g). MS (ESI) m / z [M+H]+454.4.

[0949] Intermediate 141 tert-Butyl 4-(3-(L5-dimethyl-l / / -pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)piperidine-l -carboxylate TEA (11.92 mL, 87.44 mmol) followed by PdfPPhs^CL (0.614 g, 0.87 mmol) was added to a mixture of tert-butyl 4-ethynylpiperi dine- 1 -carboxylate (3.66 g, 17.49 mmol), 1,5-dimethyl- l / 7-pyrazole-4-carbonyl chloride (3.17 g, 20 mmol) and Cui (0.167 g, 0.87 mmol) in THF (37.8 mL) and toluene (37.8 mL). The flask was evacuated and filled with N2 (g) and then stirred at rt overnight. EtOAc was added and the mixture was washed with water and brine. The organic layer was dried over MgSCU, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 30-50% EtOAc in heptane) to give the title compound (4.38 g, 76%) as orange oil. MS (ESI) m / z [(M-Boc)+H]+232.1 1H NMR (500 MHz, CDCI3, 25 °C) δ 1.45 (9H, s), 1.66-1.75 (2H, m), 1.84-1.95 (2H, m), 2.57 (3H, s), 2.79-2.85 (1H, m), 3.21 (2H, ddd), 3.71-3.79 (2H, m), 3.80 (3H, s), 7.89 (1H, s).

[0950] Intermediate 142 tert-Butyl 4-(l'.5'-dimethyl-l' / 7.2 / 7-r3.4'-bipyrazol1-5-yl)piperidine-l-carboxylate tert-Butyl 4-(3-(l,5-dimethyl-l / 7-pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)piperidine-l -carboxylate Intermediate 141 (4.38 g, 13.22 mmol) was dissolved in EtOH (41 mL) and 64% hydrazine hydrate (aq, 3 mL, 61.66 mmol) was added. The reaction mixture was stirred at rt overnight, and then concentrated under reduced pressure and dissolved in hot EtOAc and filtered immediately and cooled to afford the title compound (2.480 g, 54%) as a white solid. MS (ESI) m / z [M+H]+346.4. 1H NMR (500 MHz, CDCI3, 25 °C) δ 1.47 (9H, s), 1.65 (2H, qd), 1.91-2.01 (2H, m), 2.43 (3H, s), 2.78-2.9 (3H, m), 3.83 (3H, s), 4.08-4.29 (2H, m), 6.11 (1H, s), 7.59 (1H, s).

[0951] Intermediate 143

[0952] 2-((4-(l\5'-Dimethyl-l'J / ,2J / -r3,4'-bipyrazol1-5-yl)piperidin-l-yl)methyl)-6-ethyl-5-(3- hydroxypropyl)pyrimidin-4-ol

[0953] TFA (1 mL, 0.30 mmol) was added to a solution of tert-butyl 4-(l(5'-dimethyl-17 / ,2.H-[3,4'- bipyrazol]-5-yl)piperidine-l-carboxylate Intermediate 142 (113 mg, 0.33 mmol) in DCM (2 mL). The reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), K2CO3 (210 mg, 1.52 mmol) and 2- (chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol Intermediate 115 (70 mg, 0.30 mmol) were added and the reaction mixture was stirred at rt overnight. The mixture was filtered using a syringe filter and purified by preparative HPLC, PrepMethod D, (gradient: 10-55%), to yield the title compound (96 mg, 72%) as white solid. MS (ESI) m / z [M+H]+440.3. 1H NMR (500 MHz, CDCI3, 25 °C) δ 1.14 (3H, t), 1.71 (2H, p), 1.75-1.87 (2H, m), 1.88-1.95 (2H, m), 2.21-2.31 (2H, m), 2.35 (3H, s), 2.53 (2H, q), 2.58-2.71 (3H, m), 2.8- 2.89 (2H, m), 3.43 (2H, s), 3.55 (2H, t), 3.75 (3H, s), 6.05 (1H, s), 7.59 (1H, s).

[0954] Intermediate 144 tert-Butyl 4-(3-(l-methyl-5-(trifluoromethyl)-U / -pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carb oxy late

[0955] CDI (0.131 g, 0.81 mmol) was added to a suspension of l-methyl-5-(trifluoromethyl)-UT- pyrazole-4-carboxylic acid (0.158 g, 0.80 mmol) in THF (2.5 mL) and the mixture was stirred at rt for 4 h. In a separate flask, 1 M LiHMDS in THF (1.925 mL, 1.93 mmol) was added dropwise to a solution of tert-butyl 4-acetylpiperidine-l -carboxylate (0.175 g, 0.77 mmol) in THF (5 mL) at -78 °C and the reaction mixture was stirred at -78 °C for 1 h. The solution of the CDI-activated acid was added dropwise and the reaction mixture was stirred at -78 °C for 5 min and then at rt overnight. The reaction was quenched by addition of sat NaHCCL (aq) and the mixture was diluted with EtOAc. The layers were separated and the aqueous layer was extracted using EtOAc (x3). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to afford the title compound (0.311 g, 100%). MS (ESI) m / z [M-H]’ 402.0 Intermediate 145 terZ-Butyl 4-(l'-methyl-5Mtrifhioromethyl)-17L2J / -r3,4'-bipyrazol]-5-yl)piperidine-l- carb oxy late tert-Butyl 4-(3-(l-methyl-5-(trifluoromethyl)-U / -pyrazol-4-yl)-3-oxopropanoyl)piperidine-l- carboxylate Intermediate 144 (0.311 g, 0.77 mmol) was dissolved in 99.5% EtOH (7.5 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.056 mL, 1.16 mmol)) was added, followed by HOAc (0.075 mL) and the reaction mixture was stirred at rt overnight. Water (5mL) and sat NaHCCL (aq 0.5 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 10-100% (EtOAc / MeOH (9 / 1)) in heptane) to give the title compound (0.197 g, 64%). MS (ESI) m / z [M+H]+400.3. 1H NMR (500 MHz, DMSO-t / e, 25 °C) δ 1.40 (9H, d), 1.42-1.52 (2H, m), 1.83-1.92 (2H, m), 2.7-2.94 (3H, m), 3.85-4.13 (5H, m), 6.18 (1H, s), 7.76 (1H, s), 12.75 (1H, s).19F NMR (471 MHz, DMSO-tf,) δ -56.02.

[0956] Intermediate 146 l'-Methyl-5-(piperidin-4-yl)-5'-(trifluoromethyl)-17L2J / -3.4'-bipyrazole

[0957] / c / V-Butyl 4-(l'-methyl-5'-(trifhioromethyl)-17 / ,2J / -[3,4'-bipyrazol]-5-yl)piperidine-l- carboxylate Intermediate 145 (0.197 g, 0.49 mmol) was dissolved in DCM (4 mL) and cooled in an ice-bath. TFA (0.704 mL, 9.14 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to afford the TFA salt of the title compound (0.203 g, 100%). MS (ESI) m / z [M+H]+300.1.

[0958] Intermediate 147

[0959] 5-(3-Hydroxypropyl)-6-methyl-2-((4-(l'-methyl-5'-(trifluoromethyl)-17L2J / -r3.4'-bipyrazol]- 5-yl)piperidin-l-yl)methyl)pyrimidin-4-ol

[0960] A mixture of l'-methyl-5-(piperidin-4-yl)-5'-(trifluoromethyl)-l'J / ,2J / -3,4'-bipyrazole, TFA- salt Intermediate 146 (0.203 g, 0.49 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)-6- methylpyrimidin-4-ol Intermediate 5 (0.106 g, 0.49 mmol) and DIPEA (0.513 mL, 2.94 mmol) in DMSO (4.5 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with sat NaHCCL (aq). The organic layer was filtered through a phase separator and concentrated under reduced pressure to yield the crude title compound (0.260 g). MS (ESI) m / z [M+H]+480.4.

[0961] Intermediate 148

[0962] 2-((4-(5 -(2,4-Dimethylpyridin-3 -yl)- UT-pyrazol -3 -yDpiperidin- 1 -yl)methyl)-5 -(3 - hydroxypropyl)-6-methylpyrimidin-4-ol

[0963] TFA (0.5 mL, 0.23 mmol) was added to a solution of tert-butyl 4-(5-(2,4-dimethylpyridin-3- yl)-l / / -pyrazol-3-yl)piperidine-l -carboxylate Intermediate 47 (83 mg, 0.23 mmol) in DCM (1 mL) and the reaction mixture was stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (1.5 mL). DIPEA (250 1.44 μL, mmol) and 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol Intermediate 5 (65.0 mg, 0.30 mmol) was added and the reaction mixture was stirred at rt for 24 h. The mixture was filtered using a syringe filter and the residue was purified by preparative HPLC, PrepMethod D, (gradient: 10-50%), to give the title compound (0.078 g, 77%) as white solid. MS (ESI) m / z [M+H]+437.4. 1H NMR (500 MHz, CDC13, 25 °C) δ 1.62-1.71 (2H, m), 1.72- 1.85 (2H, m), 1.88-1.97 (5H, m), 2.19-2.31 (8H, m), 2.55-2.60 (2H, m), 2.61-2.7 (1H, m), 2.77-2.87 (2H, m), 3.40 (2H, d), 3.44-3.52 (2H, m), 5.93 (1H, d), 6.93 (1H, d), 8.22 (1H, d).

[0964] Intermediate 149

[0965] Isopropyl 5 - dimethylpyridin-3 -yl)-3 -( 1 -t(4-m ethyl -6.7 -dihy dro- pyrano[2.3 - J]pyrimidin-2-yPmethyPpiperidin-4-yP-l / / -pyrazole-l -carboxylate

[0966] 2-((4-(5 -(2,4-Dimethylpyridin-3 -yl)- 17 / -py razol -3 -yl)piperidin- 1 -yl)methyl)-5 -(3 - hydroxypropyl)-6-methylpyrimidin-4-ol Intermediate 148 (78 mg, 0.18 mmol) and PPI13 (70.3 mg, 0.27 mmol) were dissolved in THF (2 mL) and cooled in an ice-bath. DIAD (52.8 pL, 0.27 mmol) was added and the reaction mixture was stirred for 10 min and then warmed to rt and stirred for 1 h. The crude product was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (0.056 g, 62%) as a clear oil. MS (ESI) m / z [M+H]+505.6. ‘HNMR (500 MHz, CDCI3, 25 °C) δ 1.42 (6H, d), 1.75-1.88 (2H, m), 1.99- 2.06 (4H, m), 2.11 (3H, s), 2.25-2.34 (5H, m), 2.38 (3H, s), 2.65 (2H, t), 3.08-3.18 (2H, m), 3.37 (1H, tt), 3.66 (2H, s), 4.29-4.34 (2H, m), 5.19-5.29 (1H, m), 6.13 (1H, s), 6.96 (1H, d), 8.29 (1H, d). Intermediate 150 tert-Butyl 4-(3-(L4-dimethyl-U / -pyrazol-5-yl)-3 -oxoprop- l-yn-l-yl)-4-hydroxypiperi dine- 1- carb oxy late

[0967] Pd(PPh3)2Cl2(0.021 g, 0.03 mmol) was added to a solution of TEA (0.247 ml, 1.77 mmol), tert-butyl 4-ethynyl-4-hydroxypiperidine-l -carboxylate (0.133 g, 0.59 mmol), 1,4-dimethyl- lJT-pyrazole-5 -carbonyl chloride (0.103 g, 0.65 mmol) and Cui (5.63 mg, 0.03 mmol) in THF (3 mL). The reaction mixture was stirred at rt for 2.5 h. The mixture was diluted with sat NaHCCh (aq) and extracted with DCM. The combined organic layers were filtered through a phase separator and concentrated. The crude material was purified by straight phase flash chromatography on silica (10-100% EtOAc in heptane) to grant the title compound as a yellow oil (98 mg, 48%).1H NMR (500 MHz, CDC13) 1.46 (9H, s), 1.82 - 1.89 (2H, m), 1.95 - 2.03 (2H, m), 2.41 (3H, s), 3.48 (2H, m), 3.64 (2H, m), 4.12 (3H, s), 7.32 (1H, m).

[0968] Intermediate 151 tert-Butyl 4-(2'.4'-dimethyl-2Zf27 / -r3.3'-bipyrazol]-5-yl)-4-hydroxypiperidine-l -carboxylate Hydrazine hydrate (aq, 28.0 μL, 0.58 mmol) was added to a solution of tert-butyl 4-(3-(l,4- dimethyl-U / -pyrazol-5-yl)-3-oxoprop-l-yn-l-yl)-4-hydroxypiperidine-l-carboxylate Intermediate 150 (100 mg, 0.29 mmol) in EtOH (1.1 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated to grant the title compound as a white foam. MS (ESI) m / z [M+H]+362.1.

[0969] Intermediate 152

[0970] 4-(2'A'-Dimethyl-2ZL27 / -r3.3'-bipyrazol]-5-yl)piperidin-4-ol

[0971] TFA (320 μL, 4.15 mmol) was added to a solution of tert-butyl 4-(2',4'-dimethyl-2J / ,2'JT- [3,3'-bipyrazol]-5-yl)-4-hydroxypiperidine-l-carboxylate Intermediate 151 (100 mg, 0.28 mmol) in DCM (1 mL) and stirred at rt for 30 min. The mixture was concentrated to give the TFA salt of the title compound (assuming quantitative yield) as a tan foam. MS (ESI) m / z [M+H]+262.0.

[0972] Intermediate 153 tert-Butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-l -carboxylate Ethynyltrimethylsilane (5.94 mL, 42.05 mmol) was dissolved in THF (118 mL) and cooled to -78 °C. 2.5 M / / BuLi in hexane (16.82 mL, 42.05 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for 40 min and then allowed to reach rt. After 70 min, the reaction mixture was cooled to -78 °C and a solution of tert-butyl 4-oxopiperidine-l- carboxylate (7.12 g, 35.04 mmol) in THF (72 mL) was added dropwise. The mixture was warmed to rt and stirred for 3 h. The reaction was quenched with sat NH4CI (aq) followed by addition of EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCE, filtered, and concentrated under reduced pressure. Heptane was added to the residue and the mixture was heated to 45 °C and sonicated. White solid precipitated after cooling to rt. The solids were filtered off and washed with cold heptane. The mother liquor was concentrated and purified by straight phase flash chromatography on silica (gradient: 2-32% EtOAc in heptane) and the product containing fractions were collected and combined with the precipitate to give the title compound (9.444g, 91%). 1H NMR (500 MHz, CDCI3, 18 °C) δ 0.17 (9H, s), 1.45 (9H, s), 1.67 (2H, ddd), 1.83 - 2.10 (3H, m), 3.20 (2H, ddd), 3.76 - 3.84 (2H, m).

[0973] Intermediate 154 tert-Butyl 4-((trimethyl silyl )ethynyl )-3.6-dihydropyridine- l (27 / )-carboxylate tert-Butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-l-carboxylate Intermediate 153 (12.775 g, 42.95 mmol) was dissolved in DCM (120 mL) and cooled in an ice-bath. DMAP (5.77 g, 47.24 mmol) was added, followed by TEA (17.96 mL, 128.84 mmol) and a dropwise addition of methanesulfonyl chloride (10.04 mL, 128.84 mmol). The reaction mixture was allowed to warm to rt and stirred for 18 h. The mixture was poured into water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with IM HC1 and sat NaHCO3 (aq), and then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in heptane and filtered. The solids filtered off were washed with heptane. The combined filtrate was concentrated to afford the title compound (12.18 g). 1H NMR (500 MHz, CDCI3, 18 °C) δ 0.17 (9H, s), 1.45 (9H, s), 2.19 - 2.28 (2H, m), 3.47 (2H, t), 3.92 - 3.97 (2H, m), 6.06 (1H, s).

[0974] Intermediate 155 tert-Butyl 4-ethynyl-3,6-dihydropyridine- l ('27 / )-carboxylate tert-Butyl 4-((trimethylsilyl)ethynyl)-3,6-dihydropyridine-l(2rt)-carboxylate Intermediate 154 (7.31 g, 26.16 mmol) was dissolved in MeOH (132 mL). K2CO3 (7.23 g, 52.32 mmol) was added, and the reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated under reduced pressure. EtOAc and water were added, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was dissolved in heptane and filtered to afford the title compound (5.27 g, 97%) as a yellow brown oil.1H NMR (500 MHz, CDCI3, 19 °C) δ 1.46 (9H, s), 2.25 (2H, s), 2.89 (1H, s), 3.45 - 3.54 (2H, m), 3.96 (2H, s), 6.10 (1H, s).

[0975] Intermediate 156 tert-Butyl 4-(3 -oxo-3 -( L 3 , 5 -tri m eth yl - I rt-pyrazol -4-yl)prop- 1 -yn- 1 -yl)-3 , 6-dihy dropyridine- 1 (27 / )-carboxyl ate tert-Butyl 4-ethynyl-3,6-dihydropyridine-l(2J7)-carboxylate Intermediate 155 (3.35 g, 16.16 mmol) was dissolved in toluene (76 mL). Cui (0.154 g, 0.81 mmol), 1,3,5-trimethyl-UT- pyrazole-4-carbonyl chloride (3.36 g, 19.46 mmol), and TEA (4.73 mL, 33.94 mmol) were added followed by Pd(PPh3)2C12 (0.567 g, 0.81 mmol). The reaction mixture was stirred under an atmosphere of N2 (g) at rt for 3 h and then diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried using MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 50-80% EtOAc in heptane) to give the title compound (3.47 g, 63%) as orange solid. MS (ESI) m / z [M+H]+344.3. 1H NMR (500 MHz, CDCI3) 1.47 (9H, s), 2.30 - 2.39 (2H, m), 2.52 (3H, s), 2.57 (3H, s), 3.54 (2H, t), 3.75 (3H, s), 4.01 - 4.09 (2H, m), 6.36 (1H, s).

[0976] Intermediate 157 tert-Butyl 4-(l'.3'.5'-trimethyl-l'Z / .2Z / -r3.4'-bipyrazol1-5-yl)-3.6-dihydropyridine-l(2Z / l- carb oxy late

[0977] 64% Hydrazine hydrate (aq, 0.983 mL, 20.21 mmol) was added to a solution of tert-butyl 4- (3-oxo-3-(l,3,5-trimethyl- 1H-pyrazol-4-yl)prop-l-yn-l-yl)-3,6-dihydropyridine-l(2rt)- carboxylate Intermediate 156 (3.47 g, 10.10 mmol) in EtOH (32.7 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (isocratic EtOAc) to give the title compound (2.64 g, 73%) as white solid. MS (ESI) m / z [M+H]+358.5.1H NMR (500 MHz, CDC13, 25°C) δ 1.47 (9H, s), 2.25 (6H, d), 2.49-2.59 (2H, m), 3.59 (2H, t), 3.72 (3H, s), 4.00-4.08 (2H, m), 6.16 (1H, s), 6.25 (1H, s), 10.93 (1H, s).

[0978] Intermediate 158 tert-Butyl 4-(l ',3', 5'-trimethyl-l -((2-(trimethylsilyl)ethoxy)methyl)-177, 1'77-13, 4'-bipyrazol1-5- yl)-3,6-dihydropyridine-l(277)-carboxylate and tert-butyl 4-(l ', 3', 5'-trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-l 77,277-13, 4'-bipyrazol]-5- yl)-3,6-dihydropyridine-l(277)-carboxylate tert-Butyl 4-(l',3',5'-trimethyl-l'77,277-[3,4'-bipyrazol]-5-yl)-3,6-dihydropyridine-l(277)- carboxylate Intermediate 157 (5.38 g, 15.04 mmol) was dissolved in THF (72.3 mL) and NaH (60% wt% in mineral oil, 0.902 g, 22.56 mmol) was added. The reaction mixture was stirred for 10 min at rt and then cooled in an ice-bath. SEM-C1 (2.86 mL, 15.79 mmol) was added, and the reaction mixture was stirred for 30 min and then warmed to rt and stirred for 2 h. The reaction mixture was cooled in an ice-bath and the reaction was quenched with sat NaHCCE (aq). The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried using MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 10-50% EtOAc in heptane) to afford a regio isomer mixture of the title compounds (5.83 g, 79%) as brown gum. MS (ESI) m / z [M+H]+488.4.

[0979] Intermediate 159 rac-tert-Butyl (37?.47?)-3-hydroxy-4-(l'.3',5'-trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)- l'77,277-r3.4'-bipyrazol1-5-yl)piperidine-l-carboxylate

[0980] BH3S(CH3)2(0.401 mL, 4.22 mmol) was added to a solution of tert-butyl 4-(l',3',5'- trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-l'77,277-[3,4'-bipyrazol]-5-yl)-3,6- dihydropyridine-l(277)-carboxylate and tert-Butyl 4-(l',3',5'-trimethyl-l-((2- (trimethylsilyl)ethoxy)methyl)-177,l'77-[3,4'-bipyrazol]-5-yl)-3,6-dihydropyridine-l(277)- carboxylate Intermediate 158 (1.03 g, 2.11 mmol) in THF (5.64 mL) and stirred at rt overnight. The reaction was quenched by the addition of water (1 mL) and EtOH (1 mL) and stirred for 1 h. 10% NaOH (aq, 4 mL, 2.11 mmol) and H2O2 (0.518 mL, 16.89 mmol) were added and the reaction mixture was stirred at rt overnight and then heated to 50 °C for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSCU, filtered and concentrated. The crude residue was purified by preparative HPLC, PrepMethod F, (gradient: 30-70%), to grant the title compound (0.457 g, 43%) as a yellow oil. MS (ESI) m / z [M+H]+506.3. 1H NMR (500 MHz, CDC13) -0.14 (9H, s), 0.69 - 0.76 (2H, m), 1.36 (9H, s), 1.59 (1H, m), 1.91 - 1.97 (1H, m), 1.98 (3H, s), 2.02 (3H, s), 2.55 - 2.77 (3H, m), 3.39 - 3.48 (2H, m), 3.54 - 3.61 (1H, m), 3.66 (3H, s), 3.95 - 4.37 (2H, m), 5.06 (2H, s), 5.94 (1H, s).

[0981] Intermediate 160 rac-(3A,4A)-l-((4-Methylquinazolin-2-yl)methyl)-4-(l', 3', 5'-trimethyl-l 7 / 2 / 7-13, 4'- bipyrazol]-5-yl)piperidin-3-ol

[0982] TFA (1 mL, 0.15 mmol) was added to a solution of tert-butyl (3 / ?,4 / ?)-3-hydroxy-4-(l',3',5'- trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-17 / ,2Z7-[3,4'-bipyrazol]-5-yl)piperidine-l- carboxylate Intermediate 159 (50.2 mg, 0.10 mmol) in DCM (0.5 mL). The reaction mixture was stirred at rt overnight, concentrated and redissolved in DMSO (1 mL). 2-(Chloromethyl)- 4-methylquinazoline (31.2 mg, 0.16 mmol) and DIPEA (0.128 mL, 0.74 mmol) were added and the reaction mixture stirred at rt overnight. The mixture was filtered using a syringe filter and the filtrate was purified by preparative HPLC, PrepMethod A, (gradient: 5-45%) to grant the product. The product was further purified by preparative HPLC, PrepMethod D, (gradient: 15-55%) to grant the title compound (24 mg, 56%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C24H30N7O: 432.2506, found: 432.2498.

[0983] Intermediate 161 tert-Butyl 4-(3-(L5-dimethyl-lZ / -pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)-3.6-dihydropyridine- 1 (277)-carboxyl ate

[0984] Pd(PPh3)2Cl2(0.254 g, 0.36 mmol) was added to a mixture of tert-butyl 4-ethynyl-3,6- dihydropyridine-l(2 / 7)-carboxylate Intermediate 155 (1.5 g, 7.24 mmol), 1,5 -dimethyl- \H- pyrazole-4-carbonyl chloride (1.721 g, 10.86 mmol), Cui (0.069 g, 0.36 mmol) and TEA (5.04 mL, 36.18 mmol) in toluene (31.1 mL) under an atmosphere of N2 (g), and the reaction mixture was stirred at rt overnight. The mixture was diluted with water and DCM, filtered through a phase separator and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 40-100% EtOAc in heptane) to give the title compound (945 mg). MS (ESI) m / z [M+H]+330.2

[0985] Intermediate 162 tert-Butyl 4-(l \5'-dimethyl-l 77,2 / 7-13, 4'-bipyrazol]-5-yl)-3,6-dihydropyridine-l(2 / f)- carb oxy late te / 7-Butyl 4-(3-(l,5-dimethyl-l / 7-pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)-3,6-dihydropyridine- l(2 / 7)-carboxylate Intermediate 161 (940 mg, 2.85 mmol) was dissolved in EtOH (13.7 mL) and 64% hydrazine hydrate (aq, 0.555 mL, 11.41 mmol) was added. The reaction mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (468 mg, 48%). MS (ESI) m / z [M+H]+344.4. 1H NMR (500 MHz, CDC13, 25 °C) δ 1.47-1.5 (9H, m), 2.42 (3H, d), 2.51-2.61 (2H, m), 3.58-3.67 (2H, m), 3.83 (3H, d), 4.03-4.11 (2H, m), 6.16 (1H, s), 6.31 (1H, d), 7.59 (1H, s).

[0986] Intermediate 163 rac-te / 7-Butyl (3A.4A)-4-(l\5'-dimethyl-17 / .27 / -r3.4'-bipyrazol]-5-yr)-3-hydroxypiperidine-l- carboxylate and tert-butyl 4-(l'.5'-dimethyl-17 / .27 / -r3.4'-bipyrazol]-5-yl)-4-hydroxypiperidine-l -carboxylate BMS (0.388 mL, 4.09 mmol) was added to a solution of tert-butyl 4-(l',5'-dimethyl-l' / 7,2 / 7- [3,4'-bipyrazol]-5-yl)-3,6-dihydropyridine-l(2 / 7)-carboxylate Intermediate 169 (468 mg, 1.36 mmol) in THF (6.6 mL) at 0 °C. The reaction mixture was warmed to 50 °C and stirred for 2 h. The mixture was cooled to 0 °C and the reaction was quenched with water (2 mL) and EtOH (2 mL), and then stirred for a further 10 min. 10% NaOH (aq, 1.5 mL, 1.36 mmol) and 30% H2O2 (aq, 0.557 mL, 5.45 mmol) were added and the reaction mixture was heated to 50 °C and stirred overnight. The mixture was cooled to rt and diluted with brine and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative HPLC, PrepMethod F, (gradient: 15-55%), to grant the title compounds (195 mg, 40%) as an inseparable mixture of regio-isomers. MS (ESI) m / z [M+H]+362.4. Intermediate 164 rac-(3AAA)-4-(l\5'-Dimethyl-17L2.H-r3,4'-bipyrazol]-5-yl)piperidin-3-ol and 4-(l\5'-dimethyl-17L2J / -r3,4'-bipyrazol]-5-yl)piperidin-4-ol

[0987] TFA (1 mL, 0.54 mmol) was added to a solution containing the regio-isomer mixture of rac- tert-butyl (3A,4A)-4-(l',5'-dimethyl-17 / ,2rt-[3,4'-bipyrazol]-5-yl)-3-hydroxypiperidine-l- carboxylate and tert-butyl 4-(l',5'-dimethyl-17 / ,2.H-[3,4'-bipyrazol]-5-yl)-4- hydroxypiperidine-1 -carboxylate Intermediate 163 (195 mg, 0.54 mmol) in DCM ( 2 mL) and the reaction mixture was stirred at rt for 30 min. The mixture was concentrated to grant the TFA salt of the title compounds as a regio-isomer mixture (141 mg). MS (ESI) m / z [M+H]+262.2.

[0988] Intermediate 165 tert-Butyl 4-hy droxy-4-(3 -oxo-3 -( L 3.5 -trimethyl - 17 / -py razol -4-yl)prop- 1 -yn- 1 -yllpiperidine- 1 -carboxylate l,3,5-Trimethyl-U / -pyrazole-4-carboxylic acid (1.65 g, 10.70 mmol) was suspended in DCM (45 mL) and oxalyl chloride (3.8 mL, 44.91 mmol) was added. DMF (10 pL) was added, and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF (45 mL), and tert-butyl 4-ethynyl -4-hy droxypiperi dine- 1- carboxylate (2.253 g, 10 mmol), Cui (0.10 g, 0.53 mmol), Pd(PPh3)2C12 (0.3 g, 0.43 mmol), and TEA (3.9 mL, 27.90 mmol) were added under an atmosphere of Ar (g). The reaction mixture was stirred at rt overnight. Solid material formed were filtered off and set aside. The filtrate was collected and filtered through silica gel. The second filtrate was collected and combined with the solid material and concentrated to dryness to give the title compound (3.75 g) as yellow oil. MS (ESI) m / z [M+H]+362.4.

[0989] Intermediate 166 tert-Butyl 4-hydroxy-4-(l'.3'.5'-trimethyl-l'J / .2J / -r3.4'-bipyrazol1-5-yl)piperidine-l- carb oxy late

[0990] 64% Hydrazine hydrate (aq, 1 mL, 14.02 mmol) was added to a solution of crude tert-butyl 4- hy droxy-4-(3 -oxo-3 -(1,3,5 -trimethyl- 1 H-pyrazol -4-yl)prop- 1 -yn- 1 -yl)piperidine- 1 - carboxylate Intermediate 165 (3.61 g, 10 mmol) in 99.5% EtOH (50 mL) and the reaction mixture was stirred at rt for 20 h. Insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The crude material was dissolved in DMSO (20 mL) and filtered through CELITE. The residue was purified by preparative HPLC, PrepMethod G, (gradient: 15-55%) and the product containing fractions were neutralised by addition of NaHCOs (s). MeCN was removed under reduced pressure and the remaining solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.76 g, 74%). MS (ESI) m / z [M+H]+376.4. 1H NMR (500 MHz, DMSO, 25°C) δ 1.40 (9H, s), 1.71-1.79 (2H, m), 1.80-1.88 (2H, m), 2.18 (3H, s), 2.30 (3H, s), 3.10-3.28 (2H, m), 3.64-3.74 (5H, m), 5.17 (1H, s), 6.17 (1H, s), 12.45 (1H, s).

[0991] Intermediate 167 tert-Butyl 4-fluoro-4-(l\3\5'-trimethyl-l' / / ,2 / / -r3,4'-bipyrazol1-5-yl)piperidine-l -carboxylate / c / V-Butyl 4-hydroxy-4-(l',3',5'-trimethyl-177,2 / / -[3,4'-bipyrazol]-5-yl)piperidine-l- carboxylate Intermediate 166 (188 mg, 0.5 mmol) was dissolved in DCM (9 mL) under an atmosphere of Ar (g) and cooled to -78 °C. DAST (100 μL, 0.76 mmol) was added and the reaction mixture was stirred at -78 °C for 20 min, and then warmed to rt. After 2 h at rt the reaction mixture was cooled to -78 °C and additional DAST (100 μL, 0.76 mmol) was added. The reaction mixture was stirred at -78 °C for 20 min, and then warmed to rt. After 2 h at rt the mixture was washed with sat NaHCCf (aq). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound (161 mg, 85%). MS (ESI) m / z [M+H]+378.5. 1H NMR (500 MHz, CDC13) 1.46 (9H, s), 2.05 - 2.22 (4H, m), 2.27 (3H, s), 2.29 (3H, s), 3.19 - 3.35 (2H, m), 3.75 (3H, s), 3.88 - 4.07 (2H, m), 6.22 - 6.25 (1H, m).19F NMR (471 MHz, CDCI3) -152.41.

[0992] Intermediate 168

[0993] 5-(4-Fluoropiperidin-4-yl)-l'.3'.5'-trimethyl-l' / / .2 / / -3.4'-bipyrazole

[0994] / c / V-Butyl 4-fluoro-4-(l ', 3', 5'-trimethyl-177,2 / / -[3,4'-bipyrazol]-5-yl)piperidine-l -carboxylate Intermediate 167 (213 mg, 0.56 mmol) was dissolved in DCM (1 mL) and TFA (1.00 mL) was added. The reaction mixture was stirred at rt for 30 min and then concentrated in vacuo to afford the TFA-salt of the title compound (374 mg) as.19F NMR (471 MHz, D2O) δ -75.72 (s, 9H), -150.87 (s, 1H). 1H NMR (500 MHz, D2O) δ 2.35 (s, 6H), 2.37 - 2.58 (m, 4H), 3.39 - 3.50 (m, 4H), 3.90 (s, 3H), 6.61 (d, 1H). MS (ESI) m / z [M+H]+278.4.

[0995] Intermediate 169 tert-Butyl 4-methoxy-4-(l\3\5'-trimethyl-17L2.H-r3,4'-bipyrazol]-5-yl)piperidine-l- carb oxy late

[0996] 25% NaOMe in MeOH (0.4 mL, 1.6 mmol) was added to tert-butyl 4-fluoro-4-(l',3',5'- trimethyl-l'J / ,2J / -[3,4'-bipyrazol]-5-yl)piperidine-l-carboxylate Intermediate 167 (151 mg, 0.40 mmol) and the reaction mixture was stirred at rt for 10 min. Sat NH4CI (aq) was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo to afford the title compound (140 mg, 90%) as a yellow oil. MS (ESI) m / z [M+H]+390.5.1H NMR (500 MHz, CDCI3) δ 1.45 (s, 9H), 1.94 - 2.12 (m, 4H), 2.29 (s, 3H), 2.31 (s, 3H), 3.10 (s, 3H), 3.25 - 3.34 (m, 2H), 3.70 - 3.84 (m, 5H), 6.18 (s, 1H).

[0997] Intermediate 170

[0998] 5-(4-Methoxypiperidin-4-yl)-l'.3'.5'-trimethyl-17L2.H-3.4'-bipyrazole

[0999] TFA (0.5 mL) was added to a solution of tert-butyl 4-methoxy-4-(l',3',5'-trimethyl-l'J / ,2JT- [3,4'-bipyrazol]-5-yl)piperidine-l-carboxylate Intermediate 169 (137 mg, 0.35 mmol) in DCM (0.5 mL) and the reaction mixture was stirred at rt for 20 min. The mixture was concentrated in vacuo to afford the TFA-salt of the title compound (220 mg, 99%). MS (ESI) m / z [M+H]+290.4.

[1000] Intermediate 171 tert-Butyl 4-ethynyl-4-m ethoxypiperidine- 1 -carboxylate tert-Butyl 4-ethynyl-4-hydroxypiperidine-l -carboxylate (8.9 g, 37.53 mmol) was dissolved in anhydrous DMF (100 mL) and NaH (60% wt% in mineral oil, 1.876 g, 46.91 mmol) was added in portions over 5 min at rt under an atmosphere of N2 (g). The reaction mixture was stirred at rt for 25 min, then Mel (2.92 mL, 46.91 mmol) was added dropwise over 10 min under an atmosphere of N2 (g). The reaction mixture was stirred at rt for 1 h. The mixture was poured onto ice-water and when reached rt extracted with EtOAc. The organic layer was dried over MgSCU, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 5-40% EtOAc in heptane) to give the title compound (6.6 g, 74%) as colorless oil. 1H NMR (500 MHz, CDCh) 1.45 (9H, s), 1.66 - 1.74 (2H, m), 1.85 - 1.95 (2H, m), 2.52 (1H, s), 3.24 - 3.33 (2H, m), 3.38 (3H, s), 3.64 - 3.76 (2H, m).

[1001] Intermediate 172 tert-Butyl 4-m ethoxy -4-(3 -(5 -methoxy- 1 , 3 -dimethyl - U / -pyrazol -4-yl) -3 -oxoprop- 1 -yn- 1 - yl)piperidine-l -carboxylate

[1002] Zc / V-Butyl 4-ethynyl-4-methoxypiperidine-l -carboxylate Intermediate 171 (0.123 g, 0.515 mmol), 5-methoxy-l,3-dimethyl-U7-pyrazole-4-carbonyl chloride Intermediate 138 (0.146 g, 0.77 mmol), Cui (4.9 mg, 0.03 mmol) and TEA (0.431 mL, 3.09 mmol) were mixed in THF (0.9 mL) and toluene (0.9 mL). PdfPPhs^CL (0.018 g, 0.03 mmol) was added and the reaction mixture was stirred under an atmosphere of N2 (g) at rt overnight. DCM and sat NaHCCL (aq) were added, the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure to afford the title compound (0.240 g). MS (ESI) m / z [M+H]+392.3.

[1003] Intermediate 173 tert-Butyl 4-methoxy-4-(5'-methoxy-l'.3'-dimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)piperidine-l- carboxylate

[1004] Zc / 7-Buty 1 4-m ethoxy -4-(3 -(5 -methoxy- 1 , 3 -dimethyl - 17 / -py razol -4-yl) -3 -oxoprop- 1 -yn- 1 - yl)piperidine-l -carboxylate Intermediate 172 (0.202 g, 0.52 mmol) was dissolved in 99.5% EtOH (3.8 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.126 mL, 2.58 mmol) was added and the reaction mixture was stirred at rt for Ih. The mixture was poured into water (7mL) and sat NaHCCL (aq) and the mixture was extracted with EtOAc . The combined organic layers were dried over Na2SO 4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 10- 100% (EtOAc / MeOH (9 / 1)) in heptane) to give the title compound (0.083 g, 40%). MS (ESI) m / z [M+H]+406.3. 1H NMR (500 MHz, DMSO- d6) 1.40 (9H, s), 1.80 - 1.92 (2H, m), 1.96 - 2.05 (2H, m), 2.16 (3H, s), 2.95 (3H, s), 3.13 - 3.28 (2H, m), 3.51 - 3.63 (5H, m), 3.78 (3H, s), 6.25 (IH, s), 12.58f (IH, s).

[1005] Intermediate 174 5'-Methoxy-5-(4-methoxypiperidin-4-yl)-l\3'-dimethyl-17L2J / -3,4'-bipyrazole

[1006] Zc / V-Butyl 4-methoxy-4-(5'-methoxy- l ',3'-dimethyl- l ' / / ,27 / -[3,4'-bipyrazol]-5-yl)piperidine- l - carboxylate Intermediate 173 (0.083 g, 0.20 mmol) was dissolved in DCM (3 mL) and cooled in an ice-bath. TFA (0.292 mL, 3.79 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was triturated with Et2O (5 mL). The solvent was decanted, and the resulting precipitate was dried under vacuum to yield the TFA-salt of the title compound (0.086 g, 100%). MS (ESI) m / z [M+H]+306.3.

[1007] Intermediate 175 rac-te / 7-Butyl (2A,4M-2-methyl-4-(3 -oxo-3 -( L 3 , 5 -trimethyl - 1 JT-pyrazol -4-yl)prop- 1 -yn- 1 - yl)piperidine-l -carboxylate rac-tert-Butyl (2A,4S)-4-ethynyl-2-methylpiperidine-l -carboxylate (0.198 g, 0.89 mmol) was dissolved in THF (3.2 mL) and added to a solution of l,3,5-trimethyl-U / -pyrazole-4-carbonyl chloride (0.230 g, 1.33 mmol) in THF (1.6 mL). Cui (0.034 g, 0.18 mmol) and PdfPPhs^Ch (0.064 g, 0.09 mmol) were added followed by TEA (0.865 mL, 6.21 mmol). The reaction mixture was evacuated and refilled with N2 (g) (x3). The reaction mixture was stirred under an atmosphere of N2 (g) at rt overnight. DCM and sat NaHCO3 (aq) were added and the layers were separated. The organic layers were dried overNa2SO4, filtered, and concentrated under reduced pressure to afford the title compound (0.319 g, 100%). MS (ESI) m / z [M+H]+360.4.

[1008] Intermediate 176 rac-te / 7-Butyl (2AAM-2-methyl-4-(l\3'.5'-trimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)piperidine- 1 -carboxylate rac-tert-Butyl (2A,4S)-2-methyl-4-(3 -oxo-3 -(1,3,5 -trimethyl - 17 / -py razol -4-yl)prop- 1 -yn- 1 - yl)piperidine-l -carboxylate Intermediate 175 (0.319 g, 0.89 mmol) was dissolved in EtOH (4.2 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.215 mL, 4.44 mmol) was added, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into water and sat NaHCCL (aq) and the mixture was extracted with EtOAc (3*). The organic layers were combined and dried overNa2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 40-100% (EtOAc / MeOH (9 / 1)) in heptane). The obtained product was dissolved in EtOAc and treated with SILIAMETS Imidazole for 1 h. The solution was filtered and the solids were washed with EtOAc. The combined filtrate was concentrated to afford the title compound (0.200 g, 60%). MS (ESI) m / z [M+H]+374.2.

[1009] Intermediate 177 rac-l\3\5Mrimethyl-5-((2A,4A)-2-methylpiperidin-4-yl)-17L2J / -3,4'-bipyrazole rac-tert-Butyl (2A,4S)-2-methyl-4-(l',3',5'-trimethyl-l'J / ,2J / -[3,4'-bipyrazol]-5-yl)piperidine- 1-carboxylate Intermediate 176 (0.195 g, 0.52 mmol) was dissolved in EtOAc (2.6 mL). 6 M HC1 in IPA (0.870 mL, 5.22 mmol) was added dropwise and the reaction mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the HC1 salt of the title compound (0.224 g). MS (ESI) m / z [M+H]+274.2.

[1010] Intermediate 178 l-(terLButoxycarbonyl)-4-(((terLbutyldimethylsilyl)oxy)methyl)piperidine-4-carboxylic acid l -( / c / 7-Butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (0.662 g, 2.55 mmol) and imidazole (0.521 g, 7.66 mmol) were mixed in DCM (15 mL). TBDMS-C1 (0.770 g, 5.11 mmol) was added, and the reaction mixture was stirred at rt overnight. 5% Citric acid (aq, 18 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by straight phase flash chromatography on silica (isocratic DCM (1% HO Ac)). 0.1 M HC1 (aq) was added to the crude product, and the mixture was stirred and then extracted with EtOAc. The organic layer was concentrated and the crude product was purified by straight phase flash chromatography on silica (isocratic DCM with 1% HOAc) to give the title compound (0.510 g, 54%). 1H NMR (500 MHz, CDC13, 25 °C) δ 0.03 (6H, s), 0.87 (9H, s), 1.37-1.48 (11H, m), 2.01-2.1 (2H, m), 2.96-3.06 (2H, m), 3.62 (2H, s), 3.83-3.92 (2H, m).

[1011] Intermediate 179 terLButyl 4-(((terLbutyldimethylsilyl)oxy)methyl)-4-(3-oxo-3-(L3.5-trimethyl-U / -pyrazol-4- yl)propanoyl)piperidine-l -carboxylate l -( / c77-Butoxycarbonyl)-4-((( / c77-butyldimethylsilyl)oxy)methyl)piperidine-4-carboxylic acid Intermediate 178 (0.490 g, 1.31 mmol) was dissolved in THF (4.5 mL) and CDI (0.223 g, 1.38 mmol) was added. The reaction mixture was stirred at rt for 2 h. In a separate flask a solution of l -( l ,3,5-trimethyl- l / / -pyrazol-4-yl)ethan- l -one (0.200 g, 1.31 mmol) in THF (8.7 mL) was cooled to -78 °C, and 1 M LiHMDS in THF (3.28 mL, 3.28 mmol) was added. The reaction mixture was stirred at -78 °C for 30 min. The CDI-activated acid was added dropwise to the mixture over 10 min at -78 °C. The cold bath was removed, and the reaction mixture was stirred at rt overnight. 10% Citric acid (aq, 6 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, filtered through a phase separator, and concentrated under reduced pressure to afford the title compound (0.666 g, 100%). MS (ESI) m / z [M-H]’ 506.2

[1012] Intermediate 180 tert-Butyl 4-(((terLbutyldimethylsilyl)oxy)methyl)-4-(l\3\5'-trimethyl-17L2J / -r3,4'- bipyrazol]-5-yl)piperidine-l-carboxylate

[1013] / c / V-Butyl 4-((( / c / 7-butyldimethylsilyl)oxy)methyl)-4-(3-oxo-3-( l ,3,5-trimethyl- l7 / -pyrazol-4- yl)propanoyl)piperidine-l -carboxylate Intermediate 179 (0.666 g, 1.31 mmol) was dissolved in EtOH (6 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.318 mL, 6.56 mmol) was added, and the reaction mixture was stirred at rt overnight. The mixture was poured into water and sat NaHCCL (aq) and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 40-100% (EtOAc / MeOH (9 / 1)) in heptane) to give the title compound (0.271 g, 41%). MS (ESI) m / z [M+H]+504.4.

[1014] Intermediate 181

[1015] (4-(l'.3'.5'-Trimethyl-l'J / .2J / -r3.4'-bipyrazol1-5-yl)piperidin-4-yl)methanol

[1016] / c / 'Z-Butyl 4-((( / cv7-butyldimethylsilyl)oxy)rnethyl)-4-( l ',3',5'-trirnethyl- l '7 / ,27 / -[3,4'- bipyrazol]-5-yl)piperidine-l-carboxylate Intermediate 180 (0.270 g, 0.54 mmol) was dissolved in EtOAc (3.3 mL). 6 M HC1 in IPA (1.072 mL, 6.43 mmol) was added dropwise and the reaction mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the HC1 salt of the title compound (0.235 g)- MS (ESI) m / z [M+H]+290.1. 1H NMR (500 MHz, DMSO, 25 °C) δ 1.96-2.06 (2H, m), 2.15-2.39 (9H, m), 2.71- 2.83 (2H, m), 3.20 (2H, d), 3.40 (1H, s), 3.74 (3H, s), 6.39 (1H, s), 8.82 (1H, s), 9.06 (1H, s). Intermediate 182 rac-tert-Butyl (3A,4A)-3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-l -carboxylate Ethynyltrimethylsilane (4.17 mL, 30.11 mmol) was dissolved in Et2O (189 mL) and cooled in an ice-bath. 2.5 M w-BuLi in hexane (12.05 mL, 30.11 mmol) and 2 M AlMes in toluene (13.80 mL, 27.60 mmol) were added and the reaction mixture was allowed to warm to rt. A solution of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.00 g, 25.09 mmol) in Et2O (25.3 mL) was added. The reaction mixture was cooled to -78 °C and BF3*OEt2 (6.19 mL, 50.19 mmol) was added. The reaction mixture was stirred at -78 °C for 2 h and then the reaction was quenched with anhydrous MeOH (20 mL) and stirred for 15 min. Sat NH4CI (aq) (13 mL) was added. The mixture was allowed to warm to rt and diluted with MTBE and water. The layers were separated and the aqueous layer was extracted with MTBE. The combined organic layers were dried over MgSCE, filtered and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 20-30% EtOAc in heptane) to give the title compound (6.34 g, 85%) as colorless oil. 1H NMR (500 MHz, CDCI3, 25°C) δ 0.16 (9H, s), 1.22-1.34 (2H, m), 1.46 (9H, s), 1.9-2 (1H, m), 2.21 (1H, d), 2.39-2.54 (1H, m), 2.9-3.03 (1H, m), 3.59 (1H, s), 3.66-3.92 (1H, m), 4.00 (1H, dd).

[1017] Intermediate 183

[1018] 1 -Methyl -2.3-dihydro-lrt-imidazorL2-Z>]pyrazole-7-carbonyl chloride Oxalyl chloride (0.092 mL, 1.08 mmol) was added to a suspension of l-methyl-2,3-dihydro- U / -imidazo[l,2-Z>]pyrazole-7-carboxylic acid (70.0 mg, 0.42 mmol) in DCM (1.3 mL) followed by DMF (4.17 μL, 0.05 mmol). The reaction mixture was stirred at rt for 6 h and then concentrating to grant the title compound as a white solid.

[1019] Intermediate 184 rac-tert-Butyl (3A.4A)-4-ethynyl-3-hydroxypiperidine-l -carboxylate rac-tert-Butyl (3 / ?, 4 / ?)-3-hydroxy-4-((trimethyl silyl )ethynyl)piperidine- l -carboxylate Intermediate 182 (6.34 g, 21.31 mmol) was dissolved in MeOH (107 mL) and K2CO3 (5.89 g, 42.62 mmol) was added. The reaction mixture was stirred at rt for 1.5 h and then concentrated under reduced pressure. EtOAc and water were added to the residue, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSCL, filtered and concentrated to yield the title compound (4.52 g, 94%) as clear oil. 1H N (M50R0 MHz, CDC13, 25°C) δ 1.46 (9H, s), 1.52-1.61 (1H, m), 1.95-2.02 (1H, m), 2.19 (1H, d), 2.29 (1H, s), 2.42-2.51 (1H, m), 2.83-3.11 (2H, m), 3.62 (1H, s), 3.69-3.93 (1H, m), 4.01 (1H, dd).

[1020] Intermediate 185 mc-(37?,47?)-4-Ethynyl-l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol rac-tert-Butyl (37?,47?)-4-ethynyl-3-hydroxypiperidine-l-carboxylate Intermediate 191 (4.52 g, 20.05 mmol) was dissolved in DCM (65 mL) and TFA (30 mL, 20.05 mmol) was added. The reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was dissolved in MeCN (65 mL) and 2-(chloromethyl)-4-methylquinazoline (5.02 g, 26.07 mmol) and K2CO3 (16.63 g, 120.33 mmol) was added to the solution. The reaction mixture was stirred at rt for 21 h and then concentrated. The reaction mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSCL, filtered, and concentrated under reduced pressure to afford the title compound (5.64 g) as a yellow oil. MS (ESI) m / z [M+H]+282.1. 1H NMR (500 MHz, CDCI3, 25°C) δ 1.7-1.78 (1H, m), 2.07-2.18 (2H, m), 2.4-2.6 (3H, m), 2.81-2.89 (1H, m), 2.95 (3H, s), 3.04 (1H, d), 3.78-3.85 (1H, m), 3.91-4 (2H, m), 7.58-7.65 (1H, m), 7.86 (1H, ddd), 7.98-8.02 (1H, m), 8.06-8.1 (1H, m)

[1021] Intermediate 186 7-Butyldimethyl silyl )oxy )-4-ethynylpiperi din- l -yl (methyl )-4- methylquinazoline rac-(37?,47?)-4-Ethynyl- l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol Intermediate 185 (439 mg, 1.56 mmol) was dissolved in DCM (3.9 mL). Imidazole (234 mg, 3.43 mmol), DMAP (19.06 mg, 0.16 mmol) and TBDMSC1 (259 mg, 1.72 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was diluted with DCM. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSCh, filtered and concentrated. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 50-100%), to give the title compound (471 mg, 76%) as yellow oil. MS (ESI) m / z [M+H]+396.6. 1H NMR (500 MHz, CDCI3, 25°C) δ -0.01-0.11 (6H, m), 0.82 (9H, s), 1.75-1.86 (1H, m), 1.88-1.95 (1H, m), 1.95-2.04 (2H, m), 2.05-2.14 (1H, m), 2.20 (1H, dddd), 2.88-2.98 (4H, m), 3.18-3.29 (1H, m), 3.80 (1H, td), 3.88-3.98 (2H, m), 7.57 (1H, ddd), 7.82 (1H, ddd), 7.96-8.01 (1H, m), 8.02-8.06 (1H, m).

[1022] Intermediate 187 rac-3 -((3A,4A)-3-( (te / 7-Butyldimethyl silyl )oxy )-l -((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(l-methyl-2,3-dihydro-lJ / -imidazorL2-b]pyrazol-7-yl)prop-2-yn- 1-one

[1023] A solution of rac-2-(((3A,4A)-3-((te / 7-butyldimethylsilyl)oxy)-4-ethynylpiperidin-l- yl)methyl)-4-methylquinazoline Intermediate 186 (237 mg, 0.60 mmol) in toluene (2.4 mL) and THF (1.2 mL) was added to a mixture of l-methyl-2,3-dihydro-U / -imidazo[l,2- Z>]pyrazole-7-carbonyl chloride Intermediate 183 (111 mg, 0.60 mmol), Pd(PPh3)2Ch (21.06 mg, 0.03 mmol) and Cui (5.71 mg, 0.03 mmol) under an atmosphere of N2 (g). TEA (409 μL, 3.00 mmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 45-95%), to give the title compound (93 mg, 29%). MS (ESI) m / z [M+H]+545.4. 1H NMR (500 MHz, CDCI3, 25°C) δ -0.05-0.14 (6H, m), 0.77 (9H, d), 1.82-2.03 (3H, m), 2.12 (1H, t), 2.35-2.46 (1H, m), 2.88 (3H, d), 2.96 (1H, d), 3.22 (4H, d), 3.74-3.82 (2H, m), 3.83-3.96 (3H, m), 4.03-4.13 (2H, m), 7.49-7.57 (1H, m), 7.68 (1H, d), 7.75-7.82 (1H, m), 7.92-7.97 (1H, m), 7.98-8.05 (1H, m).

[1024] Intermediate 188 -4-(5-( l -Methyl-2.3-dihydro- l 7 / -imidazorL2-b1pyrazol-7-yl )- l7 / -pyrazol-3-yl )- l - ((4-methylquinazolin-2-yl)methyl)piperidin-3-ol rac-3-((3A,4A)-3-((tert-Butyldimethylsilyl)oxy)-l-((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(l-methyl-2,3-dihydro-U / -imidazo[l,2-b]pyrazol-7-yl)prop-2-yn- 1-one Intermediate 187 (93 mg, 0.17 mmol) was dissolved in EtOH (1 mL) and 64% hydrazine hydrate (aq, 0.025 mL, 0.51 mmol) was added. The reaction mixture was stirred at rt for 6 h and then concentrated under reduced pressure. The residue was dissolved in TFA (0.9 mL) and water (0.1 mL) and heated at 60 °C for 4 h. The mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (52 mg, 68%) as white solid. MS (ESI) m / z [M+H]+445.4. 1H NMR (500 MHz, CDC13, 25 °C) δ 1.9-1.99 (2H, m), 2.17 (1H, t), 2.26 (1H, td), 2.54-2.6 (1H, m), 2.91 (6H, d), 3.05-3.13 (1H, m), 3.24-3.32 (1H, m), 3.65-3.76 (2H, m), 3.88 (1H, td), 3.92-4.01 (2H, m), 4.07-4.13 (2H, m), 6.05 (1H, s), 7.44 (1H, s), 7.55-7.6 (1H, m), 7.78-7.87 (1H, m), 7.99 (1H, d), 8.02-8.08 (1H, m).

[1025] Intermediate 189 rac-3 -((3A,4A)-3-( (te / 7-Butyldimethyl silyl )oxy )-l -((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(5-methoxy-L3-dimethyl-U / -pyrazol-4-yl)prop-2-yn-l-one TEA (505 μL, 3.70 mmol) and Pd(PPh3)2C12 (26.0 mg, 0.04 mmol) were added to a mixture of rac-2-(((3A, 4 / ?)-3-(( / c / 7-butyldimethyl silyl )oxy)-4-ethynylpiperi din-1 -yl)methyl)-4- methylquinazoline Intermediate 186 (293 mg, 0.74 mmol), 5-methoxy-l,3-dimethyl-UT- pyrazole-4-carbonyl chloride Intermediate 138 (140 mg, 0.74 mmol) and Cui (7.1 mg, 0.04 mmol) in THF (1.6 mL) and toluene (1.6 mL). The reaction mixture was evacuated and filled with N2 (g) (x3) and then stirred at rt overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSCE, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, PrepMethod D, (gradient: 50-100%), to give the title compound (193 mg, 48%) as yellow oil. MS (ESI) m / z [M+H]+548.4. ‘H NMR (500 MHz, CDCI3, 25 °C) δ 0.01-0.1 (6H, m), 0.80 (9H, s), 1.86-2.08 (m), 2.16 (1H, td), 2.41-2.52 (4H, m), 2.93 (3H, s), 2.97-3.04 (1H, m), 3.26-3.34 (1H, m), 3.59 (3H, s), 3.91 (1H, td), 3.95 (2H, s), 4.03 (3Hf, s), 7.56-7.61 (1H, m), 7.84 (1H, ddd), 7.98-8.01 (1H, m), 8.03-8.08 (1H, m).

[1026] Intermediate 190

[1027] / z / cA3 / <4 / ?)-4-(5'-Methoxy- l ',3'-dirnethyl- l '7 / .27 / -r3.4'-bipyrazol1-5-yl )- l -(T4- methylquinazolin-2-yl)methyl)piperidin-3-ol rac-3-((3A,4A)-3-((te / 7-Butyldimethylsilyl)oxy)-l-((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(5-methoxy-l,3-dimethyl-U / -pyrazol-4-yl)prop-2-yn-l-one Intermediate 189 (192 mg, 0.35 mmol) was dissolved in EtOH (2 mL) and 64% hydrazine hydrate (aq, 0.1 mL, 2.06 mmol) was added. The reaction mixture was stirred at rt for 4 d and then concentrated under reduced pressure. The resulting residue was dissolved in TFA (1.8 mL) and water (0.2 mL) and stirred at 50 °C for 5 h and then cooled to rt and stirred overnight. The mixture was concentrated and the crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (138 mg, 88%) as yellow solid. MS (ESI) m / z [M+H]+448.4. 1H NMR (500 MHz, CDC13, 25°C) δ 1.93-2 (2H, m), 2.1-2.27 (5H, m), 2.56-2.65 (1H, m), 2.87 (3H, s), 3.01-3.09 (1H, m), 3.22-3.31 (1H, m), 3.56 (3H, s), 3.71 (3H, s), 3.86-3.98 (3H, m), 6.02 (1H, s), 7.51-7.56 (1H, m), 7.76-7.81 (1H, m), 7.94 (1H, d), 7.98-8.02 (1H, m).

[1028] Intermediate 191

[1029] 5-Cyclopropyl-l -methyl- l / / -pyrazole-4-carbonyl chloride 5-Cyclopropyl-l-methyl-l / / -pyrazole-4-carboxylic acid (0.083 g, 0.50 mmol) was dissolved in DCM (1 mL) and oxalyl chloride (50 μL, 0.58 mmol) was added. The reaction mixture was cooled in an ice-bath and DMF (1.936 μL, 0.03 mmol) was added. The reaction mixture was warmed to rt and stirred overnight. The mixture was concentrated under reduced pressure to yield the title compound (0.092 g). ‘H NMR (500 MHz, DMSO) 0.82 - 0.90 (2H, m), 0.96 - 1.05 (2H, m), 1.81 - 1.91 (1H, m), 3.83 (3H, s), 7.66 (1H, s).

[1030] Intermediate 192 mc-3-((3A.4A)-3-((terLButyldimethylsilyl)oxy)-l-((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(5-cyclopropyl-l-methyl-l / / -pyrazol-4-yl)prop-2-yn-l-one rac-2-(((37?, 4 / ?)-3-(( / c / 7-Butyldimethyl silyl )oxy)-4-ethynylpiperi din-l-yl )methyl )-4- methylquinazoline Intermediate 186 (316 mg, 0.80 mmol), 5 -cyclopropyl- 1 -methyl- \H- pyrazole-4-carbonyl chloride Intermediate 191 (148 mg, 0.8 mmol) and Cui (7.62 mg, 0.04 mmol) were mixed in THF (1.73 mL) and toluene (1.73 mL). TEA (546 μL, 4.00 mmol) and Pd(PPh3)2Cl2(28.1 mg, 0.04 mmol) were added. The reaction mixture was evacuated and filled with N2(g) (x3) and then stirred at rt for 4 d. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried using MgSCE, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod D, (gradient: 50-100%), to give the title compound (215 mg, 49%) as yellow oil. MS (ESI) m / z [M+H]+544.4. ‘H NMR (500 MHz, CDCI3, 25°C) δ 0.00 (3H, s), 0.05 (3H, s), 0.74-0.84 (11H, m), 1.04-1.12 (2H, m), 1.71-1.79 (1H, m), 1.83-1.93 (1H, m), 1.94-2.07 (2H, m), 2.14 (1H, td), 2.44 (1H, ddd), 2.90 (3H, s), 2.93-2.99 (1H, m), 3.22-3.29 (1H, m), 3.83-3.93 (6H, m), 7.55 (1H, ddd), 7.81 (1H, ddd), 7.87 (1H, s), 7.96 (1H, dt), 8.03 (1H, ddd). Intermediate 193 rac-(3AAA)-4-(5'-Cyclopropyl-l'-methyl-17L2J / -r3,4'-bipyrazol]-5-yl)-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol rac-3-((3A,4A)-3-((tert-Butyldimethylsilyl)oxy)-l-((4-methylquinazolin-2- yl)methyl)piperidin-4-yl)-l-(5-cyclopropyl-l-methyl-U / -pyrazol-4-yl)prop-2-yn-l-one Intermediate 192 (215 mg, 0.40 mmol) was dissolved in EtOH (2 mL) and 64% hydrazine hydrate (aq, 0.1 mL, 2.06 mmol) was added. The reaction mixture was stirred at rt overnight and then concentrated under reduced pressure. The resulting residue was dissolved in TFA (1.8 mL) and water (0.2 mL) and heated at 60 °C for 5 h and then concentrated. The crude product was purified by preparative HPLC, PrepMethod D, (gradient: 15-55%), to give the title compound (152 mg, 87%) as yellow solid. MS (ESI) m / z [M+H]+444.5.JH NMR (500 MHz, CDC13, 25 °C) δ 0.41-0.51 (2H, m), 0.87-0.96 (2H, m), 1.63 (1H, tt), 1.89-1.96 (2H, m), 2.08-2.22 (2H, m), 2.59 (1H, q), 2.86 (3H, s), 2.97-3.06 (1H, m), 3.22-3.29 (1H, m), 3.79 (3H, s), 3.83-3.95 (3H, m), 6.14 (1H, s), 7.48 (1H, s), 7.5-7.55 (1H, m), 7.74-7.79 (1H, m), 7.92-7.96 (1H, m), 7.97-8 (1H, m).

[1031] Intermediate 194 tert-Butyl 4-(3-(L5-dimethyl-lH-pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)-4-methoxypiperidine-l- carboxylate

[1032] / c / V-Butyl 4-ethynyl-4-methoxypiperidine-l -carboxylate Intermediate 171 (6.6 g, 27.58 mmol), l,5-dimethyl-U / -pyrazole-4-carbonyl chloride (6.56 g, 41.37 mmol), Cui (0.263 g, 1.38 mmol) and TEA (23.06 mL, 165.47 mmol) were mixed in THF (50 mL) and toluene (50 mL). Pd(PPh3)2Cl2(0.988 g, 1.38 mmol) was added and the reaction mixture was stirred under an atmosphere of N2(g) at rt for 2 d. DCM (250 mL) and sat NaHCCL (aq) (250 mL) were added and the mixture was stirred, filtered through a phase separator, and concentrated to give the crude title compound (15 g). MS (ESI) m / z [(M-Boc)+H]+262.1.

[1033] Intermediate 195 tert-Butyl 4-(l'.5'-dimethyl-17L2J / -r3.4'-bipyrazol]-5-yl)-4-methoxypiperidine-l -carboxylate / c / V-Butyl 4-(3-(l,5-dimethyl-U7-pyrazol-4-yl)-3-oxoprop-l-yn-l-yl)-4-methoxypiperidine-l- carboxylate Intermediate 194 (9.76 g, 27 mmol) was suspended in 99.5% EtOH (200 mL). The mixture was cooled in an ice-bath and 64% hydrazine hydrate (aq, 6.57 mL, 135.00 mmol) was added. The reaction mixture was stirred at rt for 2 h. The mixture was poured into water (200 mL) and sat NaHCCL (aq) (40 mL). The mixture was concentrated and the remaining aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure . The crude residue was purified by straight phase flash chromatography on silica (gradient 40-100% (EtOAc / MeOH (9 / 1)) to give the title compound (6.3 g, 62%). MS (ESI) m / z [M+H]+376.4.1H NMR (500 MHz, DMSO-t / e) 1.40 (9H, s), 1.77 - 2.06 (4H, m), 2.30 - 2.47 (3H, m), 2.95 (3H, s), 3.10 - 3.31 (2H, m), 3.42 - 3.66 (2H, m), 3.76 (3H, s), 6.30 (1H, s), 7.61 (1H, s), 12.68 (1H, s).

[1034] Intermediate 196

[1035] 5-(4-Methoxypiperidin-4-yl)-l\5'-dimethyl-17L2J / -3,4'-bipyrazole

[1036] / c / V-Butyl 4-(l',5'-dimethyl-17 / ,2J / -[3,4'-bipyrazol]-5-yl)-4-methoxypiperidine-l -carboxylate Intermediate 195 (5.8 g, 15.45 mmol) was dissolved in EtOAc (50 mL). 6 M HC1 in IPA (25.7 mL, 154.47 mmol) was added dropwise, and the reaction mixture was stirred at 50 °C for 3 h. The mixture was concentrated under reduced pressure to yield the HCl-salt of the title compound (6.06 g). MS (ESI) m / z [M+H]+276.2. (15H00N MMHRz, DMSO-t / 6) 2.15 - 2.33 (4H, m), 2.41 (3H, s), 2.96 (3H, s), 3.00 - 3.13 (4H, m), 3.78 (3H, s), 6.41 - 6.48 (1H, m), 7.73 - 7.83 (1H, m), 9.33 (2H, s).

[1037] Intermediate 197 tert-Butyl 4-m ethoxy -4-(3 -(5-methoxy- 1 -methyl - I / / -pyrazol -4-yl )-3 -oxoprop- 1 -yn- 1 - yl)piperidine-l -carboxylate

[1038] / c / V-Butyl 4-ethynyl-4-methoxypiperidine-l -carboxylate Intermediate 171 (0.123 g, 0.515 mmol), 5-methoxy-l-methyl-U / -pyrazole-4-carbonyl chloride Intermediate 53 (0.135 g, 0.77 mmol), Cui (4.9 mg, 0.03 mmol) and TEA (0.431 mL, 3.09 mmol) were mixed in THF (0.9 mL) and toluene (0.9 mL). Pd(PPh3)2C12 (0.018 g, 0.03 mmol) was added and the reaction mixture was stirred under an atmosphere of N2 (g) at rt overnight. DCM and sat NaHCCh (aq) were added, and the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure to afford the title compound (0.194 g, 100%). MS (ESI) m / z [(M-Boc)+H]+278.1. Intermediate 198 terZ-Butyl 4-methoxy-4-(5'-methoxy-l'-methyl-17L2 / / -r3,4'-bipyrazol]-5-yl)piperidine-l- carb oxy late

[1039] Zc / V-Butyl 4-m ethoxy -4-(3 -(5-methoxy- 1 -methyl - 177-pyrazol -4-yl )-3 -oxoprop- 1 -yn- 1 - yl)piperidine-l -carboxylate Intermediate 197 (0.194 g, 0.51 mmol) was dissolved in 99.5% EtOH (3.8 mL) and cooled in an ice-bath. 64% Hydrazine hydrate (aq, 0.125 mL, 2.57 mmol) was added, and the reaction mixture was stirred at rt overnight. The mixture was poured into water (7 mL) and sat NaHCCf (aq) (0.7 mL) and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 10- 100% (EtOAc / MeOH (9 / 1) in heptane) to give the title compound (0.032 g, 16%). MS (ESI) m / z [M+H]+392.3.

[1040] Intermediate 199

[1041] 5'-Methoxy-5-(4-methoxypiperidin-4-yl)-l'-methyl-17L2 / / -3.4'-bipyrazole

[1042] Zc / V-Butyl 4-methoxy-4-(5'-methoxy-l'-methyl-177,2 / / -[3,4'-bipyrazol]-5-yl)piperidine-l- carboxylate Intermediate 198 (0.030 g, 0.08 mmol) was dissolved in DCM (2 mL) and cooled in an ice-bath. TFA (0.109 mL, 1.42 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The residue was triturated with Et2O (5 mL). The solvent was decanted, and the resulting precipitate was dried under vacuum to yield the TFA-salt of the title compound (0.031 g, 100%). MS (ESI) m / z [M+H]+292.3.

[1043] Intermediate 200 rac-te / 7-Butyl (lA.6A)-6-((trimethylsilyl)ethynyl)-7-oxa-3-azabicyclor4.1.0]heptane-3- carb oxy late

[1044] Zc / V-Butyl 4-((trimethylsilyl)ethynyl)-3,6-dihydropyridine-l(2J7)-carboxylate Intermediate 154 (8.035 g, 28.75 mmol) was dissolved in DCM (170 mL) and the flask was kept in the dark and cooled in an ice-bath. mCPBA (19.33 g, 86.26 mmol) was dissolved in DCM (100 mL) and added dropwise via a dropping funnel. The reaction mixture was stirred at rt overnight. The mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient 3- 12% EtOAc in heptane) to give the title compound (4.30 g, 51%) as white solid.JH NMR (500 MHz, CDC13, 25 °C) δ 0.17 (9H, s), 1.44 (9H, s), 2.05-2.26 (2H, m), 2.97-3.08 (1H, m), 3.35-3.46 (1H, m), 3.46-3.68 (2H, m), 3.84-4.06 (1H, m).

[1045] Intermediate 201 rac-te / 7-Butyl (37?,4M-3-hy droxy-4-m ethoxy -4-((trimethylsilyl)ethynyl)piperi dine-1- carb oxy late rac-tert-Butyl (17?,67?)-6-((trimethylsilyl)ethynyl)-7-oxa-3-azabicyclo[4.1 ,0]heptane-3- carboxylate Intermediate 200 (4.297 g, 14.54 mmol) was dissolved in MeOH (135 mL) and TsOH (5.53 g, 29.09 mmol) was added at rt. The reaction mixture was stirred for 1 h. The reaction was quenched with sat NaHCCL (aq) and diluted with EtOAc and water. The layers were separated, and the aqueous layer extracted with EtOAc, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (3.73 g, 78%) as yellow oil. 1H NMR (500 MHz, CDCI3, 25 °C) δ 0.20 (9H, s), 1.44-1.58 (11H, m), 2.08 (1H, ddd), 3.04- 3.16 (2H, m), 3.41 (3H, s), 3.53 (1H, dd), 3.79-3.87 (1H, m), 3.96 (1H, ddd).

[1046] Intermediate 202 -4-Methoxy-4-(Ttrimethyl silyl )ethynyl )piperidin-3-ol carboxylate

[1047] TFA (12.53 mL, 162.60 mmol) was added to an ice-cold solution of rac-tert-butyl (3R,4S)-3- hydroxy-4-methoxy-4-((trimethylsilyl)ethynyl)piperidine-l -carboxylate Intermediate 201 (4.841 g, 14.78 mmol) in DCM (140 mL). The reaction mixture was stirred at rt for 1 h and then concentrated to grant the TFA salt of the title compound (6.14 g).1H NMR (500 MHz, CDCI3, 25°C) δ 0.21 (9H, m), 1.46 (1H, s), 2.04-2.12 (1H, m), 2.29-2.37 (1H, m), 3.1-3.32 (2H, m), 3.39-3.42 (3H, m), 3.9-3.96 (1H, m), 6.39 (3H, s), 7.64 (1H, s), 8.98 (1H, s).

[1048] Intermediate 203 mc-(3A.4M-4-Methoxy-l-((4-methylquinazolin-2-yl)methyl)-4- ((trimethylsilyl)ethynyl)piperidin-3-ol

[1049] A solution of rac-(3A,45)-4-methoxy-4-((trimethylsilyl)ethynyl)piperidin-3-ol Intermediate 202 (5.025 g, 14.72 mmol), 2-(chloromethyl)-4-methylquinazoline (2.95 g, 15.16 mmol) and DIPEA (15.42 mL, 88.31 mmol) in DMSO (50 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with sat NaHCCh (aq). The organic layers were filtered through a phase separator and concentrated to grant the title compound (5.65 g, 100%). MS (ESI) m / z [M+H]+384.4.

[1050] Intermediate 204 mc-(3 A,4M-4-Ethynyl-4-m ethoxy- l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol

[1051] A solution of rac-(3 / ?, 4,S')-4-methoxy- l -((4-methyl quinazol i n-2-yl (methyl )-4- ((trimethylsilyl)ethynyl)piperidin-3-ol Intermediate 203 (5.65 g, 14.73 mmol) in MeOH (67 mL) was treated with K2CO3 (4.07 g, 29.46 mmol) and stirred at rt overnight. The mixture was filtered and concentrated. The residue was diluted with EtOAc, and washed with sat NaHCOs (aq), filtered through a phase separator and concentrated. The crude product was purified by preparative HPLC, PrepMethod F, (gradient 20-50%), to grant the title compound (2.273 g, 50%) as a solid. MS (ESI) m / z [M+H]+312.2.

[1052] Intermediate 205 4A)-4-Ethynyl-4-m ethoxy- l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol Intermediate 206

[1053] (3 AAM-4-Ethynyl-4-m ethoxy- l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol rac-(3 R, 45)-4-Ethynyl-4-m ethoxy- l-((4-methylquinazolin-2-yl)methyl)piperi din-3 -ol Intermediate 204 was separated into its respective enantiomers by chiral SFC on a YMC SZ (imob C2) column (5 pm, 250^30 mm ID), eluted with 15% EtOH / DEA (100 / 20 mM) in CO2, 120 bar, at a flow rate of 140 mL / min and detected at 280 nm. The first eluted compound was collected to give the title compound Intermediate 206 (100 mg, 36%, 99.9% ee). MS (ESI) m / z [M+H]+312.2, [a]20D-2.3 (c 1, MeCN). The second eluted compound was collected to give the Intermediate 205 (95 mg, 34%, 99.9% ee). MS (ESI) m / z [M+H]+312.2. [a]20D+1.5 (c l, MeCN).

[1054] Intermediate 207 l-Methyl-5-(trifluoromethyl)-l / / -pyrazole-4-carbonyl chloride

[1055] Oxalyl chloride (89 μL, 1.00 mmol) followed by DMF (3.87 μL, 0.05 mmol) were added to a suspension of l-methyl-5-(trifluoromethyl)-l / / -pyrazole-4-carboxylic acid (97 mg, 0.5 mmol) in DCM (2.68 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h and then concentrated to afford the crude title compound.

[1056] Intermediate 208

[1057] 5-(Difluoromethyl)-l-methyl-U / -pyrazole-4-carbonyl chloride

[1058] Oxalyl chloride (0.223 mL, 2.50 mmol) followed by DMF (9.68 μL, 0.13 mmol) were added to a suspension of 5-(difluoromethyl)-l-methyl-lJ7-pyrazole-4-carboxylic acid (0.220 g, 1.25 mmol) in DCM (6.71 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h and then concentrated to afford the crude title compound.JH NMR (500 MHz, CDCh, 25°C) δ 4.11 (3H, t), 6.92-7.55 (m, overlapping with residual solvent), 8.02 (1H, m).

[1059] Intermediate 209

[1060] 3-((3A.4M-3-Hydroxy-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l-(5- methoxy-L3-dimethyl-lZ / -pyrazol-4-yl)prop-2-yn-l-one

[1061] A solution of (3A,45)-4-ethynyl-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-3- ol Intermediate 206 (209 mg, 0.67 mmol) in THF (4.10 mL) was added to a solution of 5- methoxy-l,3-dimethyl-U7-pyrazole-4-carbonyl chloride Intermediate 138 (190 mg, 1.01 mmol) and Cui (25.6 mg, 134 pmol) in THF (2.05 mL). PdfPPlr^Ch (48.1 mg, 68.5 pmol) was added followed by TEA (0.561 mL, 4.03 mmol) and the reaction mixture vessel was evacuated and refilled with N2 (g) three times. The reaction mixture was heated to 55 °C for 3 h and then allowed to cool to rt overnight. The mixture was diluted with sat NaHCCh (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to grant the crude title compound as brown oil. MS (ESI) m / z [M+H]+464.5.

[1062] Intermediate 210

[1063] 3-((3A.4M-3-Hydroxy-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l-(5- methoxy- l -methyl- l7 / -pyrazol-4-yl )prop-2-yn- l -one

[1064] A solution of (3A,45)-4-ethynyl-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-3- ol Intermediate 206 (100 mg, 0.32 mmol) in THF (2.56 mL) was added to a solution of 5- methoxy-l-methyl-U / -pyrazole-4-carbonyl chloride Intermediate 53 (84 mg, 0.48 mmol) and Cui (12.23 mg, 64.2 pmol) in THF (1.26 mL). Pd(PPh3)2C12 (23.0 mg, 32.7 pmol) was added followed by TEA (0.269 mL, 1.93 mmol) and the reaction mixture vessel was evacuated and refilled with N2 (g) three times. The reaction mixture was heated to 55 °C for 3 h and then allowed to cool to rt overnight. The mixture was diluted with sat NaHCCh (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to grant the crude title compound as brown solid. MS (ESI) m / z [M+H]+450.5.

[1065] Intermediate 211

[1066] L5-Dimethyl-U / -pyrazole-4-carbonyl chloride

[1067] Oxalyl chloride (50 μL, 0.58 mmol) was added to a suspension of 1,5 -dimethyl- UT-pyrazole- 4-carboxylic acid (70.1 mg, 0.5 mmol) in DCM (1 mL). The solution was cooled to 0 °C and DMF (1.936 μL, 0.03 mmol) was added. The reaction was warmed to rt, stirred overnight and then concentrated to afford the crude title compound. NMR (500 MHz, DMSO, 25°C) δ 2.46 (3H, s), 3.74 (3H, s), 7.68 (1H, s).

[1068] Intermediate 212

[1069] 1-(L5-Dimethyl-U / -pyrazol-4-yl)-3-((3A.4A)-3-hydroxy-4-methoxy-l-((4-methylquinazolin-

[1070] 2-yl)methyl)piperidin-4-yl)prop-2-yn-l-one

[1071] A solution of (3A,45)-4-ethynyl-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-3- ol Intermediate 206 (100 mg, 0.32 mmol) in THF (2.56 mL) was added to a solution of 1,5- dimethyl-U / -pyrazole-4-carbonyl chloride Intermediate 211 (76 mg, 0.48 mmol) and Cui (12.23 mg, 64.2 pmol) in THF (1.26 mL). PdfPPhs^CL (23.0 mg, 32.7 pmol) was added followed by TEA (0.269 mL, 1.93 mmol) and the reaction mixture vessel was evacuated and refilled with N2 (g) three times. The reaction mixture was heated to 55 °C for 3 h and then allowed to cool to rt overnight. The mixture was diluted with sat NaHCCL (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated to grant the crude title compound as brown solid. MS (ESI) m / z [M+H]+434.3.

[1072] Intermediate 213

[1073] 3-((3A.4M-3-Hydroxy-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l-(l- methyl-2.3-dihydro- imidazorL2-b1pyrazol-7-yl)prop-2-yn-l-one A solution of (3A,45)-4-ethynyl-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)piperidin-3- ol Intermediate 206 (100 mg, 0.32 mmol) in THF (1...

Claims

CLAIMS1. A compound of F ormula (I)whereinR! is selected from a 8-, 9- or 10-membered heteroaryl substituted by R8, R10 and 0, 1 or 2 substituents independently selected from R^;R^ is independently selected from H, CH3, CH2F, CHF2 and CF3;R^ is selected from a 5- or 6-membered heteroaryl substituted by R*^, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from RIS or a 8-, 9- or 10-membered heteroaryl substituted by R10, 0, 1 or 2 substituents independently selected from RH, 0, 1 or 2 substituents independently selected from R12 and 0 or 1 substituents independently selected from R13;R^ is selected from H, OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3;R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;R^ is selected from H, F, Cl, CN, C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH(CH3)2, oxetane, cyPr or cyBu;R8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;is independently selected from C ^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -O(oxetane) substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2or CF3, -CH(CH3)2, CN, F or Cl;R10 is selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;R11is independently selected from C^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^_ 2alkyl optionally substituted by 1, 2, 3, 4 or 5 F, CH2OCH3, CF^cyPr, cyPr substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3 or cyBu substituted by 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;R12 is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;R13 is selected from a 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3, or -0(6- membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from O, S or N) wherein said 6-membered heterocycloalkyl ring is optionally substituted by 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3; m is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R! is selected fromn is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 whereinR8is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3or Cl;R10is selected from H, CH3, CH2F, CHF2, CF3or CH2CH3;R11is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F,OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu;R12 is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH;4. A compound according to any one of claims 1 to 3 wherein R4is selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F.

5. A compound according to claim 4 wherein6. A compound according to claim 4 wherein7. A compound according to claim 1 whereinR4 is selected from OH, C | .3 alkyl optionally substituted by 1, 2, 3, 4 or 5 F, OC^alkyl optionally substituted by 1, 2, 3, 4 or 5 F, -CH2OH, -CH2OCH3, CN, F, Cl;R5is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2or CF3;R6 is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3 or F;R^ is selected from H, F, CH3 or CN;R8 is independently selected from H, CH3 or OCH3;R^ is independently selected from CH3, OCH3, CN, F or Cl;R10 is selected from H or CH3;R11is independently selected from CH3 or OCH3;R12 is independently selected from CH3, OCH3, CN or Cl; m is independently 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2.

8. A compound according to claim 1 selected from2-((4-(5-(4-methylpyridin-3-yl)-U7-pyrazol-3-yl)piperidin-l-yl)methyl)quinoline;2-((4-(5-(4-i sopropylpyrimidin-5-yl)- I / / -pyrazol -3 -yl)piperidin- 1 -yl)methyl)-4- methylpyrido[2,3-J]pyrimidine;2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-U7-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-J]pyrimidine;6-chloro-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;8-fluoro-4-methyl-2-((4-(5-(pyri din-3 -yl)-U7-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;8-fluoro-4-methyl-2-((4-(5-(pyri din-3 -yl)-U7-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;6-Methoxy-4-methyl-2-((4-(T,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l - yl)methyl)quinazoline;4-methyl-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)pyrido[2,3- t / ]pyrimidine;2-((4-(5-(4-chloropyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine;4-methyl-2-((4-(5-(4-methylpyri din-3 -yl)-l / / -pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine;4-methyl-2-((4-(5-(5-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine;4-methyl-2-((4-(5-(2-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l -yl)methyl)pyrido[2,3- d]pyrimidine;(3-(3-(l-((4-methylpyrido[2,3-J]pyrimidin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5- yl)pyridin-4-yl)methanol;2-((4-(5-(2-ethylpyridin-3-yl)-IT / -pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine;2-((4-(5-(2,4-di ethyl pyri di n-3 -yl )- l / / -pyrazol -3 -yl )pi peri di n- 1 -yl )methyl )-4- methylpyrido[2,3-t / ]pyrimidine;3 -((4-(5-(2,4-dimethylpyri din-3 -yl)- 177-pyrazol -3 -yl)piperidin- 1 -yl)methyl)-8- methylbenzofe] [ 1 ,2,4]triazine;2-((4-(5-(2,4-dimethylpyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylpyrido[2,3-t / ]pyrimidine;2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-d]pyrimidine,2-((4-(5'-methoxy-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-J]pyrimidine;5-methyl-2-((4-CI\3\5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-l,8- naphthyridine;4,7-dimethyl-2-((4-(T,3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)pyrido[2,3-J]pyrimidine;6-chloro-4-methyl-2-((4-(T,3',5'-trirnethyl- l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;5-chloro-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;4,6-dimethyl-2-((4-(T,3',5'-trirnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;4-methyl-2-((4-(l ',3',5'-trimethyl-l' / / , 2 / / -[3,4'-bipyrazol]-5-yl)piperidin- l - yl)methyl)quinazoline-6-carbonitrile;6-methoxy-4-methyl-2-((4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l - yl)methyl)pyrido[3,4-6?]pyrimidine;841uoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;641uoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;541uoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;741uoro-4-methyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;6-methoxy-4-methyl-2-((4-( l',3',5'-trirnethyld' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidind - yl)methyl)pyrido[3,2-d]pyrimidine;2-((4-(2',4'-dimethyl-2 / / ,2' / / -[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4,7- dimethylpyrido[2,3-d]pyrimidine;2-((4-(2\4'-dimethyl-2J7,277-[3,3'-bipyrazol]-5-yl)piperidind-yl)methyl)-4-methylpyrido[2,3- d]pyrimidine;4-(methoxy-t / 3)-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)thieno[3,2- d]pyrimidine;4-methyl-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;2-((4-(5-(2,4-dimethylpyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4,7-dimethyl-7JH- pyrrolo[2,3-d]pyrimidine;6-((4-(5-(4-methylpyridin-3-yl)-l / / -pyrazol-3-yl)piperidin-l-yl)methyl)-l / / -pyrrolo[2,3-Z>]pyridine; l-ethyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l -yl)methyl)-l / / - benzo[d]imidazole; rac-(R)-4-methyl-2-((4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)-3 ,4-dihydro-2Z / -benzo[Z>] [ 1 ,4]oxazine;4-methyl-2-((4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-5J7-pyrano[4,3-J]pyrimidine;2-((4-(2\4'-dirnethyl-2 / / ,2' / / -[3,3'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4-rnethyl-6,7- dihydro-5#-pyrano[2,3-d]pyrimidine;4-chloro-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-6J7-pyrano[3,2-J]pyrimidine;4-methyl-2-((4-(r,3',5'-trii'nethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-7,8- dihydro-6J7-pyrano[3,2-J]pyrimidine; rac'-4-methyl-2-(((2 / ?,4 / ?)-2-methyl-4-CI\3\5'-trimethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)-6,7-dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;4-ethyl-2-((4-(5'-methoxy-l'-rnethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-6,7- dihydro-5#-pyrano[2,3-d]pyrimidine;4-methyl-2-((4-(r,3',5'-trii'nethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-5,8- dihydro-6 / / -pyrano[3,4-d]pyrimidine;4-ethyl-2-((4-(5'-methoxy-l\3'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-6.7-dihydro-5J7-pyrano[2,3-J]pyrimidine;2-((4-(5'-cyclopropyl-l'-rnethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l -yl)methyl)-4- methyl-6,7-dihydro-5J7-pyrano[2,3-J]pyrimidine;4-methyl-2-((4-(r,3',5'-trii'nethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-6,7- dihydro-5#-pyrano[2,3-d]pyrimidine;2-((4-(5'-methoxy-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4-m ethyl-6.7-dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;2-((4-( l',5'-dirnethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4-rnethyl-6,7- dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;2-((4-(5'-rnethoxy-l',3'-dirnethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4- rnethyl-6,7-dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;4-ethyl-2-((4-(r,3',5'-trimethyl-r / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l -yl)methyl)-6,7- dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;2-((4-(l',5'-dirnethyl-l' / / ,2 / / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)rnethyl)-4-ethyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine;4-methyl-2-((4-(r-methyl-5'-(trifluoromethyl)-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)-6,7-dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;2-((4-(5-(2,4-dimethylpyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methyl-6,7- dihydro-5 / / -pyrano[2,3-t / ]pyrimidine;4-(2',4'-dimethyl-27 / ,2'7 / -[3,3'-bipyrazol]-5-yl)-l -((4-methylquinazolin-2-yl)methyl)piperidin- 4-ol;(3 / ?,4 / ?)-l-((4-methylquinazolin-2-yl)methyl)-4-CI\3\5'-trimethyl-l' / / ,2 / / -[3,4Lbipyrazol]-5- yl)piperidin-3-ol;4-(l\5'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2-yl)methyl)piperidin-4-ol;(3 / ?,4 / ?)-4-(r,5'-dimethyl-r7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;2-((4-fluoro-4-(r,3',5'-trimethyl-r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;1-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5- yl)piperidine-4-carbonitrile;2-((4-methoxy-4-(l\3\5'-trimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4miethoxy-4-(5'miethoxy-r,3'-dimethyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)-4-methylquinazoline; rac-4-methyl-2-(((27?,45)-2-methyl-4-(l\3\5'-trimethyl-177,2JH-[3,4'-bipyrazol]-5- yl)piperidin-l-yl)methyl)quinazoline;(l-((4-Methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-177,2JH-[3,4'-bipyrazol]-5- yl)piperidin-4-yl)metanol;1-((4-Methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-177,2JH-[3,4'-bipyrazol]-5- yl)piperidin-4-ol;(3 / ?,4 / ?)-4-(5-CI-Methyl-2,3-dihydro-l7 / -irnidazo[ l,2-A]pyrazol-7-yl)-l7 / -pyrazol-3-yl)-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol;(3 / ?,4 / ?)-4-(5'-Methoxy-l',3'-dirnethyl-l'7 / ,27 / -[3,4'd3ipyrazol]-5-yl)-l-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol;37?,47?)-4-(5'-cyclopropyl-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;(3£,45)-4-(5'-cyclopropyl-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)-l-((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;2-((4-(T,5'-dimethyl-l'7 / ,27 / -[3,4Lbipyrazol]-5-yl)-4-methoxypiperidin-l -yl)methyl)-4- methylquinazoline;2-((4-methoxy-4-(5'-methoxy-l'-methyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)- 4-methylquinazoline;(3 / ?,45)-4-methoxy-4-( l'-rnethyl-5'-(trifluorornethyl)-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol;(3 / ?,45)-4-(5'-(difliiorornethyl)-l'-rnethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-4-rnethoxy-l -((4- methylquinazolin-2-yl)methyl)piperidin-3-ol;(37?,4S)-4-methoxy-4-(5'-methoxy-r,3'-dimethyl-r7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l-((4- methylquinazolin-2-yl)methyl)piperidin-3-ol;(37?,4S)-4-methoxy-4-(5'-methoxy-r-methyl-r7 / ,27 / -[3,4'-bipyrazol]-5-yl)-l-((4- methylquinazolin-2-yl)methyl)piperidin-3-ol;(37?,4S)-4-(l(5'-dimethyl-r7 / ,27 / -[3,4'-bipyrazol]-5-yl)-4-methoxy-l-((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;(37?,4S)-4-methoxy-4-(5-(l-methyl-2,3-dihydro-17 / -imidazo[l,2-b]pyrazol-7-yl)-17 / -pyrazol-3-yl)-l-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol;(37?,4S)-l-((5-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol;(37?,4S)-l-((5-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol;(37?,4S)-l-((6-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol;(37?, 4S)-4-m ethoxy- 1 -((4-methylquinazolin-2-yl)rnethyl)-4-( l',3',5'-trirnethyl-l'7 / ,27 / -[3,4'- bipyrazol] -5 -yl)piperi din-3 -ol ;(35, 47?)-4-m ethoxy- 1 -((4-methylquinazolin-2-yl)rnethyl)-4-( l',3',5'-trirnethyl-l'7 / ,27 / -[3,4'- bipyrazol] -5 -yl)piperi din-3 -ol ;(37?,45)-4-methoxy-4-(5-(4-methylpyridin-3-yl)-17 / -pyrazol-3-yl)-l -((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;(3 / ?,45)-4-(3',5'-dimethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)-4-methoxy-l -((4-methylquinazolin-2- yl)methyl)piperidin-3-ol;(37?, 4S)-4-m ethoxy- 1 -((4-methylquinazolin-2-yl)methyl)-4-(5-(pyridin-3-yl)-lZ / -pyrazol-3- yl)piperidin-3-ol;(37?,4S)-l-((8-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- r7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-3-ol;(37?,4S)-l-((6-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(r,3',5'-trimethyl- 177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-3-ol; rac-(37?,45)-3-fluoro-l-((4-methylquinazolin-2-yl)methyl)-4-(l\3\5'-trimethyl-177,2JH-[3,4'- bipyrazol] -5 -yl)piperidin-4-ol ; rac-(37?,47?)-4-methoxy-l-((4-methylquinazolin-2-yl)methyl)-4-(r,3',5'-trimethyl-rJH,2JH-[3,4'-bipyrazol]-5-yl)piperidin-3-ol;4-methyl-2-((4-(T,3',4,5'-tetramethyl-l'7 / ,27 / -[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline; l\3\5'-trirnethyl-5-( l-((4-rnethylquinazolin-2-yl)rnethyl)piperidin-4-yl)-l'7 / ,27 / -[3,4'- bipyrazole]-4-carbonitrile;7V-methyl-5-(3-(l -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l / / -pyrazol-5-yl)pyridin-3 -amine;4-methyl-2-((4-(5-(l-methyl-lJ7-pyrrolo[2,3-Z>]pyridin-2-yl)-lJ7-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline;4-methyl-2-((4-(5-(l-methyl-lZ / -indazol-7-yl)-177-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline;4-methyl-2-((4-(5-(5-((tetrahydro-27 / -pyran-4-yl)oxy)pyridin-3-yl)-IT / -pyrazol-3- yl)piperidin-l-yl)methyl)quinazoline;4-methyl-2-((4-(5-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-1 -yl)methyl)quinazoline;1-(4-(5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJ7-pyrazol-5-yl)pyridin-3- yl)piperazin- 1 -yl)ethan- 1 -one;4-methyl-5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5- yl)nicotinonitrile;4-(5-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-177-pyrazol-5-yl)pyri din-3- yl)morpholine;2-((4-(5-(5-methoxypyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5-(5-chloropyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylquinazoline;4-methyl-2-((4-(5-(5-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;4-methyl-2-((4-(5-(4-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;4-methyl-2-((4-(5-(pyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;4-methyl-2-((4-(5-(2-methylpyri din-3 -yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)quinazoline;4-methyl-2-((4-(5-(2-(trifluoromethyl)pyridin-3-yl)-IT / -pyrazol-3-yl)piperidin-l - yl)methyl)quinazoline;2-((4-(5-(2,4-dimethylpyridin-3-yl)-177-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5-(4-(methoxymethyl)-2-methylpyridin-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4-methylquinazoline;2-({4-[3-(4-ethyl-2-methylpyridin-3-yl)-177-pyrazol-5-yl]piperidin-l-yl}methyl)-4- methylquinazoline;2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5-(l,4-dimethyl-lJ7-imidazol-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;4-methyl-2-((4-(5-(l -methyl -2, 3-dihy dro-l / / -imidazo[l,2-Z>]pyrazol -7-yl)-l / / -pyrazol-3 - yl)piperidin-l-yl)methyl)quinazoline;3-(3-( l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-IT / -pyrazol-5-yl)-5,6-dihydro-87 / - imidazo[2, 1 -c] [ 1 ,4]oxazine;3-(3-( l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-IT / -pyrazol-5-yl)-6,7-dihydro-47 / - pyrazolo[5, 1 -c] [ 1 ,4] oxazine;2-((4-(5-(5,6-dihydro-477-pyrrolo[l,2-Z>]pyrazol-3-yl)-lJH-pyrazol-3-yl)piperidin-l- yl)methyl)-4-methylquinazoline;3-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5-yl)-6,7-dihydro-5Z / - pyrazolo[5,l-Z>][l,3]oxazine;7-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lZ / -pyrazol-5-yl)-2,3- dihydropyrazolo[5, 1-Z>]oxazole;3 , 5 -dimethyl-4-(3 -( 1 -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)- 17 / -py razol -5 - yl)isoxazole;4-methyl-2-((4-(5-(l,2,4-trimethyl-lJH-imidazol-5-yl)-lJH-pyrazol-3-yl)piperidin-l- yl)methyl)quinazoline;2-((4-(5-(l,2-dimethyl-lJ7-imidazol-5-yl)-lJ7-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2.4-dimethyl-5-(3-( l -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-l / / -pyrazol-5- yl)thi azole;5-methyl-2-(3-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-5-yl)-4-(trifluoromethyl)thi azole;3 , 5 -dimethyl-4-(3 -( 1 -((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)- 1 / / -py razol -5 - yl)isothi azole;2-((4-(5-(4-ethyl-5-methyl-4J7-l,2,4-triazol-3-yl)-lJH-pyrazol-3-yl)piperidin-l-yl)methyl)-4- methylquinazoline;3.4-dimethyl-5-(5-(l-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-lJH-pyrazol-3- yl)isoxazole;2-((4-(l\5'-dimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(3\5Mimethyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;4-methyl-2-((4-(r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)quinazoline,4-methyl-2-((4-(l\3\5'-trimethyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;2-((4-(5'-cyclobutyl-l'-methyl-l' / / ,2 / / -[3,4Lbipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5'-(difluoromethyl)-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;4-methyl-2-((4-(r-methyl-5'-(trifluoromethyl)-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;2-((4-(5'-(methoxymethyl)-r-methyl-177,2JH-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5'-cyclopropyl-l'-methyl-l' / / ,2 / / -[3,4Lbipyrazol]-5-yl)piperidin-l -yl)methyl)-4- methylquinazoline;2-((4-(5'-methoxy-l',3'-dirnethyl-l' / / ,2 / / -[3,4Lbipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;4-methyl-2-((4-(2',4',5'-trimethyl-2JH,2'JH-[3,3'-bipyrazol]-5-yl)piperidin-l- yl)methyl)quinazoline;2-((4-(4',5'-dimethyl-2 / / ,2' / / -[3,3'-bipyrazol]-5-yl)piperidin- l -yl)methyl)-4- methylquinazoline;2-((4-(l\3'-dimethyl-17 / ,2J / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(2\4'-dirnethyl-2J / ,27 / -[3,3'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5'-ethyl-l\3'-dimethyl-17 / ,2J / -[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline;2-((4-(5'-methoxy-r-methyl-177,2J7-[3,4'-bipyrazol]-5-yl)piperidin-l-yl)methyl)-4- methylquinazoline; rac-(3A,45)-4-ethyl-l-((4-methylquinazolin-2-yl)methyl)-4-(l\3\5'-trimethyl-17 / ,2J / -[3,4'- bipyrazol] -5 -yl)piperi din-3 -ol ; rac-(3A,45)-4-methyl-l-((4-methylquinazolin-2-yl)methyl)-4-(l\3\5'-trimethyl-17 / ,2J / -[3,4'- bipyrazol] -5 -yl)piperi din-3 -ol ; or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use as a medicament.

10. A pharmaceutical composition comprising a compound according to any one claims 1 to 8, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A method of treating, or reducing the risk of, diseases or conditions in which inhibition of the enzyme NNMT is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11, wherein said disease or condition is chronic kidney disease (CKD).

13. The method according to claim 11, wherein said disease or condition is acute kidney injury (AKI).

14. The method according to claim 11, wherein said disease or condition is diabetic kidney disease (DKD).

15. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use as a medicament.

16. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic kidney disease (CKD).

17. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute kidney injury (AKI).

18. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic kidney disease (DKD).

19. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme NNMT is beneficial.

20. The use according to claim 19, wherein said disease or condition is chronic kidney disease (CKD).

21. The use according to claim 19, wherein said disease or condition is acute kidney injury (AKI).

22. The use according to claim 19, wherein said disease or condition is diabetic kidney disease (DKD).

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