(4-(([1 ,2,4]TRIAZOLO[4,3-A]PYRIDINE-6-YL)OXY)-1 ,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)

UREIDO DERIVATIVES AS ANTI-INFLAMMATORY P38 MAPK INHIBITORS FOR TREATING

DISEASES OF THE RESPIRATORY TRACT

This invention relates to compounds and compositions that are p38 MAPK inhibitors, useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.

Background to the invention

Mitogen activated protein kinases (MAPK) constitute a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. There are four known human isoforms of p38 MAP kinase, p38oc, ρ38β, ρ38γ and ρ38δ. The p38 kinases, which are also known as cytokine suppressive anti-inflammatory drug binding proteins (CSBP), stress activated protein kinases (SAPK) and RK, are responsible for phosphorylating (Stein et al, Ann. Rep. Med Chem., 1996, 31, 289-298) and activating transcription factors (such as ATF-2, MAX, CHOP and C/ERPb) as well as other kinases (such as MAPKAP-K2/3 or MK2/3), and are themselves activated by physical and chemical stress (e.g. UV, osmotic stress), pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) (Herlaar E. & Brown Z., Molecular Medicine Today, 1999, 5, 439-447). The products of p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including tumor necrosis factor alpha (TNF a) and interleukin- (IL)-l, and cyclooxygenase-2 (COX-2). IL-1 and TNFct are also known to stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8.

IL-1 and TNFa are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation (e.g. Dinarello et al., Rev. Infect. Disease, 1984, 6, 51). Excessive or unregulated TNF production (particularly TNFa) has been implicated in mediating or exacerbating a number of diseases, and it is believed that TNF can cause or contribute to the effects of inflammation in . IL-8 is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysaccharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes and basophils. Increase in IL-8 production is also responsible for chemotaxis of neutrophils into the inflammatory site in vivo.

Inhibition of signal transduction via p38, which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional proinflammatory proteins (e.g., IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. This expectation is supported by the potent and diverse anti-inflammatory activities described for p38 kinase inhibitors (Badger et al, J. Pharm. Exp. Thera., 1996, 279, 1453 -1461; Griswold et al, Pharmacol. Comm.,1996, 7, 323-229). In particular, p38 kinase inhibitors have been described as potential agents for treating rheumatoid arthritis. In addition to the links between p38 activation and chronic inflammation and arthritis, there is also data implicating a role for p38 in the pathogenesis of airway diseases in particular COPD and asthma. Stress stimuli (including tobacco smoke, infections or oxidative products) can cause inflammation within the lung environment. Inhibitors of p38 have been shown to inhibit LPS and ovalbumin induced airway TNF-cc, IL-Ιβ, IL-6, IL-4, IL-5 and IL-13 (Haddad et al, Br. J. Pharmacol., 2001, 132 (8), 1715- 1724; Underwood et al, Am. J. Physiol. Lung Cell. Mol. 2000, 279, 895-902; Duan et al, 2005 Am. J. Respir. Crit. Care Med., 171, 571-578; Escort et al Br. J. Pharmacol., 2000, 131, 173-176; Underwood et al, J. Pharmacol. Exp. Ther. 2000, 293, 281-288). Furthermore, they significantly inhibit neutrophilia and the release of MMP-9 in LPS, ozone or cigarette smoke animal models. There is also a significant body of preclinical data highlighting the potential benefits of inhibition of the p38 kinase that could be relevant in the lung (Lee et al, Immunopharmacology, 2000, 47, 185-200). Thus, therapeutic inhibition of p38 activation may be important in the regulation of airway inflammation.

The implication of the p38MAPK pathway in various diseases has been reviewed by P. Chopra et al (Expert Opinion on Investigational Drugs, 2008, 17(10), 1411-1425). It is believed that the compounds of the present invention can be used to treat p38 mediated diseases such as: chronic obstructive pulmonary disease (COPD), asthma, chronic or acute bronchoconstriction, bronchitis, acute lung injury and bronchiectasis, pulmonary artery hypertension, tuberculosis, lung cancer, inflammation generally (e.g. inflammatory bowel disease), arthritis, neuroinflammation, pain, fever, fibrotic diseases, pulmonary disorders and diseases (e.g., hyperoxic alveolar injury), cardiovascular diseases, post -ischemic reperfusion injury and congestive heart failure, cardiomyopathy, stroke, ischemia, reperfusion injury, renal reperfusion injury, brain edema, neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn's disease, ophthalmic diseases, ophthalmological conditions, glaucoma, acute injury to the eye tissue and ocular traumas, diabetes, diabetic nephropathy, skin-related conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, graft rejection, bone resorption diseases, multiple sclerosis, psoriasis, eczema, disorders of the female reproductive system, pathological (but non-malignant) conditions, such as hemangiomas, angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and malignant tumors/neoplasia including cancer, leukaemia, lymphoma, systemic lupus erythematosus (SLE), angiogenesis including neoplasia, haemorrhage, coagulation, radiation damage, and/or metastasis. Chronic release of active TNF can cause cachexia and anorexia, and TNF can be lethal. TNF has also been implicated in infectious diseases. These include, for example, malaria, mycobacterial infection and meningitis. These also include viral infections, such as HIV, influenza virus, and herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella- zoster virus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), human herpesvirus-7 (HHV7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.

Known P38 kinase inhibitors have been reviewed by G. J. Hanson (Expert Opinions on Therapeutic Patents, 1997, 7, 729-733) J Hynes et al. (Current Topics in Medicinal Chemistry, 2005, 5, 967-985), C. Dominguez et al (Expert Opinions on Therapeutics Patents, 2005, 15, 801-816) and L. H. Pettus & R. P. Wurtz (Current Topics in Medicinal Chemistry, 2008, 8, 1452-1467). P38 kinase inhibitors are known in the art, for example WO2014/195400 and WO 2013/083604.

The object of the present invention is to identify more potent anti-inflammatory agents to be used in the treatment of diseases of the respiratory tract.

Another object of the present invention is to identify novel potent p38 mitogen activated protein kinase inhibitors which show an appropriate developability profile on inhalatory administration to effectively treat respiratory obstructive or inflammatory diseases. It is to be understood that such profile may be achieved in a number of different ways by modulation of specific properties; by way of example, it could be achieved by administration of a low effective dose of the drug thus limiting side effects or via a long duration of action in the lungs which may reduce the frequency of administration.

Brief Description of the Invention

The compounds of the invention are inhibitors of p38 mitogen activated protein kinase ("p38 MAPK", "p38 kinase" or "p38"), including p38oc kinase, and are inhibitors of cytokine and chemokine production including TNFa and IL-8 production. They have a number of therapeutic applications, in the treatment of inflammatory diseases, particularly allergic and non-allergic airways diseases, more particularly obstructive or inflammatory airways diseases such as chronic obstructive pulmonary disease ("COPD") and asthma; therefore are particularly suited for pulmonary delivery, by inhalation by nose or mouth.

Description of the invention

According to the invention there is provided a compound of formula (I)

(I) wherein A is selected from the group consisting of (Ia)-(Id

B is

(lie)

( ^|lf ) (llg) (Ilh) (Hi)

Ri is H or is selected from -CN, linear or branched (Ci-C ₄ )alkyl-, (Rs)(R ₉ )NC(0)-; R ₁₂ 0-(C ₁ -C ₄ )alkylene-; (R ₈ )(R ₉ )N-(C ₁ -C ₄ )alkylene-; (C ₁ -C )alkyl-C(0)0-(C ₁ - C ₄ )alkylene-; (Rs)C(0)0-; (C ₁ -C ₄ )alkyl-S(0) ₂ NH-; (C ₁ -C ₄ )alkyl-S-; (R ₈ )(R ₉ )N-; (R«)(R ₉ )N-(C ₁ -C ₄ )alkylene-C(0)NH-(C ₁ -C ₄ )alkylene-; optionally substituted (C ₃ -C ₇ )heterocycloalkyl-C(0)NH-(C ₁ -C ₄ )alkylene-; (C ₁ -C ₄ )alkyl-OC(0)-; (R ₈ )(R ₉ )N-(C ₁ - C ₄ )alkylene-0-(C ₁ -C ₄ )alkylene-;

R ₂ is H or selected from linear or branched (Ct-C^alkyl- and (Ci-C^alkyl-O-; R ₃ is H or linear or branched (d-C^alkyl-;

R4 is H or linear or branched (C ₁ -C ₄ )alkyl-;

R ₅ is H or selected from linear or branched (d-G alkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene- and R ₁₂ 0-;

R ₆ is H or linear or branched (O-C^alkyl-;

R7 is H or linear or branched (d-C^alkyl-;

or R ⁶ and R ⁷ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;

X is selected from a group consisting of -CH ₂ -, (R ₃ )N- and -0-;

Rs is H or selected from linear or branched -(C ₁ -C ₄ )alkyl- and Ri20-(Ci- C ₄ )alkylene-;

R9 is H or is selected from linear or branched (d-C^alkyl-, optionally substituted

(C ₃ -C ₇ )heterocycloalkyl-, optionally substituted (C3-C ₇ )cycloalkyl-, Ri20-(Ci- C ₄ )alkylene-, (Rio)(Rii)N-(Ci-C4)alkylene- and (R ₁₀ )(Rii)N-(C ₁ -C ₄ )alkylene-O-(C ₁ - C4)alkylene-, wherein said (C ₁ -C ₄ )alkylene- in (C ₃ -C ₇ )cycloalkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene- , (RioXRi N-CCi-GOalkylene- and (R ₁ o)(R ₁₁ )N-(C ₁ -C ₄ )alkylene-0-(C ₁ -C ₄ )alkylene can be optionally substituted with one or more groups selected from linear or branched (Ci-C ₄ )alkyl-, spiro-(C ₁ -C6)cycloalkyl and spiro-(C ₁ -C ₆ )heterocycloalkyl;

or R ⁸ and R ⁹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;

R ₁₀ is H or is selected from linear or branched (Ci-G^alkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene-

, (C ₃ -C ₇ )cycloalkyl- and (C ₃ -C ₇ )heterocycloalkyl-;

Rn is H or is selected from linear or branched (C ₁ -C ₄ )alkyl-, and R ₁₂ 0-(C ₁ - C ₄ )alkylene-;

or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;

n is an integer from 1 to 4;

m is an integer from 1 to 2;

z is an integer from 1 to 2;

and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (Ci-C^alkyl-, halo, R ₁₂ 0-(C ₁ -C ₄ )alkylene-, R ₁₂ 0-, oxo, (Ci-a)alkyl(Ci-C4)alkyl)N-;

R ₁₂ is H or linear or branched (Ci-C ₄ )alkyl-; with the proviso that when A is (lb) then Ri is not H, CH ₃ or CN.

Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and re-crystallization techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).

Embodiments of the Invention

All preferred groups or embodiments described herebelow for compounds of formula (I) may be combined among each other and apply as well to compounds of formula (la) mutatis mutandis.

In one embodiment, the invention is directed to compounds of formula (I)

B is selected from the group consisting of (Ila)-(IIe) and (Ilg)-(IIi)

(lla) (lib) (lie) (lid) (He)

(iig) (llh) (Hi)

Ri is H or is selected from -CN, linear or branched (d-C ₄ )alkyl, (Rs)(R9)NC(0)-; R ₁₂ 0-(C ₁ -C ₄ )alkylene-; (R ₈ )(R ₉ )N-(C ₁ -C ₄ )alkylene-; (C ₁ -C ₄ )alkyl-S(0) ₂ NH-; (Ci- C ₄ )alkyl-S-; (Ci-C4)alkyl-OC(0)-; (R ₈ )(R ₉ )N-(C ₁ -C ₄ )alkylene-0-(C ₁ -C ₄ )alkylene-; R ₂ is H or selected from linear or branched (C ₁ -C4)alkyl- and (d-C^alkyl-O-; R ₃ is H or linear or branched (d-C ₄ )alkyl-; Rt is H, or linear or branched (d-C ₄ )alkyl-; R ₅ is H or selected from linear or branched (d-C ₄ )alkyl-, R ₁ 20-(C ₁ -C ₄ )alkylene- and R ₁₂ 0-; R ⁶ and R ⁷ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; Rs is H or selected from linear or branched -(C ₁ -C ₄ )alkyl-; R ₉ is selected from linear or branched (C ₁ -C ₄ )alkyl-, optionally substituted (C ₃ -C ₇ )cycloalkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene-, (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- wherein said (C ₁ -C ₄ )alkylene- in (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (C ₁ -C ₄ )alkyl-, spiro-(C ₁ -C ₆ )cycloalkyl and spiro-(Ci-C ₆ )heterocycloalkyl; or R ⁸ and R ⁹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₀ is selected from linear or branched (C ₁ -C ₄ )alkyl-, (C ₃ -C ₇ )cycloalkyl-; Rn is selected from linear or branched (d-C ₄ )alkyl-, and R ₁₂ 0-(d-C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or mtrogen heteroatom; n is 3; m is 1 ; z is 1 ; and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (Ci-C ₄ )alkyl- , halo, R ₁₂ 0-(C!-C ₄ )alkylene-, R ₁₂ 0-, oxo, (C ₁ -C ₄ )alkyl(C ₁ -C )alkyl)N-; R ₁₂ is H or linear or branched (CirC ₄ )aikyl-; with the proviso that when A is (lb) then is not H, CH ₃ or CN.

In another embodiment, the invention is directed to compounds of formula (I) wherein A is group (la)

(la)

B is selected from the group consisting of (Ila) and (He)

("a) (lie)

Ri is H or is selected from (R8)(R ₉ )NC(0)-; R ₃ is linear or branched (d-C^alkyl-; R4 is H, or linear or branched (d-C^alkyl-; R ₅ linear or branched (C ₁ -C ₄ )alkyl-, R ₁₂ 0-(d- C ₄ )alkylene- and R ₁₂ 0-; Rs is H; R ₉ (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- wherein said (d-C )alkylene- in (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (d-C ₄ )alkyl-; R ₁₀ linear or branched (C ₁ -C ₄ )alkyl-; Rn linear or branched (d-C ₄ )alkyl-, and R ₁₂ 0-(d-C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₂ is H or linear or branched (d-C ₄ )alkyl-; and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (C ₁ -C ₄ )alkyl-, halo, R ₁₂ 0-(d-C ₄ )alkylene-, R ₁₂ 0- , oxo, (C ₁ -C ₄ )alkyl(C ₁ -C ₄ )alkyl)N-; with the proviso that when A is (lb) then Ri is not H, CH ₃ or CN.

In another embodiment, the invention is directed to compounds of formula (I) wherein A is group (lb)

(lb)

selected from the group consisting of (Ila) and (He)

( ^|la ) (lie)

Ri is H or is selected from (Rs)(R9)NC(0)-; R ₃ is linear or branched (C ₁ -C ₄ )alkyl-; R4 is H, or linear or branched (Ci-C4)alkyl-; R ₅ linear or branched (Ci-C4)alkyl-, Ri20-(Ci- C ₄ )alkylene- and R ₁₂ 0-; Rs is H; R ₉ (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- wherein said (C ₁ -C ₄ )alkylene- in (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (d-C^alkyl-; R ₁₀ linear or branched (C ₁ -C ₄ )alkyl-; Rn linear or branched and R ₁ 20-(C ₁ -C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₂ is H or linear or branched (C ₁ -C ₄ )alkyl-; and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (C ₁ -C ₄ )alkyl-, halo, R ₁₂ 0-(C ₁ -C ₄ )alkylene-, R ₁₂ 0- , oxo, (Ci-C ₄ )alkyl(C ₁ -C ₄ )alkyl)N-; with the proviso that when A is (lb) then Ri is not H, CH ₃ or CN.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is (la)

(la)

B is selected from the group consisting of (Ila)-(IIe) and (Ilg)-(IIi)

(lla) (Mb) (lie) (lid) (lie)

Rt is H or linear or branched (d-C^alkyl, (Rs)(R ₉ )NC(0)-; R ₁₂ 0-(Ci-C ₄ )alkylene-;

(R ₈ )(R ₉ )N-(C ₁ -C ₄ )alkylene-; (Ci-C4)alk l-S(0)2NH-; (d-C^alkyl-S-; (C ₁ -C ₄ )alkyl- OC(O)-; (R ₈ )(R ₉ )N-(C ₁ -C ₄ )alkylene-0-(C ₁ -C ₄ )alkylene-; R ₃ is H or linear or branched (C ₁ -C ₄ )alkyl-; R4 is H, or linear or branched (C ₁ -C4)alkyl-; R ₅ is H or selected from linear or branched (C ₁ -C ₄ )alkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene- and R ₁₂ 0-; R ⁶ and R ⁷ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; Rs is H or selected from linear or branched -(Ci-C ₄ )alkyl-; R ₉ is selected from linear or branched (C]-C ₄ )alkyl-, optionally substituted (C ₃ -C ₇ )cycloalkyl-, Ri20-(C ₁ -C ₄ )alkylene-, (R ₁ o)(R ₁₁ )N-(C ₁ -C ₄ )alkylene- wherein said (d-C^alkylene- in (R ₁₀ )(R ₁₁ )N-(C ₁ -C4)alkylene- can be optionally substituted with one or more groups selected from linear or branched (C ₁ -C ₄ )alkyl-, spiro-(C ₁ -C ₆ )cycloalkyl and spiro-id- C6)heterocycloalkyl; or R ⁸ and R ⁹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₀ is selected from linear or branched (Ci-G alkyl-, (C3-C ₇ )cycloalkyl-; Rn is selected from linear or branched (Ci-C ₄ )alkyl-, and R ₁₂ 0-(d-C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 merhbered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; n is 3; m is 1 ; z is 1 ; and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (d-C ₄ )alkyl-, halo, R ₁₂ 0-(d- C ₄ )alkylene-, R ₁₂ 0-, oxo, (C ₁ -C ₄ )alkyl(C ₁ -C ₄ )alkyl)N-;

R ₁₂ is H or linear or branched (d-C ₄ )alkyl-.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is (lb)

(lb)

B is selected from the group consisting of (Ha), (lie) and (He)

(Ma) (lie) (He)

Ri is H or is selected from (Rg)(R ₉ )NC(0)-; R ₁₂ 0-(d-C4)alkylene-; (d-C ₄ )alkyl-

S(0) ₂ NH-; R ₃ is linear or branched (d-C ₄ )alkyl-; R4 is H, or linear or branched (Ci-C ₄ )alkyl-; R ₅ is selected from linear or branched (C ₁ -C ₄ )alkyl-, R ₁₂ 0-(d-C4)alkylene- and Ri ₂ 0-; Rs is H; R ₉ is selected from a group consisting of R ₁₂ 0-(C ₁ -C ₄ )alkylene-, (R ₁ o)(Rii)N-(C ₁ -C ₄ )alkylene- wherein said (d-C ₄ )alkylene- in (R ₁₀ )(R ₁₁ )N-(C ₁ - C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (d-C ₄ )alkyl-; R ₁₀ is selected from linear or branched (C ₁ -C ₄ )alkyl-; Rn is selected from linear or branched (d-C )alkyl-, and R ₁₂ 0-(d-C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; and wherein "optionally substituted" means a substitution by one or more Ri ₂ 0; R ₁₂ is H or linear or branched (Ci-C4)alkyl- with the proviso that when A is (lb) then Ri is not H, CH ₃ or CN.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is selected from the group consisting of (Ic) and (Id)

B is selected from the group consisting of (Ila) and (lie)

(Ha) (Me)

Ri is H or is selected from -CN, (R ₈ )(R ₉ )NC(0)-; R ₂ is selected from linear or branched (C ₁ -C ₄ )alkyl- and (C ₁ -C ₄ )alkyl-0-; R ₃ is H or linear or branched (C ₁ -C ₄ )alkyl-; R4 is linear or branched (d-C ₄ )alkyl-; R ₅ is linear or branched (d-C^alkyl-, Rs is H, R ₉ is (R ₁₀ )(R ₁₁ )N-(C ₁ -C ₄ )alkylene-, R ₁₀ linear or branched (d-C ₄ )alkyl-; Rn is linear or branched (d-C^alkyl- or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is selected from the group consisting of (Ia)-(Id)

(lb) (Ic) B is

(Ila)

Ri is selected from the group consisting of (R8)(R9)NC(0)-; (Re)(R.9)N-(Ci- C ₄ )alkylene-; (R ₈ )(R9)N-(C ₁ -C ₄ )alkylene-0-(C ₁ -C ₄ )alkylene-; R ₃ is linear or branched (d- C ₄ )alkyl-;

R4 is H, or linear or branched (d-G alkyl-; R ₅ is selected from linear or branched (O-C^alkyl-, R ₁₂ 0-(C ₁ -C ₄ )alkylene- and R ₁₂ 0-; Rs is H or selected from linear or branched -(Ci-C ₄ )alkyl-; R9 is selected from a group consisting of optionally substituted (C ₃ -C ₇ )cycloalkyl-, Ri ₂ 0-(Ci-C )alkyleiie-, (Ri ₀ )(Rii)N-(Ci-C4)alkyleiie- wherein said (C i -C ₄ )alkylene- in (Ri o)(Ri 1 )N-(C 1 -C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (d-C^alkyl-, spiro-(Ci-C ₆ )cycloalkyl and spiro-(Ci -C ₆ )heterocycloalkyl;

or R ⁸ and R ⁹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₀ is selected from linear or branched (0-C ₄ )alkyl-; (C ₃ -C ₇ )cycloalkyl-; Rn is selected from linear or branched (Ct-C^alkyl-, and R ₁₂ 0-(C ₁ -C )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;

and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (Ci-C ₄ )alkyl-, halo, R ₁ 20-(C ₁ -C ₄ )alkylene-, R ₁₂ 0-, oxo, (Ci-C4)alk l(Ci-C4)alkyl)N-; R ₁₂ is H or linear or branched (C ₁ -C )alkyl-.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is selected from the group consisting of (Ia)-(Id)

B is selected from the group consisting of (lib) and (lie)

(lib) (Me)

Ri is H or is selected from -CN, linear or branched (C ₁ -C ₄ )alkyl, (R8)(R ₉ )NC(0)-; R ₂ is selected from linear or branched (C ₁ -C ₄ )alkyl- and (Ci-C^alkyl-O-; R ₃ is H or linear or branched (C ₁ -C ₄ )alkyl-; R4 is linear or branched (d-G^alkyl-; Rs is H; R9 is selected from linear or branched (Ci-C ₄ )alkyl-, R ₁₂ 0-(C ₁ -C )alkylene-, (R ₁₀ )(Ri ₁ )N-(C ₁ -C ₄ )alkylene-; R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; R ₁₂ is H; with the proviso that when A is (lb) then Ri is not H, CH ₃ or CN.

In one embodiment, the invention is directed to compounds of formula (I) wherein A is selected from the group

(la) (lb)

B is selected from the group consisting of (lid), (He), (Ilg), (Ilh) and (IK)

(lid) (iig) (Hi) Ri is selected from the group consisting of (R8)(R ₉ )NC(0)-; R ₃ is linear or branched (Ci-C ₄ )alkyl-; R ₄ is linear or branched (C ₁ -C ₄ )alkyl-; R ⁶ and R ⁷ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom; Rs is H; R ₉ is selected from a group consisting of R ₁ 20-(C ₁ -C ₄ )alkylene-, (Rio)(Rn)N-(C ₁ -C )alkylene- wherein said (C ₁ -C ₄ )alkylene- in (Rio)(Rii)N-(Ci- C ₄ )alkylene- can be optionally substituted with one or more groups selected from linear or branched (d-C^alkyl-; R ₁₀ is selected from linear or branched (C ₁ -C ₄ )alkyl-; Rn is selected from linear or branched (Ci-C ₄ )alkyl-, and R ₁₂ 0-(C ₁ -C ₄ )alkylene-; or R ¹⁰ and R ¹¹ may form together with the nitrogen atom to which they are attached an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroaiom; n is 3; m is 1 ; z is 1 ; and wherein "optionally substituted" means a substitution by one or more groups selected from linear or branched (C ₁ -C ₄ )alkyl-; R ₁₂ is H.

In one embodiment, a compound of formula (I) is selected from

4-(tert-Butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((l S,4R)-4-((3- (tert-pentyl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4 tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((l S,4R)-4-((3-(tert-pentyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((l S,4R)-4-((3- (tert-pentyl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((l S,4R)-4-((3-(pentan-3-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-N-(2-(3-methoxyazetidin-l-yl)ethyl)-6-(3-((lS ,4R)-4-((3-(pentan-3- yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)-2-methylpropyl)-6-(3-((l S,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)-2- methylpropyl)pyrimidine-2-carboxamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- y l)oxy] - 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl } ureido)-N-(2-(4-hydroxypiperidin- 1 - yl)ethyl)picolinamide;

6-(tert-Butyl)-4-(3 -(( 1 S,4R)-4-((3 -(diethylamino)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide;

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (ethyl(methyl)arnino)ethyl)pyrimidine-2-carboxarnide;

4-(tert-butyl)-6-(3 -((IS ,4R)-4-((3 -(2-methoxypropan-2-yl)- [ 1 ,2,4]triazolo [4,3 - a]pyridin-6-yl)oxy]- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

l-(6-(tert-butyl)-2-(hydroxymethyl)pyrimidin-4-yl)-3-((lS,4R )-4-((3-(2- methoxypropan-2-yl)-[l ,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l ,2,3,4- tetrahydronaphthalene- 1 -yl)urea;

l-(6-(tert-Butyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-l,2-d imethylpyrrolidin-2- yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahyd ronaphthalen-l-yl)urea; l-(6-(tert-Butyl)-2-((dimethylamino)methyl)pyrimidin-4-yl)-3 -((lS,4R)-4-((3-((S)- 2-methylpiperidin- 1 -yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-hydroxyethyl)pyrimidine-2- carboxamide;

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-isopropyl- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-6-(3-((l S,4R)-4-((3-((2R,6S)-2,6-dimethylpiperidin-l -yl)-

[ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- mo holinoethyl)pyrimidine-2-carboxamide;

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((2R,6S)-2,6-dimethylpipe ridin-l-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- hydroxyethyl)pyrimidine-2-carboxamide;

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((2R,6S)-2,6- dimethylpiperidin-l-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)o xy)-l, 2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

l-(6-(tert-Butyl)-2-(morpholinomethyl)pyrimidin-4-yl)-3-((lS ,4R)-4-((3-(tert- butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l -yl)urea;

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(2-(4- methylpiperazin- 1 -y l)propan-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

l-(6-(tert-Butyl)-2-(hydroxymethyl)pyrimidin-4-yl)-3-((lS,4R )-4-((3-(2-(4- methylpiperazin- 1 -yl)propan-2-yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

N-((4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]t riazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidin-2-yl)methyl)-2- (dimethylamino)acetamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(l -methylcyclopentyl)-[l ,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

(4-(tert-butyl)-6-(3-((l S,4R)-4-((3-((S)-l ,2-dimethylpyrrolidin-2-yl)-

[ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidin-2-yl)methyl acetate;

1 -(6-(tert-butyl)-2-(hydroxymethyl)pyrimidin-4-yl)-3-((l S,4R)-4-((3-((S)-l ,2- dimethylpyrrolidin-2-yl)- [1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrrolidin-2-yl)- [1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N-(2- hydroxyethyl)pyrimidine-2-carboxamide;

N-(4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrro lidin-2-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidin-2-yl)methanesulfonamide;

l-(6-(tert-butyl)-2-(4-methylpiperazin-l-yl)pyrimidin-4-yl)- 3-((lS,4R)-4-((3-((S)- 1 ,2-dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(l- methylcyclopropyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-hydroxyethyl)-6-(3-((lS,4R)-4-((3-(morph oline-4-carbonyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxarnide; 4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-2- methylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)ox y)-l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

l-(5-(tert-butyl)-2-methoxypyridin-3-yl)-3-((lS,4R)-4-((3-(( S)-l-methylpyrrolidin- 2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrah ydronaphthalen-l-yl)urea hydrochloride salt;

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxylate;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((l S,4R)-4-((3-((S)-2- methylpiperidin- 1 -yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N- methylpyrimidine-2-carboxamide;

l-(4-(tert-butyl)-6-cyanopyridin-2-yl)-3-((lS,4R)-4-((3-((R) -l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(6-(tert-Butyl)-2-methylpyrimidin-4-yl)-3-((lS,4R)-4-((3-( (S)-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(6-(tert-Butyl)-2-ethylpyrimidin-4-yl)-3-((lS,4R)-4-((3-(( S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

l-(6-(tert-Butyl)-2-isopropylpyrimidin-4-yl)-3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(6-(tert-Butyl)-2-(methoxymethyl)pyrimidin-4-yl)-3-((lS,4R )-4-((3-((S)-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(4-(tert-butyl)pyridin-2-yl)-3-((lS,4R)-4-((3-((S)-l,2-dim ethylpyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)urea;

l-(6-(tert-butyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-2-met hylpiperidin-l-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)urea;

l-(6-(tert-butyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-l-met hylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridine-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalene- 1 -yl)urea hydrochloride;

l-(6-(tert-butyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-l-iso propylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridine-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalene- 1 -yl)urea hydrochloride;

l-(6-(tert-butyl)-2-(methylthio)pyrimidin-4-yl)-3-((lS,4R)-4 -((3-((S)-l- [l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l,2,3,4-tetrahydron aphthalen-l-yl)urea;

l-(6-(tert-butyl)-2-(methylthio)pyrimidin-4-yl)-3-((lS,4R)-4 -((3-((S)-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridine-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(2-(tert-Butyl)-5-methylpyridin-4-yl)-3-((lS,4R)-4-((3-((S )-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

l-(2-(tert-Butyl)-6-(hydroxymethyl)pyridin-4-yl)-3-((lS,4R)- 4-((3-((S)-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

1 -(5-(tert-butyl)-2-methoxypyridin-3-yl)-3-((l S,4R)-4-((3-((S)-l ,2- dimethylpyrrolidin-2-yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N- methylpicolinamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(methoxy-2- methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphtlialen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(3-methyloxetan-3- yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahyd ronaphthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-l- methoxyethyl)- [ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalene- 1 - yl)ureido)pyrimidin-2-carboxamide;

l-(2-(tert-butyl)-6-((2-mo holinoethoxy)methyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3- (2-methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)ox y)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-neopentyl- [ 1 ,2,4] triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-hydroxyethyl)-6-(3-((l S,4R)-4-((3-isobutyl-[l ,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

6-(tert-Butyl)-4-(3-((l S,4R)-4-((3-((S)- 1 ,2-dimethylpyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N-(2- hydroxyethyl)picolinamide;

6-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)picolinamide;

l-(6-(tert-Butyl)-2-((2-mo holinoethoxy)methyl)pyrimidin-4-yl)-3-((lS,4R)-4- ((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3 ,4-tetrahydronaphthalen- 1 - yl)urea;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-cyclopentyl-[l,2,4]triazo lo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)pyrimidine-2-carboxamide ;

4-(tert-butyl)-N-(2-hydroxyethyl)-6-(3 -(( 1 S,4R)-4-((3 -isopropyl- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -isopropyl-[ 1 ,2,4]triazolo [4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-morpholinoethyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)ethyl)pyrimidine-2-carboxarnide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-morpholinoethyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-N-(2-morpholinoethyl)-6-(3-((lS,4R)-4-((3-(pe ntan-3-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -isopropyl- [1 ,2,4]triazolo [4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(morpholine-4- carbonyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-te trahydronaphthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-hydroxyethyl)-6-(3-((lS,4R)-4-((3-(penta n-3-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-methoxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3- (pentan-3 -yl)- [ 1 ,2,4] triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-cyclopentyl-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-cyclopentyl-[l,2,4]triazo lo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-morpholinoethyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-cyclopentyl-[l,2,4]triazo lo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- hydroxyethyl)(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -hydroxyazetidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

l-(6-(tert-butyl)-2-(3,3-difluoroazetidine-l-carbonyl)pyrimi din-4-yl)-3-((lS,4R)-4- ((3 -(tert-butyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)urea;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)-N-(3-moφh olinopropyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(l -methylazetidin-3-yl)pyrimidine- 2-carboxamide; 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-hydroxyethyl)-N- methylpyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)-N-((ls,3R) -3- (hydroxymethyl)cyclobutyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(l-methylazetidin-3-yl)-6-(3-((lS,4R)-4-((3 -(pentan-3-yl)- [ 1 ,2 ,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

N-(2-(bis(2-methoxyethyl)amino)ethyl)-4-(tert-butyl)-6-(3-(( l S,4R)-4-((3-(pentan-

3- yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

1 -(2-((bis(2-methoxyethyl)an ino)methyl)-6-(tert-butyl)pyrimidin-4-yl)-3 - ((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -y l)urea;

1 -(2-((bis(2-hydroxyethyl)amino)methyl)-6-(tert-butyl)pyrimid in-4-yl)-3-((l S,4R)-

4- ((3 -(tert-butyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)urea;

l-(6-(tert-butyl)-2-(((2-hydroxyethyl)(methyl)an ino)methyl)pyrimidin-4-yl)-3- ((1 S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

N-(2-(l,4-oxazepan-4-yl)ethyl)-4-(tert-butyl)-6-(3-((lS,4R)- 4-((3-(tert-butyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-isobutyl-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-

1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-mo holinoethyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-isobutyl- [1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

N-(2-(bis(2-methoxyethyl)amino)ethyl)-4-(tert-butyl)-6-(3-(( lS,4R)-4-((3-(tert- butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((R)-3 -hydroxypyrrolidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((S)-3 -hydroxypyrrolidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[l ,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((l S,4R)-4-((3-(2-methoxypropan-

2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tet rahydronaphthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(3-methyloxetan-3-yl)-[l, 2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-morpholinoethyl)-6-(3-((lS,4R)-4-((3-neo pentyl- [1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

- 4-(tert-butyl)-6-(3-((l S,4R)-4-((3-((S)-sec-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l-methoxyethyl)-[l,2 ,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-((S)-sec-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-mo holinoethyl)pyrimidine-2- carboxamide;

N-((4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]t riazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)pyrimidin-2 -yl)methyl)-3- moφholinopropanamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -methoxyazetidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)- 1,2,3 ,4-tetrahydronaphthalen- l-yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-methoxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3- ((S)- 1 -methoxyethyl)- [ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(methyl(oxetan-3- yl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(4-hydroxypiperidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methylcyclobutyl)-[l,2 ,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide; (S)-N-((4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2 ,4]triazolo[4,3-a]pyridin- 6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l -yl)ureido)pyrimidin-2-yl)methyl)-l - methylpyrrolidine-2-carboxamide;

N-(3-(l,4-Oxazepan-4-yl)propyl)-4-(tert-butyl)-6-(3-((lS,4R) -4-((3-(tert-butyl)- [l,2,4]triazolo[4,3-a]pyridm-6-yl)oxy)-l,2,3,4-tetrahydronap hthalen-l- yl)ureido)pyrimidine-2-carboxamide partial formate salt;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-buryl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(l -(dimethylamino)-2- methylpropan-2-yl)pyrimidine-2-carboxamide;

l-(6-(tert-Butyl)-2-((3-oxopiperazin-l-yl)methyl)pyrirnidin- 4-yl)-3-((lS,4R)-4-((3- (tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4 -tetrahydronaphthalen-l-yl)urea partial formate salt;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (ethyl(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)ethyl)-N- methylpyrimidine-2-carboxamide;

1 -(6-(tert-butyl)-2-(4-(2 -hydroxy ethyl)piperazine- 1 -carbonyl)pyrimidin-4-yl)-3 - ((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)-2- methylpropyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(3 - (dimethylamino)propyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -(tert-butyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(4-methylpiperazin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

N-(2-(bis(2-hydroxyethyl)amino)ethyl)-4-(tert-butyl)-6-(3-(( lS,4R)-4-((3-(tert- butyl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N-(3- mo holinopropyl)pyrimidine-2-carboxamide;

N-(2-(l,4-oxazepan-4-yl)ethyl)-4-(tert-butyl)-6-(3-((lS,4R)- 4-((3-(l-methoxy-2- methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)-[ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[l ,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(3 - mo holinopropyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(2- methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

N-((4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]t riazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidin-2-yl)methyl)- 1 - methylazetidine-3-carboxamide;

N-((4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]t riazolo[4,3-a]pyridin^ yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidin-2-yl)methyl)-3 - (dimethylamino)propanamide;

1 -(6-(tert-butyl)-2-(4-methylpiperazine- 1 -carbonyl)pyrimidin-4-yl)-3 -((IS ,4R)-4- ((3-(tert-butyl)-[l,2,4]1xiazolo[4,3-a]pyridin-6-yl)oxy)-l,2 ,3,4-tetrahydronaphthalen-l- yl)urea

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-((R)- 1 -methylpyrrolidin-3 - yl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(2- (dimethylamino)ethoxy)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-morpholinoethyl)-6-(3 -(( 1 S,4R)-4-((3 -(tert-pentyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(3-mo holinopropyl)-6-(3-((lS,4R)-4-((3-(tert-pentyl)- [1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

1 -(6-(tert-butyl)-2-(4-methyl- 1 ,4-diazepane- 1 -carbonyl)pyrimidin-4-yl)-3 - ((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-6-(3-(( 1 S,4R)-4-((3 -(tert-butyl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-( 1 -methylpiperidin-4-yl)pyrimidine- 2-carboxamide;

l-(6-(tert-Butyl)-2-((4-methyl-2-oxopiperazin-l-yl)methyl)py rimidin-4-yl)-3- ((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea formate salt;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-((S)- 1 -methylpyrrolidin-3 - yl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-methoxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(l- methylcyclopropyl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide; 4-(tert-butyl)-N-(2-(3-methoxyazetidin-l-yl)ethyl)-6-(3-((lS ,4R)-4-((3-(l- methylcyclopropyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetra ydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-hydroxyethyl)-6-(3-((lS,4R)-4-((3-(2-(4- methylpiperazin-l- yl)propan-2-yl)-[ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

N-(2-(azetidin-l-yl)ethyl)-4-(tert-butyl)-6-(3-((lS,4R)-4-(( 3-(tert-butyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)-2-methylpropyl)-6-(3-((l S,4R)-4-((3-(2- methoxypropan-2-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)-2- methylpropyl)pyrimidine-2-carboxamide;

l-(6-(tert-butyl)-2-((2-morpholinoethoxy)methyl)pyrimidin-4- yl)-3-((lS,4R)-4-((3- (2-methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)ox y)-l,2,3,4- tetrahydronaphthalen- 1 -yl)urea;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(l- methylcyclopropyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-((S)-sec-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (ethyl(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)-2-ethylbutyl)-6-(3-((lS, 4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(ethyl(methyl)amino)-2- methylpropyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-((l-(dimethylamino)cyclopropyl)methyl)-6-(3 -((lS,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl )methyl)-6-(3- ((1 S,4R)-4-((3 -( 1 -methoxy-2-methylpropan-2-yl)- [ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-methyl-2-(4-methylpiperazin- 1 - yl)propyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(ethyl(methyl)amino)-2-methylpropyl)-6-( 3-((l S,4R)-4-((3-(l - methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l, 2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-((l -(dimethylamino)cyclohexyl)methyl)-6-(3-((l S,4R)-4-((3-(l - methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l, 2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-((l -(dimethylamino)cyclopentyl)methyl)-6-(3-((l S,4R)-4-((3-(l - methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yl)- [1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l -yl)ureido)-N-(2- methyl-2-(4-methylpiperazin-l-yl)propyl)pyrimidine-2-carboxa mide;

4-(tert-butyl)-N-(2-(ethyl(methyl)amino)-2-methylpropyl)-6-( 3-((lS,4R)-4-((3-(2- methoxypropan-2-yl)-[ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetra ydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[l ,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-methyl-2-(4- methylpiperazin- 1 -yl)propyl)pyrimidine-2-carboxamide;

4-(tert-Butyl)-N-((l-(dimethylamino)cyclobutyl)methyl)-6-(3- ((lS,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l,2,3,4- tetrahydronaphthalen-1 -yl)ureido)pyrimidine-2-carboxamide formate salt;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-((l - (dimethylamino)cyclopropyl)methyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-((4-(dimethylamino)tetrahydro-2H- pyran-4-yl)methyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(( 1 -

(dirnethylamino)cyclohexyl)methyl)pyrimidine-2-carboxamid e;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l -yl)ureido)-N-((l - (dimethylamino)cyclobutyl)methyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(( 1 - (dimethylamino)cyclopentyl)methyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (cyclopropyl(methyl)amino)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-((l S,2S)-2- (dimethylarnino)cyclohexyl)pyrimidine-2-carboxamide; 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N-(2- (3 -methoxyazetidin- 1 -yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(3-methoxyazetidin-l -yl)ethyl)-6-(3-((l S,4R)-4-((3-(2- methoxypropan-2-yl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)-2- ethylbutyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-((S)-sec-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -methoxyazetidin- 1 - yl)ethyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -methoxyazetidin- 1 -yl)-2- methylpropyl)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -( 1 -methoxy-2-methylpropan-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (3-methoxyazetidin-l-yl)-2-methylpropyl)pyrimidine-2-carboxa mide;

4-(tert-butyl)-N-(2-(3-methoxyazetidin-l-yl)-2-methylpropyl) -6-(3-((lS,4R)-4-((3- (2-methoxypropan-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-methyl-2-(4-methylpiperazin-l-yl)propyl) -6-(3-((lS,4R)-4-((3- (pentan-3 -yl)-[ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide formate salt;

4-(tert-butyl)-N-(2-(3-methoxyazetidin-l-yl)-2-methylpropyl) -6-(3-((lS,4R)-4-((3- (pentan-3-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide formate salt;

4-(tert-butyl)-N-(2-(dimethylamino)-2-methylpropyl)-6-(3-((l S,4R)-4-((3-(pentan- 3 -yl)-[ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide formate salt;

4-(tert-butyl)-N-(2-(ethyl(methyl)amino)-2-methylpropyl)-6-( 3-((lS,4R)-4-((3- (pentan-3-yl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)-2-methylpropyl)pyrirnidine-2-car boxamide;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -( 1 -methoxy-2-methylpropan-2-yl)- [1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- ((2-methoxyethyl)(methyl)amino)-2-methylpropyl)pyrimidine-2- carboxamide;

4-(tert-butyl)-N-(2-((2-methoxyethyl)(methyl)amino)-2-methyl propyl)-6-(3- ((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a] pyridin-6-yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((l S,4R)-4-((3-(2-ethoxypropan-2- yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)pyrimidine-2-carboxamide formate salt;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(l- methylcyclopentyl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

N-(2-(l ,4-oxazepan-4-yl)ethyl)-4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(l - methylcyclopentyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-(dimethylamino)-2-methylpropyl)-6-(3-((l S,4R)-4-((3-(l- methylcyclopentyl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- l-yl)ureido)pyrimidine-2-carboxamide;

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(l-methylcyclopentyl)-[l, 2,4]triazolo[4,3- a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(3 - morpholinopropyl)pyrimidine-2-carboxamide formate salt;

6-(tert-butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-(2-methoxypropan- 2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrah ydronaphthalen-l- yl)ureido)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l-yl)ureido)-N-(3-mo^holinopropy l)picolinarnide;

6-(tert-butyl)-4-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- hydroxyethyl)(methyl)amino)ethyl)picolinamide;

N-(2-(l,4-oxazepan-4-yl)ethyl)-6-(tert-butyl)-4-(3-((lS,4R)- 4-((3-(tert-butyl)- [1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l - yl)ureido)picolinamide;

6-(tert-butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-(l-methoxy-2- methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen- 1 -yl)ureido)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (ethyl(methyl)amino)ethyl)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l -yl)ureido)-N-(2-((2- methoxyethyl)(methyl)amino)ethyl)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -methoxyazetidin- 1 - yl)ethyl)picolinamide

6-(tert-butyl)-N-(2-(dimethylarnino)-2-methylpropyl)-4-(3-(( lS,4R)-4-((3-(2- methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((S)-3 -hydroxypyrrolidin- 1 - yl)ethyl)picolinamide;

6-(tert-butyl)-N-(2-(dimethylamino)-2-methylpropyl)-4-(3-((l S,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l, 2,3,4- tetrahydronaphthalen- 1 -yl)ureido)picolinamide;

6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3-hydroxyazetidin- 1 - yl)ethyl)picolinamide;

l-(2-(tert-butyl)-6-(hydroxymethyl)pyridin-4-yl)-3-((lS,4R)- 4-((3-(2-(4- methylpiperazin- 1 -yl)propan-2-yl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)urea;

6-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((l S,4R)-4-((3-(2-(4- methylpiperazin-l-yl)propan-2-yl)-[l,2,4]triazolo[4,3-a]pyri din-6-yl)oxy)-l, 2,3,4- tetrahydronaphthalen-l-yl)ureido)picolinamide formate salt;

6-(tert-Butyl)-N-(2-hydroxyethyl)-4-(3-((lS,4R)-4-((3-(2-(4- methylpiperazin-l- yl)propan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2, 3,4-tetrahydronaphthalen-l- yl)ureido)picolinamide formate salt;

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide formate salt;

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(dimethylamino)-2- methylpropyl)picolinamide formate salt;

6-(tert-butyl)-4-(3 -(( 1 S,4R)-4-((3 -(tert-butyl)-[ 1 ,2,4]triazolo [4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(4-methoxypiperidin- 1 - yl)ethyl)picolinamide;

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3-a]pyridin-6- yl)oxy)-l ,2,3,4-tetra ydronaphthalen-l-yl)ureido)-N-(2-(dimethylamino)-2- methylpropyl)picolinamide formate salt;

6-(tert-Butyl)-4-(3 -(( 1 S,4R)-4-((3 -(diethylamino)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2- (ethyl(methyl)amino)ethyl)picolinamide formate salt;

6-(tert-butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-(tert-pentyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona plitlialen-l- yl)ureido)picolinamide;

6-(tert-butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-(pentan-3-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)ureido)picolinamide;

4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-((2- hydroxyethyl)(methyl)amino)ethyl)picolinamide formate salt;

N-(2-(l,4-oxazepan-4-yl)ethyl)-4-(tert-butyl)-6-(3-((lS,4R)- 4-((3-(tert-butyl)- [1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l - yl)ureido)picolinamide formate salt;

4-(tert-butyl)-6-(3-((l S,4R)-4-((3-(tert-butyl)-[l ,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(2-(3 -methoxyazetidin- 1 - yl)ethyl)picolinamide formate salt;

4-(tert-butyl)-6-(3 -(( 1 S,4R)-4-((3 -(tert-butyl)-[ 1 ,2,4]triazolo[4,3 -a]pyridin-6- yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)-N-(-(2-(4-hydroxypiperidin- 1 - yl)ethyl)picolinamide formate salt;

N-(6-(tert-butyl)-4-(3-((l S,4R)-4-((3-((S)-l,2-dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)ureido)pyridin- 2-yl)methanesulfonamide; N-(6-(tert-butyl)-4-(3-((l S,4R)-4-((3-((S)-l,2-dimethylpyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)ureido)pyridin- 2-yl)ethanesulfonamide;

4-(tert-butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((R)-4- methylmorpholin-3 -yl)-[ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yl)oxy)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide;

4-(tert-butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3- ((R)-4-methylmo holin-3-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4- tetrahydronaphthalen- 1 -yl)ureido)pyrimidine-2-carboxamide

and pharmaceutically acceptable salts thereof.

Chemical Names of the compounds were generated with Chem Draw version 15.1 using the embedded Name to Structure tool, Copyright of Perkin Elmer Informatics, Inc.

As mentioned above the compounds of the invention are p38MAPK inhibitors, and thus may have utility for the treatment of diseases or conditions which benefit from inhibition of the p38 enzyme. Such diseases and conditions are known from the literature and several have been mentioned above. However, the compounds are generally of use as anti-inflammatory agents, particularly for use in the treatment of respiratory disease. In particular, the compounds may be used in the treatment of chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, or smoking-induced emphysema, intrinsic (non-allergic asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, steroid resistant asthma, neutrophilic asthma, bronchitic asthma, exercise induced asthma, occupational asthma and asthma induced following bacterial infection, cystic fibrosis, pulmonary fibrosis and bronchiectasis.

The invention provides the use of the compounds of formula (I) for the prevention and/or treatment of any disease or condition which benefit from inhibition of the p38 enzyme.

In a further aspect, the invention provides the use of compounds (I) for the preparation of a medicament for the prevention and/or treatment of any disease or condition which benefit from inhibition of the p38 enzyme.

Moreover the invention provides a method for prevention and/or treatment of any disease which benefit from inhibition of the p38 enzyme, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I)

The compounds of the invention are p38 kinase inhibitors, and are useful in the treatment of several diseases for example inflammatory diseases of the respiratory tract. Examples of such diseases are referred to above, and include asthma, rhinitis, allergic airway syndrome, bronchitis and chronic obstructive pulmonary disease.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art. The daily dose range for oral administration will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, in single or divided doses. The daily dose range for inhaled administration will lie within the range of from about 0.1 μg to about lmg per kg body weight of a human, preferably 0.1 μg to 50 μg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. For the purpose of the invention, inhaled administration is preferred.

The compounds of the invention may be prepared for administration by any route consistent with their pharmacokinetic properties. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl -hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

However, for the treatment of an inflammatory disease of the respiratory tract, the compounds of the invention may also be formulated for inhalation, for example as a nasal spray, or dry powder or aerosol inhalers. For delivery by inhalation, the active compound is preferably in the form of microparticles whichmay be prepared by a variety of techniques, including spray-drying, freeze-drying and micronization. Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.

By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellants suitable for use in a PMDI are known, and include CFC-12, HFA-134a, HFA-227, HCFC-22 and HFA-152. In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).

Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μπι.

In the case of an aerosol-based formulation, an example is:

Compound of the invention 24 mg / canister

Lecithin, NF Liq. Cone. 1.2 mg / canister

Trichlorofluoromethane, NF 4.025 g / canister

Dichlorodifluoromethane, NF 12.15 g / canister.

The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Additionally, the compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.

Other compounds may be combined with compounds of the invention for the prevention and treatment of inflammatory diseases, in particular respiratory diseases. The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and one or more other therapeutic agents. Examples of suitable therapeutic agents for a combination therapy with the compounds of the invention include: (1) corticosteroids, such as fluticasone propionate, fluticasone furoate, mometasone furoate, beclometasone dipropionate, ciclesonide, budesonide, GSK 685698, GSK 870086, QAE 397, QMF 149, TPI-1020; (2) p2-adrenoreceptor agonists such as salbutamol, albuterol, terbutaline, fenoterol, and long acting 2-adrenoreceptor agonists such as salmeterol, indacaterol, formoterol (including formoterol fumarate), arformoterol, carmoterol, GSK 642444, GSK 159797, GSK 159802, GSK 597501, GSK 678007, AZD3199; (3) corticosteroid/long acting β2 agonist combination products such as salmeterol/ fluticasone propionate (Advair/Seretide), formoterol/budesonide (Symbicort), formoterol/fluticasone propionate (Flutiform), formoterol/ciclesonide, formoterol/mometasone furoate, formoterol/ beclometasone dipropionate, indacaterol/mometasone furoate, Indacaterol/QAE 397, GSK 159797/GSK 685698, GSK 159802/GSK 685698, GSK 642444/GSK 685698, GSK 159797/GSK 870086, GSK 159802/GSK 870086, GSK 642444/GSK 870086, arformoterol/ciclesonide;(4) anticholinergic agents, for example muscarinic-3 (M3) receptor antagonists such as ipratropium bromide, tiotropium bromide, Aclidinium (LAS-34273), NVA-237, GSK 233705, Darotropium, GSK 573719, GSK 961081, QAT 370, QAX 028, EP-101; (5) dual pharmacology M3-anticholinergic/ 2-adrenoreceptor agonists such as GSK961081, AZD2115 and LAS 190792; (6) leukotriene modulators, for example leukotriene antagonists such as montelukast, zafirlukast or pranlukast or leukotriene biosynthesis inhibitors such as Zileuton or BAY- 1005, or LTB4 antagonists such as Amelubant, or FLAP inhibitors such as GSK 2190914, AM- 103; (7) phosphodiesterase-IV (PDE-IV) inhibitors (oral or inhaled), such as roflumilast, cilomilast, Oglemilast, ONO-6126, Tetomilast, Tofimilast, UK 500,001, GSK 256066; (8) antihistamines, for example selective histamine- 1 (HI) receptor antagonists, such as fexofenadine, citirizine, loratidine or astemizole or dual H1 H3 receptor antagonists such as GSK 835726, GSK 1004723, or selective histamine-4 (H4) receptor antagonists, such as ZPL3893787; (9) antitussive agents, such as codeine or dextramorphan; (10) a mucolytic, for example N acetyl cysteine or fudostein; (11) a expectorant/mucokinetic modulator, for example ambroxol, hypertonic solutions (e.g. saline or mannitol) or surfactant; (12) a peptide mucolytic, for example recombinant human deoxyribonuclease I (dornase-alfa and rhDNase) or helicidin; (13) antibiotics, for example azithromycin, tobramycin and aztreonam; (14) non-selective COX- 1 / COX-2 inhibitors, such as ibuprofen or ketoprofen; (15) COX-2 inhibitors, such as celecoxib and rofecoxib; (16) VLA-4 antagonists, such as those described in WO97/03094 and WO97/02289; (17) TACE inhibitors and TNF-a inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; (18) inhibitors of matrix metalloprotease, for example MMP-12; (19) human neutrophil elastase inhibitors, such as ONO-6818 or those described in WO2005/026124, WO2003/053930 and WO06/082412; (20) A2b antagonists such as those described in WO2002/42298; (21) modulators of chemokine receptor function, for example antagonists of CCR3 and CCR8; (22) compounds which modulate the action of other prostanoid receptors, for example a thromboxane A ₂ antagonist; DPI antagonists such as MK-0524, CRTH2 antagonists such as ODC9101 and OC000459 and AZD1981 and mixed DP1/CRTH2 antagonists such as AMG 009 and AMG853; (23) PPAR agonists including PPAR alpha agonists (such as fenofibrate), PPAR delta agonists, PPAR gamma agonists such as Pioglitazone, Rosiglitazone and Balaglitazone; (24) methylxanthines such as theophylline or aminophylline and methylxanthine/corticosteroid combinations such as theophylline/budesonide, theophylline/fluticasone propionate, theophylline/ciclesonide, theophylline/mometasone furoate and theophylline/beclometasone dipropionate; (25) A2a agonists such as those described in EP1052264 and EP1241176; (26) CXCR2 or IL-8 antagonists such as SCH 527123 or GSK 656933; (27) IL-R signalling modulators such as kineret and ACZ 885; (28) MCP-1 antagonists such as ABN-912.

The invention is also directed to a kit comprising the pharmaceutical compositions of compounds of formula (I) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.

The invention also provides a process for the preparation of compounds offormula (I) . In the following reaction schemes, unless otherwise indicated, the groups mentioned assume the same meaning as those reported for compounds of formula (I). The skilled person may introduce, where appropriate, suitable variations to the conditions specifically described in the experimentals in order to adapt the synthetic routes to the provision of further compounds of the invention. Such variations may include use of appropriate starting materials to generate different compounds, changes in the solvent and temperature of reactions, replacements of reactives with analogous chemical role, introduction or removal of protection/deprotection stages of functional groups sensitive to reaction conditions and reagents, as well as introduction or removal of specific synthetic steps oriented to further functionalisation of the chemical scaffold. The process described is particularly advantageous as it is susceptible of being properly modulated, through any proper variant known to the skilled person, so as to obtain any of the desired compounds of the invention.

From all of the above, it should be clear to the skilled person that any of the described groups may be present as such or in any properly protected form.

In particular, functional groups present in the intermediate and compounds and which could generate unwanted side reaction and by-products, need to be properly protected before the alkylation, acylation, coupling or sulfonylation takes place. Likewise, subsequent deprotection of those same protected groups may follow upon completion of the said reactions.

In the present invention, unless otherwise indicated, the term "protecting group" designates a protective group adapted to preserve the function of the group it is bound to. Typically, protective groups are used to preserve amino, hydroxyl, or carboxyl functions. Appropriate protecting groups may thus include, for example, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like, which are well known [see, for a reference, T.W. Green; Protective Groups in Organic Synthesis (Wiley, N.Y. 1981)].

Likewise, selective protection and deprotection of any of the said groups, for instance including carbonyl, hydroxyl or amino groups, may be accomplished according to well known methods.

Optional salification of the compounds of formula (I) may be carried out by properly converting any of the free acidic or amino groups into the corresponding pharmaceutically acceptable salts. In this case too, the operative conditions being employed for the optional salification of the compounds of the invention are all within the ordinary knowledge of the skilled person.

From all of the above, it should be clear that the above process, comprehensive of any variant thereof for the preparation of suitable compounds of the invention, may be conveniently modified so that to adapt the reaction conditions to the specific needs, for instance by choosing appropriate condensing agents, solvents and protective groups, as the case may be.

For example, compounds of the invention of formula (la) may be prepared according to Scheme 1 :

Scheme 1

(1a) (la) wherein E is a suitable group that can facilitate a transformation to give compounds (la): for example E may include esters or a hydroxymethyl group. Compounds (la) may be prepared by derivatisation of compounds (la) by known reactions. For example, compounds (la) may be prepared from compounds (la) by reaction with an appropriate amine or amide in a solvent such as methanol or ethanol at a range of temperatures, preferably between RT and 90 °C.

Compounds (la) may be prepared according to Scheme 2: Scheme 2

(2a) (2b) (1 a)

Compounds (la) may be prepared from compounds (2b) by reaction with a compound (2a) wherein X is a suitable known chemical group selected such that it can facilitate a suitable coupling reaction such as metal catalysed cross coupling: for example, X may include halogen or a suitable leaving group such as mesylate or triflate. Examples of the coupling conditions used may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110 °C.

Alternatively, compounds (la) may be prepared according to Scheme 3:

Scheme 3

(4a) (2b) (la)

Compounds (la) may be prepared from compounds (2b) by reaction with a compound (4a) wherein X is a suitable chemical group selected such that it can facilitate a suitable coupling reaction such as metal catalysed cross coupling: for example X may include halogen or a suitable leaving group such as mesylate or triflate. Examples of the coupling conditions used may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1 ,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110 °C. Compounds (2a) and (4a) are known or may be prepared according to Scheme 4: Scheme 4

(3c) (3b) (3a) (2a) (4a)

Compounds (4a) may be prepared from compounds (2a) using a reducing agent such as sodium borohydride in a solvent such as EtOH at a range of temperatures preferably between 0 °C to room temperature. Compounds (2a) may be prepared from compounds (3 a) by reaction with neat POCl ₃ or SOCl ₂ or in a solvent such as DMF, toluene or acetonitrile in a range of temperatures, preferably between RT and 100 °C. Compounds (3 a) may be prepared from compounds (3 b) by hydrogenation in the presence of hydrogen gas in the presence of a suitable catalyst such as palladium on carbon or platinum on carbon in a solvent such as ethanol or methanol at a range of temperatures, preferably between RT and 60°C. Compounds (3b) may be synthesised from the commercially available compound (3 c) by reaction with the relevant acid chloride in a solvent such as pyridine, DCM, toluene, acetonitrile or 2-methyltetrahydrofuran in the presence of a base such as pyridine, TEA or potassium carbonate, at a range of temperatures, preferably between 0 °C and RT.

Compounds (4a) may be also prepared according to Scheme 5:

Scheme 5

(5c) (5b) (5a) (4a) Compounds (4a) may be prepared from compounds (5a) by reaction with neat

POCb or SOCl ₂ or in a solvent such as DMF, toluene or acetonitrile at a range of temperatures, preferably between RT and 100 °C. Compounds (5a) may be prepared from compounds (5c) by condensation with compounds (5b) in the presence of a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium carbonate in a solvent such as methanol, ethanol or H ₂ 0 at a range of temperatures, preferably between

RT and 90 °C.

Alternatively, compounds (la) may be prepared according to Scheme 6:

Scheme 6

Compounds (la) may be prepared from compounds (6b) by reaction with a compound (6al) wherein Ar is a suitable aryl group such as phenyl or 4-nitrophenyl in a solvent such as EtOAc, DCM, 1,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the presence of a base such as diisopropylethylamine, sodium bicarbonate or sodium hydroxide at a range of temperatures, preferably between RT and 100 °C. Alternatively, compounds (la) may be prepared from compounds (6b) by reaction with a compound (6a2) in a solvent such as dimethyl sulfoxide, 1,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the presence of a base such as diisopropylethylamine or TEA at a range of temperatures, preferably between RT and 100 °C.

Compounds (6al) are either known in the literature or may be prepared from amines (6c) according to known procedures (e.g. US 2011/0311474, J Med. Chem., 2012, 55,

Compounds (6a2) are known or may be prepared according to Scheme 7: Scheme 7

Compounds (6a2) may be prepared from compounds (6c) by reaction with 2,2,2- trichloroethyl chloroformate in a solvent such as DCM, THF, 2-methyltetrahydrofuran or acetonitrile at a range of temperatures, preferably between RT and 100°C. Microwave conditions may also be applied to increase temperatures, preferably between RT and 150°C.

Compounds (6c) are known or may be prepared from compounds (4a) by reaction with ammonia hydroxide solution or a solution of NH ₃ in MeOH or 1 ,4-dioxane, in a solvent such as IP A, MeOH or 1,4-dioxane. Microwave conditions may also be applied to increase temperatures, preferably between RT and 180°C.

Compounds (2b) may be prepared according to Scheme 8:

Scheme 8

Compounds (2b) may be prepared from compounds (6b) by reaction with phosgene or triphosgene in a solvent such as DCM or THF in the presence of a base such as TEA or DIPEA at a range of temperatures, preferably between 0°C and RT, followed by adding the mixture to a solution of ammonia in a solvent such as methanol or water. Alternatively, compounds (2b) may be prepared from compounds (6b) by reaction with (trimethylsilyl)isocyanate in a solvent such as DCM or THF or in a mixture of solvents, such as DCM/MeOH.

Compounds (6b) may be prepared according to Scheme 9. Scheme 9

Compounds (6b) may be prepared from compounds (9b) by reaction with compound (9a), wherein G is a group that can facilitate a coupling reaction such as nucleophilic displacement or metal catalysed cross coupling: for example G may include halogen such as a fluorine. Examples of the coupling conditions may include using a base such as sodium hydride or potassium tert-butoxide and 18-crown-6 in a solvent such as N,N-dimethylformamide or 2-methyl-THF at a range of temperatures, preferably between RT and 150°C.

Compounds (9b) may be prepared according to Scheme 10:

Scheme 10

O

I A R ₂ ^(10b1)

Compounds (9b) may be prepared from compounds (lOe) as above reported using a suitable oxidant such as chloramine T, lead tetracetate or phenyl iodine(III) diacetate, in a solvent such as dichloromethane or ethanol at a range of temperatures, preferably between RT and 100 °C.

Compounds (lOe) may be prepared from compounds (10a) by reaction with an aldehyde (10c) in a solvent such as ethanol or tetrahydrofuran at a range of temperatures, preferably between RT and 80 °C. Compounds (10a) and (10c) are commercially available, known or may be prepared by known methods.

Alternatively, compounds (9b) may be prepared from compounds (lOd) using a suitable dehydrating agent such as Burgess' reagent, triphenyl phosphine and hexachloroethane, phosphorus oxychloride, acetic acid or Mitsunobu conditions (diethylazodicarboxylate/triphenylphosphine/trimethylsilylaz ide), in the absence or presence of a suitable solvent such as tetrahydrofuran, toluene or NMP, at a range of temperatures, preferably between RT and 120 °C.

Compounds (lOd) may be prepared from compounds (10a) by reaction with a compound (lObl) using a suitable acylating/dehydrating agent such as triphenylphosphine/trichloroacetonitrile/HOBt/2-(7-aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 - tetramethyluronium hexafluorophosphate or l-ethyl-3-(3-dimethylaminopropyl)- carbodiimide in the presence of a base such as diisopropylethylamine, in a solvent such as dichloromethane or acetonitrile, at a range of temperatures, preferably between RT and 150 °C.

Alternatively, compounds (lOd) may be prepared from compounds (10a) by reaction with a compound (10b2) in the presence of a base such as diisopropylethylamine, in a solvent such as dichloromethane or THF at a range of temperatures preferably between -10 °C and the boiling point of the solvent.

Compounds of formulae (lObl) and (10b2) are commercially available, known or may be prepared by adapting appropriate methods.

Compound (9a) is disclosed in WO2014/195402.

Compounds (lb) may be prepared according to Scheme 11 :

Scheme 11

(1 1a) (lb) wherein E is a suitable group that can facilitate a transformation to give compounds (lb): for example E may include esters or a hydroxymethyl group. Compounds (lb) may be prepared by derivatisation of compounds (11a) by known reactions. For example, compounds (lb) may be prepared from compounds (11a) by reaction with an appropriate amine or amide in a solvent such as methanol or ethanol at a range of temperatures, preferably between RT and 90 °C.

Compounds (1 la) may be prepared according to Scheme 12:

Scheme 12

(12a) (2b) (11a)

Compounds (11a) may be prepared from compounds (2b) by reaction with a compound (12a) wherein X is a suitable chemical group that can facilitate a coupling reaction such as metal catalysed cross coupling: for example X may include halogen or a suitable leaving group such as mesylate or inflate. Examples of the coupling conditions may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110 °C.

Alternatively, compounds (lb) may be prepared according to Scheme 13:

Scheme 13

(14a) (2b) (lb)

Compounds (lb) may be prepared from compounds (2b) by reaction with a compound (14a) wherein X is a known suitable group selected such that it can facilitate a suitable coupling reaction such as metal catalysed cross coupling: for example, X may include halogen or a suitable leaving group such as mesylate or trifiate. Examples of the coupling conditions used may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110 °C.

Compounds (12a) and (14a) may be prepared according to Scheme 14:

Scheme 14

(14b) (14a)

Compounds (14a) can be prepared from compounds (14b) using an alcohol such as

4-(2-hydroxyehtyl)morpholine with a base such as sodium hydride in a solvent such as THF preferably between RT and 130°C. Compounds (14b) can be prepared from compounds (14c) using a suitable activating reagent such methylsulfonic anhydride with a suitable base such as trimethylamine in a solvent such as DCM preferably between -10°C and RT. Compounds (14c) and be prepared from compounds (12a) when E is a known suitable group, for example ester by reduction using a suitable reducing agent such as sodium borohydride in a solvent such as a mixture of THF/EtOH, preferably between 0°C and RT. Compounds (12a) may be prepared from compounds (13a) by reaction with aqueous H ₂ S0 ₄ or aqueous HC1 in a solvent such as methanol or ethanol a range of temperatures, preferably between RT and 130 °C. Compounds (13a) may be prepared from compounds (13b) by reaction with trimethylsilyl cyanide or zinc cyanide according to known procedures (e.g. J Med. Chem., 2013, 56, 9874-9896, WO 2013/102145, WO 2013/026866). Compounds (13b) may be synthesised from the commercially available compounds (13c) by oxidation of the pyridine with a suitable oxidant, such as m-CPBA, oxone or dimethyldioxirane in a solvent such as DCM, acetone or cyclohexanone at a range of temperatures, preferably between 0°C and RT.

Compounds (14a) may be also prepared according to Scheme 15:

Scheme 15

(15b) (15a) (14a)

Compounds (14a) may be prepared from compounds (15a) by reaction with the relevant Ri compounds, such as methanesulfonamide and ethanesulfonamide and where X is a known suitable chemical group selected such that it can facilitate a suitable metal catalysed cross coupling: for example X may include halogen or a suitable leaving group such as mesylate or triflate. Examples of the coupling conditions used may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110°C. Compounds (15a) may be prepared from compounds (15b) by reaction with neat POCl ₃ or SOCl ₂ in a solvent such as DMF, toluene, N,N-dimethylbenzenamine or DCM at a range of temperatures, preferably between RT and 130°C.

Compounds (Ic) may be prepared according to Scheme 16:

Scheme 16

(16a) (Ic) wherein E is a suitable group that can facilitate a transformation to give compounds (Ic): for example E may include esters or a hydroxymethyl group. Compounds (Ic) may be prepared by derivatisation of compounds (16a) by known reactions. For example, compounds (Ic) may be prepared from compounds (16a) by reaction with an appropriate amine or amide in a solvent such as methanol or ethanol at a range of temperatures, preferably between RT and 90 °C.

Compounds (16a) may be prepared according to Scheme 17:

(17a) (2b) (16a)

Compounds (16a) may be prepared from compounds (2b) by reaction with a compound (17a) wherein X is a group that can facilitate a coupling reaction such as metal catalysed cross coupling: for example X may include halogen or a suitable leaving group such as mesylate or triflate. Examples of the coupling conditions used may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and 110°C.

Alternatively, compounds (Ic) may be prepared according to Scheme 18:

Scheme 18

Compounds (Ic) may be prepared from compounds (2b) by reaction with a compound (17b) wherein X is a suitable chemical group selected such that it can facilitate a suitable known coupling reaction such as metal catalysed cross coupling: for example X may include halogen or a suitable leaving group such as mesylate or triflate. Examples of the coupling conditions may include a catalyst such as palladium acetate or Pd ₂ (dba) ₃ , a ligand such as xantphos or X-phos in a solvent such as 1,4-dioxane, 2-methylTHF, THF or toluene, in the presence of a base such as cesium carbonate, potassium carbonate, potassium tert-butoxide or potassium phosphate at a range of temperatures, preferably between RT and l lO°C.

Compounds (17a) and (17b) are known or may be prepared according to Scheme

19:

Scheme 19

(18c2) (18b2)

Compounds ( 17b) can be prepared from compounds (17a) wherein E is a group that can facilitate a transformation for example E may include esters or a hydroxymethyl group. Compounds (17b) may be prepared by derivatisation of compounds (17a) for example, by reaction with an appropriate amine in a solvent such as methanol or ethanol at a range of temperatures, preferably between RT and 90°C. Compounds (17a) may be prepared from compounds (18a) by reaction with aqueous H ₂ S0 ₄ or aqueous HC1 in a solvent such as methanol or ethanol at a range of temperatures, preferably between RT and 130 C. Compounds (18a) may be prepared from compounds ( 18b 1 ) by reaction with trimethylsilyl cyanide or zinc cyanide according to known procedures (e.g. J. Med. Chem., 2013, 56, 9874-9896, WO 2013/102145, WO 2013/026866). Compounds (18bl) may be synthesised from compounds (18cl) by oxidation of the pyridine with a suitable oxidant, such as m- CPBA, oxone or dimethyldioxirane in a solvent such as DCM, acetone or cyclohexanone at a range of temperatures, preferably between 0°C and RT. Compounds (18cl) may be synthesised from commercially available compounds (18d) by reaction with neat POCl ₃ or SOCl ₂ in a solvent such as DMF, toluene, N,N-dimethylbenzenamine or DCM at a range of temperatures, preferably between RT and 130°C. Alternatively, compounds (18a) may be prepared from compounds (18b2) by reaction with neat POCl ₃ or SOCl ₂ in a solvent such as DMF, toluene, N,N-dimethylbenzenamine or DCM at a range of temperatures, preferably between RT and 130°C. Compounds (18b2) may be synthesised from compounds (18c2) by oxidation of the pyridine with a suitable oxidant, such as m-CPBA, oxone or dimethyldioxirane in a solvent such as DCM, acetone or cyclohexanone at a range of temperatures, preferably between 0°C and RT. Compounds (18c2) may be prepared from compounds (18d) by reaction with trimethylsilyl cyanide or zinc cyanide according to known procedures (e.g. J Med. Chem., 2013, 56, 9874-9896, WO 2013/102145, WO 2013/026866).

Alternatively compounds (Ic) may be prepared according to Scheme 20:

Scheme 20

(19a) (2b) (Ic)

Compounds (Ic) may be prepared from compounds (2b) by reaction with a compound (19a) wherein Ar is a suitable aryl group such as phenyl or 4-nitrophenyl in a solvent such as EtOAc, DCM, 1,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the presence of a base such as diisopropylethylamine, sodium bicarbonate or sodium hydroxide at a range of temperatures, preferably between RT and 100 °C.

Compounds (19a) may be prepared from amines (19b) according to known procedures

(e.g. Tetrahedron Letters, 2014, 55, 1540-1543, WO 2006/074025, WO 2014/186313).

Compounds (Id) may be prepared according to Scheme 21 :

Scheme 21

(20a2)

Compounds (Id) may be prepared from compounds (2b) by reaction with a compound (20al) wherein Ar is a suitable aryl group such as phenyl or 4-nitrophenyl in a solvent such as EtOAc, DCM, 1 ,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the presence of a base such as diisopropylethylamine, sodium bicarbonate or sodium hydroxide at a range of temperatures, preferably between RT and 100°C. Alternatively, compounds (Id) may be prepared from compounds (2b) by reaction with a compound (20a2) in a solvent such as dimethyl sulfoxide, 1,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the presence of a base such as diisopropylethylamine or TEA at a range of temperatures, preferably between RT and 100°C.

Compounds (20al) and (20a2) may be prepared from amines (20b) according to known procedures (e.g. WO 2009/1 00652).

All the other specific syntheses are described in the experimental session.

Experimental details

Abbreviations used in the experimental section: aq. = aqueous; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMF = N,N-dimethylformarnide; DMSO = dimethyl sulfoxide; EDC = l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride; EtOAc = ethyl acetate; EtOH = ethanol; Et ₂ 0 = diethyl ether; FCC = flash column chromatography; h = hour; H ₂ 0 = water; HOBt = 1-hydroxy-benzotriazole; HPLC = high performance liquid chromatography; IMS = industrial methylated spirit; LCMS = liquid chromatography mass spectrometry; mCPBA = meta-Chloroperbenzoic acid; MDAP = mass-directed auto-purification; MeCN = acetonitrile; MeOH = methanol; min = minutes; NaOH = sodium hydroxide; NH ₃ = ammonia; NMR = nuclear magnetic resonance; PPh ₃ = triphenylphosphine; RT = room temperature; Rt = retention time; sat. = saturated; SCX-2 = strong cation exchange chromatography; SFC = supercritical fluid chromatography; TEA = trimethylamine; TFA = trifluoroacetic acid; THF = Tetrahydrofuran.

In the procedures that follow, after each starting material, reference to an Intermediate/Example number is usually provided. The starting material may not necessarily have been prepared from the batch referred to.

When reference is made to the use of a "similar" or "analogous" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

Stereochemical assignments of compounds are based on comparisons with data reported in WO2008/043019 for key intermediates. All reactions were carried out under anhydrous conditions and an atmosphere of nitrogen or argon unless specified otherwise.

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300 MHz. Shifts are given in ppm relative to tetramethylsilane (δ = 0 ppm). J values are given in Hz through-out. NMR spectra were assigned using DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version 3. Where products were purified by flash column chromatography (FCC), 'flash silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution or use of the CombiFlash® Companion purification system or use of the Biotage SP1 purification system. All solvents and commercial reagents were used as received.

Compounds purified by preparative HPLC were purified using a CI 8-reverse-phase column (100 ^χ 22.5 mm i.d. Genesis column with 7 μπι particle size), or a Phenyl-Hexyl column (250 x 21.2 mm i.d. Gemini column with 5 μηι particle size), UV detection between 220 - 254 nm, flow 5-20 mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile (containing 0.1% TFA or 0.1% formic acid) or a CI 8-reverse-phase column (19 x 250 mm, XBridge OBD, with 5 μιτι particle size), eluting with gradients from 100-0 to 0-100% water/acetonitrile (containing 0.1% NH ₄ OH); or a ChiralPak IC column (10 x 250 mm i.d., with 5 μπι particle size), unless otherwise indicated. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic solvent removed by evaporation, and the remaining aqueous residue lyophilised, to give the final product. Products purified by preparative HPLC were isolated as free base, formate or TFA salts, unless otherwise stated.

The Liquid Chromatography Mass Spectroscopy (LCMS) systems used are:

Method 1

Waters ZMD quadrupole mass spectrometer with a CI 8-reverse-phase column

(30 x 4.6 mm Phenomenex Luna 3 μηι particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5 Detection - MS, ELS, UV (200 μΐ split to MS with in-line HP1100 DAD detector). MS ionization method - Electrospray (positive and negative ion).

Method 2

Acquity i-Class (quaternary pump/PDA detector) + Quattro Micro Mass Spectrometer with an ACQUITY UPLC BEH C ₁₈ 1.7 μηι, 100 ^χ 2.1 mm, maintained at 40°C. Elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 0.4 95 5

0.40 0.4 95 5

6.00 0.4 5 95

6.80 0.4 5 95

7.00 0.4 95 5

8.00 0.4 95 5

Detection - MS, UV PDA. MS ionization method - Electrospray (positive and negative ion).

Method 3

Waters micromass ZQ2000 quadrupole mass spectrometer with an Acquity BEH C 18 1.7 um 100 x 2.1 mm, Acquity BEH Shield RP 18 1.7 um 100 x 2.1 mm, Acquity UPLC BEH Phenyl 1.7 μπι, 100 x 2.1mm or Acquity HSST3 1.8 um 100 x 2.1 mm, maintained at 40°C. Elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 0.4 95 5

0.40 0.4 95 5

6.00 0.4 5 95

6.80 0.4 5 95

7.00 0.4 95 5

8.00 0.4 95 5 Detection - MS, UV PDA. MS ionization method - Electrospray (positive and negative ion).

Method 4

Acquity H-Class (quaternary pump/PDA detector) + QDa Mass Spectrometer, Acquity UPLC BEH CI 8 1.7 μ, 50 2.1mm at 50 °C or at 40°C or Acquity UPLC CSH CI 8 1.7 μ, 50 ^χ 2.1mm at 40°C. Elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 1.0 97 3

1.50 1.0 1 99

1.90 1.0 1 99

2.00 1.0 97 3

2.50 1.0 97 3

Detection - MS, UV diode array 190-450nm. MS ionization method - Electrospray (positive and negative ion).

Method 5

Acquity H-Class (quaternary pump/PDA detector) + QDa Mass Spectrometer, Acquity UPLC BEH C18 1.7μ, 50 x 2.1mm at 50 °C or XBridge BEH C18 2.5μ, 50 ^χ 2.1 mm at 40 °C or at 50 °C. Elution with A: water + 0.1% aqueous ammonia; B : acetonitrile + 0.1% aqueous ammonia. Gradient:

Gradient - Time flow mL/min %A %B

0.00 1.0 97 3

1.50 1.0 1 99

1.90 1.0 1 99

2.00 1.0 97 3

2.50 1.0 97 3

Detection - MS, UV diode array 190-450nm. MS ionization method - Electrospray (positive and negative ion). Example 1

4-(tert-Butyl)-6-(3 (lS,4R)-4-((3-(tert-butyI)-[l,2,4]triazolo[4,3-a]pyridin-6-y I)oxy)- l,2 _» 4-tetrahydronaphthalen-l-yI)ureido)-N-(2-(dimethyIamin o)ethyl)-pyrimidine-

2-carboxamide

a. 3-(tert-ButyI)isoxazol-5-amine (Intermediate la)

A solution of sodium hydroxide (250g, 6.25 mol) in water (1250 ml) was added with pivaloylacetonitrile (CAS: 59997-51-2, 250g, 2.0 mol) followed by hydroxylamine hydrochloride (150g, 2.16 mol). The mixture was heated to 60 °C during which time it became homogeneous and then began to deposit a solid. After 3h the mixture was cooled to RT and the solid removed by filtration, washed well with water and dried at 45°C under vacuum to give the title compound (245. lg, 88%). The aqueous filtrate was extracted with DCM (2 x 100 ml) and the combined DCM layers were dried (Na ₂ S0 ₄ ) and evaporated. (10.9& 4%).

¾ NMR (300MHz, CDC1 ₃ ) 1.28 (9H, s), 4.31 (2H, br s), 5.03 (1H, s).

b. Ethyl 2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoacetate (Intermediate lb)

A solution of Intermediate la (125g, 892.9 mmol) and pyridine (77.6g, 79.3 mL, 982.1 mmol) in ethyl acetate (1250 ml) was cooled in ice and treated dropwise, over ca. 30 min with ethyl chlorooxoacetate (134g, 109.7 mL, 982.1 mmol), keeping the internal temperature ca. 15-20°C. The ice bath was removed and stirring continued for lh. The mixture was transferred to a separating funnel and washed with water, 1M HCl solution, brine, dried (Na ₂ S0 ₄ ) and evaporated. The residue was triturated with iso-hexane to afford the title compound (205.7g, 96%).

¾ NMR (300MHz, CDC1 ₃ ) 1.34 (9H, s), 1.44 (3H, t, J - 7.1 Hz), 4.45 (2H, q, J = 7.1 Hz), 6.41 (1H, s), 9.53 (1H, br s).

c. Ethyl 6-(tert-butyl)-4-oxo-l,4-dihydropyrimidine-2-carboxylate (Intermediate

A solution of Intermediate lb (144 g, 600 mmol) and 1 -methyl- 1-cyclohexene (172.8 g, 1.8 mol) in IMS (720 ml) was treated, under an inert atmosphere, with 10% palladium on carbon (14 g, dry weight). The mixture was heated to reflux and stirred for ca. 6 h. The flask was evacuated / purged with nitrogen and the mixture filtered through Celite®. The filtrate was evaporated to afford the title compound (135.3 g, >100%).

H NMR (300MHz, CDC1 ₃ ) 1.29 (9H, s), 1.45 (3H, t, J = 7.1 Hz), 4.49 (2H, q, J = 7.1 Hz), 6.57 (1H, s), 11.23 (1H, br s).

d. Ethyl 4-(tert-butyl)-6-chloropyrimidine-2-carboxyIate (Intermediate Id)

A solution of Intermediate lc (321g, 1.42 mol) in POCl ₃ (350 ml) was heated to 55 °C (block temperature) and stirred for lh. The solution was evaporated and the residue stirred with ice water, adding ice periodically, until any residual POCl ₃ was destroyed. The mixture was carefully basified by adding solid K ₂ C0 ₃ in portions and then DCM was added and the layers were separated and the aqueous phase further extracted with DCM (x2). The combined organic layers were dried (Na ₂ S0 ₄ ) and evaporated. The residue was dissolved in DCM and treated with silica gel and filtered. The filtrate was evaporated to afford the title compound (333g, 96%).

¾ NMR (300MHz, CDC1 ₃ ): 1.39 (9H, s), 1.44 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 7.46 (1H, s).

e. N'-(5-Fluoropyridin-2-yl)pivaIohydrazide (Intermediate le)

A solution of (5-fluoro-pyridin-2-yl) hydrazine (WO2014/195402, 12.7 g, 100 mmol) and DIPEA (19.3 g, 150 mmol) in DCM (150 ml) was cooled in ice and treated dropwise with pivaloyl chloride (14.5 g, 120 mmol) over ca. 15 mins. The mixture was stirred cold for ca. 30 mins. The reaction mixture was evaporated and the residue partitioned between EtO Ac and water. The two phases were separated and the organic layer extracted with an aqueous 1M HCl solution. The HCl layer was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ extracting into EtOAc. The organic layer was dried (Na ₂ S0 ₄ ) and evaporated to give the title compound (15.5 g, 73%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.29 (9H, s), 6.63 (1H, dd, J = 9.0, 3.5 Hz), 6.7 (1H, br d), 7.22-7.35 (1H, m), 7.84 (1H, br d), 8.04 (1H, d, J = 2.9 Hz)

f. 3-(tert-Butyl)-6-fluoro-[l,2,4]triazolo[4,3-a]pyridine (Intermediate If)

A solution of Intermediate le (15.5 g, 73.4 mmol) in 2-methyl THF (300 ml) was treated with triethylamine (29.7 g, 294 mmol), triphenylphosphine (38.5 g, 147 mmol) and finally with hexachloroethane (CAS : 67-72- 1 , 34.8 g, 147 mmol). The reaction mixture was stirred and the internal temperature maintained ca. 30 °C by external cooling. After 1 h the RM was washed with water and then extracted with 1M HCl solution. The HCl layer was washed with Et ₂ 0 and basified with solid K ₂ C0 ₃ extracting into DCM (x3). The combined DCM layers were dried (Na ₂ S0 ₄ ) and evaporated under reduced pressure to give the title compound (12.7 g, 90%). ¾ NMR (300 MHz, CDC1 ₃ ): 1.60 (9H, s), 7.16 (1H, ddd, J = 10, 7.3, 2.2 Hz), 7.77 (1H, ddd, J = 10, 5.2, 0.8 Hz), 8.10 (1H, ddd, J = 4, 2.1, 0.8 Hz),

g. (lS,4R)-4-((3-(tert-ButyI)-[l,2,4]triazoIo[4,3-a]pyridin-6-y l)oxy)-l,2,3,4- tetrahydronaphthalen-l-amine (Intermediate lg)

A solution of Intermediate If (12.7 g, 65.8 mmol) in 2-methyl THF (200 ml) was treated with (1R, 4S)-4-amino-l,2,3,4-tetrahydronaphthalen-l-ol (WO2014/195402, 10.7 g, 65.8 mmol) and 18-crown-6 (1.77 g, 6.6 mmol) and the mixture was cooled to 0-5°C and treated with KO ^l Bu (8.47 g, 75.7 mmol). The flask was evacuated and purged with nitrogen (x 3) and stirred at RT under nitrogen. After ca. 2 h the reaction was quenched with water and the aqueous phase extracted with 2-methyl THF. The combined organic layers were extracted with 10% citric acid solution and the citric acid layer basified with solid K ₂ C0 ₃ extracting into DCM. The DCM layer was dried (Na ₂ S0 ₄ ) and evaporated. The residue was purified by silica gel plug filtration eluting with DCM followed by 10% 2M NH ₃ in MeOH / DCM to afford the title compound (14.9 g, 86%).

¾ MR (300 MHz, CDC1 ₃ ): 1.56 (9H, s), 1.68 (2H, br s), 1.87-2.13 (3H, m), 2.32- 2.44 (1H, m), 3.63-3.77 (1H, m), 4.00 (1H, dd, J = 8.1, 5.1 Hz), 5.22 (1H, t, J = 4.5 Hz), 7.13 (1H, dd, J = 10, 2 Hz), 7.22-7.43 (3H, m), 7.60 (1H, br d, J = 7.7 Hz), 7.69-7.77 (2H, m).

h. l-((lS,4R)-4-((3-(tert-Butyl)-[l,2,4]triazolo[4,3-a]pyridin- 6-yl)oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea (Intermediate lh)

A solution of Intermediate lg (3.0 g, 8.9 mmol) and trimethylsilyl isocyanate (2.05 g, 17.9 mmol) in DCM (40 ml) was stirred at RT for 18 h and then treated MeOH (5 ml). The solution was evaporated and the residue purified by silica gel plug filtration eluting with 5% 2M NH ₃ in MeOH / DCM to give the title compound (3.38 g, 100%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.51 (9H, s), 2.00-2.18 (3H, m), 2.25-2.38 (1H, m), 4.99-5.13 (3H, m), 5.15-5.24 (1H, m), 6.28 (1H, br d, J = 9.0 Hz), 7.00 (1H, dd, J = 9.9, 2.0 Hz), 7.19-7.37 (3H, m), 7.47-7.55 (2H, m), 7.70 (1H br d, J = 1.3 Hz),

i. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]- pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2- carboxylate (Intermediate li)

A solution of Intermediate lb. (5.7 g, 15.0 mmol) in dioxane (125 ml) was treated with Intermediate Id (3.65 g, 15.0 mmol), Pd(OAc) ₂ (170 mg, 0.75 mmol), XantPhos (870 mg, 1.5 mmol) and Cs ₂ C0 ₃ (6.8 g, 21.0 mmol). The reaction mixture was purged with nitrogen and then heated at 95 °C for 18 h. The reaction mixture was cooled at RT and filtered through a pad of Celite® and the filtrate evaporated. The residue was purified by silica gel plug filtration, eluting with EtOAc followed by 10% IMS / EtOAc to afford the title compound (4.8 g, 55%).

¾ NMR (300MHz, CDC1 ₃ ): 1.14 (3H, t, J = 7.1 Hz), 1.36 (9H, s), 1.57 (9H, s), 2.11-2.51 (4H, m), 4.14-4.36 (2H, m), 5.18-5.33 (2H, br m), 7.13 (1H, dd, J = 10.0, 2.1 Hz), 7.20-7.42 (4H, m), 7.58 (1H, br d, J = 7.6 Hz), 7.79 (1H, d, J = 1.3 Hz), 7.87 (1H, d, J = 10.0 Hz), 9.81 (1H, br s), 10.12 (1H, br s).

J- Example 1

A solution of Intermediate li (2.8 g, 4.79 mmol) and N,N-dimethylethylenediamine (2.1 g, 23.9 mmol) in MeOH (30 ml) was heated to 55 °C and stirred for 18 h. The RM was evaporated and the residue partitioned between water and EtOAc. The two phases were separated and the organic layer extracted into 10% citric acid solution. The citric acid layer was washed with Et ₂ 0 and basified with solid K ₂ C0 ₃ extracting into DCM. The DCM layer was dried (Na ₂ S0 ₄ ) and evaporated to give the title compound (2.8 g, 93%).

LCMS (Method 3): Rt 3.29 min, m/z 628.3 [MH ⁺ ]. ¾ NMR (300MHz, CDC1 ₃ ):

1.31 (9H, s), 1.53 (9H, s), 1.91-2.28 (10H, m), 2.39 (2H, t, J = 6.6 Hz), 3.28-3.40 (2H, m, peak partially obscured by solvent), 4.95-5.04 (1H, m), 5.64 (1H, t, J = 3.8 Hz), 7.28-7.47 (5H, m), 7.73-7.76 (2H, m), 8.15 (1H, d, J = 1.3 Hz), 8.25 (1H, br s), 8.58 (1H, t, J = 5.7 Hz), 9.90 (1H, br s).

Example 2

4-(tert-Butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-(tert- pentyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetr ahydronaphthaIen-l- yl)ureido)pyrimidine-2-carboxamide

N'-(5 diate 2a)

A solution of (5-fluoro-pyridin-2-yl)-hydrazine (WO 2014/195402, 40.6 g, 320 mmol) and HOBt (4.34 g, 32 mmol) in DCM (440 ml) was cooled down to 0 °C and then treated with 2,2-dimethylbutanoic acid (40 mL, 320 mmol). EDC (76.7 g, 400 mmol) was added slowly to the reaction, which was left to stir at 0 °C for 30 minutes and then 90 minutes at RT. The reaction mixture was diluted with DCM (100 mL) and washed with brine (100 mL). The organic phase was dried withNa ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was triturated with Et ₂ 0, filtered and dried to give the title compound (57. ,7 g, 80%). Ή NMR (300 MHz, CDC1 ₃ ): 0.89 (3H, t, J = 7.7 Hz), 1.24 (6H, s), 1.63 (2H, q, J = 7.7 Hz), 6.66 (1H, dd, J = 9.0, 3.5 Hz), 6.71 (1H, d, J = 3.6 Hz), 7.26-7.32 (1H, m), 7.58 (1H, br s), 8.03 (1H, d, J = 2.9 Hz).

b. 6-FIuoro-3-(pentan-3- I)- [1 -a] pyridine (Intermediate 2b)

Hexachloroethane (108.8 g, 459.5 mmol) was portionwise added to a cooled solution of Intermediate 2a (48.5 g, 229.8 mmol), triphenylphosphine (120.5 g, 459.5 mmol) and TEA (125 g, 919.2 mmol) in 2-methyltetrahydrofuran (1000 ml) at 0 °C, while stirring. The reaction mixture was stirred at 0 °C for 30 minutes and then at RT for 2 h (maintaining the reaction temperature <30 °C). The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was taken up in DCM (150 mL) and washed with aqueous 6M HCl solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (46 g, 96%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.76 (3H, t, J = 8.9 Hz), 1.59 (6H, s), 1.93 (2H, q, J = 9.0 Hz), 7.16 (1H, ddd, J = 9.7, 7.4, 2.2 Hz), 7.77 (1H, ddd, J = 9.9, 5.2, 0.9 Hz), 8.06-8.10 (1H, m).

c. (lS,4R)-4-((3-(tert-Pentyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen-1 -amine (Intermediate 2c)

A stirred solution of Intermediate 2b (13.1 g, 63.3 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 10.3 g, 63.3 mmol) and 18-crown- 6 (1.67 g, 6.3 mmol) in 2-methyltetrahydrofuran (300 ml) at 0 °C under nitrogen was added with potassium tert-butoxide (8.20 g, 72.8 mmol). The reaction mixture was evacuated and purged with argon (x 3), warmed at RT and stirred for 4 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N NH ₃ in MeOH/DCM afforded the title compound (19.6 g, 88%).

H NMR (300 MHz, CDC1 ₃ ): 0.74 (3H, t, J - 7.6 Hz), 1.54 (3H, s), 1.55 (3H, s), 1.63 (2H, br s), 1.82-2.14 (5H, m), 2.30-2.43 (1H, m), 3.97-4.05 (1H, m), 5.18-5.24 (1H, t, J = 4.2 Hz), 7.08-7.16 (1H, dd, J = 10.0, 2.6 Hz), 7.22-7.33 (2H, m), 7.34-7.43 (1H, dd, J = 7.8, 2.2 Hz), 7.60 (1H, d, J = 7.6 Hz), 7.70 (1H, s), 7.73 (1H, d, J = 9.9 Hz),

d. l-((lS,4R)-4-((3-(Pentan-3-yl)-[l,2,4]triazolo[4,3-a]pyridin -6-yI)oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea (Intermediate 2d)

A solution of Intermediate 2c (5.0 g, 14.3 mmol) in DCM (50 ml) was treated with (trimethylsilyl)isocyanate (3.3 g, 28.6 mmol) at 0 °C. The reaction mixture was warmed at RT and stirred for 15 minutes. Methanol (0.5 ml) was added and the reaction mixture was stirred for 15 minutes. The solvents were removed under reduced pressure and the residue was taken up in DCM and applied directly to a pad of silica gel eluting with DCM followed by 5% MeOH/DCM. Evaporation under reduced pressure of the relevant fractions afforded the title compound (5.6 g, 100%).

Ή NMR (400 MHz, CDC1 ₃ ): 0.71 (3H, t, J = 7.6 Hz), 1.49 (3H, s), 1.50 (3H, s), 1.87 (2H, q, J = 7.5 Hz), 1.99-2.18 (3H, m), 2.23-2.38 (1H, m), 5.07 (3H, bm), 5.18 (1H, t, J = 5.1 Hz), 6.21 (1H, d, J = 9.2 Hz), 7.00 (1H, dd, J = 10.3, 2.1 Hz), 7.21-7.35 (3H, m), 7.48-7.53 (2H, m), plus one proton not observed.

e. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(tert-pentyI)- [1,2,4] triazolo [4,3- a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido )pyrimidine-2- carboxylate (Intermediate 2e)

A solution of Intermediate 2d (5.6 g, 14.2 n mol), Intermediate Id (3.46 g, 14.2 mmol), XantPhos (0.82 g, 1.42 mmol) in dioxane (100 ml) was treated with Cs ₂ C0 ₃ (6.5 g, 19.9 mmol) and Pd(OAc) ₂ (0.16 g, 0.71 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 95 °C for 18 hours. The reaction mixture was cooled at RT and then filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% IMS/EtOAc afforded the title compound (4.48 g, 52%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.74 (3H, t, J = 7.4 Hz), 1.13 (3H, t, J = 7.4 Hz), 1.36 (9H, s), 1.55 (6H, s), 1.90 (2H, q, J = 7.2 Hz), 2.10-2.29 (3H, m), 2.31-2.44 (1H, m), 4.15- 4.33 (2H, m), 5.17-5.30 (2H, m), 7.09 (1H, br s), 7.11 (1H, dd, J = 9.9, 1.9 Hz), 7.27-7.39 (3H, m), 7.57 (1H, d, J = 7.6 Hz), 7.77 (1H, d, J = 1.8 Hz), 7.83 (1H, d, J = 9.5 Hz), 9.43 (lH, br s), 9.79 (1H, br s).

f. Example 2

A solution of Intermediate 2e (4.4 g, 7.34 mmol) in IMS (100 ml) was treated with N-(2-hydroxyethyl)-N-methylethylenediamine (CAS: 5753-50-4, 2.35 g, 22 mmol).

The reaction mixture was heated at 55 °C for 18 h. The reaction mixture was cooled at

c

RT and the solvent was removed under reduced pressure. The residue was dissolved in EtO Ac and extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then it was basified with solid K ₂ C0 ₃ . The aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM, followed by crystallisation with acetonitrile afforded the title compound (2.74 g, 55%).

LCMS (Method 3): Rt 3.37 min, m/z 672 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.63 (3H, t, J = 8.8 Hz), 1.31 (9H, s), 1.49 (6H, s), 1.89-2.15 (5H, m), 2.16-2.21 (1H, m), 2.23 (3H, s), 2.46 (2H, t, J = 6.9 Hz), 2.52 (2H, t, J = 6.9 Hz, partially obscured by the solvent peak), 3.33-3.37 (2H, m, partially obscured by the water peak), 3.47 (2H, q, J = 6.0 Hz), 4.35 (1H, t, J = 6.0 Hz), 4.96-5.03 (1H, m), 5.62 (1H, t, J = 4.0 Hz), 7.26-7.39 (3H, m), 7.42 (2H, d, J = 8.1 Hz), 7.72 (1H, br s), 7.75 (1H, d, J = 9.8 Hz), 8.10 (1H, d, J = 1.4 Hz), 8.27 (1H, br s), 8.6 (1H, t, J = 5.5 Hz), 9.92 (1H, s).

Example 3

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(tert-pentyl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthalen-l- yl)ureido)pyrimidine~2-carboxamide

A solution of Intermediate 2e (6.36 g, 10.6 mmol) in MeOH (120 ml) was treated with Ν,Ν-dimethylethylene diamine (9.36 g, 106 mmol). The reaction mixture was heated at 55 °C for 18 h. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was back extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was dissolved in MeCN (15-20 mL) and left to stir at RT for 3 h and then filtered and desiccated for 18 h to afford the title compound (5.0 g, 74%).

LCMS (Method 3): Rt 3.35 min, m/z 642 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.63 (3H, t, J = 5.9 Hz), 1.31 (9H, s), 1.49 (6H, s), 1.87-2.13 (6H, m), 2.17 (6H, s), 2.40 (2H, t, J = 7.8 Hz), 3.34 (2H, m, partially obscured by the water peak), 4.99 (1H, m), 5.62 (1H, t, J = 3.9 Hz), 7.26-7.39 (3H, m), 7.42 (2H, d, J = 7.2 Hz), 7.71-7.76 (2H, m), 8.10 (1H, d, J = 1.4 Hz), 8.27 (1H, br s), 8.58 (1H, t, J = 6.3 Hz), 9.90 (1H, s).

Example 4

4-(tert-Butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl) -6-(3-((lS,4R)-4-((3-(tert- penty 1)- [ 1 ,2,4] triazolo [4,3-a] pyridin-6-y l)oxy)-l ,2,3,4-tetrahy dronaphthalen-1- yI)ureido)pyrimidine-2-carboxamide

A solution of Intermediate 2e (5.00 g, 8.34 mmol) in MeOH (120 ml) was treated with Nl-(2-methoxyethyl)-Nl -methyl- 1,2-ethanediamine (CAS: 14165-17-4, 4.41 g, 33.35 mmol). The reaction mixture was heated at 55 °C for 18 hours. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was back extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM, followed by crystallisation with acetonitrile afforded the title compound (4.08 g, 71%).

LCMS (Method 3): Rt 3.49 min, m/z 686 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.63 (3H, t, J = 7.5 Hz), 1.31 (9H, s), 1.49 (6H, s), 1.85-2.14 (5H, m), 2.17-2.22 (1H, m), 2.23 (3H, s), 2.51-2.57 (4H, m, partially obscured by the solvent peak), 3.21 (3H, s), 3.33- 3.37 (2H, m, partially obscured by the water peak), 3.41 (2H, t, J = 5.8 Hz), 5.00 (1H, m), 5.62 (1H, t, J = 4.2 Hz), 7.26-7.39 (3H, m), 7.39-7.44 (2H, d, J = 7.9 Hz), 7.71 (1H, br s), 7.74 (1H, d, J = 8.9 Hz), 8.10 (1H, d, J = 1.8 Hz), 8.3 (1H, br s), 8.58 (1H, t, J = 5.4 Hz), 9.93 (1H, s).

Example 5

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4 -((3-(pentan-3-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 ₅ 4-tetrahydronaphthalen-l- yI)ureido)pyrimidine-2-carboxamide

a. 2-Ethyl-N'-(5-fluoropyridin-2-yl)butane hydrazide (Intermediate 5a)

A solution of (5-fluoro-pyridin-2-yl)-hydrazine (WO 2014/195402, 12.7 g, 100 mmol), HOBt (1.53 g, 10 mmol) and EDC (19.15 g, 100 mmol) in DCM (250 ml) was treated with 2-ethylbutyric acid (11.6 g, 100 mmol). The reaction mixture was stirred at RT for 1 h maintaining the reaction temperature <25 °C. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and H ₂ 0. The organic phase was extracted with aqueous 1M HCl solution. The aqueous phase was washed with Et ₂ 0 and then it was basified with solid K ₂ C0 ₃ . The aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure to give the title compound (17.3 g, 77%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.93 (6H, t, J = 7.4 Hz), 1.49-1.72 (4H, m), 1.95-2.05 (1H, m), 6.66 (1H, dd, J = 9.0, 3.5 Hz), 6.94 (1H, d, J = 3.9 Hz), 7.24-7.31 (1H, m), 7.83 (1H, d, J = 3.3 Hz), 8.02 (1H, d, J = 2.9 Hz).

b. 6-Fluoro-3-(pentan-3-yI)-[l, -a]pyridine (Intermediate 5b)

Hexachloroethane (36.4 g, 153.8 mmol) was portionwise added to a stirred solution of Intermediate 5a (17.3 g, 76.9 mmol), triphenylphosphine (40.3 g, 153.8 mmol) and TEA (31.1 g, 307.6 mmol) in 2-methyltetrahydrofuran (300 ml). The reaction mixture was stirred at RT for 1 h maintaining the reaction temperature <30°C. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with an aqueous 1M HC1 solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Trituration with Et ₂ 0/petrol (v/v 1:1) afforded the title compound (12.7 g, 80%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.89 (6H, t, J = 7.4 Hz), 1.86-2.07 (4H, m), 2.92-3.01 (1H, m), 7.17 (1H, ddd, J = 9.8, 7.5, 2.2 Hz), 7.76 (1H, ddd, J = 10.0, 5.0, 0.8 Hz), 7.85- 7.88 (lH, m).

c. (lS,4R)-4-((3-(Pentan-3-yl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4- tetrahydronaphthalen-l-amine (Intermediate 5c)

A stirred solution of Intermediate 5b (12.7 g, 61.3 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 10.0 g, 61.3 mmol) and 18-crown- 6 (1.62 g, 6.1 mmol) in 2-methyltetrahydrofuran (250 ml) at 0 °C under nitrogen was added potassium tert-butoxide (7.90 g, 70.6 mmol). The reaction mixture was evacuated and purged with argon (x 3), warmed at RT and stirred for 3 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K2CO3. The resulting aqueous phase was extracted with DCM. The organic phase was dried with Na ₂ S0 and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N NH ₃ in MeOH/DCM afforded the title compound (15.06 g, 70%).

Ή NMR (300 MHz, CDCI3): 0.85 (3H, t, J = 7.4 Hz), 0.89 (3H, t, J = 7.4 Hz), 1.82- 2.12 (7H, m), 2.33-2.42 (1H, m), 2.89-2.98 (1H, m), 3.98-4.03 (1H, m), 5.24 (1H, t, J = 7.4 Hz), 7.12 (1H, dd, J = 9.8, 2.1 Hz), 7.24-7.42 (3H, m), 7.50 (1H, d, J = 1.3 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.70 (1H, dd, J = 9.9, 0.8 Hz), plus two protons not observed,

d. l-((lS,4R)-4-((3-(Pentan-3-yl)-[l,2,4]triazolo[4,3-a]pyridin -6-yI)oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea (Intermediate 5d)

A stirred solution of triphosgene (8.54 g, 28.8 mmol) in DCM (140 ml) at -10 °C was slowly added with a solution of Intermediate 5c (9.15 g, 26.1 mmol) and TEA (10.5 g, 104.4 mmol). The reaction mixture was stirred at 0 °C for 1 h and then added to a solution of NH ₃ in MeOH (7M, 75 ml, 522 mmol) pre-cooled at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes and then the volatiles were removed under reduced pressure. The residue was dissolved in DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 2), the combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure. The crude was purified by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM and the residue was partitioned between DCM and a saturated aqueous NaHC0 ₃ solution. The two phases were separated and the organic phase was washed with saturated aqueous NaHC0 ₃ solution. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure to give the title compound (10.9 g, quant.).

Ή NMR (300 MHz, CDC1 ₃ ): 0.81 (3H, t, J = 7.4 Hz), 0.84 (3H, t, J = 7.4 Hz), 1.75- 2.15 (7H, m), 2.25-2.33 (1H, m), 2.87-2.94 (1H, m), 5.01-5.22 (4H, m), 6.48 (1H, d, J = 8.7 Hz), 6.98-7.02 (1H, m), 7.21-7.33 (3H, m), 7.48-7.53 (3H, m).

e. Ethyl 4-(tert-butyI)-6-(3-((lS,4R)-4-((3-(pentan-3-yl)-[l,2,4]tria zolo[4,3-a]pyridin- 6-yI)oxy)-l^,3,4-tetrahydronaphthalen-l-yl)ureido)pyrimidine -2-carboxylate (Intermediate 5e)

A solution of Intermediate 5d (10.9 g, 26.0 mmol), Intermediate Id (6.60 g, 27.3 mmol), XantPhos (3.10 g, 5.4 mmol) in dioxane (150 ml) was treated with Cs ₂ C0 ₃ (12.7 g, 39.0 mmol) and Pd(OAc) ₂ (0.58 g, 2.6 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 100 °C for 90 minutes. The reaction mixture was cooled to RT and stirred overnight. The mixture was diluted with DCM and EtOH and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% IMS/DCM afforded the title compound (8.83 g, 57%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.85 (3H, t, J = 7.4 Hz), 0.88 (3H, t, J = 7.4 Hz), 1.13 (3H, t, J = 7.1 Hz), 1.36 (9H, s), 1.76-2.06 (5H, m), 2.17-2.40 (3H, m), 2.91-3.01 (1H, m), 4.15-4.33 (2H, m), 5.23-5.28 (2H, m), 7.12 (1H, dd, J = 9.9, 2.0 Hz), 7.20 (1H, br s), 7.28- 7.38 (3H, m), 7.54-7.59 (2H, m), 7.83 (1H, dd, J = 9.8, 0.8 Hz), 9.75 (2H, br s).

f. Example 5

A solution of Intermediate 5e (3.80 g, 6.34 mmol) in methanol (40 ml) was treated with AyV-dimethylethylenediamine (1.40 g, 15.9 mmol). The reaction mixture was heated at 55 °C for 18 h. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was dissolved in EtO Ac and extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then it was basified with solid K ₂ C0 ₃ . The aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N NH ₃ in MeOH DCM, followed by crystallisation with acetonitrile afforded the title compound (1.82 g, 45%).

LCMS (Method 3): Rt 3.37 min, m/z 642 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.77 (3H, t, J = 7.4 Hz), 0.80 (3H, t, J = 7.4 Hz), 1.31 (9H, s), 1.75-2.26 (14H, m), 2.39 (2H, t, J = 6.6 Hz), 3.34-3.38 (2H, m, partially obscured by the solvent peak), 4.98-5.04 (1H, m), 5.57 (1H, t, J = 4.0 Hz), 7.25-7.43 (5H, m), 7.70 (1H, dd, J = 9.8, 0.5 Hz), 7.74 (1H, br s), 8.25 (1H, br s), 8.28 (1H, d, J = 1.3 Hz), 8.55 (1H, t, J = 5.8 Hz), 9.89 (1H, s), plus one proton obscured by the solvent peak.

Example 6

4-(tert-Butyl)-N-(2-(3-methoxyazetidin-l-yl)ethyl)-6-(3-((lS ,4R)-4-((3-(peiitan-3-yI)-

[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3,4-tetrahydr onaphthalen-l- yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate 5e (4.40 g, 7.34 mmol) in ethanol (20 ml) was treated with 2-(3-methoxyazetidin-l-yl)ethan-l -amine (CAS: 911300-65-7, 2.50 g, 19.2 mmol).

The reaction mixture was heated at 70 °C for 6 h. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. Purification by FCC, eluting with

0-10% 2N NH ₃ in MeOH/DCM, afforded the title compound (4.49 g, 89%).

LCMS (Method 3): Rt 3.48 min, m/z 684 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO):

0.78 (3H, t, J = 7.4 Hz), 0.80 (3H, t, J = 7.4 Hz), 1.32 (9H, s), 1.76-2.25 (8H, m), 2.54 (2H, t, J = 6.4 Hz), 2.80-2.83 (2H, m), 3.12 (3H, s), 3.24 (2H, q, J = 6.2 Hz), 3.50-3.54 (2H, m), 3.93 (1H, quintet, J = 5.8 Hz), 4.99-5.04 (1H, m), 5.57 (1H, t, J = 3.8 Hz), 7.25-7.43 (5H, m), 7.69-7.73 (2H, m), 8.24-8.34 (2H, br s), 8.56 (1H, t, J = 5.9 Hz), 9.90 (1H, s), plus one proton obscured by the solvent peak.

Example 7

4-(tert-Butyl)-N-(2-(dimethylamino)-2-methylpropyl)-6-(3-((l S,4R)-4-((3-(l- methoxy-2-methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6 -yl)oxy)-l,2,3 ₅ 4- tetrahydronaphthaIen-l-yl)ureido)pyrimidine-2-carboxamide

a. N'-iS-fluoropyridin- -y^-S-methoxy^j -dimethylpropanehydrazide

(Intermediate 7a)

A solution of 3-methoxy-2,2-dimethyl-propanoic acid (CAS: 64241-78-7, 4.9 g, 37.1 mmol), 5-fluoro-2-pyridyl)hydrazine (WO 2014/195402, 4.71 g, 37.1 mmol) and HOBt Hydrate (0.57 g, 3.7 mmol) in DCM (100 ml) was treated with EDC.HC1 (7.11 g, 37.1 mmol). The reaction mixture was placed in water bath and stirred for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between 2-methyltetrahydrofuran and H ₂ 0. The two phases were separated and the organic phase was extracted with aqueous 1M HCl solution. The aqueous phase was washed with Et ₂ 0 and basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM and the organic phase was dried with NaS0 ₄ and the solvent was removed under reduced pressure. Trituration with Et ₂ 0/Petrol afforded the title compound (6.9 g, 77%).

'H MR (300 MHz, CDC1 ₃ ): 1.23 (6H, s), 3.40 (2H, s), 3.46 (3H, s), 6.58-6.54 (2H, m), 7.24-7.31 (1H, m), 8.03 (1H, d, J = 2.9 Hz), 8.68 (1H, d, J = 3.1 H)

b. (4-(tert-Butyl)-6-chloropyrimidiii-2-yI)methyl acetate (Intermediate 7b)

A solution of Intermediate 7a (6.9 g, 28.6 mmol), triphenylphosphine (15.0 g, 57.3 mmol) and TEA (11.6 g, 114.5 mmol) in 2-methyltetrahydrofuran (200 ml) was treated with hexachloroethane (13.6 g, 57.3 mmol). The reaction mixture was stirred at RT (maintaining the reaction temperature <30 °C). The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with an aqueous 1M HC1 solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM and the organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Trituration with Et ₂ 0/petrol (v/v 1 :1) afforded the title compound (5.88 g, 92%).

'H NMR (300 MHz, CDC1 ₃ ): 1.62 (6H, s), 3.33 (3H, s), 3.59 (2H, s), 7.17 (1H, ddd, J = 9.6, 7.2, 2.2 Hz), 7.71 (1H, ddd, J = 10.0, 5.2, 0.8 Hz), 8.57 (1H, ddd, J = 4.89, 2.2, 0.8 Hz).

c. (lS,4R)-4-((3-(l-methoxy-2-methylpropan-2-yl)-[l,2,4]triazol o[4,3-a]pyridiii- 6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthaIen-l-amine (Intermediate 7c)

A stirred solution of Intermediate 7b (5.8 g, 26.0 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydro-naphthalen- 1 -ol (WO 2014/195402, 4.24 g, 26.0 mmol) and 18-crown-6 (0.7 g, 2.6 mmol) in 2-methyltetrahydrofuran (150 ml) at 0 °C under nitrogen was added with potassium tert-butoxide (3.35 g, 29.9 mmol). The reaction mixture was evacuated and purged with argon (x 3), warmed to RT and stirred for 3 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with EtOAc. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was applied to a plug of silica, eluting with 0-5% 2N NH ₃ in MeOH/DCM to afford the title compound (7.42 g, 81%).

Ή NMR (300 MHz, CDCI3): 1.61 (6H, s), 1.91-2.12 (3H, m), 2.30-2.38 (1H, m),

3.31 (3H, s), 3.56 (2H, s), 3.96-4.01 (1H, m), 5.19 (1H, t, J = 4.5 Hz), 7.08 (1H, dd, J = 9.8, 2.1 Hz), 7.25-7.41 (3H, m), 7.60 (1H, d, J = 7.7 Hz), 7.67 (1H, dd, J = 9.9, 0.8 Hz), 8.27 (1H, dd, J = 2.0, 0.6 Hz) plus two protons not observed.

d. l-((lS,4R)-4-((3-(l-Methoxy-2-methylpropan-2-yl)-[l,2,4]tria zolo[4,3- a]pyridin-6-yI)oxy)-l,2, ntermediate 7d)

A solution of Intermediate 7c (5.00 g, 13.7 mmol) in DCM (50 ml) was treated with (trimethylsilyl)isocyanate (3.14 g, 27.4 mmol) at 0 °C. The reaction mixture was warmed at RT and stirred overnight. A further aliquot of (trimethylsilyl)isocyanate (0.39 g, 3.4 mmol) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was treated with methanol and the solvents were removed under reduced pressure. The residue was applied to a plug of silica, eluting with 0-5% 2N N¾ in MeOH/DCM to afford the title compound (5.7 g, >100%, contains DCM).

Ή NMR (300 MHz, CDC1 ₃ ): 1.55 (6H, s), 2.03-2.18 (3H, m), 2.27-2.35 (1H, m), 3.29 (3H, s), 3.55 (2H, s), 4.97-5.18 (4H, m), 6.20 (1H, d, J = 8.8 Hz), 6.97 (1H, dd, J = 9.8, 2.1 Hz), 7.23-7.36 (3H, m), 7.45-7.51 (2H, m), 8.30 (1H, d, J = 1.6 Hz)

e. Ethyl 4-(tert-butyI)-6-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yI)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthaIen-l- yI)ureido)pyrimidine-2-carboxylate (Intermediate 7e)

A solution of Intermediate 7d (5.59 g, 13.7 mmol) in dioxane (150 ml) was treated with Intermediate Id (3.31 g, 13.7 mmol), Pd(OAc) ₂ (0.15 g, 0.7 mmol), XantPhos (0.79 g, 1.4 mmol) and Cs ₂ C0 ₃ (6.2 g, 19.1 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3) and then heated at 95 °C overnight. The reaction mixture was cooled to RT and filtered through a pad of Celite® and the solvent was removed under reduced pressure. The residue was applied to a plug of silica, eluting with EtOAc followed by 10% IMS/EtOAc to afford the title compound (5.60 g, 67%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.10 (3H, t, J = 7.1 Hz), 1.35 (9H, s), 1.61 (6H, s), 2.11-2.43 (4H, m), 3.32 (3H, s), 3.59 (2H, s), 4.15-4.33 (2H, m), 5.21-5.26 (2H, m), 7.05 (1H, dd, J = 9.9, 2.1 Hz), 7.16 (1H, br s), 7.28-7.42 (3H, m), 7.54-7.58 (1H, m), 7.83 (1H, d, J = 9.9 Hz), 8.36 (1H, d, J = 1.6 Hz), 9.58 (1H, br s), 9.78 (1H, br s).

f. Example 7

A solution of Intermediate 7e (5.6 g, 9.1 mmol) in methanol (50 ml) was treated with (2-amino-l,l-dimethylethyl)dimethylamine (CAS: 76936-44-2, 2.1 1 g, 18.2 mmol). The reaction mixture was heated at 55 °C for overnight. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was purified by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM. The resulting foam was crystallised from acetonitrile to give the title compound (3.7 g, 59%).

LCMS (Method 3): Rt 3.37 min, m/z 686 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO):

0.98 (6H, s), 1.30 (9H, s), 1.52 (6H, s), 1.91-2.25 (10H, m), 3.23 (5H, s), 3.66 (2H, s), 4.97- 5.02 (1H, m), 5.54 (1H, t, J = 4.0 Hz), 7.29-7.45 (5H, m), 7.73 (1H, dd, J = 9.8, 0.4 Hz), 7.78 (1H, br s), 8.16 (1H, br s), 8.28 (1H, d, J = 1.3 Hz), 8.51 (1H, t, J = 5.2 Hz), 9.89 (1H, s).

Example 8

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3 _» 4-tetrahydronaphthalen-l-yl)ureido)-N-(2-(dimethylamin o)-2- methylpropyl)pyrimidine-2-carboxamide

a. (S)-N'-(5-Fluoropyridin-2-yI)-2-methylbutanehydrazide (Intermediate 8a)

A solution of (5-fluoro-pyridin-2-yl)-hydrazine (WO 2014/195402, 6.22 g, 49.0 mmol), HOBt (665 mg, 4.9 mmol) and (S)-(+)-2-methylbutyric acid (5.00 g, 49.0 mmol) in DCM (50 ml) was treated with EDC (11.7 g, 61.25 mmol). The reaction mixture was stirred at RT overnight, partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Titration with Et ₂ 0 afforded a first crop of the title compound (5.38 g). The solvent of the filtrate was removed under reduced pressure. Purification by FCC, eluting with 0-8% MeOH/DCM afforded a second crop of the title compound (2.91 g). The two batches were unified to give the title compound (8.29 g, 80%).

ΉΝΜΙ (300 ΜΗζ, CDC1 ₃ ): 0.96 (3H, t, J = 7.4 Hz), 1.21 (3H, d, J - 6.9 Hz), 1.43- 1.78 (2H, m), 2.24 (1H, q, J = 7.3 Hz), 6.66 (1H, dd, J = 9.0, 3.5 Hz), 6.71 (1H, d, J = 3.6 Hz), 7.26-7.32 (1H, m), 7.58 (1H, br s), 8.03 (1H, d, J = 2.9 Hz).

b. (S)-3-(sec-Butyl)-6-fluoro-[l -a]pyridine (Intermediate 8b)

Hexachloroethane (18.6 g, 78.4 mmol) was portionwise added to a stirred solution of Intermediate 8a (8.29 g, 39.2 mmol), triphenylphosphine (20.56 g, 78.4 mmol) and TEA (22 ml, 156.8 mmol) in 2-methyltetrahydrofuran (200 ml). The reaction mixture was stirred at RT for 3 hours. The solvent was removed under reduced pressure and the residue was loaded to an SCX-2 cartridge (70 g). The cartridge was washed with MeCN/MeOH (v/v 1:1) and then the product was eluted with 2N N¾ in MeOH. The solvent of the first wash was removed under reduced pressure and the residue was loaded to another SCX-2 cartridge (70 g). The cartridge was washed with MeCN/MeOH (v/v 1 :1) and then the product was eluted with 2N NH ₃ in MeOH. The two basic elutions were unified together and the solvent was removed under reduced pressure to afford the title compound (7.17 g,

95%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.97 (3H, t, J = 7.4 Hz), 1.51 (3H, d, J = 7.0 Hz), 1.77- 2.12 (2H, m), 3.13 (1H, sextet, J = 7.0 Hz), 7.17 (1H, ddd, J = 10.0, 7.5, 2.2 Hz), 7.76 (1H, ddd, J = 10.0, 5.0, 0.9 Hz), 7.83-7.86 (1H, m).

c. (lS,4R)-4-((3-((S)-sec-ButyI)-[l,2,4]triazolo[4,3-a]pyridin- 6-yl)oxy)-l,2,3,4- tetrahydronaphthalen-1 -amine (Intermediate 8c)

A stirred solution of Intermediate 8b (6.00 g, 31.05 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 5.07 g, 31.05 mmol) and 18-crown- 6 (4.10 g, 15.5 mmol) in 2-methyltetrahydrofuran was evacuated and purged with argon (x 3). Potassium tert-butoxide (4.53 g, 40.36 mmol) was added and the reaction mixture was evacuated and purged with argon (x 3). The reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the organic phases were washed with brine. The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (7.13 g, 68%, ratio cis/trans 96:4).

Ή NMR (400 MHz, CDC1 ₃ ): 0.97 (3H, t, J = 7.4 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.78-2.12 (5H, m), 2.34-2.42 (1H, m), 3.09 (1H, sextet, J = 7.0 Hz), 3.99-4.02 (1H, m), 5.24 (1H, t, J = 4.6 Hz), 7.12 (1H, dd, J = 9.9, 2.1 Hz), 7.25-7.33 (2H, m), 7.37-7.41 (1H, m), 7.48 (1H, d, J = 1.5 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.70 (1H, dd, J = 9.8, 0.5 Hz), plus two protons not observed. d. l-((lS,4R)-4-((3-((S)-sec-Butyl)-[l,2,4]triazolo[4 -a]pyridin-6-yl)oxy)-l,2,3,4- tetrahydronaphthaIen-l-yl)urea (Intermediate 8d)

A solution of Intermediate 8c (7.13 g, 21.2 mmol) in DCM (120 ml) was treated with (trimethylsilyl)isocyanate (4.88 g, 42.38 mmol) at 0 °C. The reaction mixture was warmed at RT and stirred for 15 minutes. Methanol (15 ml) was added and the reaction mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The organic phases were combined and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% MeOH/DCM afforded the title compound (5.48 g, 68%).

Ή NMR (400 MHz, CDC1 ₃ ): 0.81 (3H, t, J = 7.4 Hz), 0.84 (3H, t, J = 7.4 Hz), 1.75- 2.15 (5H, m), 2.25-2.33 (1H, m), 2.87-2.94 (1H, m), 5.01-5.22 (4H, m), 6.48 (1H, d, J = 8.7 Hz), 6.98-7.02 (1H, m), 7.21-7.33 (3H, m), 7.48-7.53 (3H, m).

e. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yI)ureido)pyrimidine-2- carboxylate (Intermediate 8e)

A solution of Intermediate 8d (5.48 g, 14.43 mmol), Intermediate Id (3.50 g, 14.43 mmol), XantPhos (833 mg, 1.44 mmol) in dioxane (100 ml) was treated with Cs ₂ C0 ₃ (6.58 g, 20.20 mmol) and Pd(OAc) ₂ (161 mg, 0.72 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 90 °C for 70 hours. The reaction mixture was cooled at RT, diluted with EtOAc and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (3.61 g, 43%).

Ή NMR (400 MHz, CDC1 ₃ ): 0.96 (3H, t, J = 7.4 Hz), 1.13 (3H, t, J = 7.1 Hz), 1.36

(9H, s), 1.44 (3H, d, J = 7.0 Hz), 1.77-1.87 (1H, m), 1.99-2.27 (4H, m), 2.36-2.42 (1H, m), 3.11 (1H, sextet, J = 6.9 Hz), 4.15-4.32 (2H, m), 5.23-5.29 (2H, m), 7.12 (1H, dd, J = 9.9, 2.0 Hz), 7.24 (1H, br s), 7.28-7.38 (3H, m), 7.52 (1H, d, J = 1.4 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.83 (1H, d, J = 9.8 Hz), 9.84 (1H, br s), 9.94 (1H, s).

f. Example 8

A solution of Intermediate 8e (4.38 g, 7.48 mmol) in methanol (50 ml) was treated with (2-amino-l,l-dimethylethyl)dimethylamine (CAS: 76936-44-2, 2.95 g, 25.38 mmol). The reaction mixture was heated at 60 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the solvent was removed under reduced pressure. The crude was crystallised from acetonitrile, followed by a further purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM. The resulting foam was crystallised from acetonitrile to give the title compound (3.75 g, 76%).

LCMS (Method 3): Rt 3.39 min, m/z 656 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO):

0.87 (3H, t, J = 7.4 Hz), 0.98 (6H, s), 1.31 (9H, s), 1.34 (3H, d, J = 6.9 Hz), 1.75 (1H, quintet, J = 7.1 Hz), 1.87-2.26 (11H, m), 3.23 (2H, d, J = 5.3 Hz), 3.44 (1H, q, J = 6.9 Hz), 4.98-5.03 (1H, m), 5.57 (1H, t, J = 4.0 Hz), 7.25-7.44 (5H, m), 7.70 (1H, dd, J = 9.8, 0.6 Hz), 7.78 (1H, br s), 8.20 (1H, br s), 8.24 (1H, d, J = 1.3 Hz), 8.52 (1H, d, J = 5.1 Hz), 8.89 (1H, s).

Example 9

6-(ter^Butyl)-4-(3-((lS,4R)-4-((3-(tert-butyI)-[l,2,4]triazo lo[4^-a]pyridin-6-yl)oxy]- l,2,3 _? 4-tetrahydronaphthalen-l-yl}ureido)-N-(2-(4-liydroxypi peridin-l- yI)ethyI)picoIinamide

a. 2-(tert-Butyl)-4-chloropyrid diate 9a)

A suspension of copper cyanide (9.99 g, 111.0 mmol) in THF (500 mL) at or below -60°C was dropwise added with tert-butyl magnesium chloride (IN in THF, 213 mL, 213 mmol) then left at -70°C for 20 minutes before 2-bromo-4-chloropyridine (18.65 g, 97.3 mmol) was dropwise added at or slightly below -60°C. This solution was stirred at - 70°C for 20 minutes before the cold bath was removed and the reaction mixture was left to warm to RT over 2 hours. The mixture was diluted with saturated sodium bicarbonate solution and an equal volume of Et ₂ 0 was added. The resulting emulsion was filtered through Celite®, separated and the aqueous layer was partitioned with Et ₂ 0. The combined organic layers were dried over MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-20% EtOAc in cyclohexane afforded the title compound (15.86 g, 48%).

¾ NMR (300MHz, CDC1 ₃ ): 1.36 (9H, s), 7.11 (1H, dd, J = 1.9, 5.3 Hz), 7.34 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 5.3 Hz).

b. 2-(feri-Butyl)-4-chloropyrimidine 1-oxide (Intermediate 9b)

A stirred solution of Intermediate 9a (24.0 g, 142 mmol) in DCM (500 mL) was added with meta-chloroperbenzoic acid (73.7 g, 426 mmol) and left at RT for 24 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting 0 - 100% EtOAc/cyclohexane afforded the title compound (22.85 g, 86%).

LCMS (Method 4): Rt = 1.16 min, m/z 186 [M+H ⁺ ].

c. 6-(ferf-Butyl)-4-chloropicolinonitrile (Intermediate 9c)

A solution of Intermediate 9b (22.80 g, 122.5 mmol) in DCM (40 mL) was treated with trimethylsilyl cyanide (19.98 g, 202 mmol) followed by a solution of dimethyl carbamic chloride (26.6 g, 248.6 mmol) in DCM (10 mL) exotherming to a vigorous boil. The reaction was allowed to cool to RT and was partitioned between saturated sodium bicarbonate and DCM. The organic layer was washed with 10% citric acid solution. The acidic layer was basified with 10% potassium carbonate solution and partitioned into DCM. This DCM layer was dried over solid Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC 0 - 25% EtOAc/cyclohexane afforded the title compound

(8.00 g, 33%).

1H NMR (300 MHz, CDC1 ₃ ): 1.36 (9H, s), 7.51 (1H, d, J = 1.7 Hz), 7.54 (1H, d, J = 1.7 Hz).

d. Ethyl 6-(teri-butyl)-4-chloropicolinate (Intermediate 9d)

A stirred solution of Intermediate 9c (8.0 g, 41.2 mmol) in sulphuric acid (80%, 28.5 g, 247.0 mmol) was heated at 130 °C for 0.5 hours then allowed to cool to RT. Ethanol (360 mL) was cautiously added and the reaction mixture was heated at reflux for 5.5 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated brine and EtOAc. The two phases were separated and the aqueous phase was extracted with EtOAc (x 2). The combined organic layers were washed with saturated sodium bicarbonate solution, dried over solid MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (8.0 g, 80%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.39 (9H, s), 1.42 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J =

7.1 Hz), 7.49 (1H, d, J = 1.8 Hz), 7.88 (1H, d, J = 1.7 Hz).

e. Ethyl 6-(te - -butyl)-4-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triazolo[4,3 - a]pyradin-6-yl)oxy)-l,2,3j4-tetrahydronaphthalen-l-yl)ureido )picolinate

(Intermediate 9e)

A solution of Intermediate lh (2.71 g, 6.62 mmol), Intermediate 9d (1.59 g, 6.62 mmol), Pd(OAc) ₂ (150 mg, 0.66 mmol), Xantphos (770 mg. 1.32 mmol) and Cs ₂ C0 ₃ (3.24 g, 9.93 mmol) in dioxan (40 mL) was degassed by bubbling argon through the mixture under sonication for 10 minutes. The reaction mixture was stirred at 100°C for 6 hours then filtered through Celite® washing well with DCM and EtOH. The solvent was removed under reduced pressure and the crude mixture was purified by FCC eluting with 0-10% EtOH/DCM to afford the title compound (2.90 g, 75%).

LCMS (Method 4): Rt = 1.50 min, m/z 585 [M+H ⁺ ], m/z 607 [M+Na ⁺ ].

e. Example 9

Intermediate 9e (2.90 g, 4.96 mmol) and l-(2-aminoethyl)-4-piperidinol (2.24 g,

15.55 mmol) in ethanol (10 mL) were warmed to 70°C for 24 hours then allowed to cool to RT. The solvent was removed under reduced pressure and the mixture was partitioned between water and DCM (x 3). The combined organic layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting 0-10% (2M NH ₃ in MeOH)DCM produced the title compound (1.90 g, 90% pure). This product was suspended in boiling MeCN (30 mL) and MeOH (25 mL) was added at boiling to obtain a complete solution. This mixture was left at RT for 2 days and the title compound was collected (1.33 g, 39%).

LCMS (Method 3): Rt 3.34 min, m/z 683 [M+H ⁺ ], sample assessed as ca. 99.2%. ¾ NMR (400 MHz, d ₆ DMSO): 1.34 (9H, s), 1.36-1.48 (2H, m), 1.52 (9H, s), 1.66-1.78 (2H, m), 1.90-2.24 (6H, m), 2.48 (2H, t, J = 6.3 Hz, partially obscured by the solvent peak), 2.70-2.81 (2H, m), 3.38 (2H, q, J = 6.1 Hz), 3.42-3.52 (1H, m), 4.57 (1H, d, J = 3.8 Hz), 4.93 (1H, q, J = 8.2 Hz), 5.63 (1H, t, J = 3.4 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.28 (1H, dd, J = 2.0, 9.9 Hz), 7.31 (1H, dd, J = 1.5, 7.2 Hz), 7.34-7.45 (3H, m), 7.68 (1H, d, J = 1.9 Hz), 7.76 (1H, d, J = 9.8 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.14 (1H, s), 8.69 (1H, t, J = 5.3 Hz), 9.09 (1H, s).

Example 10

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yI)ureido)-N-(2- (dimethylamino)ethyl)picolinamide

N,N-DiethyI-2-(5-fluoropyridin-2-yl)hydrazine-l-carboxamide (Intermediate

A solution of (5-fluoro-pyridin-2-yl)hydrazine (12.7 g, 100 mmol) and DIPEA (19.4 g, 150 mmol) in DCM (150 ml) was treated with diethylcarbamoyl chloride (13.5 g, 100 mmol) and the mixture was stirred at RT for 18 h. The RM was evaporated and the residue partitioned between EtOAc and 5% citric acid solution. The organic layer was washed with water, brine, dried (Na ₂ S0 ₄ ) and evaporated. The residue was triturated with Et ₂ 0 to give the title compound (14.6 g, 65%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.20 (6H, t, J = 7.1 Hz), 3.33 (4H, q, J = 7.1 Hz), 6.39 (1H, br s), 6.51 (1H, br s), 6.74 (1H, dd, J = 9.0, 3.6 Hz), 7.22-7.33 (1H, m), 8.02 (1H, d, J = 2.9 Hz).

b. N,N-Diethyl-6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3-amine (Intermediate 10b)

A solution of Intermediate 10a (14.6 g, 64.6 mmol) in 2-methyl THF (250 ml) was treated with TEA (26.1 g, 258.4 mmol), PPh ₃ (33.8 g, 129.2 mmol) and finally with hexachloroethane (30.6 g, 129.2 mmol). The reaction mixture was stirred and the internal temperature kept ca. 30 °C by external cooling. After 2 h the RM was washed with water and then extracted with 1M HC1 solution. The HC1 layer was washed with Et ₂ 0 and basified with solid K ₂ C0 ₃ extracting into DCM (x3). The combined DCM layers were dried (Na ₂ S0 ₄ ) and evaporated under reduced pressure. The residue was purified by FCC eluting with 0-5% MeOH / EtOAc to give the title compound (5.68 g, 42%).

'HNMR (300 MHz, CDC1 ₃ ): 1.12 (6H, t, J = 7.1 Hz), 3.29 (4H, q, J = 7.1 Hz), 7.11 (1H, ddd, J = 9.9, 7.6, 2.3 Hz), 7.64 (1H, ddd, J = 9.9, 4.8, 0.9 Hz), 7.76 (1H, ddd, J = 3.2, 2.3, 0.9 Hz).

c. 6-(((lR,4S)-4-Amino-l,2,3,4-tetrahydronaphthalen-l-yl)oxy)-N ,N-diethyl- [l,2,4]triazolo[4,3-a]pyridin-3-amine (Intermediate 10c)

A solution of Intermediate 10b (5.6 g, 26.9 mmol) in 2-methyl THF (100 ml) was treated with (1R, 4S)-4-amino-l,2,3,4-tetrahydronaphthalen-l-ol (WO 2014/195402, 4.39 g, 26.9 mmol) and 18-crown-6 (710 mg, 2.7 mmol). The mixture was cooled to 0 °C and treated with KO'Bu (3.50 g, 31.0 mmol). The flask was evacuated and purged with nitrogen and the RM was stirred at RT under nitrogen for ca. 18 h. The reaction was quenched with water and the aqueous phase extracted with 2-methyl THF (x 3). The combined organic layers were extracted with 10% citric acid solution and the citric acid layer basified with solid K ₂ C0 ₃ extracting into DCM. The DCM layer was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was purified by silica gel FCC eluting with 0-10% 2M NH ₃ in MeOH / DCM to afford the title compound (5.18 g, 55%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.56 (6H, t, J = 7.1 Hz), 1.64 (2H, br s), 1.84-2.14 (3H, m), 2.28-2.42 (1H, m), 3.27 (4H, q, J = 7.1 Hz), 3.98 (1H, dd, J = 8.4, 5.1 Hz), 5.22 (1H, t, J = 4.5 Hz), 7.05 (1H, dd, J = 9.9, 2.1 Hz), 7.22-7.47 (4H, m), 7.55-7.64 (2H, m). d. l-((lS,4R)-4-((3-(Diethylamino)-[l,2,4]triazolo[4,3-a]pyridi n-6-yl)oxy)- l,2,3,4-tetrahydronaphthaIen-l-yl)urea (Intermediate lOd)

A solution of Intermediate 10c (5.18 g, 14.8 mmol) and trimethylsilylisocyanate

(3.39 g, 29.5 mmol) in DCM (50 ml) was stirred at RT for 15 mins and then treated with MeOH (0.5 ml) and stirring continued for 15 mins. The solution was evaporated and the residue partitioned between water and EtOAc. The organic layer was dried (Na ₂ S0 ₄ ) and evaporated. The residue was purified by FCC eluting with 0-10% 2M NH ₃ in MeOH/DCM to afford the title compound (5.26 g, 91%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.06 (6H, t, J = 7.1 Hz), 1.93-2.18 (3H, m), 2.23-2.37 (1H, m), 3.21 (4H, q, J = 7.1 Hz), 4.98-5.11 (3H, m), 5.15-5.25 (1H, m), 6.27 (1H, br d, J = 9.0 Hz), 6.93 (1H, dd, J = 9.8, 2.1 Hz), 7.20-7.54 (6H, m).

e. Ethyl 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo[4,3- a]pyridin-6-yl)oxy)-l,2 _? 4-tetrahydronaphthalen-l-yl)ureido)picoIinate (Intermediate lOe)

A solution of Intermediate lOd (2.6 g, 6.6 mmoi) in dioxane (50 ml) was treated with Intermediate 9d (1.75 g, 7.3 mmol), Pd(OAc) ₂ (74 mg, 0.33 mmol), XantPhos (380 mg, 0.66 mmol) and Cs ₂ C0 ₃ (3.0 g, 9.2 mmol). The mixture was purged with nitrogen and then heated at 95 °C for 18 hours. The RM was cooled at RT and filtered through a pad of Celite® and the filtrate evaporated. Purification by silica gel plug filtration, eluting with EtOAc followed by 10% IMS / EtOAc followed by FCC eluting with 0-5% 2M NH3 in MeOH / DCM afforded the title compound (1.23 g, 31%).

¾NMR (300MHz, CDC1 ₃ ): 1.06 (6H, t, J = 7.1 Hz), 1.35-1.45 (12H, m), 2.06-2.42

(4H, m), 3.25 (4H, q, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.18-5.31 (2H, br m), 6.93 (1H, dd, J = 9.9, 2.1 Hz), 7.19-7.38 (4H, m), 7.45 (1H, d, J = 1.4 Hz), 7.56 (1H, br d, J = 7.5 Hz), 7.96 (1H, d, J = 1.9 Hz), 8.08-8.19 (2H, m), 9.32 (1H, br s).

f. Example 10

A solution of Intermediate lOe (1.23 g, 2.05 mmol) and N,N- dimethylethylenediamine (900 mg, 23.9 mmol) in MeOH (25 ml) was heated to 55 °C and stirred for 18 h. The RM was evaporated and the residue partitioned between water and EtOAc and the organic layer extracted into 10% citric acid solution. The citric acid layer was washed with Et ₂ 0 and basified with solid ₂ C0 ₃ extracting into DCM. The DCM layer was dried (Na ₂ S0 ₄ ) and evaporated and the residue dissolved in warm MeCN (10 ml) and the solution cooled to RT. The mixture was filtered and the solid washed with MeCN and dried to afford the title compound (1.19 g, 90%).

LCMS (Method 3): Rt 3.34 min, m/z 642 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.02 (6H, t, J = 7.1 Hz), 1.33 (9H, s), 1.89-2.20 (4H, m), 2.21 (6H, s), 2.43 (2H, t, J = 6.6 Hz), 3.24 (4H, q, J = 7.1 Hz), 3.39 (2H, q, J = 6.5 Hz), 4.88-4.98 (1H, m), 5.55 (1H, t, J = 3.9 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.1 Hz), 7.27-7.44 (4H, m), 7.64 (1H, dd, J = 9.8, 0.5 Hz), 7.68 (1H, d, J = 1.9 Hz), 7.72 (1H, d, J = 1.5 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.58 (1H, t, J = 5.8 Hz), 9.06 (1H, br s).

Example 11

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4] triazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)-N-(2- (ethyl(methyI)amino)ethyl)pyrimidine-2-carboxamide

a. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(diethylamino)-[l,2,4]tri azolo [4,3- a]pyridm-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido) pyrimidine-2- carboxylate (Intermediate 11a)

A solution of Intermediate lOd (2.50 g, 6.33 mmol), Intermediate Id (1.54 g, 6.33 mmol), XantPhos (366 mg, 0.63 mmol) in dioxane (25 ml) was treated with Cs ₂ C0 ₃ (2.90 g, 8.86 mmol) and Pd(OAc) ₂ (72 mg, 0.32 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3) and then heated at 90 °C overnight. The reaction mixture was cooled at RT, diluted with IMS and filtered through a pad of Celite®. The solvents were removed under reduced pressure. The crude was loaded on a silica pad, which was subsequently eluted with DCM, EtOAc and IMS to afford the title compound (8.83 g, 57%).

H NMR (300 MHz, CDC1 ₃ ): 1.06-1.13 (9H, m), 1.36 (9H, s), 2.13-2.43 (4H, m),

3.28 (4H, q, J = 9.5 Hz), 4.11-4.30 (2H, m), 5.21-5.28 (2H, m), 6.97 (1H, br s), 7.03 (1H, dd, J = 13.0, 2.9 Hz), 7.30-7.40 (3H, m), 7.47-7.57 (2H, m), 7.64 (1H, dd, J = 13.0, 1.0 Hz), 8.56 (1H, br s), 9.79 (1H, br s). b. Example 11

A solution of Intermediate 11a (120 mg, 0.20 mmol) in methanol (2.5 ml) was treated with (2-aminoethyl)(ethyl)methylamine (CAS: 70111-47-6, 82 mg, 0.80 mmol). The reaction mixture was heated at 55 °C for 6 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (74 mg, 56%).

LCMS (Method 3): Rt 3.32 min, m/z 658 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.97-1.03 (9H, m), 1.31 (9H, s), 1.90-2.27 (7H, m), 2.39 (2H, q, J = 7.1 Hz), 2.45-2.49 (2H, m, partially obscured by the solvent peak), 3.23 (4H, q, J = 7.1 Hz), 3.32-3.37 (2H, m, partially obscured by the water peak), 4.97-5.03 (1H, m), 5.54 (1H, t, J = 4.0 Hz), 7.23-7.43 (5H, m), 7.63 (1H, dd, J = 9.8, 0.7 Hz), 7.71-7.72 (1H, m), 8.33 (1H, br s), 8.60 (1H, d, J = 5.6 Hz), 8.55 (1H, t, J = 5.8 Hz), 9.92 (1H, s).

Example 12

N-(2-(l,4-Oxazepan-4-yl)ethyl)-4-(tert-butyl)-6-(3-((lS,4R)- 4-((3-(2-methoxypropan-

2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tet rahydronaphthalen-l- yl)ureido)pyrimidine-2-carboxamide

a. A^-(5-Fluoropyridin-2-yl)-2-methoxy-2-methylpropanehyd

(Intermediate 12a)

A solution of 2-methoxy-2-methylpropanoic acid (4.0 g, 33.4 mmol) and (5-fluoro- 2-pyridyl)hydrazine (4.3 g, 33.4 mmol) in DCM (100 ml) was treated with HOBt (4.66 g, 33.9 mmol) and EDC (7.8 g, 40.7 mmol). The reaction mixture was stirred at 20 °C for 20 hours then diluted with DCM and washed with water. The organic phase was dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc in cyclohexane afforded the title compound (7.20 g, 74%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.44 (6H, s), 3.36 (3H, s), 6.22 (1H, d, J = 3.5 Hz), 6.50 (1H, t, J = 4.0 Hz), 7.28 (1H, dt, J = 2.9, 8.0 Hz), 8.04 (1H, d, J = 2.9 Hz), 8.64 (1H, s).

b. 6-FIuoro-3-(2-methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyri dine

(Intermediate 12b)

A solution of Intermediate 12a (7.20 g, 31.7 mmol) in 2-methyltetrahydrofuran (140 mL) was treated with triphenylphosphine (8.30 g, 63.4 mmol) and triethylamine (12.80 g, 126.8 mmol) and cooled to 0 °C before hexachloroethane (15.0 g, 63.40 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight and then the reaction mixture was filtered, washing the solid with diethyl ether. The filtrate was washed with water, dried over solid MgS0 ₄ and the solvent removed under reduced pressure. Purification by FCC eluting 0 to 7% MeOH in DCM gave a pale brown solid which was triturated with diethyl ether/cyclohexane (1 : 1, 8 mL) to afford the title compound (4.16 g, 62%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.79 (6H, s), 3.10 (3H, s), 7.21 (1H, dt, J = 2.3, 7.4 Hz), 7.77 (1H, dq, J = 0.8, 5.0 Hz), 8.46 (1H, dq, J = 0.8, 2.3 Hz). LCMS (Method 4): Rt = 0.93 min, m/z 210 [M+H ⁺ ], m/z 232 [M+Na ⁺ ].

c. (lS,4R)-4-((3-(2-Methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]p yridine-6- yl)oxy)-l,2,3,4-tetrahydron ate 12c)

A solution of Intermediate 12b (4.16 g, 19.90 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (WO 2014/195402, 3.24 g, 19.90 mmol) and 18-crown-6 ether (2.62 g, 9.95 mmol) in 2-methyltetrahydrofuran (50 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture, then cooled to 0 °C and potassium tert- butoxide (2.67 g, 23.88 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight with stirring. The reaction mixture was partitioned with DCM and water and the two phases were separated. The aqueous phase was extracted with DCM, combined organic layers were dried over solid MgS0 ₄ and the solvent removed under reduced pressure. Purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (5.52 g, 78%).

l NMR (300 MHz, CDCh): 1.65 (2H, s), 1.77 (6H, d, J = 5.90 Hz), 1.87-1.99 (1H, m), 2.00-2.14 (2H, m), 2.32-2.45 (1H, m), 3.05 (3H, s), 3.99 (1H, dd, J = 5.1, 8.3 Hz), 5.24 (1H, t, J = 4.3 Hz), 7.14 (1H, dd, J = 2.2, 9.9 Hz), 7.22-7.34 (2H, m), 7.38 (1H, dt, J = 1.6, 7.4 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.71 (1H, dd, J = 0.7, 9.9 Hz), 8.10 (1H, d, J = 1.5 Hz). LCMS (Method 4): Rt = 0.77 min, m/z 353 [M+H ⁺ ], m/z 375 [M+Na ⁺ ].

d. l-((lS,4R)-4-((3-(2-Methoxypropan-2-yl)-[l,2,4]triazolo[4,3- a]pyridine-6- yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l-yI)urea (Intermediate 12d)

A solution of Intermediate 12c (1.59 g, 4.51 mmol) and trimethylsilyl isocyanate (1.22 mL, 9.02 mmol) in DCM (20 mL) was stirred at RT for 2 hours prior to adding few drops of MeOH. The resulting solution was stirred at RT for 18 hours. The reaction solvents were removed under reduced pressure and the residues were partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were dried over solid MgS0 ₄ . The solvent was removed under reduced pressure and purification by FCC eluting 0 to 10% (2N N¾ in MeOH) in DCM afforded the title compound (1W mg, 44%). ¾ NMR (300 MHz, CDC1 ₃ ): 1.54 (3H, s), 1.77 (3H, s), 2.04-2.18 (3H, m), 2.32-2.46 (1H, m), 3.00 (3H, s), 4.85 (2H, s), 5.06 (1H, q, J = 5.9 Hz), 5.34 (1H, q, J = 3.5 Hz), 5.85 (1H, d, J = 8.4 Hz), 7.08 (1H, dd, J = 2.8, 9.9 Hz), 7.19-7.34 (3H, m), 7.47 (1H, d, J = 7.3 Hz), 7.60 (1H, dd, J = 0.6, 9.9 Hz), 7.86 (1H, d, J = 1.6 Hz). LCMS (Method 4): Rt = 1.00 min, m/z 396 [M+H ⁺ ], m/z 418 [M+Na ⁺ ].

e. Ethyl 4-(ferM>utyl)-6-(3-((l S,4R)-4-((3-(2-methoxypropan-2yl)- [l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l,2,3,4-tetrahydron aphthalen-l- yl)ureido)pyrimidine-2-carboxylate (Intermediate 12e)

A solution of Intermediate 12d (780 mg, 1.97 mmol), Intermediate Id (480 mg,

1.97 mmol), palladium(II)acetate (22 mg, 0.1 mmol), Xantphos (116 mg, 0.2 mmol) and cesium carbonate (900 mg, 2.76 mmol) in dioxan (30 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication then warmed to 95 °C for 20 hours. The reaction mixture was filtered through a pad of Celite® washing with DCM and EtOH. The liquor was evaporated to dryness under reduced pressure and purification by FCC eluting 0 to 10% EtOH in DCM afforded the title compound (940 mg, 79%).

^J H NMR (300 MHz, CDC1 ₃ ): 1.11 (3H, t, J = 7.1 Hz), 1.36 (9H, s), 1.77 (3H, s), 1.81 (3H, s), 2.13-2.30 (3H, m), 2.33-2.46 (1H, m), 3.09 (3H, s), 4.07-4.33 (2H, m), 5.17- 5.31 (2H, m), 7.12 (2H, dd, J = 2.2, 9.9 Hz), 7.26-7.42 (3H, m), 7.55 (1H, d, J = 7.7 Hz), 7.78 (1H, d, J = 9.9 Hz), 8.13 (1H, d, J = 1.6 Hz), 8.97 (1H, s), 9.62 (1H, br s). LCMS (Method 4): Rt = 1.47 min, m/z 602 [M+H ⁺ ], m/z 624 [M+Na ⁺ ].

f. Example 12

Intermediate 12e (940 mg, 1.56 mmol) and 2-(l,4-oxazepan-4-yl)ethan-l -amine (CAS: 878155-50-1, 790 mg, 5.46 mmol) in methanol (30 mL) were warmed to 55 °C for 18 hours then allowed to cool to RT. The solvent was removed under reduced pressure. Purification by FCC eluting 0-5% (2M NH ₃ in MeOH)/DCM produced the title compound (726 mg, 66%).

LCMS (Method 3): Rt 3.29 min, m/z 700 [M+H ⁺ ]. ¾ NMR (400 MHz, d ₆ DMSO): 1.32 (9H, s), 1.69 (6H, s), 1.76-1.82 (2H, m), 1.88-2.35 (4H, m), 2.60-2.72 (6H, m), 2.98 (3H, s), 3.33-3.41 (2H, m, partially obscured by the water peak), 3.60 (2H, t, J = 4.5 Hz), 3.68 (2H, t, J = 6.0 Hz), 5.00 (1H, q, J = 9.0 Hz), 5.49 (1H, t, J = 3.7 Hz), 7.26-7.48 (5H, m), 7.72 (1H, s), 7.81 (1H, d, J = 9.9 Hz), 8.14 (1H, s), 8.29 (1H, br s), 8.66 (1H, t, J = 5.6 Hz), 9.93 (1H, s).

Intermediate AA

(4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-2-methyIpiperidi n-l-yl)-[l,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yI)ureido )pyriinidiii-2-yl)inethyl methanesulfonate

a. l-((lS,4R)-4-((3-((S)-2-MethyIpiperidin-l-yl)-[l,2,4]triazol o[4,3-a]pyridin-6- yl)oxy)-l ,2,3 _? 4-tetrahydronaphthalen-l-yl)urea (Intermediate AAa)

A solution of triphosgene (4.32g, 14.57 mmol) in DCM (80 ml) was cooled to -10 °C and treated portionwise with a solution of (lS,4R)-4-[3-((S)-2-methyl-piperidin-l- yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yloxy]-l ,2,3,4-tetrahydro-naphthalen-l -ylamine (WO2014/194956, 5.0g, 13.25 mmol) and trimethylamine (5.35g, 52.98 mmol) in DCM (80 ml) maintaining the temperature between -5 and -10 °C. The resulting mixture was stirred at -10 °C for 1 hour and then added to a solution of 2M NH ₃ in MeOH (300 ml) pre- cooled to -10 °C. The resulting mixture was allowed to reach RT over ca. 1.5 hours and then evaporated under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was further extracted with DCM. The combined organic layers were washed with brine, passed through a phase separator and evaporated under reduced pressure. The crude mixture was purified by FCC, eluting with 0-10% 2M NH ₃ in MeOH/DCM to afford the title compound (4.18 g, 75%).

^J H NMR (300 MHz, CDC1 ₃ ): 0.94 (3H, br d, J = 6.0 Hz), 1.40-2.36 (10H, br m), 2.93-3.16 (2H, br m), 3.27-3.42 (1H, br m), 4.72 (2H, br s), 5.00-5.13 (1H, br m), 5.29 (1H, br s), 5.53 (1H, br d, J = 8.3 Hz), 6.98 (1H, br d, J = 9.8 Hz), 7.21-7.56 (6H, br m).

b. (4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-2-methylpiperidin-l -yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidin-2-yI)methyl acetate (Intermediate AAb)

A solution of Intermediate XX (220 mg, 0.91 mmol), Intermediate AAa (457 mg, 1.09 mmol), XantPhos (52 mg, 0.091 mmol) in dioxane (20 ml) was treated with K ₃ P0 ₄ (269 mg, 1.27 mmol) and Pd(OAc) ₂ (10 mg, 0.045 mmol). The reaction mixture was degassed with argon for a few minutes and then evacuated and purged with argon (x 3). The reaction mixture was heated at 90 °C for 3 hours. The reaction mixture was cooled at RT, diluted with EtOAc and filtered through a pad of Celite® . The filtrate was washed with water and brine (x 2) and the organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N N¾ in MeOH/DCM afforded the title compound (311 mg, 55%).

LCMS (Method 1): Rt 3.79 min, m/z 627 [MH ⁺ ].

c. l-(6-(tert-Butyl)-2-(hydroxymethyI)pyrimidin-4-yl)-3-((lS,4R )-4-((3-((S)-2- methyIpiperidin-l-yl)-[l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy )-l,2,3 _» 4- tetrahydronaphthalen-l-yI)urea (Intermediate AAc)

A solution of Intermediate AAb (297 mg, 0.47 mmol) in methanol (6 ml) and H ₂ 0 (1 ml) was treated with K ₂ C0 ₃ (131 mg, 0.95 mmol). The reaction mixture was stirred at RT for 2 hours, partitioned between DCM and H ₂ 0 and the two phases were separated. The organic phase was washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to give the title compound (266 mg, 97%).

LCMS (Method 1): Rt 3.39 min, m/z 585 [MH ⁺ ].

c. Intermediate AA

A solution of Intermediate AAc (297 mg, 0.47 mmol) in DCM (1.5 ml) at 0 °C was treated with TEA (71 μΐ, 0.51 mmol) and mesyl chloride (17 μΐ, 0.22 mmol). The reaction mixture was stirred at 0 °C for 30 minutes and at RT for 40 minutes. Another aliquot of mesyl chloride (17 μΐ, 0.22 mmol) was added and the resulting mixture was stirred at RT for 50 minutes. The reaction mixture was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to give the title compound (140 mg, quant.).

LCMS (Method 1): Rt 3.67 min, m/z 663 [MH ⁺ ].

Intermediate BB

Phenyl (6-(tert-butyI)pyrimidin-4-yl)carbamate

A solution of 6-t-butyl-4-aminopyridine (400 mg, 2.64 mmol) in tetrahydrofuran (10 ml) at 0 °C was treated with TEA (810 μΐ, 5.81 mmol) and a slow addition of phenyl chloroformate (500 μΐ, 3.96 rnmol). The reaction mixture was warmed at RT overnight. The reaction mixture was partitioned between EtOAc and a saturated aqueous NaHC0 ₃ solution and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0- 40% EtOAc/cyclohexane gave the title compound (327 mg, 46%).

LCMS (Method 4): Rt 1.47 min, m/z 272 [MH ⁺ ].

Intermediate CC

Ethyl 4-(tert-butyI)-6-(3-((lS,4R)-4-((3-isopropyl-[l,2,4]triazolo [4,3-a]pyridin-6- yl)oxy)-l,2,3 _» 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carbox ylate

a. l-((lS,4R)-4-((3-Isopropyl-[l,2,4]triazolo[4,3-a]pyridin-6-y l)oxy)- l,2,3,4-tetrahydronaphtha!en-l-yl)urea (Intermediate CCa)

A stirred solution of triphosgene (4.05 g, 13.7 rnmol) in DCM (50 ml) at -10 °C was slowly added with a solution of (lS,4R)-4-((3-isopropyl-[l,2,4]triazolo[4,3-a]pyridin- 6-yl)oxy)-l, 2,3 ,4-tetrahydronaphthalen-l -amine (WO2013/083206, 4.0 g, 12.4 rnmol) and TEA (6.6 ml, 49.6 rnmol) cooled at -10 °C. The reaction mixture was stirred at 0 °C for 1 hour and then added to a solution of NH ₃ in MeOH (2M, 160 ml) pre-cooled at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour and at RT for 72 hours. The solvents were removed under reduced pressure and the residue was dissolved in DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM, followed by a trituration with Et ₂ 0 afforded the title compound (2.77 g, 59%).

LCMS (Method 4): Rt 0.89 min, m/z 366 [MH ⁺ ].

b. Intermediate CC

A solution of Intermediate CCa (400 mg, 1.05 mmol), Intermediate Id (255 mg, 1.05 mmol), XantPhos (64 mg, 0.11 mmol) in dioxane (20 ml) was treated with Cs ₂ C0 ₃ (479 mg, 1.47 mmol) and Pd(OAc) ₂ (12 mg, 0.055 mmol). The reaction mixture was degassed for a few minutes with argon and then it was evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 18 hours, cooled at RT, diluted with DCM and MeOH and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-6% 2N NH ₃ in MeOH/DCM afforded the title compound (415 mg, 69%, isolated as a mixture of ethyl and methyl esters (ratio ethyl/methyl 1:8)).

LCMS (Method 5): Ethyl ester: Rt 1.80 min, m/z 572 [MH ⁺ ]; methyl ester: Rt 1.74 min, m/z 558 [MH ⁺ ].

Intermediate DP

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((2R,6S)-2,6-dimethyIpipe ridin-l-yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthalen-l- yI)ureido)pyrimidine-2-carboxylate

a. l-((lS,4R)-4-((3-((2R,6S)-2,6-Dimethylpiperidin-l-yl)-[l,2,4 ]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)urea (Intermediate DDa) A stirred solution of triphosgene (2.92 g, 9.83 mmol) in DCM (50 ml) at -10 °C was slowly added with a solution of (lS,4R)-4-((3-((2S,6R)-2,6-dimethylpiperidin-l-yl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine

(WO2013/083604, 3.50 g, 8.94 mmol) and TEA (4.8 ml, 35.8 mmol) pre-cooled at -10 °C. The reaction mixture was stirred at 0 °C for 1 hour and then added to a solution of NH ₃ in MeOH (2M, 140 ml) pre-cooled at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes and at RT for 72 hours. The solvents were removed under reduced pressure and the residue was dissolved in DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (3.30 g, 85%).

LCMS (Method 4): Rt 1.11 min, m/z 435 [MH ⁺ ].

b. Intermediate DD

A solution of Intermediate DDa (450 mg, 1.04 mmol), Intermediate Id (251 mg,

1.04 mmol), XantPhos (60 mg, 0.10 mmol) in dioxane (20 ml) was treated with Cs ₂ C0 ₃ (474 mg, 1.46 mmol) and Pd(OAc) ₂ (12 mg, 0.052 mmol). The reaction mixture was degassed for a few minutes with argon and then it was evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 18 hours, cooled at RT and other aliquots of XantPhos (60 mg, 0.10 mmol) and Pd(OAc) ₂ (12 mg, 0.052 mmol) were added. The reaction mixture was degassed for a few minutes with argon and then it was evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 5 hours, cooled at RT, diluted with DCM and MeOH and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N NH ₃ in MeOH/DCM afforded the title compound (387 mg, 58%, isolated as a mixture of ethyl and methyl esters (ratio ethyl/methyl 1 :2)).

LCMS (Method 5): Ethyl ester: Rt 2.13 min, m/z 641 [MH ⁺ ]; methyl ester: Rt 2.06 min, m/z 627 [MH ⁺ ]. Intermediate EE

(4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]tria zoIo[4,3-a]pyridin-6-yl)oxy)- l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidin-2-yI)meth yl methanesulfonate

a. (4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(tert-butyI)-[l,2,4]tria zolo[4,3-a]pyridiii-6- yl)oxy)-l,2,3,4-tetrahydronaphthaIen-l-yl)ureido)pyrimidin-2 -yI)methyI acetate (Intermediate EEa

A solution of Intermediate XX (307 mg, 1.26 mmol), Intermediate lh (500 mg, 1.26 mmol), XantPhos (73 mg, 0.126 mmol) in dioxane (25 ml) was treated with Cs ₂ C0 ₃ (573 mg, 1.77 mmol) and Pd(OAc) ₂ (14 mg, 0.06 mmol). The reaction mixture was degassed with argon for a few minutes and then evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 18 hours. The reaction mixture was cooled at RT, diluted with MeOH and filtered through a pad of Celite®. The solvent was removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N N¾ in MeOH/DCM afforded the title compound (525 mg, 71%).

LCMS (Method 5): Rt 2.04 min, m/z 586 [MH ⁺ ].

b. l-(6-(tert-Butyl)-2-(hydroxymethyl)pyrimidin-4-yI)-3-((lS,4R )-4-((3-(tert- butyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3,4-tetra hydronaphthalen-l-yl)urea (Intermediate EEb)

A solution of Intermediate EEa (525 mg, 0.90 mmol) in methanol (10 ml) and H ₂ 0 (2 ml) was treated with K ₂ C0 ₃ (250 mg, 1.80 mmol).The reaction mixture was stirred at RT for 2 hours, partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the combined organic phases were passed through a phase separator. The solvent was removed under reduced pressure to give the title compound (467 mg, 95%).

LCMS (Method 4): Rt 1.25 min, m/z 544 [MH ⁺ ].

c. Intermediate EE

A solution of Intermediate EEb (467 mg, 0.86 mmol) in DCM (8 ml) at 0 °C was treated with TEA (360 μΐ, 2.58 mmol) and mesyl chloride (137 μΐ, 1.77 mmol). The reaction mixture was stirred at 0 °C for 30 minutes and at RT for 50 minutes. The reaction mixture was partitioned between DCM and a saturated aqueous Na ₂ C0 ₃ solution and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to give the title compound (586 mg, quant.).

LCMS (Method 5): Rt 1.94 min, m/z 622 [MH ⁺ ].

Intermediate FF

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(2-(4-methylpiperazin-l-y l)propan-2-yI)-

[l,2,4]triazoIo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l- yI)ureido)pyrimidine-2-carboxylate

a. N'-(5-FIuoropyridin-2-yl)-2-methyl-2-(4-methylpiperazin-l- yl)propanehydrazide (Intermediate FFa) A solution of (5-fluoro-2-pyridyl) hydrazine (935 mg, 7.36 mmol) in DCM (25 ml) was treated with 2-methyl-2-(4-4-methylpiperazin-l-yl) propanoic acid dihydrobromide (2.5g, 7.18 mmol), DIPEA (2.5 ml, 14.4 mmol), HOBt.xH ₂ 0 (97 mg, 0.72 mmol) and finally EDC (1.7g, 8.85 mmol). The mixture was stirred at RT overnight. The reaction mixture was washed with water and the aqueous phase was extracted with DCM (x 3). The combined organic phases were passed through a phase separator and evaporated under reduced pressure. The crude mixture was purified by FCC, eluting with 0-8% 2M NH ₃ in MeOH/DCM to afford the title compound (1.29 g, 61%).

^X NMR (300 MHz, CDC1 ₃ ): 1.27 (6H, s), 2.32 (3H, s), 2.35-2.78 (8H, br m), 6.53 (1H, br d, J = 4.0 Hz), 6.61 (1H, dd, J = 8.9, 3.5 Hz), 7.22-7.32 (1H, m), 8.01 (1H, d, J = 2.8 Hz), 9.09 (1H, br d, J = 3.5 Hz).

b. 6-fluoro-3-(2-(4-methylpiperazin-l-yl)propan-2-yl)-[l,2,4]tr iazolo[4,3- a] pyridine (Intermediate FFb)

A solution of Intermediate FFa (1.21g, 4.10 mmol) in THF was treated with triethylamine (4.57 ml, 32.8 mmol) and triphenylphosphine (2.15g, 8.20 mmol). The mixture was treated portionwise with hexachloroethane (1.94g, 8.20 mmol) and stirred at RT for 5 hours. The reaction mixture was filtered and evaporated under reduced pressure. The residue was partitioned between DCM and an aqueous 1M HCl solution and the two phases were separated. The organic layer was further extracted with an aqueous 1M HCl solution (x 3). The combined aqueous layers were washed with Et ₂ 0 and then basified with solid Na ₂ C0 ₃ and extracted with DCM (x4). The combined DCM layers were passed through a phase separator and evaporated under reduced pressure to give the title compound (1.08g, 95%).

lH NMR (300 MHz, CDC1 ₃ ): 1.63 (6H, s), 2.29 (3H, s), 2.33-2.59 (8H, br m), 7.17

(1H, ddd, J = 10.0, 10.0, 2.4 Hz), 7.73 (1H, ddd, J = 10.0, 5.0, 0.8 Hz), 8.94 (1H, ddd, J = 4.5, 2.5, 0.8 Hz).

c. (lS,4R)-4-((3-(2-(4-Methylpiperazin-l-yl)propan-2-yl)-[l,2,4 ]triazolo[4,3- a] pyridin-6-yl)oxy)-l ,2,3,4-tetrahy dronaphthalen- 1 -amine (Intermediate FFc)

A solution of Intermediate FFb (225 mg, 0.81 mmol) in 2-methyltetrahydrofuran

(5 ml) was treated with (1R, 4S)-4-amino-l,2,3,4-tetrahydronaphthalen-l-ol (WO 2014/195402, 132 mg, 0.81 mmol) and 18-crown-6 (106 mg, 0.4 mmol) and the flask was evacuated and purged with argon. The mixture was treated with KO ^l Bu (136 mg, 1.22 mmol) and stirred at RT overnight under argon. The reaction was quenched with water and the aqueous phase extracted with 2-methyltetrahydrofuran and DCM. The combined organic layers were dried (Na ₂ S0 ₄ ) and evaporated. The residue was purified by FCC, eluting with 0-10% 2M NH ₃ in MeOH/DCM to afford the title compound (69 mg, 20%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.63 (6H, s), 1.87-2.64 (16H, m), 3.63-3.77 (1H, m), 3.96-4.04 (1H, m), 5.22 (1H, t, J = 4.1 Hz), 7.11 (1H, dd, J = 10.0, 2.2 Hz), 7.21-7.31 (5H, m), 8.72 (lH, d, J = 1.8 Hz).

d. l-((lS,4R)-4-((3-(2-(4-Methylpiperazin-l-yl)propan-2-yI)-[l, 2,4]triazolo[4,3- a]pyridm-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)urea (Intermediate FFd)

A stirred solution of triphosgene (831 mg, 2.80 mmol) in DCM (10 ml) at -10 °C was slowly added with a solution of Intermediate FFc (1.07 g, 2.54 mmol) and TEA (1.03 ml, 10.2 mmol). The reaction mixture was stirred at 0 °C for 1 hour and then added to a solution of NH ₃ in MeOH (2M, 30 ml) pre-cooled at 0 °C. The resulting mixture was stirred at 0 °C for 90 minutes and at RT for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3) and DCM with 5% of MeOH (x 3). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0- 10% 2N NH ₃ in MeOH/DCM afforded the title compound (613 mg, 50%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.59 (3H, s), 1.60 (3H, s), 2.06-2.61 (15H, m), 4.94

(2H, s), 5.07-5.14 (1H, m), 5.23 (1H, t, J = 4.5 Hz), 6.15 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 9.8, 2.2 Hz), 7.29-7.41 (3H, m), 7.50-7.54 (2H, m), 8.75 (1H, d, J = 1.8 Hz),

e. Intermediate FF

A solution of Intermediate FFd (613 mg, 1.28 mmol), Intermediate Id (310 mg, 1.28 mmol), XantPhos (74 mg, 0.128 mmol) in dioxane (30 ml) was treated with Cs ₂ C0 ₃ (584 mg, 1.79 mmol) and Pd(OAc) ₂ (14 mg, 0.064 mmol). The reaction mixture was degassed for a few minutes with argon and then evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-7% 2N NH ₃ in MeOH/DCM afforded the title compound (580 mg, 68%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.09 (3H, t, J = 7.1 Hz), 1.36 (9H, s), 1.63 (3H, s), 1.64 (3H, s), 2.17-2.62 (15H, m), 4.09-4.33 (2H, m), 5.23-5.29 (2H, m), 7.00 (1H, s), 7.07 (1H, dd, J = 9.9, 2.2 Hz), 7.32-7.45 (3H, m), 7.54-7.57 (1H, m), 7.75 (1H, d, J = 9.9 Hz), 8.66 (1H, br s), 8.77 (1H, d, J = 1.7 Hz), 9.80 (1H, br s).

Intermediate GG

(4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(2-(4-methylpiperazin-l- yl)propan-2-yl)- [l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidin-2-yI)methyl acetate

A solution of Intermediate FFd (110 mg, 0.24 mmol), Intermediate XX (58 mg, 0.24 mmol), XantPhos (14 mg, 0.024 mmol) in dioxane (3 ml) was treated with Cs ₂ C0 ₃ (110 mg, 0.34 mmol) and Pd(OAc) ₂ (3 mg, 0.012 mmol). The reaction mixture was degassed for a few minutes with argon and then evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-7% 2N NH ₃ in MeOH/DCM afforded the title compound (113 mg, 70%).

LCMS (Method 4): Rt 1.10 min, m/z 670 [MH ⁺ ].

Intermediate HH

Ethyl 4-(tert-butyI)-6-(3-((lS,4R)-4-((3-(2-ethoxyprop^

a]pyridm-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yI)ureM ^

2-Ethoxy-N'-(5-fluoropyridin-2-yl)-2-methylpropanehydrazide (Intermediate

The title compound (8.97 g, 98%) was prepared starting from (5-fluoro-pyridin-2- yl)-hydrazine (WO 2014/195402, 4.81 g, 37.8 mmol) and 2-ethoxy-2-methylpropanoic acid (5.00 g, 37.8 mmol) using the procedure described to make Intermediate 8a.

H NMR (300 MHz, CDC1 ₃ ): 1.28 (3H, t, J = 7.0 Hz), 1.45 (6H, s), 3.55 (2H, q, J = 7.0 Hz), 6.62-6.66 (2H, m), 7.27-7.33 (1H, m), 8.03 (1H, d, J = 2.9 Hz), 8.64 (1H, br s). b. 3-(2-Ethoxypropan-2-yl)-6-fluoro- [1 ,2,4] triazolo [4,3-a] pyridine (Intermediate HHb) The title compound (6.53 g, 79%, containing -7% of Ph ₃ P=0 by NMR) was prepared starting from Intermediate HHa (8.97 g, 37.2 mmol) using the procedure described to make Intermediate 8b.

^X HNMR (300 MHz, CDC1 ₃ ): 1.16 (3H, t, J = 7.0 Hz), 1.80 (6H, s), 3.22 (1H, q, J = 7.0 Hz), 7.21 (1H, ddd, J = 9.9, 7.4, 2.3 Hz), 7.77 (1H, ddd, J = 10.0, 5.0, 0.8 Hz), 8.51- 8.53 (1H, m).

c. (lS,4R)-4-((3-(2-Ethoxypropan-2-yI)-[l,2,4]triazolo[4,3-a]py ridin-6-yl)oxy)- 1,2,3,4-tetrahydronaphthaIen-l-amine (Intermediate HHc)

The title compound (950 mg, 58%) was prepared starting from Intermediate HHb (1.00 g, 4.48 mmol) using the procedure described to make Intermediate 8c.

Ή NMR (300 MHz, CDC1 ₃ ): 1.14 (3H, t, J = 7.0 Hz), 1.79 (3H, s), 1.80 (3H, s), 1.88-2.12 (3H, m), 2.30-2.39 (1H, m), 3.23 (2H, dq, J = 7.0, 1.5 Hz), 3.96-4.00 (1H, m), 5.23 (1H, t, J = 4.6 Hz), 7.14 (1H, dd, J = 9.9, 2.2 Hz), 7.24-7.42 (3H, m), 7.61 (1H, d, J = 7.7 Hz), 7.71 (1H, dd, J = 9.9, 0.8 Hz), 8.21 (1H, d, J = 1.4 Hz), plus two protons not observed.

d. l-((lS,4R)-4-((3-(2-Ethoxypropan-2-yl)-[l,2,4]triazolo[4,3-a ]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)urea (Intermediate HHd)

The title compound (1.08 g, quant.) was prepared starting from Intermediate HHc (950 mg, 2.59 mmol) using the procedure described to make Intermediate 8d.

Ή NMR (300 MHz, CDC1 ₃ ): 1.12 (3H, t, J = 7.0 Hz), 1.65 (3H, s), 1.78 (3H, s), 2.07-2.18 (3H, m), 2.32-2.42 (1H, m), 3.13-3.24 (2H, m), 4.68 (2H, s), 5.04-5.12 (1H, m), 5.31-5.38 (2H, m), 7.10 (1H, dd, J = 9.9, 2.2 Hz), 7.24-7.36 (3H, m), 7.46-7.50 (1H, m), 7.65 (1H, dd, J = 9.9, 0.8 Hz), 8.01 (1H, d, J = 1.4 Hz),

e. Intermediate HH

The title compound (189 mg, 50%) was prepared starting from Intermediate HHd (193 mg, 0.79 mmol) using the procedure described to make Intermediate 8e.

Ή ΝΜΡν (300 ΜΗζ, CDC1 ₃ ): 1.09 (3H, t, J = 7.1 Hz), 1.15 (3H, t, J = 6.9 Hz), 1.36 (9H, s), 1.80 (3H, s), 1.81 (3H, s), 2.12-2.43 (4H, m), 3.20-3.29 (2H, m), 4.15-4.33 (2H, m), 5.21-5.28 (2H, m), 7.06 (1H, br s), 7.11 (1H, dd, J = 9.9, 2.1 Hz), 7.28-7.41 (3H, m), 7.54-7.57 (1H, m), 7.77 (1H, dd, J = 9.9, 0.5 Hz), 8.23 (1H, d, J = 1.4 Hz), 8.97 (1H, br s), 9.71 (1H, br s).

Intermediate II

l-(2-(AminomethyI)-6-(tert-butyl)pyrimidin-4-yl)-3-((lS,4 R)-4-((3-(tert-butyl)- [l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)urea

A solution of Intermediate EEb (170 mg, 0.31 mmol) in DCM (10 ml) was treated with TEA (90 μΐ, 0.62 mmol) and mesyl chloride (30 μΐ, 0.38 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was added with NH ₃ in MeOH (2N, 10 ml) and the resulting mixture was stirred at RT for 20 hours and at 40 °C for 24 hours. Another aliquot of NH ₃ in MeOH (2N, 10 ml) was added and the reaction mixture was stirred at 40 °C for 24 hours and then another aliquot of NH ₃ in MeOH (2N, 10 ml) was added and the reaction mixture was stirred at 40 °C for 5 hours. The volatiles were removed under reduced pressure. Purification by FCC, eluting with 0-8% 2N NH ₃ in MeOH/DCM afforded the title compound (154 mg, 92%).

LCMS (Method 4): Rt 1.05 min, m/z 543 [MH ⁺ ].

Intermediate JJ

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methyIcyclopentyI)-[l, 2,4]triazolo[4,3- a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2- carboxylate

a. ΝΉ (5-Fluoropyridin-2-yI)-l-methyIcyclopentane-l-carbohydrazide

(Intermediate JJa)

A solution of (5-fluoro-pyridin-2-yl)-hydrazine (WO 2014/195402, 4.95 g, 39 mmol), HOBt (530 mg, 3.9 mmol) and EDC (8.23 g, 43 mmol) in DCM (60 ml) was treated with 1-methylcyclopentanecarboxylic acid (5.00 g, 39 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was partitioned between DCM and H ₂ 0. The organic phase was passed through a phases separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc/DCM, followed by trituration with Et ₂ 0 afforded the title compound (6.5 g, 70%).

¾NMR (300 MHz, CDC1 ₃ ): 1.31 (3H, d, J = 5.6 Hz), 1.47-1.51 (2H, m), 1.63-1.74 (1H, m), 1.99 (1H, br s), 2.04-2.14 (1H, m), 2.34 (1H, br s), 3.88-3.96 (1H, m), 4.40 (1H, dd, J = 8.1, 3.5 Hz), 6.54 (1H, br s), 6.67 (1H, dd, J = 9.0, 3.5 Hz), 7.24-7.30 (1H, m), 8.03 (1H, d, J = 2.9 Hz), 8.71 (1H, br s).

b. 6-Fluoro-3-(l-methylcyclopentyl)-[l,2,4]triazolo[4,3-a]pyrid ine (Intermediate

Hexachloroethane (13 g, 54.8 mmol) was portionwise added at 0 °C to a stirred solution of Intermediate JJa (6.5 g, 27.4 mmol), triphenylphosphine (7.2 g, 54.8 mmol) and TEA (15.3 ml, 110 mmol) in 2-methyltetrahydrofuran (120 ml). The reaction mixture was warmed at RT and stirred for 3 hours. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was purified by FCC, eluting with 100% EtOAc. The residue was partitioned between EtOAc and an aqueous 6M HC1 solution. The two phases were separated and the aqueous phase was washed with EtOAc (x 2) and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM (x 2), the combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (4.8 g, 80%).

LCMS (Method 4): Rt 0.93 min, m/z 220 [MH ⁺ ].

c. (lS,4R)-4-((3-(l-Methylcyclopentyl)-[l,2,4]triazolo[4,3-a]py ridin-6-yI)oxy)- 1,2,3,4-tetrahydronaphthalen-l-amine (Intermediate JJc)

A stirred solution of Intermediate JJb (4.8 g, 21.9 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 3.57 g, 21.9 mmol) and 18-crown- 6 (2.9 g, 11.0 mmol) in 2-methyltetrahydrofuran (50 ml) at 0 °C under nitrogen was added with potassium tert-butoxide (2.95 g, 26.3 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3), warmed at RT and stirred for 18 hours. The reaction mixture was partitioned between EtOAc and H ₂ 0 and the two phases were separated. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (5.05 g, 64%).

LCMS (Method 4): Rt 0.83 min, m/z 363 [MH ⁺ ].

d. l-((lS,4R)-4-((3-(l-Methylcyclopentyl)-[l,2,4]triazolo[4,3-a ]pyridin-6-yl)oxy)- l,2,3,4-tetrahydronaphthalen-l-yI)urea (Intermediate JJd)

The title compound (4.0 g, 80%) was prepared starting from Intermediate JJc (4.0 g, 11 mmol) using the procedure described to make Intermediate 5d.

Ή NMR (400 MHz, CDC1 ₃ ): 1.47 (3H, s), 1.73-1.94 (6H, m), 2.01-2.18 (3H, m),

2.27-2.35 (1H, m), 2.43-2.51 (2H, m), 4.50 (2H, s), 5.02-5.09 (2H, m), 5.19 (1H, t, J = 3.9 Hz), 7.06 (1H, dd, J = 9.9, 2.1 Hz), 7.27-7.40 (3H, m), 7.51 (1H, d, J = 7.5 Hz), 7.63-7.67 (2H, m).

e. Intermediate JJ

The title compound (1.1 g, 60%) was prepared starting from Intermediate JJd (1.0 g, 2.5 mmol) and Intermediate Id (600 mg, 2.5 mmol) using the procedure described to make Intermediate 5e.

LCMS (Method 4): Rt 1.53 min, m/z 612 [MH ⁺ ].

Intermediate KK

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-cycIopentyl-[l,2,4]triazo lo[4,3-a]pyridin-6- yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yI)ureido)pyrimidine-2-carbox ylate

The title compound (1.1 g) was prepared following the procedures outlined for Intermediate JJ starting from cyclopentanecarboxylic acid (CAS: 3400-45-1, 1.0 g, 2.5 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (600 mg, 2.5 mmol).

LCMS (Method 4): Rt 1.48 min, m/z 598 [MH ⁺ ].

Intermediate LL

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-2-methylpiperidin-l- yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3,4-tetrahydrona phthaleii-l- yI)ureido)pyrimidine-2-

The title compound (413 mg, 53%) was prepared starting from Intermediate AAa (624 mg, 1.48 mmol) and Intermediate Id (300 mg, 1.24 mmol) using the procedure described to make Intermediate 5e.

LCMS (Method 1): Rt 3.79 min, m/z 627 [MH ⁺ ].

Intermediate MM

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-2-methylpiperidin-l- yl)-[l,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2- carboxylic acid

A solution of Intermediate LL (200 mg, 0.32 mmol) in THF (2 ml) was treated with LiOH (8.4 mg, 0.35 mmol) and water (0.2 ml) and the resulting mixture stirred at RT for 18 h. The mixture was partitioned between DCM and aqueous 1 M HCl solution and the two phases were separated. The aqueous layer extracted with DCM (x2), the combined organic layers were passed through a phase separator and evaporated to afford the title compound (165 mg, 86%).

LCMS (Method 1): Rt 3.34 min, m/z 599 [MH ⁺ ].

Intermediate NN

2,2,2-Trichloroethyl (6-(tert-butyl)-2-(methylcarbamoyI)pyrimidin-4-yl)carbamate

o a. Ethyl 4-((tert-butoxycarbonyl)amino)-6-(tert-butyl)pyriinidine-2-c arboxylate (Intermediate NNa)

A mixture of Intermediate Id (1.0 g, 4.12 mmol), tert-butylcarbamate (579 mg, 4.94 mmol), XPhos (196 mg, 0.41 mmol), Pd(OAc) ₂ (46 mg, 0.21 mmol) and Cs ₂ C0 ₃ (1.88 g, 5.77 mmol) was degassed with argon and refluxed for 2 h. The reaction mixture was cooled to RT, diluted with EtOAc, filtered through Celite® and the filtrate washed with water. The two phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was purified by FCC eluting with 0-30% EtOAc in cyclohexane to afford the title compound (1.05 g, 79%).

¾ NMR (300MHz, CDC1 ₃ ): 1.39 (9H, s), 1.44 (3H, t, J = 7.2 Hz), 1.53 (9H, s), 4.47 (2H, q, J = 7.2 Hz), 7.53 (1H br s), 8.05 (1H, s).

b. tert-Butyl (6-(tert-butyl)-2-(methylcarbamoyl)pyrimidin-4-yl)carbamate (Intermediate NNb)

Intermediate NNa (500 mg, 1.55 mmol) was dissolved in 2M methylamine in THF (3.87 ml, 7.74 mmol) and the solution stirred at RT for 2.5 h. The RM was evaporated to leave the title compound (400 mg, 83%).

¾ NMR (300MHz, CDC1 ₃ ): 1.37 (9H, s), 1.52 (9H, s), 3.06 (3H, d, J = 5.2 Hz), 7.69 (1H br s), 8.03 (1H, s), 8.05 (1H, br s). c. 4-Amino-6-(tert-butyI)-N-methylpyrimidine-2-carboxamide (Intermediate

Intermediate NNb (400 mg, 1.29 mmol) was dissolved in 4M HC1 in dioxan (5 ml) and the solution was stirred for 18 h. The reaction mixture was evaporated and the residue loaded onto a pre-conditioned SCX-2 cartridge. The cartridge was washed with DCM, DCM/MeOH (1 :1) and MeOH and then the product was eluted with 2M NH ₃ in MeOH. Evaporation of the last elution afforded the title compound (231 mg, 86%).

¾ NMR (300MHz, CDC1 ₃ ): 1.29 (9H, s), 3.02 (3H, d, J = 5.2 Hz), 5.98 (2H br s), 6.42 (1H, s), 8.09 (1H, br s).

d. Intermediate NN

A solution of Intermediate NNc (100 mg, 0.48 mmol), 2,2,2-trichloroethyl chloroformate (165 μΐ, 1.20 mmol) and Et ₃ N (67μ1, 0.48 mmol) in dioxan (2 ml) was heated to 150 °C for 1.5 h in the microwave. The reaction mixture was evaporated and purification by FCC eluting with 0-50% EtOAc in cyclohexane afforded the title compound (87 mg, 47%).

^! H NMR (300MHz, CDC1 ₃ ): 1.39 (9H, s), 3.07 (3H, d, J = 5.2 Hz), 4.84 (2H, s), 8.05 (2H, br s), 8.13 (lH, br s)

Intermediate OO

Ethyl 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 ₅ 4-tetrahydronaphthalen-l- yl)ureido)picolinate

a. l-((lS,4R)-4-((3-((S)-l,2-Dimethylpyrrolidin-2-yl)-[l,2,4]tr iazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthaleii-l-yI)urea (Intermediate OOa)

A stirred solution of triphosgene (2.22 g, 7.49 mmol) in DCM (40 ml) at -10 °C was slowly added with a solution of (lS,4 )-4-[3-((S)-l,2-dimethyl-pyrrolidin-2- yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yloxy]-l,2,3,4-tetrahydr o-naphthalen-l-ylamine (WO 2013/083604, 2.57 g, 6.81 mmol) and TEA (3.8 ml, 27.2 mmol). The reaction mixture was stirred at 0 °C for 1 hour and then added to a solution of NH ₃ in MeOH (2M, 250 ml, 511 mmol) pre-cooled at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes and then the volatiles were removed under reduced pressure. The residue was dissolved in DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were washed with brine (x 2), passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (2.08 g, 73%).

LCMS (Method 1): Rt 0.36 min, m/z 443 [MNa ⁺ ].

b. Intermediate OO

The title compound (250 mg, 43%) was prepared starting from Intermediate OOa (90 mg, 0.90 mmol) and Intermediate 9d (270 mg, 1.1 mmol) using the procedure described to make Intermediate 5e.

LCMS (Method 1): Rt 2.72 mins, m/z 648 [M+Na ⁺ ].

Intermediate PP

4-(tert-Butyl)-6-chloro-2-methylpyrimidine

a. 6-(tert-Butyl)-2-methylpyrim ne (Intermediate PPa)

A solution of acetamidine hydrochloride (1.99 g, 21.1 mmol) and methyl pivaloylacetate (4.0 g, 25.3 mmol) in MeOH (100 ml) was treated with sodium methoxide (2.85 g, 52.7 mmol). The mixture was heated to 75 °C for 18 h. The reaction mixture was cooled to RT and evaporated under vacuum. The residue was partitioned between EtOAc and a saturated aqueous NaHC0 ₃ solution and the two phases were separated. The organic layer was washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was triturated with acetone (2.34 g, 67%).

'H NMR (400MHZ, d ₆ -DMSO) 1.17 (9H, s), 2.26 (3H, s), 6.01 (1H, s), 12.20 (1H, br s).

b. Intermediate PP

A suspension of Intermediate PPa (2.33 g, 14.0 mmol) in POCl ₃ (15 ml) was heated to 90 °C (block temperature) and stirred for 1.5 h. The volatiles were evaporated and the residue stirred with water (50 ml) and neutralised with 1M NaOH solution. The mixture was filtered and the solid washed with water and dried to afford the title compound (2.37 g, 87%).

*H NMR (400MHz, d ₆ -DMSO): 1.28 (9H, s), 2.59 (3H, s), 7.48 (1H, s).

Intermediate QQ

4-(tert-Butyl)-6-chloro-2-ethylpyrimidine

a. 6-(tert-Butyl)-2-ethylpyrimidin-4(lH)-one (Intermediate QQa) The title compound (3.15 g, 83%) was prepared starting from propanamidine hydrochloride (2.29 g, 21.1 mmol) using the procedure described to make Intermediate PPa. The product was purified by FCC eluting with 0-20% MeOH / DCM.

'H NMR (400MHz, d ₆ -DMSO): 1.17 (3H, t, J = 7.6 Hz), 1.18 (9H, s), 2.53 (2H, q, J = 7.6 Hz signal partially obscured by solvent signal), 6.01 (IH, s), 12.16 (IH, br s). b. Intermediate QQ

The title compound (3.32 g, 96%) was prepared starting from Intermediate QQa (3.14 g, 17.4 mmol) using the procedure described to make Intermediate PP.

l NMR (400MHz, d ₆ -DMSO): 1.26 (3H, t, J = 7.6 Hz), 1.29 (9H, s), 2.86 (2H, q, J = 7.6 Hz), 7.48 (IH, s).

Intermediate RR

4-(tert-ButyI)-6-chloro-2-isopropylpyrimidine

a. 6-(tert-ButyI)-2-isopropylpyrimidin-4(lH)-one (Intermediate RRa)

The title compound (2.98 g, 73%) was prepared starting from 2- methylpropanamidine hydrochloride, (2.58 g, 21.1 mmol) using the procedure described to make Intermediate PPa.

¾ NMR (400MHz, d ₆ -DMSO): 1.16-1.20 (15H, m), 2.79 (IH, septet, J = 6.9 Hz), 6.00 (IH, s), 12.12 (IH, br s).

b. Intermediate RR

The title compound (3.09 g, 95%) was prepared starting from Intermediate RRa (2.97 g, 15.3 mmol) using the procedure described to make Intermediate PP. ^l R NMR (400MHz, d ₆ -DMSO): 1.26 (6H, d, J = 6.9 Hz), 1.29 (9H, s), 3.09 (1H, septet, J = 6.9 Hz), 7.47 (1H, s).

Intermediate SS

4-(tert-butyI)-6-Chloro-2-(methoxymethyl)pyrimidine

6-(tert-butyI)-2-(methoxymethyl)pyrimidin-4(lH)-one (Intermediate SSa)

The title compound (2.86 g, 69%) was prepared starting from 2- methoxyacetamidine hydrochloride, (2.62 g, 21.1 mmol) using the procedure described to make Intermediate PPa. The product was purified by FCC eluting with 0-20% MeOH / DCM.

'H NMR (400MHZ, d ₆ -DMSO): 1.19 (9H, s), 3.34 (3H, s, signal partially obscured by solvent signal), 4.25 (2H, s), 6.10 (1H, s), 12.21 (1H, br s).

b. Intermediate SS

The title compound (2.98 g, 96%) was prepared starting from Intermediate SSa

(2.85 g, 14.5 mmol) using the procedure described to make Intermediate PP.

lU NMR (400MHz, d ₆ -DMSO): 1.30 (9H, s), 3.40 (3H, s), 4.55 (2H, s), 7.60 (1H, s).

Intermediate TT

l-((lS,4R)-4-((3-((R)-l,2-dimethylpyrrolidin-2-yl)-[l,2,4 ]triazolo [4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)urea

a. (R)-l,2-Dimethyl-pyrrolidine-2-carboxylic acid hydrochloride salt

(Intermediate TTa)

A solution of 2-methyl-D-proline hydrochloride salt (10.0 g, 60.4 mmol) in EtOH (150 ml) was added with formaldehyde (37% in water, 12.0 ml, 148 mmol) and palladium on carbon (10% Pd, 1.5 g). The vessel was evacuated and filled with hydrogen (x 3) and the reaction mixture was stirred overnight at RT under hydrogen. The reaction mixture was filtered through a pad of celite and the solvent was removed under reduced pressure. The residue was triturated with ether to give the title compound (10.7 g, 99%).

¾NMR (300 MHz, d ₆ -DMSO): 1.54 (3H, br s), 1.86-2.14 (3H, m), 2.28 (1H, br s), 2.76 (3H, s), 3.22-3.64 (3H, m).

b. (R)-l,2-Dimethyl-pyrrolidine-2-carboxylic acid N'-(5-Fluoro-pyridine-2-yl)- hydrazide (Intermediate TTb)

A solution of Intermediate TTa (10.6 g, 59.1 mmol), (5-fluoro-pyridin-2-yl)- hydrazine (WO 2014/195402, 7.50 g, 59.1 mmol), HOBt (0.90 g, 5.91 mmol) and DIPEA (10.1 ml, 59.1 mmol) in DCM (150 ml) was treated with EDC (11.3 g, 59.1 mmol). The reaction mixture was stirred at RT for 2 hours. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and H ₂ 0. The organic phase was washed with H ₂ 0 and brine, dried withNa ₂ S0 ₄ and the solvent was removed under reduced pressure. The crude was purified by FCC eluting with DCM, followed by 10% acetone/DCM and finally 0-5% 2M NH ₃ in MeOH/DCM. The resulting solid was triturated with petrol ether to give the title compound (7.60 g, 51%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.24 (3H, s), 1.73-1.92 (3H, m), 2.12-2.30 (1H, m), 2.38 (3H, s), 2.50-2.63 (1H, m), 3.07-3.18 (1H, m), 6.53 (1H, br s), 6.60 (1H, dd, J = 9.0, 3.6 Hz), 7.22-7.33 (1H, m), 8.03 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).

c. 3-((R)-l,2-Dimethyl-pyrrolidin-2-yI)-6-fluoro-[l,2,4]triazol o[4,3-a]pyridine (Intermediate TTc)

Hexachloroethane (2.22 g, 9.40 mmol) was portionwise added to a stirred solution of Intermediate TTb (7.50 g, 29.8 mmol), triphenylphosphine (15.6 g, 59.5 mmol) and TEA (16 ml, 118.9 mmol) in 2-methyltetrahydrofuran (150 ml) and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled at RT, diluted with H ₂ 0 and the two phases were separated. The organic phase was washed with H ₂ 0 and extracted with an aqueous 0.5M citric acid solution. The aqueous phase was washed with 2- methyltetrahydrofuran and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM (x 3). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (6.74 g, 97%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.65 (3H, s), 1.85-2.28 (7H, m), 2.74 (1H, q, J = 8.7 Hz), 3.20-3.30 (1H, m), 7.17 (1H, ddd, J - 9.9, 7.3, 2.1 Hz), 7.73 (1H, dd, J = 9.9, 5.0 Hz), 8.82 (1H, m).

d. (lS,4R)-4-[3-((R)-l,2-Dimethyl-pyrrolidin-2-yl)-[l,2,4]triaz olo[4,3-a]pyridin- 6-yloxy]-l,2,3,4-tetrahydro-naphthalen-l-ylamine (Intermediate TTd)

A stirred solution of Intermediate TTc (6.50 g, 27.8 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 4.53 g, 27.8 mmol) and 18-crown- 6 (750 mg, 2.8 mmol) in 2-methyltetrahydrofuran (100 ml) at 0 °C under nitrogen was added with potassium tert-butoxide (3.58 g, 32.0 mmol). The reaction mixture was warmed at RT, stirred overnight and quenched with H ₂ 0. The two phases were separated and the organic phase was washed with H ₂ 0 and extracted with an aqueous 0.5M citric acid solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (8.32 g, 79%).

'HNMR (300 MHz, CDC1 ₃ ): 1.65 (3H, s), 1.84-2.13 (10H, m), 2.18-2.39 (2H, m), 2.73 (1H, q, J = 8.9 Hz), 3.11-3.21 (1H, m), 3.98 (1H, dd, J = 8.4, 5.1 Hz), 5.17 (1H, t, J = 4.5 Hz), 7.11 (1H, dd, J = 9.9, 2.3 Hz), 7.29 (1H, d, J = 7.2 Hz), 7.33-7.43 (2H, m), 7.60 (1H, d, J = 7.7 Hz), 7.68 (1H, dd, J = 9.9, 0.8 Hz), 8.57 (1H, d, J = 2.2 Hz) plus one proton obscured by water,

e. Intermediate TT

A solution of Intermediate TTd (5 g, 14.3 mmol) in THF (50 ml) was treated with TEA (118 iL, 0.795 mmol) and p-nitro-phenyl chloroformate (128 mg, 0.636 mmol) and the reaction mixture was stirred at RT for 20 min. An aqueous 33% ammonia solution was then added to the RM, which was then left to stir at RT for further 30 minutes. The solvents were removed under reduced pressure and the residue was taken up in saturated aqueous NaHC0 ₃ solution and extracted with DCM. The organic phase was separated with a phase separating cartridge and the solvent was removed under reduced pressure. Purification by FCC, eluting with 100% EtOAc followed by 10% 2M NH3 in MeOH/DCM gave the title compound (170 mg, 70%).

LCMS (Method 4): Rt 0.61 min, m/z 421 [MH ⁺ ].

Intermediate UU

Phenyl (5-(tert-butyI)-2-methylpyridin-3-yl)carbamate

The title compound (45 mg, 19%) was prepared starting from 5-(tert-butyl)-2- methylpyridin-3 -amine (US2005/0245536, 134 mg, 0.82 mmol) using the procedure described to make Intermediate BB.

LCMS (Method 4): Rt 1.01 min, m/z 285 [MH ⁺ ].

Intermediate W

5-(tert-Butyl)-3-isocyanato-2-methoxypyridine

A solution of 5-(tert-butyl)-2-methoxypyridin-3 -amine (WO2000/055139, 151 mg, 0.84 mmol) in DCM (12 ml) was treated with saturated aqueous NaHC0 ₃ solution (8 ml) and the mixture cooled in ice. A 15% solution of phosgene in toluene (2.4 ml, 3.4 mmol) was added and the mixture was stirred at 0 °C for 1 hour. The two phases were separated and the aqueous phase extracted with DCM. The combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (168 mg, 97%).

¾ NMR (400MHz, CDC1 ₃ ): 1.29 (9H, s), 4.03 (3H, s), 7.26 (1H, d, J = 2.5 Hz), 7.97 (lH, d, J = 2.5 Hz).

Intermediate WW

Lithium 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethyIpyrrolid in-2-yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthaIen-l- yI)ureido)pico!inate

A solution of Intermediate OO (200 mg, 0.32 mmol) in MeOH (2.4 ml)/THF (0.3 ml)/H ₂ 0 (0.8 ml) was treated with LiOH.H ₂ 0 (28 mg, 0.67 mmol) and the mixture stirred at RT for 90 minutes. The reaction mixture was diluted with water, filtered and the solid washed with water, Et ₂ 0 and dried at 50°C under vacuum to afford the title compound (173 mg, 90%).

LCMS (Method 1): Rt 2.30 min, m/z 596 [M-H ⁺ ].

Intermediate XX

(4-(tert-Butyl)-6-chloropyrimidin-2-yI)methyl acetate

a. (4-(tert-ButyI)-6-chIoropyrimidin-2-yI)methanol (Intermediate XXa)

A solution of with Intermediate Id (1 g, 4.12 mmol) in THF (10 ml) and IMS (5 ml) was treated with NaBH ₄ (234 mg, 6.18 mmol) at 0 °C under argon. The reaction mixture was stirred at RT overnight. The reaction mixture was quenched with H ₂ 0 and extracted with EtOAc. The organic phase was washed with brine, dried with MgS0 ₄ and the solvent was removed under reduced pressure. The residue was applied to a plug of silica, eluting with 0-100% EtOAc/Cyclohexane to afford the title compound (623 mg, 75%).

^! H NMR (300 MHz, CDC1 ₃ ): 1.35 (9H, s), 3.61 (1H, t, J = 4.9 Hz), 4.78 (1H, dd, J = 4.9, 0.7 Hz), 7.23 (1H, s).

b. Intermediate XX

A solution of Intermediate XXa (300 mg, 1.49 mmol) in pyridine (3 ml) was treated with acetic anhydride (283 μΐ, 2.99 mmol). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and washed with aqueous HC1 1M solution. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with aqueous HC1 1M solution and brine, dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (333 mg, 92%).

¾NMR (300 MHz, CDC1 ₃ ): 1.32 (9H, s), 2.21 (3H, s), 5.25 (2H, s), 7.21 (1H, s). Intermediate YY

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthaIen-l- yl)ureido)pyrimidine-2-carboxylic acid

a. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [ 1 ,2,4] triazolo [4,3-a] py ridin-6-y l)oxy)- 1 ,2,3,4-tetrahy d ronaphthalen- 1 - yI)ureido)pyrimidine-2-carboxylate (Intermediate YYa)

A solution of Intermediate OOa (1.04 g, 2.47 mmol) in dioxane (50 ml) was treated with Intermediate Id (0.5 g, 2.06 mmol), Pd(OAc) ₂ (23.1 mg, 0.10 mmol), XantPhos (119 mg, 0.20 mmol) and Cs ₂ C0 ₃ (940 mg, 2.88 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 90 °C for 1.25 h. The reaction mixture was cooled to RT and filtered through a pad of Celite®. The filtrate was partitioned between EtOAc and H ₂ 0 and the two phases were separated. The organic phase was washed with brine, dried with MgS0 ₄ and the solvent was removed under reduced pressure. The residue was applied to a plug of silica, eluting with 0-5% 2N NH ₃ in MeOH/DCM to afford the title compound (548 mg, 42%).

'HNMR (300 MHz, CDC1 ₃ ): 1.09 (3H, t, J = 7.1 Hz), 1.35 (9H, s), 1.87- 2.42 (11H, m), 2.73 (1H, q, J = 9.0 Hz), 3.13-3.20 (1H, m), 4.11-4.32 (2H, m), 5.18-5.28 (2H, m), 7.05- 7.09 (2H, m), 7.29-7.41 (3H, m), 7.55 (1H, d, J = 7.2 Hz), 7.74 (1H, d, J = 9.8 Hz), 8.58 (1H, d, J = 1.6 Hz), 9.05 (1H, s), 9.77 (1H, br s), plus three protons not observed. b. Intermediate YY

A solution of Intermediate YYa (300 mg, 0.48 mmol) in THF (3 ml) and H ₂ 0 (0.3 ml) was treated with LiOH (12.6 mg, 0.53 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was acidified to pH 1 with aqueous 1M HC1 solution, diluted with EtOAc and the two phases were separated. The organic phase was washed with brine and the combined aqueous phases were extracted with DCM and DCM with a few drops of methanol. The combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (198 mg, 69%).

Ή NMR (300 MHz, d- ₆ -DMSO):1.29 (9H, s), 1.75- 2.28 (12H, br s), 2.59 (1H, br s), 3.05 (3H, br s), 3.66-3.92 (1H, m), 4.93-5.03 (1H, m), 5.71 (1H, br s), 7.27-7.49 (6H, m), 7.79 (1H, br s), 7.89 (1H, d, J = 9.9 Hz), 8.12-8.27 (1H, m), 9.84-9.94 (1H, m).

Intermediate ZZ

N-(4-(tert-Butyl)-6-chloropyrimidin-2-yl)methanesuIfonamide

6-(tert-Butyl)-2-(methylthio)pyrimidin-4-oI (Intermediate ZZa)

A solution of S-methylisothiourea hemisulfate salt (CAS: 867-44-7, 5.25 g, 37.7 mmol) in H ₂ 0 (89 ml) was treated with Na ₂ C0 ₃ (7.27 g, 68.6 mmol) and methyl 4,4- dimethyl-3-oxo-pentanoate (CAS: 55107-14-7, 5.42 g, 34.3 mmol) and the reaction mixture was stirred at RT for 4 days. The reaction mixture was neutralised to pH 7-8 with aqueous 1M HC1 solution and the reaction mixture was filtered. The solid was washed with H ₂ 0 followed by Et ₂ 0. The Et ₂ 0 filtrate was diluted with EtOAc and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organics were washed with brine, dried with NaS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (1.24 g, 18%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.25 (9H, s), 2.58 (3H, s), 6.17 (1H, s) plus one proton not observed.

b. 4-(tert-ButyI)-6-chloro-2-(methylthio)pyrimidine (ZZb)

Intermediate ZZa (1.24 g, 6.3 mmol) was treated with POCl ₃ (2.9 ml, 31.3 mmol) and the reaction mixture was stirred at 80 °C for 2.5 h. The volatiles were evaporated under reduced pressure and the residue was azeotroped with toluene. The residue was partitioned between EtOAc and saturated aqueous NaHC0 ₃ solution and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated NaHC0 ₃ solution. The organic phase was washed with brine, dried with NaS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (1.09 g, 81%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.31 (9H, s), 2.56 (3H, s), 6.96 (1H, s).

c. 4-(tert-Butyl)-6-chIoro-2-(methylsulfonyl)pyrimidine (Intermediate ZZc)

A solution of Intermediate ZZb (550 mg, 2.5 mmol) in DCM (10 ml) was treated with mCPBA (1.32 g, 7.6 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with DCM and saturated aqueous NaHC0 ₃ solution and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were washed with saturated NaHC0 ₃ solution, dried with NaS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-25% EtOAc/cyclohexane afforded the title compound (440 mg, 70%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.39 (9H, s), 3.37 (3H, s), 7.51 (1H, s). d. Intermediate ZZ

A suspension of NaH (60% dispersion, 85 mg, 2.1 mmol) in dry DMF (5 ml) under nitrogen was treated with MeS0 ₂ NH ₂ (200 mg, 2.1 mmol) and the reaction mixture was stirred at RT for 30 min. A solution of Intermediate ZZc (440 mg, 1.8 mmol) in DMF (3 ml) was added to the reaction mixture and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and H ₂ 0 and the two phases were separated. The aqueous phase was acidified to pH 4 with aqueous 1M HC1 solution, extracted with EtOAc and the combined organic phases were washed with brine, dried with NaS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc/cyclohexane afforded the title compound (55 mg, 12%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.32 (9H, s), 1.57 (1H, br s), 3.47 (3H, s), 7.02 (1H, s).

Intermediate AB

4-(tert-ButyI)-6-chIoro-2-(4-methylpiperazin-l-yI)pyrimidine

a. 6-(tert-ButyI)-2-(4-methylpiperazin-l-yl)pyrimidin-4(lH)-one (ABa)

A solution of 4-methylpiperazine-l-carboximidamide (CAS: 45798-01-4, 5.00 g, 35.2 mmol) and ethyl pivaloylacetate (CAS: 17094-34-7, 5.30 ml, 30.2 mmol) in methanol (150 ml) was treated with tBuO (17.0 g, 150.0 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. H ₂ 0 was added and the reaction mixture was acidified to pH 5 with 6M HC1 solution and washed with EtOAc. The aqueous phase was applied to a SCX cartridge, eluting with methanol followed by 2N NH ₃ in MeOH. The organic was dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (548 mg, 7%).

LCMS (Method 1): Rt 1.96 min, m/z 251 [MH ⁺ ].

b. Intermediate AB

Intermediate ABa (548 mg, 2.2 mmol) was treated with POCl ₃ (2 ml, 22.0 mmol) and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was cooled to RT, quenched by slow addition of methanol and the volatiles were evaporated under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM, followed by a further FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (143 mg, 24%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.25 (9H, s), 2.49 (3H, s), 2.68 (4H, br s), 3.99 (4H, br s), 6.56 (1H, s), plus one proton not observed.

Intermediate AC

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(l-methylcyclopropyl)-[l, 2,4]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthaIen-l-yl)ureido )pyrimidine-2- carboxylate

a. N'-(5-Fluoropyridin-2-yl)-l-methylcyclopropane-l-carbohydraz ide

(Intermediate ACa)

A solution of 1-methylcyclopropane-l-carboxylic acid (CAS: 6914-76-7, 5 g, 50.0 mmol), (5-fluoro-2-pyridyl)hydrazine (WO 2014/195402, 6.35 g, 50.0 mmol) and HOBt hydrate (0.77 g, 5.0 mmol) in DCM (75 ml) was cooled in ice and treated with EDC.HCl (9.60 g, 50.0 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was partitioned between 2-methyltetrahydrofuran and H ₂ 0. The two phases were separated and the organic phase was extracted with aqueous 1M HCl solution. The aqueous phase was washed with Et ₂ 0 and basified with solid K2CO3. The resulting aqueous phase was extracted with DCM, the organic phase was dried with NaS0 ₄ and the solvent was removed under reduced pressure. Trituration with 20% Et ₂ 0/Petrol afforded the title compound (6.1 g, 58%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.66 (2H, dd, J = 6.6, 4.0 Hz), 1.24 (2H, dd, J = 6.6, 4.0 Hz), 1.43 (3H, s), 6.66 (1H, dd, J = 9.0, 3.5 Hz), 6.81 (1H, d, J = 3.8 Hz), 7.24-7.31 (1H, m), 7.97 (1H, d, J = 2.8 Hz), 8.02 (1H, d, J = 2.8 Hz).

b. 6-Fluoro-3-(l-methylcyclopropyl)-[l,2,4]triazolo[4,3-a]pyrid ine (Intermediate

A solution of Intermediate ACa (6.0 g, 28.7 mmol), triphenylphosphine (15.0 g, 57.2 mmol) and TEA (11.6 g, 114.8 mmol) in 2-methyltetrahydrofuran (120 ml) was treated with hexachloroethane (13.6 g, 57.3 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H 0 and the two phases were separated. The organic phase was extracted with an aqueous 1M HCl solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K2CO3. The resulting aqueous phase was extracted with DCM, the organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Trituration with 10% Et ₂ 0/petrol (v/v 1 :1) afforded the title compound (4.35 g, 79%).

Ή NMR (300 MHz, CDCI3): 0.98 (2H, dd, J = 6.6, 4.0 Hz), 1.18 (2H, dd, J = 6.6, 4.0 Hz), 1.50 (3H, s), 7.20 (1H, ddd, J = 9.8, 7.6, 2.2 Hz), 7.74 (1H, ddd, J = 10.0, 5.0, 0.8 Hz), 8.07 (1H, ddd, J = 3.1, 2.2, 0.8 Hz)

c. (lS,4R)-4-((3-(l-Methylcyclopropyl)-[l,2,4]triazolo[4,3-a]py ridin-6-yl)oxy)- 1,2,3,4-tetrahydronaphthalen-l-amine (Intermediate ACc)

A stirred solution of Intermediate ACb (4.35 g, 22.8 mmol), (lR,4S)-4-amino- 1,2,3,4-tetrahydro-naphthalen-l-ol (WO 2014/195402, 3.70 g, 23.0 mmol) and 18-crown- 6 (0.6 g, 2.3 mmol) in 2-methyltetrahydrofuran (100 ml) at 0 °C under nitrogen was added with potassium tert-butoxide (2.93 g, 26.2 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3), warmed to RT and stirred for 2 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The organic phase was extracted with aqueous 10% citric acid solution. The aqueous phase was washed with Et ₂ 0 and then basified with solid K ₂ C0 ₃ . The resulting aqueous phase was extracted with DCM. The organic phase was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was applied to a plug of silica, eluting with DCM followed by 5% 2N NH ₃ in MeOH/DCM to afford the title compound (6.6 g, 87%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.90-0.94 (2H, m), 1.13-1.16 (2H, m), 1.46 (3H, s), 1.88-2.15 (3H, m), 2.35-2.45 (1H, m), 3.99-4.03 (1H, m), 5.27 (1H, t, J = 4.5 Hz), 7.15 (1H, dd, J = 9.6, 2.3 Hz), 7.25-7.34 (3H, m), 7.37-7.44 (1H, m), 7.61 (1H, d, J = 7.7 Hz), 8.27 (1H, dd, J = 8.1, 0.8 Hz) plus two protons not observed.

d. l-((lS,4R)-4-((3-(l-MethylcyclopropyI)-[l,2,4]triazolo[4,3-a ]pyridin-6- yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)urea (Intermediate ACd)

A solution of Intermediate ACc (1.00 g, 3.00 mmol) in DCM (10 ml) was treated with (trimethylsilyl)isocyanate (0.5 ml, 3.6 mmol) at 0 °C. The reaction mixture was warmed at RT and stirred overnight. The reaction mixture was cooled and treated with methanol and the solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (798 mg, 70%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.93-0.95 (2H, m), 1.14-1.17 (2H, m), 1.47 (3H, s), 1.99-2.21 (3H, m), 2.29-2.37 (1H, m), 4.46 (2H, s), 5.03-5.10 (1H, m), 5.25 (1H, t, J = 3.4 Hz), 7.10 (1H, dd, J = 7.4, 1.5 Hz), 7.26-7.40 (4H, m), 7.51 (1H, d, J = 5.7), 7.66 (1H, d, J = 7.4), 7.71 (1H, d, J = 1.5 Hz),

e. Intermediate AC

A solution of Intermediate ACd (798 mg, 2.11 mmol) in dioxane (20 ml) was treated with Intermediate Id (513 mg, 2.11 mmol), Pd(OAc) ₂ (25 mg g, 0.11 mmol), XantPhos (121 mg, 0.21 mmol) and Cs ₂ C0 ₃ (1.08 g, 3.00 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3) and then heated at 90 °C overnight. The reaction mixture was cooled to RT, filtered and washed with ETOAc and the filtrate was evaporated under reduced pressure. The residue was applied to a plug of silica, eluting with EtOAc followed by 10% IMS/EtOAc to afford the title compound (580 mg, 47%).

'H NMR (300 MHz, CDC1 ₃ ): 0.94-0.96 (2H, m), 1.08 (3H, t, J = 5.3 Hz), 1.16-1.19

(2H, m), 1.36 (9H, s), 1.49 (3H, s), 2.13-2.43 (4H, m), 4.15-4.28 (2H, m), 5.20-5.30 (2H, m), 6.78 (1H, s), 7.11 (1H, dd, J = 7.4, 1.5 Hz), 7.26-7.39 (5H, m), 7.51-7.56 (1H, m), 7.70 (1H, d, J = 7.3 Hz), 7.74 (1H, d, J = 1.1 Hz).

Intermediate AD

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-(morpholine-4-carbonyl)-[ l,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3j4-tetrahydronaphthalen-l-yl)ureido )pyrimidine-2- carboxylate

Ethyl 6-fluoro- [1,2,4] triazolo [4,3-a] pyridine-3-carboxylate (Intermediate

A solution of (5-fluoro-2-pyridyl)hydrazine (WO 2014/195402, 12.7 g, 100.0 mmol) in methanol (300 ml) was treated with ethyl 2-oxoacetate 50% in toluene (CAS: 924-44-7, 20.5 g, 100.0 mmol) and the reaction mixture was heated to 60 °C for 1 h. The reaction mixture was cooled to RT and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (300 ml) and treated with PhI(OAc) ₂ and the reaction mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure. Trituration with MeCN afforded the title compound (15.5 g, 74%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.51 (3H, t, J = 7.1 Hz), 4.59 (2H, q, J = 7.1 Hz), 7.43

(1H, ddd, J = 9.8, 7.4, 2.2 Hz), 7.96 (1H, ddd, J = 10.0, 4.8, 0.8 Hz), 9.14 (1H, ddd, J = 3.4, 2.2, 0.8 Hz)

b. (6-FIuoro-[l,2,4]triazoIo[4,3-a]pyridin-3-yI)(morpholino)met hanone

(Intermediate ADb)

A solution of morpholine (3.6 g, 41.3 mmol) in THF (100 ml) was cooled to -78 °C and treated with n-BuLi (16 M, 27.5ml, 44 mmol). The reaction mixture was stirred for 10 min. A solution of Intermediate ADa in THF was added to the reaction mixture and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with H ₂ 0 and extracted with EtOAc. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc/cyclohexane afforded the title compound (1.99 g, 25%).

Ή NMR (300 MHz, CDC1 ₃ ): 3.82 (6H, m), 4.58 (2H, t, J = 4.7 Hz), 7.38 (1H, ddd, J = 9.8, 7.3, 2.3 Hz), 7.87 (1H, ddd, J = 10.0, 5.0, 0.8 Hz), 9.14 (1H, ddd, J = 4.2, 2.3, 0.8 Hz) c. (6-(((lR,4S)-4-Amino-l,2,3,4-tetrahydronaphthalen-l-yI)oxy)- [l,2,4]triazolo[4,3-a]pyridin-3-yl)(morphoIino)methanone (Intermediate ADc)

A solution of Intermediate ADb (125 mg, 0.5 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydro-naphthalen-l-ol (WO 2014/195402, 81.5 mg, 0.5 mmol) and 18-crown-6 (66 mg, 0.25 mmol) in 2-methyltetrahydrofuran (3 ml) at 0 °C under mtrogen was added with potassium tert-butoxide (67.2 mg, 0.6 mmol). The reaction mixture was evacuated and purged with argon (x 3), warmed to RT and stirred for 1 h. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with EtOAc and DCM. The combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (238 mg, 61%).

'H NMR (400 MHz, CDC1 ₃ ): 1.85-1.95 (2H, m), 2.04-2.14 (1H, m), 2.34-2.41 (1H, m), 3.84-3.88(6H, m), 3.96-4.00 (1H, m), 4.60 (2H, t, J = 4.5 Hz), 5.35 (1H, t, J = 3.3 Hz), 7.25-7.41 (4H, m), 7.61 (1H, d, J = 7.7 Hz), 7.79 (1H, dd, J = 9.8, 0.8 Hz), 8.94 (1H, d, J = 2.0 Hz) plus two protons not observed.

d. 1-((1 S,4R)-4-((3-(Morpholine-4-carbonyl)- [1 ,2,4] triazolo [4,3-a] py ridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)urea (Intermediate ADd)

A solution of triphosgene (176 mg, 0.6 mmol) in DCM (20 ml) was cooled to -10 °C. A solution of Intermediate ADc (212 mg, 0.5 mmol) in DCM (20 ml) was cooled to -10 °C and added to the reaction mixture. The reaction mixture was stirred for 1 h, treated with 2N NH ₃ in MeOH and stirred for a further 2 h. The solvents were removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated aqueous NaHC0 ₃ solution. The organic phase was dried with MgS0 ₄ and the solvent was evaporated under reduced pressure to afford the title compound. (Crude taken forward assuming quantitative yield: 235 mg, 100%).

'H NMR (400 MHz, CDC1 ₃ ): 2.02-2.22 (3H, m), 2.47-2.56 (1H, m), 3.74-3.89 (6H, m), 4.47-4.62 (4H, m), 4.98-5.06 (1H, m), 5.45-5.48 (1H, m), 5.57 (1H, d, J = 7.8 Hz), 7.32- 7.37 (2H, m), 7.48 (1H, d, J = 7.6 Hz), 7.78 (1H, dd, J = 9.8, 0.7 Hz), 8.48 (1H, d, J = 1.5 Hz), plus two protons obscured by solvent peak.

e. Intermediate AD

A solution of Intermediate ADd (235 mg, 0.54 mmol) in dioxane (20 ml) was treated with Intermediate Id (131 mg, 0.54 mmol), Pd(OAc) ₂ (6 mg, 0.03 mmol), XantPhos (31 mg, 0.05 mmol) and Cs ₂ C0 ₃ (247 mg, 0.75 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3) and then heated at 95 °C overnight. The reaction mixture was diluted with H ₂ 0 and extracted with EtOAc. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc/cyclohexane followed by further purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (195 mg, 56%).

Ή NMR (400 MHz, CDC1 ₃ ): 1.12 (3H, t, J = 7.0 Hz), 1.36 (9H, s), 2.11-2.24 (3H, m), 2.45-2.54 (1H, m), 3.77-3.97 (6H, m), 4.17-4.33 (2H, m), 4.52-4.68 (2H, m), 5.16-5.23 (1H, m), 5.42-5.47 (1H, m), 7.14 (1H, br s), 7.22-7.40 (4H, m), 7.50-7.53 (1H, m), 7.80 (1H, dd, J = 9.8, 0.6 Hz), 8.16 (1H, br s), 8.77 (1H, br s), 9.21 (1H, br s).

Intermediate AE

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-2-methylpyrrolidin-2 -yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthaIen-l- yl)ureido)pyrimidine a. tert-Butyl (S)-2-(2-(5-fluoropyridin-2-yI)hydrazine-l-carbonyl)-2- methylpyrrolidine-l-carboxylate (Intermediate AEa)

A solution of N-Boc-2-methyl-L-proline (CAS: 103336-06-7, 5.9 g, 38.7 mmol), (5-fluoro-2-pyridyl)hydrazine (WO 2014/195402, 5.8 g, 46.4 mmol) and HOBt Hydrate (0.63 g, 4.6 mmol) in DCM (100 ml) was treated with EDC.HC1 (9.60 g, 50.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0. The aqueous phase was extracted with 2- methyltetrahydrofuran, the combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (Crude taken forward assuming quantitative yield: 13.0 g, 100%).

LCMS (Method 4): Rt 1.28 min, m/z 339 [MH ⁺ ].

b. tert-Butyl (S)-2-(6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3-yl)-2-

A solution of Intermediate AEa (13 g, 38.7 mmol), triphenylphosphine (20.3 g, 77.4 mmol) and TEA (22 ml, 155.0 mmol) in 2-methyltetrahydrofuran (150 ml) was treated with hexachloroethane (18.1 g, 77.4 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between 2-methyltetrahydrofuran and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with 2- methyltetrahydrofuran and the combined organic phases was dried with MgS0 ₄ . The solvent was removed under reduced pressure and the residue was purified by FCC, eluting with 0-100% EtOAc/Cyclohexane to afford the title compound (15 g, >100%).

LCMS (Method 4): Rt 1.11 min, m/z 321 [MH ⁺ ]. c. (S)-6-Fluoro-3-(2-methylpyrrolidin-2-yI)-[l,2,4]triazolo[4,3 -a]pyridine (Intermediate AEc)

A solution of Intermediate AEb (15 g, 38.7 mmol) in DCM (50 ml) was treated with TFA (50 ml) and the reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was purified by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM. The resulting solid was triturated with MeCN and the mother liquors were evaporated and triturated with MeCN (x 3) to afford the title compound (2.5 g, 30%).

LCMS (Method 4): Rt 1.18 min, m/z 221 [MH ⁺ ].

d. (lS,4R)-4-((3-((S)-2-Methylpyrrolidin-2-yl)-[l,2,4]triazolo[ 4,3-a]pyridin-6- yl)oxy)-l,2,3.4-tetrahydronaphthalen-l-amine (Intermediate AEd)

A stirred solution of Intermediate AEc (1.1 g, 5 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydro-naphthalen-l-ol (WO 2014/195402, 0.82 g, 5 mmol) in dry DMF (15 ml) was treated with NaH (60% dispersion in oil, 0.6 g, 15.0 mmol) and the reaction mixture was heated to 60 °C overnight. The reaction mixture was cooled at RT, quenched with MeOH and H ₂ 0. The aqueous phase was extracted with DCM and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM followed by further purification, eluting with 0-10% 2N NH ₃ afforded the title compound (590 mg, 32%).

LCMS (Method 4): Rt 1.40 min, m z 364 [MH ⁺ ].

e. l-((lS,4R)-4-((3-((S)-2-Methylpyrrolidin-2-yl)-[l,2,4]triazo lo[4,3-a]pyridin-6- yl)oxy)-l,2,3 _> 4-tetrahydronaphthalen-l-yl)urea (Intermediate AEe)

A solution of Intermediate AEd (278 mg, 0.76 mmol) in THF (10 ml) was treated with (trimethylsilyl)isocyanate (71 μΐ, 0.84 mmol) and the reaction mixture was stirred at RT for 2 h. A further aliquot of (trimethylsilyl)isocyanate (6 μΐ, 0.08 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with methanol and stirred for 3 h and the solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (202 mg, 65%).

LCMS (Method 4): Rt 1.29 min, m/z 407 [MH ⁺ ].

e. Intermediate AE

A solution of Intermediate AEe (202 mg, 0.5 mmol) in dioxane (10 ml) was treated with Intermediate Id (121 mg, 0.5 mmol), Pd(OAc) ₂ (5.6 mg , 0.03 mmol), XantPhos (29 mg, 0.05 mmol) and Cs ₂ C0 ₃ (228 mg, 0.7 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 95 °C for 5.5 h. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was partitioned between H ₂ 0 and DCM and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were evaporated under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (37 mg, 12%).

LCMS (Method 4): Rt 1.90 min, m/z 613 [MH ⁺ ]. Intermediate AF

2,2,2-Trichloethyl(6-(teri-butyI)-2-(methylthio)pyrimidin-4- yl)carbamate

(Intermediate AF)

a. 6-(ferf-Butyl)-2-(methylthio)pyrimidin-4-amine (Intermediate AFa)

A partial suspension of Intermediate ZZb (50 mg, 0.23 mmol) in IPA (0.7 mL) was added with ammoma solution (0.14 mL, 33% in H ₂ 0) and the reaction mixture was warmed under microwave irradiation at 150 °C for 10 hours. Another aliquot of ammonia solution (0.30 mL, 33% in H ₂ 0) was added and the reaction mixture was warmed under microwave irradiation at 180 °C for a further 1 hour. The solvent was removed under reduced pressure and the resulting gum was eluted onto SCX-2 ion exchange resin in MeOH followed by 2N ammonia in MeOH. The methanolic ammonia fraction was evaporated under reduced pressure to afford the title compound (33 mg, 72%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.26 (9H, s), 2.51 (3H, s), 4.70 (2H, br s), 6.09 (1H, s).

b. Intermediate AF

A stirred solution of Intermediate AFa (28 mg, 0.14 mmol) in dioxan (1.4 mL) was added with triethylamine (30 μί, 0.21 mmol) and phenylchloro formate (20μί, 0.16 mmol), then warmed to 150°C for 0.5 hours under microwave irradiation. 2,2,2- Trichloroethylchloroformate (22μί, 0.16 mmol) was added and the reaction mixture was warmed for 1 hour to 150 °C under microwave irradiation. The resulting mixture was allowed to cool to 20°C and filtered, washing with dioxan. The liquors were partitioned with EtOAc and water and the two phases were separated. The aqueous phase was extracted with EtOAc (x 2) and the combined organic layers were washed with 10% citric acid solution, saturated NaHC0 ₃ solution and brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting 0-5% EtOAc in cyclohexane afforded the title compound (25 mg, 56%).

lH NMR(300 MHz, CDC1 ₃ ): 1.33 (9H, s), 2.54 (3H, s), 4.83 (2H, s), 7.50 (1H, br s), 7.59 (1H, s).

Intermediate AG

Ethyl 4-(ter/-butyI)-6-(3-((lS,4R)-4-((3-isobutyI-[l,2,4]triazoIo[ 4,3-a]pyridine-6- yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carbox yIate

a. i\ -(5-Fluoropyridin-2-yl)-3-methylbutanehydrazine (Intermediate AGa)

A solution of isovaleric acid (8.02 g, 78.62 mmol) in DCM (120 ml) was treated with EDC (16.62 g, 86.56 mmol), HOBt hydrate (1.06 g, 7.85 mmol) and (5-fluoro-2- pyridyl)hydrazine (10.0 g, 78.74 mmol). The reaction mixture was stirred at 20 °C for 18 hours and then diluted with DCM and water. The two layers were separated and the organic phase was dried with MgS0 ₄ . The solvent was removed under reduced pressure. Purification by FCC, eluting 0-100% EtOAc in cyclohexane, followed by trituration with diethyl ether afforded the title compound (3.49g, 21%).

LCMS (Method 4): Rt = 0.94 min, m/z 212 [M+H ⁺ ], m/z 234 [M+Na ⁺ ].

b. 6-Fluoro-3-isobutyl-[l,2,4]triazolo[4,3-a]pyridine (Intermediate AGb)

A solution of Intermediate AGa (3.39 g, 16.5 mmol) in 2-methyltetrahydrofuran (70 n L) was treated with triphenylphosphine (4.33 g, 33.08 mmol), triethylamine (6.67 g, 66.0 mmol) and cooled to 0 °C before hexachloroethane (7.84 g, 33.08 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight. The reaction mixture was filtered, washing the precipitate with diethyl ether. The liquors were washed with water, dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-10% MeOH/DCM followed by trituration with diethyl ether afforded the title compound (2.60 g, 81%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.05 (6H, d, J = 6.64 Hz), 2.22-2.37 (1H, m), 2.94 (2H, d, J = 7.23 Hz), 7.17 (1H, dt, J = 2.2, 7.5 Hz), 7.75 (1H, q, J = 4.9 Hz), 7.81 (1H, t, J = 2.4 Hz). LCMS (Method 4): Rt = 0.96 min, m/z 194 [M+H ⁺ ], m/z 216 [M+Na ⁺ ].

c. (lS,4R)-4-((3-Isobutyl-[l,2,4]triazolo[4,3-a]pyridine-6-yI)o xy)-l,2,3,4- tetrahydronaphthalen-l-amine (Intermediate AGc)

A solution of Intermediate AGb (2.60 g, 13.47 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (2.20 g, 13.47 mmol) and 18-crown-6 ether (1.77 g, 6.73 mmol) in 2-methyltetrahydrofuran (30 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture. The reaction mixture was cooled at 0 °C and potassium tert-butoxide (1.81 g, 16.16 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight, diluted with EtOAc and washed with water. The organic phase was dried with MgS0 ₄ . The solvent removed under reduced pressure. Purification by FCC eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (3.47 g, 76%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.02 (6H, dd, J = 6.6, 0.8 Hz), 1.87-1.99 (2H, m), 2.00-2.15 (3H, m), 2.18-2.31 (1H, m), 2.32-2.44 (1H, m), 2.90 (2H, dd, J = 3.2, 7.3 Hz), 4.00 (1H, dd, J = 5.0, 8.1 Hz), 5.25 (1H, t, J = 4.6 Hz), 7.11 (1H, dd, J = 2.1, 9.9 Hz), 7.22- 7.34 (2H, m), 7.35-7.44 (1H, m), 7.46 (1H, d, J = 1.4 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 9.9 Hz). LCMS (Method 4): Rt = 0.76 min, m/z 337 [M+H ⁺ ], m/z 359 [M+Na ⁺ ]. d. l-((lS,4R)-4-((3-Isobutyl-[l,2,4]triazolo[4,3-a]pyridine-6-y I)oxy)-l,2,3,4- tetrahydronaphthalen-l-yI)urea (Intermediate AGd)

A solution of triphosgene (970 mg, 3.27 mmol) in DCM (15 mL) under nitrogen was cooled to -10 °C and a solution of Intermediate AGc (1.0 g, 2.97 mmol) and triethylamine (1.20 g, 11.88 mmol) in DCM (15mL) was dropwise added keeping the temperature <-10 °C. This solution was stirred at 0 °C for one hour before a solution of NH ₃ in MeOH (2N, 18 mL, 35.64 mmol) pre-cooled to 0 °C was added. The reaction mixture was allowed to warm to 20 °C. The mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were dried over solid MgSC¼. The solvent removed under reduced pressure. Purification by FCC eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (970 mg, 86%).

¾ NMR (300 MHz, CDC1 ₃ ): 0.98 (6H, dd, J = 4.7 Hz), 1.98-2.20 (4H, m), 2.29- 2.39 (1H, m), 2.81 (2H, t, J = 6.2 Hz), 4.86 (2H, br s), 5.03-5.12 (1H, m), 5.25 (1H, t, J = 4.3 Hz), 5.84 (1H, d, J = 8.7 Hz), 7.00 (1H, dd, J = 2.1, 9.9 Hz), 7.22-7.38 (4H, m), 7.47- 7.56 (2H, m). LCMS (Method 4): Rt = 1.00 min, m/z 380.3 [M+H ⁺ ], m/z 402.2 [M+Na ⁺ ]. e. Intermediate AG

A solution of intermediate AGd (950 mg, 2.50 mmol), Intermediate Id (610 mg, 2.50 mmol), Pd(Ac) ₂ (30 mg, 0.125 mmol), Xantphos (150 mg, 0.25 mmol) and cesium carbonate (1.14 g, 0.35 mmol) in dioxan (15 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication. The reaction mixture was heated at 90°C for 20 hours. The reaction mixture was cooled at RT, filtered through a pad of Celite®, washing the precipitate with DCM and MeOH. The liquor was evaporated under reduced pressure. Purification by FCC eluting 0 to 10% MeOH in DCM afforded the title compound (1.14 g, 78%).

*HNMR (300 MHz, CDC1 ₃ ): 1.02 (6H, dd, J = 2.1, 6.7 Hz), 1.12 (3H, t, J = 7.1 Hz), 1.36 (9H, s), 2.11-2.32 (4H, m), 2.33-2.46 (ΙΗ, ηι), 2.90 (2H, q, J = 3.9 Hz), 4.12-4.34 (2H, m), 5.19-5.35 (2H, m), 6.90-6.98 (1H, m), 7.11 (1H, dd, J = 2.1, 9.9 Hz), 7.14-7.42 (5H, m), 7.50 (1H, d, J = 1.3 Hz), 7.57 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 9.9 Hz). LCMS (Method 4): Rt = 1.48 min, mix 586 [M+H ⁺ ], m/z 608 [M+Na ⁺ ].

Intermediate AH

Ethyl 4-(teri-butyl)-6-(3-((lS,4R)-4-((3-(l-methyIoxetan-3-yI)-[l, 2,4]triazoIo[4,3- a]pyridine-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureid o)pyrimidine-2- carboxylate

A^-(5-FIuoropyridin-2-yl)-3-methyIoxetene-3-carbohydrazide (Intermediate

A solution of 3-methoxy-2,2-dimethylpropionoc acid (5.00 g, 43.10 mmol) and (5- fluoro-2~pyridyl)hydrazine (5.47 g, 43.10 mmol) in DCM (100 ml) was treated with HOBt hydrate (0.66 g, 4.30 mmol), and cooled in an ice bath before adding EDC (8.25 g, 43.1 mmol). The reaction mixture was stirred at 0 °C for 5 minutes and at RT for 1 hour and then the solvent was removed under reduced pressure. The residue was partitioned between water and 2-methyltetrahydrofuran. The two phases were separated and the organic layer was washed with water, brine and dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure. The residue was dissolved in DCM, stirred with flash silica and filtered washing the silica with DCM. The solvent was removed under reduced pressure and the resulting brown solid was triturated with diethyl ether to afford the title compound (5.60 g, 58%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.67 (3H, s), 4.51 (2H, d, J = 6.1 Hz), 4.97 (2H, d, J = 6.1), 6.67 (1H, dd, J = 3.5, 9.0 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.31 (1H, dt, J = 2.9, 7.8 Hz), 8.03 (1H, d, J = 2.9 Hz), 8.09 (1H, s).

b. 6-Fluoro-3-(l-methyloxetan-3-yl)- [1,2,4] triazolo [4,3-a] pyridine (Intermediate

A solution of Intermediate AHa (5.60 g, 24.90 mmol) in 2-methyltetrahydrofuran (100 mL) was treated with triphenylphosphine (13.00 g, 49.60 mmol), triethylamine (10.10 g, 100.0 mmol) and finally hexachloroethane (14.1 g, 59.50 mmol) was added. The reaction mixture was stirred for 1 hour and then washed with water, 10% citric acid solution and aqueous IN HCl solution. The HCl layer was basified with solid potassium carbonate and extracted into DCM (x 3). The combined DCM layers were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (1.00 g, 19%).

1H NMR (300 MHz, CDC1 ₃ ): 1.98 (3H, s), 4.90 (2H, d, J = 6.4 Hz), 5.17 (2H, d, J = 6.4 Hz), 7.21-7.25 (1H, m), 7.82 (1H, dq, J = 0.8, 5.0 Hz), 8.23 (1H, dt, J = 0.8, 2.2 Hz), c. (lS,4R)-4-((3-MethyIoxetan-3-yl)-[l,2,4]triazolo[4,3-a]pyrid ine-6-yl)oxy)- 1,2,3,4-tetrahydronaphthalen-l-amine (Intermediate AHc)

A solution of Intermediate AHb (1.00 g, 4.83 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (790 mg, 4.83 mmol) and 18-crown-6 ether (130 mg, 0.50 mmol) in 2-methyltetrahydrofuran (50 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture. The mixture was then cooled to 0°C and potassium tert-butoxide (620 mg, 5.54 mmol) was added. The reaction mixture was allowed to warm to 20°C overnight with stirring. This mixture was washed with water and 10% citric acid solution. The citric acid solution was washed with diethyl ether, then basified with solid potassium carbonate and extracted with DCM (x 2). The combined organic layers were dried with Na ₂ S0 ₄ to afford the title compound (970 mg, 57%).

'H MR (300 MHz, CDC1 ₃ ): 1.88-2.11 (6H, m), 2.34-2.43 (1H, m), 3.98-4.02 (1H, m), 4.82 (2H, q, J = 6.3 Hz), 5.15 (2H, q, J = 3.0 Hz), 5.26 (1H, t, J = 4.7 Hz), 7.17 (1H, dd, J = 2.1, 9.9 Hz), 7.22-7.31 (2H, m), 7.38 (1H, dt, J = 1.9, 6.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.75 (1H, dd, J = 0.8, 9.9 Hz), 7.79 (1H, d, J = 1.3 Hz), plus two protons not observed. d. l-((lS,4R)-4-((3-(l-Methyloxetan-3-yI)-[l,2,4]triazolo[4,3-a ]pyridine-6- yI)oxy)-l,2,3,4-tetrahydronaphthalen-l-yI)urea (Intermediate AHd)

A solution of triphosgene (470 mg, 1.58 mmol) in DCM (8 mL) under nitrogen was cooled to -10°C and a solution of Intermediate AHc (500 mg, 1.43 mmol) and triethylamine ( 580 mg, 5.72 mmol) in DCM (8mL) was dropwise added keeping the temperature <-10 °C. This solution was stirred at 0 °C for one hour before a solution of NH ₃ in MeOH (2N, 8.6 mL, 17.10 mmol) pre-cooled to 0 °C was added. The reaction mixture was allowed to warm to 20°C. The mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were dried over solid MgS0 ₄ . The solvent removed under reduced pressure and purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (480 mg, 85%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.97 (3H, s), 2.05-2.21 (3H, m), 2.33-2.45 (1H, m), 4.53 (2H, s), 4.71 (2H, q, J = 6.7 Hz), 4.82 (1H, d, J = 6.8 Hz), 4.97-5.05 (1H, m), 5.09 (1H, d, J = 6.6 Hz), 5.32-5.38 (1H, m), 5.78 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 2.1, 9.9 Hz), 7.19-7.24 (2H, m), 7.28-7.34 (1H, m), 7.46 (1H, d, J = 8.0 Hz), 7.72 (1H, d, J = 9.9 Hz), 7.75 (1H, d, J = 1.3 Hz),

e. Intermediate

A solution of Intermediate AHd (480 mg, 1.22 mmol), Intermediate Id (300 mg,

1.22 mmol), palladium(II)acetate (14 mg, 0.06 mmol), Xantphos (70 mg, 0.120 mmol) and cesium carbonate (560 mg, 1.70 mmol) in dioxan (8 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication. The reaction mixture was warmed to 90°C for 20 hours. The reaction mixture was filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were removed under reduced pressure and the residue was purified by FCC eluting 0 to 10% EtOH in DCM to afford the title compound (520 mg, 71%).

LCMS (Method 4): Rt = 1.39 min, m/z 600 [M+H ⁺ ], m/z 622 [M+Na ⁺ ].

Intermediate AI

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-neopentyl)-[l,2,4]triazol o[4,3-a]pyridine-6- yl)oxy)-l,2,3 ₅ 4-tetrahydronaphthalen-l-yI)ureido)pyrimidine-2-carbox ylate

a. iV-(5-Fluoropyridin-2-yl)-3,3-dimethylbutanehydrazide (Intermediate Ala)

A solution of 3,3-dimethylbutanoic acid (5.00 g, 43.10 mmol) and (5-fluoro-2- pyridyl)hydrazine (5.47 g, 43.10 mmol) in DCM (100 ml) was treated with HOBt hydrate (0.66 g, 4.30 mmol), and cooled in an ice bath before adding EDC (8.25 g, 43.1 mmol). The reaction mixture was warmed at RT and stirred for 1 hour and then the solvent was removed under reduced pressure. The residue was partitioned between water and 2- methyltetrahydrofuran and the two phases were separated. The organic layer was extracted with IN HC1 solution. The combined aqueous layers were washed with diethyl ether and basified with solid potassium carbonate and then extracted with DCM (x 3). The combined organic layers were dried over solid sodium sulphate and the solvent was removed under reduced pressure. The resulting solid was triturated with diethyl ether to afforded the title compound (6.60 g, 68%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.07 (9H, s), 2.14 (2H, s), 6.67 (1H, dd, J = 3.5, 9.0), 6.84 (1H, d, J = 3.6 Hz), 7.28 (1H, dt, J - 2.9, 7.8 Hz), 7.65 (1H, s), 8.02 (1H, d, J = 2.9 Hz).

b. 6-Fluoro-3-neopentyl-[l,2,4]triazolo[4,3-a]pyridine (Intermediate Alb)

A solution of Intermediate Ala (6.60 g, 29.30 mmol) in 2-methyltetrahydrofuran (300 mL) was treated with triphenylphosphine (15.40 g, 58.80 mmol), triethylamine (11.90 g, 117.8 mmol) and finally hexachloroethane (13.9 g, 58.60 mmol) was added. The reaction mixture was stirred for 1 hour and then it was washed with water and 10% citric acid solution. The organic phase was extracted with IN HC1 aqueous solution and this layer was washed with diethyl ether, basified with solid K ₂ C0 ₃ and extracted into DCM (x 3). The combined organic layers were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (5.23 g, 86%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.08 (9H, s), 2.97 (2H, s), 7.16 (1H, dq, J = 2.2, 7.5 Hz), 7.8 (1H, dq, J = 0.8, 4.8 Hz), 7.88 (1H, dq, J = 0.8, 2.2 Hz),

c. (lS,4R)-4-((3-Neopentyl)-[l,2,4]triazolo[4,3-a]pyridine-6-yl )oxy)-l,2,3,4- tetrahydronaphthalen-l-amine (Intermediate Ale)

A solution of Intermediate Alb (5.00 g, 24.20 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (3.94 g, 24.2 mmol) and 18-crown-6 ether (640 mg, 2.40 mmol) in 2-methyltetrahydrofuran (150 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture. The mixture was then cooled to 0 °C and potassium fert-butoxide (3.10 g, 27.70 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight. This mixture was washed with water and extracted with 10% citric acid solution. The aqueous phase was washed with diethyl ether, then basified with K ₂ C0 ₃ and extracted with DCM (x 3). The combined organic layers were dried over Na ₂ S0 ₄ and the solvent was removed under reduced pressure. This product was triturated with diethyl ether to afford the title compound (7.18 g, 85%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.04 (9H, s), 1.87-1.99 (1H, m), 1.99-2.13 (2H, m), 2.32-2.43 (1H, m), 2.93 (2H, d, J = 5.8 Hz), 4.00 (1H, q, J = 5.0 Hz), 5.24 (1H, t, J = 4.6 Hz), 7.11 (1H, dd, J = 2.1, 9.9 Hz), 7.22-7.33 (2H, m), 7.38 (1H, dt, J = 1.7, 7.2 Hz), 7.53 (1H, d, J = 1.4 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.69 (1H, dd, J = 0.8, 9.9 Hz), two protons were not seen.

d. l-((lS,4R)-4-((3-(3-Neopentyl)-[l,2,4]triazolo[4,3-a]pyridin e-6-yl)oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea (Intermediate Aid)

A solution of triphosgene (470 mg, 1.58 mmol) in DCM (8 mL) under nitrogen was cooled to -10°C and a solution of Intermediate Ale (500 mg, 1.43 mmol) and triethylamine ( 580 mg, 5.72 mmol) in DCM (8mL) was dropwise added keeping the temperature <-10°C. This solution was stirred at 0°C for one hour before 2N NH ₃ in MeOH (8.6 mL, 17.10 mmol, pre-cooled to 0°C) was added and the reaction mixture was allowed to warm to 20°C. The mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were dried over solid MgS0 ₄ . The solvent removed under reduced pressure and purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (540 mg, 96%).

LCMS (Method 4): Rt = 1.06 min, m/z 394 [M+H ⁺ ], m/z 416 [M+Na ⁺ ].

e. Intermediate AI

A solution of Intermediate Aid (540 mg, 1.37 mmol), Intermediate Id (330 mg,

1.37 mmol), palladium(II)acetate (15 mg, 0.07 mmol), Xantphos (80 mg, 0.140 mmol) and cesium carbonate (625 mg, 1.92 mmol) in dioxan (8 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication. The reaction mixture was warmed to 90°C for 20 hours, cooled at RT and filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were removed under reduced pressure. Purification by FCC eluting 0 to 10% EtOH in DCM afforded the title compound (440 mg, 53%).

LCMS (Method 4): Rt = 1.51 min, m/z 600 [M+H ⁺ ], m/z 622 [M+Na ⁺ ].

Intermediate AJ

Ethyl 4-(te/-i-butyl)-6-(3-((lS,4R)-4-((3-((S)-l-methoxyethyl)-[l, 2,4]triazolo [4,3- a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthaIen-l-yl)ureido)pyrimidine-2- carboxylate

(S)-N'-(5-Fluoropyridin-2-yl)-2-methoxypropanehydrazide (Intermediate

A stirred solution of (R)-2-methoxypropanoic acid (1.0 g, 9.6 mmol), in DCM (50 ml) was treated with EDC (2.4 g, 12.5 mmol), HOBt hydrate (400 mg, 1.15 mmol) and (5- fluoro-2-pyridyl)hydrazine (1.2 g, 11.5 mmol). After 2 hours the reaction mixture was washed with water and the organic layer was dried over solid magnesium sulphate. The solvent was removed under reduced pressure to afford the title compound which was used in the next step as crude.

LCMS (Method 4): Rt 0.80 min, m/z 214 [M+H ⁺ ], m/z 236 [M+Na ⁺ ].

b. (S)-6-Fluoro-3-(l-methoxyethyl)-[l,2,4]triazoIo[4,3-a]pyridi ne (Intermediate

A solution of Intermediate AJa (2.04 g, 9.6 mmol mmol) in 2- methyltetrahydrofuran (150 mL) was treated with triphenylphosphine (5.03 g, 19.2 mmol), triethylamine (3.88 g, 38.4 mmol) and hexachloroethane (4.49 g, 19.2 mmol) stirring for 1 hour at RT. The reaction mixture was partitioned between water and 2- methyltetrahydrofuran and the two phases were separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (x 2). The combined organic layers were washed with IN HCl solution (x 3). The combined acidic layers were basified with solid sodium hydrogen carbonate and partitioned with DCM (x 3). The combined DCM were passed through a phase separator and the solvent was removed under reduced pressure to afford the title compound (1.43 g, 76%).

LCMS (Method 4): Rt 1.15 min, m/z 196 [M+H ⁺ ].

c. (lS,4R)-4-((3-((S)-l-Methoxyethyl)-[l,2,4]triazolo[4,3-a]pyr idin-6-yI)oxy)- 1,2,3,4-tetrahydronaphthaIen

A solution of Intermediate AJb (1.43 g, 7.3 mmol), (lR,4S)-4-amino-l, 2,3,4- tetrahydronaphthalen-l-ol (1.2 g, 7.3 mmol) and 18-crown-6 ether (482 mg, 1.8 mmol) in 2-methyltetrahydrofuran (160 mL) was added with potassium tert-butoxide (981 mg, 8.76 mmol). The reaction mixture was left overnight and washed with water, dried over solid MgS0 ₄ and the solvent removed under reduced pressure. Purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (1.34 g, 55%).

LCMS (Method 4): Rt 1.43 min, m/z 339 [M+H ⁺ ].

d. l-((lS,4R)-4-((3-((S)-l-Methoxyethyl)-[l,2,4]triazolo[4,3-a] pyridin-6-yI)oxy)- l,2,3 _? 4-tetrahydronaphthalen-l-yI)urea (Intermediate AJd)

A stirred solution of Intermediate AJc (676 mg, 2.0 mmol) in THF (5 mL) was added with trimethylsilylisocyanate (255 mg, 2.2 mmol) and DCM to break up the solid formed. The reaction mixture was stirred for 18 hours and the solvent was removed under reduced pressure. Purification by FCC eluting 0 to 5% (2M NH ₃ in MeOH) in DCM afforded the title compound (639 mg, 84%).

LCMS (Method 4): Rt 1.26 min, m/z 382 [M+H ⁺ ], m/z 404 [M+Na ⁺ ].

e. Intermediate AJ

A solution of Intermediate AJd (639 mg, 1.68 mmol), Intermediate Id (406 mg, 1.68 mmol), palladium(II)acetate (38 mg, 0.168 mmol), Xantphos (194 mg, 0.34 mmol) and cesium carbonate (767 mg, 2.35 mmol) in dioxan (20 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication. The reaction mixture was warmed to 55°C for 24 hours, cooled at RT and partitioned between water and DCM. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC eluting 0 to 8% (2M NH ₃ in MeOH) in DCM afforded the title compound (651 mg, 65%), isolated as a mixture of ethyl and methyl esters (ratio ethyl/methyl 1 :4)).

LCMS (Method 4): Ethyl ester: Rt 1.79 min, m/z 588 [M+H ⁺ ]; methyl ester: Rt 1.85 min, m/z 574 [M+H ⁺ ].

Intermediate AK

Ethyl 4-(ter/-butyl)-6-(3-((lS,4R)-4-((3-(l-methylcyclobutyl)-[l,2 ,4]triazolo[4,3- a]pyridine-6-yI)oxy)-l,2,3 ₅ 4-tetrahydronaphthalen-l-yI)ureido)pyrimidine-2- carboxylate

a. A^-(5-Fluoropyridin-2-yI)-l-methylcyclobutane-l-carbohydrazi de

(Intermediate AKa)

A solution of 3-methoxy-2,2-dimethylpropionoc acid (5.00 g, 43.90 mmol) and (5- fluoro-2-pyridyl)hydrazine (5.57 g, 43.90 mmol) in DCM (100 ml) was treated with HOBt hydrate (0.67 g, 4.40 mmol), and cooled in an ice bath before adding EDC (8.40 g, 43.90 mmol). The reaction mixture was warmed at RT and stirred for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between water and 2- methyltetrahydrofuran. The organic layer was washed with water and extracted with aqueous IN HCl solution. The acidic layer was washed with diethyl ether, then basified with solid potassium carbonate and extracted with DCM (x 3). The combined organic layers were dried over solid sodium sulphate and the solvent was removed under reduced pressure. This residue was triturated with diethyl ether to afforded the title compound as a light purple solid (6.10 g, 62%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.51 (3H, s), 1.80-1.94 (2H, m), 1.97-2.12 (1H, m), 2.44-2.56 (2H, m), 6.64 (1H, dd, J = 3.5, 9.0 Hz), 6.71 (1H, d, J = 3.9 Hz), 7.29 (1H, dt, J = 2.9, 7.9 Hz), 7.65 (1H, d, J = 3.1 Hz), 8.04 (1H, d, J = 2.9 Hz).

b. 6-FIuoro-3-(l-methylcycIobutyl)-[l,2,4]triazolo[4,3-a]pyridi ne (Intermediate

A solution of Intermediate AKa (5.60 g, 24.90 mmol) in 2-methyltetrahydrofuran (100 mL) was treated with triphenylphosphine (13.00 g, 49.60 mmol), triethylamine (10.10 g, 100.0 mmol) and hexachloroethane (14.1 g, 59.50 mmol). The reaction mixture was stirred for 1 hour and then it was washed with water, 10% citric acid solution and extracted with aqueous IN HCl solution. The HCl layer was basified with solid potassium carbonate and extracted into DCM (x 3). The combined organic layers were dried over solid sodium sulphate and the solvent was removed under reduced pressure to afford the title compound (1.00 g, 19%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.98 (3H, s), 4.90 (2H, d, J = 6.4 Hz), 5.17 (2H, d, J = 6.4 Hz), 7.20-7.26 (1H, m), 7.82 (1H, dq, J = 0.8, 5.0 Hz), 8.23 (1H, dt, J = 0.8, 2.2 Hz), plus two protons not observed.

c. (lS,4R)-4-((l-MethyIcyclobutyI)-[l,2,4]triazoIo[4,3-a]pyridi ne-6-yl)oxy)- 1,2,3,4-tetrahydronaphthalen-l-amine (Intermediate AKc)

A solution of Intermediate AKb (4.70 g, 22.90 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (3.74 g mg, 22.90 mmol) and 18-crown-6 ether (610 mg, 2.30 mmol) in 2-methyltetrahydrofuran (100 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture. The mixture was then cooled to 0 °C and potassium tert-butoxide (2.95 g, 26.30 mmol) was added. The reaction mixture was allowed to warm to 20 °C overnight. This mixture was washed with water (x 2) and extracted with 10% citric acid solution. The citric acid solution was washed with diethyl ether, then basified with solid potassium carbonate and extracted with DCM (x 2). The combined organic layers were dried over solid sodium sulphate and the solvent was removed under reduced pressure to afford the title compound (7.98 g, 99%).

lH NMR (300 MHz, CDC1 ₃ ): 1.61 (3H, s), 1.80-2.14 (4H, m), 2.14-2.42 (4H, 2.74-2.92 (2H, m), 3.99 (1H, q, J = 5.1 Hz), 5.19 (1H, t, J = 4.5 Hz), 7.12 (1H, dd, J = 2.1, 6.9 Hz), 7.2-7.4 (4H, m), 7.60 (1H, d, J = 7.8 Hz), 7.71 (1H, dd, J = 0.8, 9.9 Hz), plus three protons not observed.

d. l-((lS,4R)-4-((3-(l-Methylcyclobutyl)-[l,2,4]triazoIo[4,3-a] pyridine-6-yl)oxy)- l,2,3,4-tetrahydronaphthalen-l-yl)urea (Intermediate AKd)

A solution of triphosgene (470 mg, 1.58 mmol) in DCM (8 mL) under nitrogen was cooled to -10 °C and a solution of Intermediate AKc (500 mg, 1.43 mmol) and triethylamine ( 580 mg, 5.72 mmol) in DCM (8mL) was dropwise added keeping the temperature <- 10 °C. This solution was stirred at 0 °C for one hour before 2N NH ₃ in MeOH (8.6 mL, 17.10 mmol, pre-cooled to 0 °C) was added and the reaction mixture was allowed to warm to 20°C. The mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were dried over solid MgS0 ₄ . The solvent removed under reduced pressure and purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (450 mg, 80%). LCMS (Method 4): Rt = 1.02 min, m/z 392 [M+H ⁺ ], m/z 414 [M+Na ⁺ ].

e. Intermediate AK

A solution of Intermediate AKd (450 mg, 1.15 mmol), Intermediate Id (280 mg,

1.15 mmol), palladium(II)acetate (13 mg, 0.058 mmol), Xantphos (70 mg, 0.120 mmol) and cesium carbonate (530 mg, 1.61 mmol) in dioxan (8 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication. The reaction mixture was warmed to 90 °C for 20 hours, cooled at RT and filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were removed under reduced pressure and purification by FCC eluting 0 to 10% EtOH in DCM afforded the title compound (520 mg, 75%).

LCMS (Method 4): Rt = 1.46 min, m/z 598 [M+H ⁺ ], m/z 620 [M+Na ⁺ ].

Example 13

l-(6-(tert-ButyI)-2-(hydroxymethyl)pyrimidin-4-yI)-3-((lS ,4R)-4-((3-(2- methoxypropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy) -l,2,3 _? 4- tetrahydronaphthalene-l-yl)urea

a. (4-(teri-Butyl)-6-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[ l,2,4]triazolo[4,3- a]pyridine-6-yl)oxy)-l,2,3,4-tetrahydronaphthalene-l-yl)urei do)pyrimidin-2- yl)methyl acetate (Example 13a)

Intermediate XX (190 mg, 0.79 mmol), Intermediate 12d (310 mg, 0.79 mmol), Palladium acetate (10%, 20 mg, 0.08 mmol), Xantphos (20%, 93 mg, 0.16 mmol) and cesium carbonate (390 mg, 1.19 mmol) in 1,4-dioxan (10 ml) were warmed to 100 °C for 2 hours. The resulting reaction mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure. Purification by FCC eluting 0-10% (2N NH ₃ in MeOH)/DCM afforded the title compound (320 mg, 67%).

LCMS (Method 4): Rt 1.71 min, m/z 611 [M+H ⁺ ].

b. Example 13

A stirred solution of Intermediate 13a (320 mg, 0.53 mmol) in THF/MeOH (8 ml, 5:3) was added with IN sodium hydroxide solution (0.586 mmol, 0.586 mL). The mixture was stirred at 20 °C for 5 hours. The resulting reaction mixture was acidified to pH ~4 with 10% citric acid solution and diluted with water. This aqueous solution was extracted with EtOAc (x3), the combined organic phases were dried over MgS0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP afforded the title compound (270 mg, 90%).

LCMS (Method 3): Rt 4.09 min, m/z 560 [M+H ⁺ ], sample assessed as ca. 99.65%. ¾ NMR (400 MHz, deDMSO): 1.27 (9H, s), 1.69 (6H, s), 1.87-2.30 (4H, m), 2.98 (3H, s), 4.42 (2H, d, J = 4.1 Hz), 4.93-5.07 (2H, m), 5.49 (1H, t, J = 3.8 Hz), 7.26-7.33 (1H, m), 7.33-7.46 (5H, m), 7.80 (1H, dd, J = 0.6, 9.9 Hz), 8.13 (1H, d, J = 1.4 Hz), 8.51 (1H, br s), 9.58 (1H, s).

Intermediate AL

(4-(teri-ButyI)-6-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[ l,2,4]triazolo[4,3- a]pyridine-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidin-2- yl)methyl methanesulphonate

A solution of Example 13 (210 mg, 0.37 mmol), in DCM (5 mL) at 0 °C was added with a solution of methylsulphonyl methanesulfonate (113 mg, 0.66 mmol) and triethyl amine (95 mg, 0.93 mmol) in DCM (5 mL). The reaction mixture was allowed to warm to RT, diluted with saturated sodium bicarbonate solution and extracted with EtOAc (x 2). The combined organic layers were dried over solid magnesium sulphate and the solvent was removed under reduced pressure. Purification by FCC eluting 0 to 10% (2M NH ₃ in MeOH) in DCM afforded the title compound (140 mg, -29%) as a 1:1 mixture with the ether dimer of Intermediate AL. This mixture was used as crude in the next step.

LCMS (Method 4): Rt = 1.48 min, m/z 638 [M+H ⁺ ], m/z 660 [M+Na ⁺ ].

Intermediate AM

Ethyl 6-(teri-butyl)-4-(3-((lS,4R)-4-((3-(2-methoxypropan-2-yl)-[l ,2,4]triazolo[4,3- a]pyradin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yI)ureido)picolinate

A solution of Intermediate 12d (200 mg, 0.568 mmol), Intermediate 9d (137 mg,

0.568 mmol), palladium(II)acetate (6 mg, 0.03 mmol), xantphos (32 mg. 0.057 mmol) and cesium carbonate (280 mg, 0.852 mmol) in dioxan (3 niL) was degassed by bubbling argon through the mixture under sonication for 10 minutes. The reaction mixture was stirred at 90 °C for 20 hours, cooled at RT and filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were evaporated under reduced pressure and the crude mixture was purified by FCC eluting with 0-10% EtOH/DCM to afford the title compound (220 mg, 64%).

LCMS (Method 4): Rt = 1.48 min, m/z 601 [M+H ⁺ ], m/z 623 [M+Na ⁺ ].

Intermediate AN

Ethyl 6-(ter/-butyl)-4-(3-((lS,4R)-4-((3-(l-methoxy-2-methylpropan -2-yl)- [1 ,2,4] triazolo [4,3-a] pyradin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthaIen-l- yl)ureido)picolinate

A solution of Intermediate 7d (200 mg, 0.50 mmol), Intermediate 9d (130 mg, 0.55 mmol), palladium(II)acetate (11 mg, 0.05 mmol), xantphos (58 mg. 0.10 mmol) and cesium carbonate (250 mg, 0.75 mmol) in dioxan (4 mL) was degassed by bubbling argon through the mixture under sonication for 10 minutes. The reaction mixture was stirred at 100 °C for 18 hours, cooled at RT and filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were evaporated under reduced pressure and the crude mixture was purified by FCC eluting with 0-10% EtOH/DCM to afford the title compound (160 mg, 52%).

LCMS (Method 4): Rt = 1.43 min, m/z 615 [M+H ⁺ ], m/z 637 [M+Na ⁺ ].

Intermediate AO

(6-(feri-Butyl)-4-chIoropyridin-2-yl)methyl methanesulphonate

a. (6-(fert-ButyI)-4-chloropyridin-2-yl)methanoI (Intermediate AOa)

A stirred solution of Intermediate 9d (1.0 g, 4.14 mmol) in THF/IMS (24 mL, 5:1) at 0°C was added with sodium borohydride (240 mg, 6.22 mmol) portionwise keeping the temperature <0°C. The reaction mixture was left at 0°C for 30 minutes before allowing it to warm to RT for 30 minutes. A second portion of sodium borohydride (240 mg, 6.22 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was then partitioned between saturated sodium bicarbonate solution and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2), the combined organic layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting 0 - 40% EtOAc/cyclohexane afforded the title compound (630 mg, 76%). LCMS (Method 4): Rt = 1.40 min, m/z 200 [M+H ⁺ ].

b. Intermediate AO

A solution of methylsulphonic anhydride (950 mg, 5.53 mmol) and trimethylamine (730 mg, 7.27 mmol) in DCM (10 mL) was added to Intermediate AOa (630 mg, 3.16 mmol) in DCM (lOmL) keeping the temperature <-10°C. The reaction was stirred at -10°C for 1 hour then quenched with saturated sodium bicarbonate solution and the two phases were separated. The aqueous layer was extracted with EtOAc (x 2) and the combined organic layers were dried over solid MgS0 ₄ . The solvent was removed under reduced pressure and purification by FCC 0 - 40% EtOAc/cyclohexane afforded the title compound (800 mg, 91%).

LCMS (Method 4): Rt = 1.59 min, m/z 278 [M+H ⁺ ].

Intermediate AP

4-(2-((tert-Butyl)-4-chloropyridin-2-yl)methoxy)ethyl)morpho line

A solution of 4-(2-hydroxyehtyl)morpholine (310 mg, 2.38 mmol) in THF (30 mL) was treated with sodium hydride (40% in oil, 170 mg, 4.32 mmol) and stirred at RT for 1 hour before Intermediate AO (600 mg, 2.16 mmol) in THF (30 mL) was added. The reaction mixture was warmed to reflux for 1 hour, allowed to cool to RT, diluted with brine and extracted with EtOAc (x 3). The combined organic layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0- 10% EtOAc/cyclohexane afforded the title compound (490 mg, 72%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.32 (9H, s), 2.53 (4H, t, J = 4.6 Hz), 2.65 (2H, t, J = 5.6 Hz), 3.70 (2H, t, J = 5.6 Hz), 3.75 (4H, t, J = 4.7 Hz), 4.61 (2H, s), 7.18 (1H, d, J = 1.8 Hz), 7.28 (1H, J = 1.8 Hz).

Intermediate AO

(6-(tert-ButyI)-4-(3-((lS,4R)-4-((3-(2-(4-methylpiperazin-l- yl)propan-2-yl)- [l,2,4]triazoIo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthaIen-l- yl)ureido)pyridin-2-yl)methyl acetate

a. (6-(tert-Butyl)-4-chIoropyridin-2-yI)methyl acetate (Intermediate AQa)

A solution of Intermediate AOa (148 mg, 0.74 mmol, purity -60%) in pyridine (2.5 ml) was treated with acetic anhydride (140 μΐ, 1.48 mmol). The reaction mixture was stirred at RT for 5 hours and left standing overnight. The reaction mixture was partitioned between EtOAc and an aqueous 1M HC1 solution. The two phases were separated and the aqueous phase was extracted with EtOAc (x 3). The combined organic phases were washed with brine, passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% EtOAc/cyclohexane afforded the title compound (142 mg, 19%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.33 (9H, s), 2.19 (3H, s), 5.19 (2H, s), 7.13 (1H, d, J = 1.7 Hz), 7.23 (1H, d, J = 1.7 Hz),

b. Intermediate AQ

A solution of Intermediate FFd (110 mg, 0.24 mmol), Intermediate AOa (75 mg, 0.31 mmol), XantPhos (28 mg, 0.05 mmol) in dioxane (3 ml) was treated with Cs ₂ C0 ₃ (110 mg, 0.34 mmol) and Pd(OAc) ₂ (6 mg, 0.025 mmol). The reaction mixture was degassed for a few minutes with argon and then evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite® . The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-6% 2N NH ₃ in MeOH/DCM afforded the title compound (106 mg, 66%). LCMS (Method 4): Rt 0.86 min, m/z 669 [MH ⁺ ].

Intermediate AR

Ethyl 6-(tert-butyI)-4-(3-((lS,4R)-4-((3-(2-(4-methyIpiperazin-l-y l)propan-2-yl)- [1 ,2,4] triazolo [4,3-a] pyridin-6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l- yI)ureido)pico!ina

A solution of Intermediate FFd (130 mg, 0.28 mmol), Intermediate 9d (88 mg, 0.36 mmol), XantPhos (33 mg, 0.06 mmol) in dioxane (3 ml) was treated with Cs ₂ C0 ₃ (128 mg, 0.39 mmol) and Pd(OAc) ₂ (6.7 mg, 0.03 mmol). The reaction mixture was degassed for a few minutes with argon and then evacuated and purged with argon (x 3). The reaction mixture was heated at 95 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-8% 2N NH ₃ in MeOH/DCM afforded the title compound (168 mg, 90%).

LCMS (Method 4): Rt 1.08 min, m/z 669 [MH ⁺ ].

Intermediate AS

Ethyl 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-((S)-sec-butyl)-[l,2,4]tr iazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)picolinate

A solution of Intermediate 8d (350 mg, 0.92 mmol), Intermediate 9d (290 mg, 1.2 mmol), XantPhos (106 mg, 0.18 mmol) in dioxane (9 ml) was treated with Cs ₂ C0 ₃ (420 mg, 1.29 mmol) and Pd(OAc) ₂ (20 mg, 0.09 mmol). The reaction mixture was degassed for a few minutes with argon, evacuated and purged with argon (x 3) and then heated at 95 °C for 18 hours. Other aliquots of Pd(OAc) ₂ (7 mg, 0.03 mmol) and XantPhos (32 mg, 0.06 mmol) were added and the reaction mixture was stirred at 95 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-5% 2N NH ₃ in MeOH/DCM afforded the title compound (294 mg, 55%).

Ή NMR (300 MHz, CDC1 ₃ ): 0.92 (3H, t, J = 7.4 Hz), 1.37-1.45 (15H, m), 1.80 (1H, heptet, J = 6.9 Hz), 1.99 (1H, heptet, J = 7.2 Hz), 2.11-2.40 (4H, m), 3.12 (1H, sextet, J = 9.2 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.21-5.30 (2H, m), 6.95 (1H, dd, J = 9.9, 2.0 Hz), 7.28- 7.35 (4H, m), 7.48 (1H, br s), 7.55-7.59 (1H, m), 7.82 (1H, br s), 7.97 (1H, d, J = 1.8 Hz), 8.10 (1H, d, J = 1.8 Hz), 9.11 (1H, s).

Intermediate AT

N-(6-(tert-Butyl)-4-chloropyridi namide

2-(tert-Butyl)-4,6-dichloropyridine (Intermediate AT a)

A solution of 6-tert-butyl-4-hydroxy-l,2-dihydropyridin-2-one (CAS: 857428-73- 0, 3.47 g, 17.2 mmol) in phosphoryl chloride (20 ml) was stirred at RT for 10 minutes and then treated with DMF (5 ml). The reaction mixture was stirred at RT for 30 minutes and cooled at 0 °C. Another aliquot of DMF (11 ml) was added and the reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was cooled at RT, quenched with H ₂ 0 and extracted with cyclohexane. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with cyclohexane afforded the title compound (3.45 g, 98%). Ή NMR (300 MHz, CDC1 ₃ ): 1.34 (9H, s), 7.16 (1H, d, J = 2.0 Hz), 7.22 (1H, d, J = 2.0 Hz).

b. Intermediate AT

A solution of Intermediate ATa (204 mg, 1.0 mmol), methanesulfonamide (124 mg, 1.3 mmol), XantPhos (58 mg, 0.1 mmol) inNMP (15 ml) was treated with K ₃ P0 ₄ (276 mg, 1.3 mmol) and Pd(OAc) ₂ (11 mg, 0.05 mmol). The reaction mixture was degassed for a few minutes with argon and then heated at 110 °C for 16 hours. The reaction mixture was cooled at RT, diluted with H ₂ 0 and extracted with EtOAc. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-40% EtOAc/cyclohexane afforded the title compound (60 mg, 23%).

LCMS (Method 4): Rt 1.15 min, m/z 263 [MH ⁺ ].

Intermediate AU

N-(6-(tert-ButyI)-4-chloropyridin-2-yl)ethanesuIfonamide

A solution of Intermediate ATa (200 mg, 0.98 mmol), XantPhos (58 mg, 0.1 mmol), Cs ₂ C0 ₃ (424 mg, 1.3 mmol) and Pd(OAc) ₂ (11 mg, 0.05 mmol) in dioxane (15 ml) was treated with ethanesulfonamide (164 mg, 1.5 mmol). The reaction mixture was degassed for a few minutes with argon and then subjected to microwave conditions (140 °C for 1 hour). The reaction mixture was cooled at RT, diluted with H ₂ 0 and extracted with EtOAc. The organic phase was dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-30% EtOAc/cyclohexane afforded the title compound (126 mg, 46%).

LCMS (Method 4): Rt 1.21 min, m/z 277 [MH ⁺ ].

Intermediate AV

Ethyl 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(tert-pentyl)-[l,2,4]tria zolo[4,3-a]pyridin-6- yI)oxy)-l ,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)picolinate

A solution of Intermediate 2d (500 mg, 1.27 mmol), Intermediate 9d (307 mg, 1.27 mmol), XantPhos (74 mg, 0.13 mmol) in dioxane (10 ml) was treated with Cs ₂ C0 ₃ (646 mg, 1.78 mmol) and Pd(OAc) ₂ (14 mg, 0.06 mmol). The reaction mixture was degassed for a few minutes with argon, evacuated and purged with argon (x 3) and then heated at 90 °C for 72 hours. The reaction mixture was cooled at RT, diluted with EtO Ac and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% IMS/EtOAc afforded the title compound (312 mg, 41%).

Ή NMR (400 MHz, CDC1 ₃ ): 0.71 (3H, t, J = 7.4 Hz), 1.38-1.42 (12H, m), 1.52- 1.53 (6H, m), 1.85-1.91 (2H, m), 2.09-2.35 (4H, m), 4.39 (2H, q, J = 7.0 Hz), 5.20-5.27 (2H, m), 6.88 (1H, dd, J = 10.0, 2.0 Hz), 7.08 (1H, br s), 7.24-7.36 (4H, m), 7.57 (1H, d, J = 7.6 Hz), 7.72-7.74 (1H, m), 7.92 (1H, d, J = 1.9 Hz), 8.05 (1H, d, J = 1.9 Hz), 8.56 (1H, br s).

Intermediate AW

Ethyl 6-(tert-butyl)-4-(3-((lS,4R)-4-((3-(pentan-3-yl)-[l,2,4]tria zolo[4,3-a]pyridin-6- yl)oxy)-l,2,3 _» 4-tetrahydronaphthalen-l-yl)ureido)picolinate

A solution of Intermediate 5d (500 mg, 1.27 mmol), Intermediate 9d (307 mg, 1.27 mmol), XantPhos (74 mg, 0.13 mmol) in dioxane (10 ml) was treated with Cs ₂ C0 ₃ (644 mg, 1.78 mmol) and Pd(OAc) ₂ (14 mg, 0.06 mmol). The reaction mixture was degassed for a few minutes with argon, evacuated and purged with argon (x 3) and then heated at 90 °C for 72 hours. The reaction mixture was cooled at RT, diluted with EtOAc and filtered through a pad of Celite®. The solvents were removed under reduced pressure. Purification by FCC, eluting with 0-10% IMS/EtOAc afforded the title compound (87 mg, 11%).

'HNMR (400 MHz, CDC1 ₃ ): 0.83 (3H, t, J = 7.3 Hz), 0.86 (3H, t, J = 7.5 Hz), 1.38-

1.42 (12H, m), 1.82-2.00 (4H, m), 2.11-2.36 (4H, m), 2.92-2.99 (1H, m), 4.40 (2H, q, J = 7.2 Hz), 5.22-5.26 (2H, m), 6.93-6.96 (1H, m), 7.17-7.71 (7H, m), 7.95-7.96 (1H, m), 8.03- 8.04 (1H, m), 8.70 (1H, br s).

Intermediate AX

4-(tert-ButyI)-6-chloropicolinonitri

a. 4-(tert-Butyl)picolinonitrile (Intermediate AXa)

A solution of 4-tert-butylpyridine 1-oxide (CAS: 23569-17-7, 830 mg, 5.44 mmol) in DCM (6 ml) was added to trimethyl silyl cyanide (674 mg, 6.8 mmol). A solution of dimethyl carbamoyl chloride (626 μΐ, 6.8 mmol) in DCM (2 ml) was added to the mixture and the reaction mixture was stirred at RT overnight. The RM was quenched with the slow addition of 10% K ₂ C0 ₃ solution and the reaction mixture was stirred at RT for 30 min. The two phases were separated and the organic was evaporated under reduced pressure to afford the title compound (871 mg, 100% - quantitative).

LCMS (Method 1): Rt 3.53 min, m/z 161 [MH ⁺ ].

b. Intermediate AX

A solution of Intermediate AXa (871 mg, 5.44 mmol) in acetic acid (6 ml) and H ₂ 0 ₂ (30% in H ₂ 0, 4.5 ml) was refluxed for 4 h and more H ₂ 0 ₂ (30% in H ₂ 0, 4.5 ml) was added. The reaction mixture was quenched with sodium thiosulfate until no more peroxide was detected. The solvent was removed under reduced pressure and H ₂ 0 was added and evaporated again. The residue was treated with Na ₂ C0 ₃ and was extracted with DCM. The phases were separated with a phase separating cartridge, and the organic was removed under reduced pressure to afford 4-(tert-butyl)-2-cyanopyridine 1 -oxide (958 mg, 100%- quantitative). This intermediate (561 mg, 3.03 mmol) was dissolved in toluene (40 ml) and treated with POCl ₃ (1 ml, 10.9 mmol). The reaction mixture was heated at 100 °C for 8 h, cooled at RT and the solvent was evaporated under reduced pressure. Saturated NaHC0 ₃ solution was added to the residue and extracted with EtOAc (x 3). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-100% EtOAc/DCM afforded the title compound (118 mg, 20%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.34 (9H, s), 7.50 (1H, d, J = 1.5 Hz), 7.61 (1H, d, J = 1.5 Hz).

Intermediate AY

Ethyl 4-(ter/-butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridine-6- yI)oxy)-l,2,3,4-tetrahydronaphthaIen-l-yI)ureido)picolinate (NSJ4226-095-01)

a. 4-(feri'-Butyl)-2-chloropyridine 1-oxide (Intermediate AYa)

A stirred solution of 2-chloro-4-(l,l-dimethylethyl)-pyridine (8.92 g, 52.7 mmol) in DCM (500 mL) was added with 7weta-chloroperbenzoic acid (27.4 g, 158.3 mmol). After 1 hour the reaction mixture was washed with saturated sodium bicarbonate solution (x 3). The organic layer was dried over solid MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (7.89 g, 80%).

LCMS (Method 4): Rt = 1.04 min, m/z 186 [M+H ⁺ ], m/z 208 [M+Na ⁺ ].

b. 4-(ferf-ButyI)-6-chloropicoUnonitrile (Intermediate AX-second synthetic route)

A solution of intermediate AYa (7.50 g, 40.5 mmol) and trimethylsilylcyanide (8.03 g, 81.1 mmol) in MeCN (110 mL) was added with dimethylcarbamylchloride (8.75 g, 81.1 mmol) and warmed to 60 °C for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned with saturated sodium bicarbonate solution and Et ₂ 0. The two phases were separated and the aqueous phase was extracted with Et ₂ 0 (x 2). The combined organic layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-100% Et ₂ 0/cyclohexane afforded the title compound (5.0 g, 63%).

LCMS (Method 4): Rt = 1.55 min, m/z 195 [M+H ⁺ ].

c. Ethyl 4-(fert-butyl)-6-chloropicolinate (Intermediate AYc)

A solution of Intermediate AX (5.88 g, 30.3 mmol) was dissolved in H ₂ S0 ₄ (21 mL, 95-97%) and warmed to 130 °C for 0.5 hours, then allowed to cool to RT and EtOH (250 mL) was cautiously added. This reaction mixture was warmed to reflux for 3.5 hours and cooled to RT before the solvent was removed under reduced pressure. The residue was partitioned between brine and Et ₂ 0. The two phases were separated and the aqueous phase was extracted with Et ₂ 0 (x 2). The combined organic layers were washed with saturated NaHC0 ₃ solution and dried over solid MgS0 ₄ . The solvent was removed under reduced pressure to afford the title compound (6.0 g, 82%).

LCMS (Method 4): Rt = 1.57 min, m/z 242 [M+H ⁺ ], m/z 264 [M+Na ⁺ ].

d. Intermediate AY

A solution of Intermediate lh (2.07g, 5.46 mmol), Intermediate AYc (1.0 g, 4.15 mmol), palladium(II)acetate (50 mg, 0.21 mmol), xantphos (250 mg. 0.42 mmol) and cesium carbonate (2.0 g, 6.23 mmol) in dioxan (30 n L) was degassed by bubbling argon through the mixture under sonication for 10 minutes. The reaction mixture was stirred at 100 °C for 1.5 hours then filtered through a pad of Celite® washing the precipitate with DCM and EtOH. The solvents were evaporated under reduced pressure and the crude mixture was purified by FCC eluting with 0-10% EtOH/DCM to afford the title compound (2.49 g, quant.).

LCMS (Method 4): Rt = 1.59 min, m/z 585.4 [M+H ⁺ ], m/z 607.4 [M+Na ⁺ ].

Example 14

l-(6-(tert-Butyl)pyrimidin-4-yI)-3-((lS,4R)-4-((3-((S)-l, 2-dimethylpyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)urea

A solution of Intermediate BB (125 mg, 0.46 mmol) and (lS,4R)-4-[3-((S)-l,2- dimethyl-pyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3-a]pyridin-6-yloxy] - 1 ,2,3 ,4-tetrahydro- naphthalen-l-ylamine (WO 2013/083604, 158 mg, 0.42 mmol) in dioxane (4.5 ml) under argon was treated with DIPEA (91 μΐ, 0.52 mmol). The reaction mixture was heated at 60 °C for 48 hours. The reaction mixture was cooled at RT and partitioned between EtOAc and H ₂ 0. The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with an aqueous 1M NaOH solution, H ₂ 0 and brine, passed through a phase separator and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (80 mg, 34%).

LCMS (Method 3): Rt 3.33 min, m/z 555 [MH ⁺ ]. ^l YL NMR (400 MHz, d- ₆ -DMSO): 1.27 (9H, s), 1.51 (3H, s), 1.79-2.23 (11H, m), 2.65 (1H, q, J = 8.6 Hz), 3.13-3.18 (1H, m), 4.96-5.02 (1H, m), 5.36 (1H, t, J = 4.0 Hz), 7.28-7.43 (5H, m), 7.65 (1H, d, J = 0.8 Hz), 7.76 (1H, dd, J = 9.8, 0.6 Hz), 8.20 (1H, d, J = 8.2 Hz), 8.45 (1H, d, J = 1.5 Hz), 8.64 (1H, d, J = 1.2 Hz), 9.52 (1H, br s).

Example 15

l-(6-(tert-Butyl)-2-((dimethylamino)methyl)pyrimidiii-4-y l)-3-((lS,4R)-4-((3-((S)-2- methylpiperidin-l-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy )-l,2,3 _? 4- tetrahydronaphthalen-l-yl)urea

A solution of Intermediate AA (100 mg, 0.15 mmol) in tetrahydrofuran (4 ml) was treated with K ₂ C0 ₃ (28 mg, 0.2 mmol) and a solution of dimethylamine in tetrahydrofuran (2.0M, 0.75 ml, 1.5 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled at RT and the solvent was .removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by HPLC (Gemini C18, 10-50% MeCN in H ₂ 0, 0.1% HC0 ₂ H, 18 ml/min) afforded the title compound as formate salt. The residue was partitioned between DCM and a saturated aqueous NaHC0 ₃ solution and the two phases were separated. The aqueous phase was extracted with DCM (x 2), the combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The obtained solid was dissolved in MeCN (1 ml) and H ₂ 0 (1 ml) and the mixture was lyophilised to afford the title compound as a free base (2.5 mg, 3%).

LCMS (Method 3): Rt 3.53 min, m/z 612 [MH ⁺ ]. ¾NMR (400 MHz, d- ₆ -DMSO): 0.89 (3H, d, J = 6.3 Hz), 1.25 (9H, s), 1.44-1.82 (6H, m), 1.91-2.25 (9H, m), 2.84-2.91 (1H, m), 3.10-3.16 (1H, m), 3.26-3.30 (2H, m), 3.42 (2H, d, J = 3.2 Hz), 4.98-5.04 (1H, m), 5.56 (1H, t, J = 4.4 Hz), 7.22-7.43 (6H, m), 7.65-7.67 (2H, m), 8.99 (1H, br s), 9.69 (1H, br s).

Example 16

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6-yI)oxy)- l,2,3,4-tetrahydronaphthaIen-l-yl)ureido)-N-(2-hydroxyethyl) pyrimidine-2- carboxamide

A solution of Intermediate li (100 mg, 0.17 mmol) in methanol (2 ml) was treated with Na ₂ C0 ₃ (22 mg, 0.20 mmol) and ethanolamine (123 μΐ, 2.04 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and diluted with DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 4). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (70 mg, 69%).

LCMS (Method 3): Rt 3.87 min, m/z 601 [MH ⁺ ]. 'HNMR (400 MHz, d- ₆ -DMSO):

1.32 (9H, s), 1.53 (9H, s), 1.93-2.26 (4H, m), 3.32-3.38 (2H, m, partially obscured by water peak), 3.50-3.54 (2H, m), 4.81 (1H, br s), 4.96-5.03 (1H, m), 5.63 (1H, t, J = 3.8 Hz), 7.28- 7.45 (5H, m), 7.74-7.76 (2H, m), 8.15 (1H, d, J = 1.4 Hz), 8.24 (1H, br s), 8.57 (1H, t, J = 5.9 Hz), 9.92 (1H, s).

Example 17

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-isopropyl-

[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l- yl)ureido)pyrimidin A solution of Intermediate CC (130 mg, 0.23 mmol) in methanol (2.5 ml) was treated with N,N-dimethylethylenediamine (100 μΐ, 2.04 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM followed by a titration with Et ₂ 0 afforded the title compound (123 mg, 87%).

LCMS (Method 3): Rt 3.13 min, m/z 614 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.31 (9H, s), 1.36-1.40 (6H, m), 1.91-2.27 (10H, m), 2.39 (2H, t, J = 6.6 Hz), 3.33-3.39 (2H, m, partially obscured by water peak), 3.57 (1H, quintet, J = 6.8 Hz), 4.98-5.03 (1H, m), 5.57 (1H, t, J = 3.9 Hz), 7.27 (1H, dd, J = 9.8, 2.1 Hz), 7.29-7.43 (4H, m), 7.70 (1H, dd, J = 9.8, 0.6 Hz), 7.74 (1H, br s), 8.23 (1H, d, J = 1.3 Hz), 8.26 (1H, br s), 8.58 (1H, t, J = 5.8 Hz), 9.88 (1H, s).

Example 18

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((2R,6S)-2,6-dimethylpipe ridin-l-yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthalen-l-yl)ureido)-N-

(2-morpholinoethyI)pyrimidine-2-carboxamide

A solution of Intermediate DD (110 mg, 0.17 mmol) in methanol (2.5 ml) was treated with 4-(2-aminoethyl)morpholine (82 μΐ, 0.62 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (88 mg, 71%).

LCMS (Method 3): Rt 3.68 min, m/z 725 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.33 (9H, s), 1.41-1.60 (3H, m), 1.67- 1.82 (3H, m), 1.92-2.25 (4H, m), 2.42 (4H, br s), 3.13-3.23 (2H, m), 3.39 (2H, q, J = 5.9 Hz), 3.58 (4H, t, J = 4.4 Hz), 4.97-5.04 (1H, m), 5.57 (1H, t, J = 3.8 Hz), 7.26-7.43 (5H, m), 7.67 (1H, dd, J = 9.8, 0.6 Hz), 7.71 (1H, br s), 7.92 (1H, d, J = 1.4 Hz), 8.32 (1H, br s), 8.69 (1H, t, J = 5.7 Hz), 9.93 (1H, s), plus two protons obscured by the solvent peak.

Example 19

4-(tert-ButyI)-6-(3-((lS,4R)-4-((3-((2R,6S)-2,6-dimethylpipe ridin-l-yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)-N-

(2-hydroxyethyl)pyrimidine-2-carboxamide

A solution of Intermediate DD (110 mg, 0.17 mmol) in methanol (2.5 ml) was treated with ethanolamine (51 μΐ, 0.85 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-8% 2N NH ₃ in MeOH/DCM afforded the title compound (96 mg, 86%).

LCMS (Method 3): Rt 4.43 min, m/z 656 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.32 (9H, s), 1.38-1.60 (3H, m), 1.68- 1.82 (3H, m), 1.91-2.23 (4H, m), 3.13-3.22 (2H, m), 3.36 (2H, q, J = 5.8 Hz, partially obscured by water peak), 3.52 (2H, q, J = 5.6 Hz), 4.80 (1H, t, J = 5.4 Hz), 4.97-5.03 (1H, m), 5.57 (1H, t, J = 3.8 Hz), 7.26-7.43 (5H, m), 7.67 (1H, dd, J = 9.8, 0.6 Hz), 7.74 (1H, br s), 7.93 (1H, d, J = 1.4 Hz), 8.24 (1H, br s), 8.57 (1H, t, J = 6.0 Hz), 9.90 (1H, s).

Example 20

4-(tert-ButyI)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((2R,6S)-2,6- dimethylpiperidin-l-yI)-[l,2,4]triazoIo[4,3-a]pyridin-6-yI)o xy)-l,2,3,4- tetrahydronaphthaIen-l-yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate DD (110 mg, 0.17 mmol) in methanol (2.5 ml) was treated with N _^ V-dimethylethylenediamine (93 μΐ, 0.85 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (91 mg, 78%).

LCMS (Method 3): Rt 3.71 min, m/z 683 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.31 (9H, s), 1.39-1.58 (3H, m), 1.69- 1.81 (3H, m), 1.91-2.23 (10H, m), 2.39 (2H, t, J = 6.6 Hz), 3.12-3.22 (2H, m), 4.97-5.03 (1H, m), 5.57 (1H, t, J = 3.8 Hz), 7.26-7.43 (5H, m), 7.67 (1H, dd, J = 9.8, 0.6 Hz), 7.73 (1H, br s), 7.92 (1H, d, J = 1.4 Hz), 8.28 (1H, br s), 8.58 (1H, t, J = 5.7 Hz), 9.88 (1H, s), plus two protons obscured by the solvent peak.

Example 21

l-(6-(tert-Butyl)-2-(morpholinomethyl)pyrimidin-4-yl)-3-( (lS,4R)-4-((3-(tert-butyl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l-yI)urea

A solution of Intermediate EE (145 mg, 0.23 mmol) in tetrahydrofuran (2.5 ml) was treated with morpholine (102 μΐ, 1.17 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and diluted with DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (66 mg, 47%).

LCMS (Method 3): Rt 3.37 min, m/z 613 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.25 (9H, s), 1.52 (9H, s), 1.96-2.25 (4H, m), 2.34 (4H, t, J = 4.5 Hz), 3.34-3.40 (4H, m, partially obscured by water peak), 3.48 (1H, d, J = 14.2 Hz, AB system), 3.53 (1H, d, J = 14.2 Hz, AB system), 4.99-5.05 (1H, m), 5.64 (1H, t, J = 3.7 Hz), 7.21-7.42 (6H, m), 7.77 (1H, d, J = 9.8 Hz), 8.11 (1H, d, J = 1.2 Hz), 9.03 (1H, br s), 9.75 (1H, s).

Example 22

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4 -((3-(2-(4-methyIpiperazin- l-yl)propan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l, 2,3,4- tetrahydron

A solution of Intermediate FF (125 mg, 0.19 mmol) in methanol (2.5 ml) was treated with N,N-dimethylethylenediamine (207 μΐ, 1.9 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N N¾ in MeOH/DCM afforded the title compound (113 mg, 84%). LCMS (Method 3): Rt 2.63 min, m/z 712 [MH ⁺ ]. ¾NMR (400 MHz, d- ₆ -DMSO): 1.31 (9H, s), 1.54 (3H, s), 1.55 (3H, s), 2.07-2.46 (19H, m), 3.33-3.37 (2H, m, partially obscured by water peak), 4.99-5.05 (1H, m), 5.48 (1H, t, J = 4.0 Hz), 7.31-7.48 (5H, m), 7.73-7.75 (2H, m), 8.23 (1H, br s), 8.57 (1H, t, J = 5.7 Hz), 8.72 (1H, d, J = 1.8 Hz), 9.87 (1H, s), plus four protons obscured by the solvent peak.

Example 23

l-(6-(tert-Butyl)-2-(hydroxymethyI)pyrimidin-4-yl)-3-((lS ,4R)-4-((3-(2-(4- methylpiperazin-l-yI)propan-2-yl)-[l,2,4]triazolo[4,3-a]pyri din-6-yI)oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea

A solution of Intermediate GG (113 mg, 0.17 mmol) in methanol (3 ml) and H ₂ 0 (0.5 ml) was treated with K ₂ C0 ₃ (47 mg, 0.34 mmol). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the combined organic phases were passed through a phase separator. The solvent was removed under reduced pressure. Purification by HPLC (Kinetex C18, 10-45% MeCN in H ₂ 0, 0.1% HC0 ₂ H, 18 ml/min) afforded the title compound as formate salt. The residue was partitioned between DCM and a saturated aqueous NaHC0 ₃ solution and the two phases were separated. The aqueous phase was extracted with DCM (x 4), the combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. The obtained solid was dissolved in MeCN (1 ml) and H ₂ 0 (1 ml) and the mixture was lyophilised to afford the title compound as a free base (30 mg, 28%).

LCMS (Method 2): Rt 3.09 min, m/z 628 [MH ⁺ ]. *H NMR (400 MHz, d-e-DMSO): 1.26 (9H, s), 1.54 (3H, s), 1.55 (3H, s), 1.93-2.48 (15H, m), 4.42 (2H, d, J = 6.0 Hz), 4.97- 5.03 (2H, m), 5.48 (1H, t, J = 4.0 Hz), 7.31-7.47 (5H, m), 7.74 (2H, d, J = 9.8 Hz), 8.15 (1H, br s), 8.72 (1H, d, J = 1.7 Hz), 9.58 (1H, s).

Example 24

N-((4-(tert-ButyI)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]t riazolo[4,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)pyrimidin-2 -yl)methyl)-2- (dimethylamino)acetamide

A solution of Intermediate II (37 mg, 0.07 mmol), HOBt (1 mg, 0.007 mmol) and 2-(dimethylamino)acetic acid (11 mg, 0.1 mmol) in DCM (3 ml) was treated with EDC (19 mg, 0.1 mmol). The reaction mixture was stirred at RT for 2 hours, partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 4) and the combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (28 mg, 64%).

LCMS (Method 3): Rt 3.21 min, m/z 628 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.26 (9H, s), 1.52 (9H, s), 2.00-2.18 (4H, m), 2.20 (6H, s), 2.79 (1H, d, J = 15.6 Hz, AB system), 2.85 (1H, d, J = 15.6 Hz, AB system), 4.27 (1H, dd, J = 17.0, 5.4 Hz, AB system), 4.37 (1H, dd, J = 17.0, 5.8 Hz, AB system), 4.97 (1H, q, J = 8.1 Hz), 5.61-5.65 (1H, m), 7.29-7.49 (6H, m), 7.75 (1H, d, J = 9.9 Hz), 8.18-8.22 (3H, m), 9.51 (1H, s).

Example 25

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-(l-methylcyclopentyl)- [l,2,4]triazolo[4,3-a]pyridiii- 6-yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)ureido)-N-(2- morpholinoethyl)pyrimidine-2-carboxamide A solution of Intermediate JJ (60 mg, 0.1 mmol) in methanol (2 ml) was treated with 4-(2-aminoethyl)morpholine (40 μΐ, 0.3 mmol). The reaction mixture was heated at 55 °C for 18 hours. The reaction mixture was cooled at RT and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (25 mg, 40%).

LCMS (Method 3): Rt 3.51 min, m/z 696 [MH ⁺ ]. ¾NMR (400 MHz, d- ₆ -DMSO): 1.32 (9H, s), 1.43 (3H, s), 1.62-1.81 (4H, m), 1.90-2.13 (5H, m), 2.21-2.29 (1H, m), 2.32- 2.42 (6H, m), 2.46-2.48 (2H, m, partially obscured by the solvent peak), 3.38 (2H, q, J = 6.4 Hz), 3.58 (4H, t, J = 4.4 Hz), 4.97-5.03 (1H, m), 5.60 (1H, t, J = 3.9 Hz), 7.28-7.44 (5H, m), 7.71 (1H, br s), 7.74 (1H, dd, J = 9.8, 0.5 Hz), 7.98 (1H, d, J = 1.2 Hz), 8.31 (1H, br s), 8.68 (1H, t, J = 5.6 Hz), 9.95 (1H, s).

Example 26

(4-(tert-ButyI)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethyIpyrroIi din-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalea-l- yl)ureido)pyrimidin-2-yl)methyl acetate

A solution of Intermediate XX (50 mg, 0.21 mmol) in dioxane (2 ml) was treated with Intermediate OOa (104 mg, 0.25 mmol), Pd(dba) ₃ (9.4 mg, 0.01 mmol), Xantphos (11.9 mg, 0.02 mmol) and K ₃ P0 ₄ .H ₂ 0 (66.7 mg, 0.29 mmol). The reaction mixture was purged with argon and treated with microwave irradiation at 150 °C for 30 mins. The reaction mixture was cooled at RT, filtered and concentrated under reduced pressure. The residue was passed through a plug of silica, eluting with 0-10% 2N NH ₃ in MeOH/DCM followed by further purification by prep HPLC, eluting with 10-98% MeCN/H ₂ 0, 0.1% HC0 ₂ H in 2 injections. The residue was dissolved in DCM, washed with saturated NaHC0 ₃ and the solvent was removed under reduced pressure to afford the title compound (52 mg, 40%).

LCMS (Method 3): Rt 3.68 min, m/z 627 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.25 (9H, s), 1.51 (3H, s), 1.78-2.33 (14H, m), 2.65 (1H, q, J = 8.6 Hz), 3.12-3.17 (1H, m), 4.97-5.08 (3H, m), 5.36 (1H, t, J = 4.0 Hz), 7.27-7.45 (6H, m), 7.76 (1H, dd, J = 9.8, 0.6 Hz), 8.32 (1H, br s), 8.44 (1H, d, J = 1.5 Hz), 9.64 (1H, s).

Example 27

l-(6-(tert-ButyI)-2-(hydroxymethyl)pyrimidin-4-yl)-3-((lS ,4R)-4-((3-((S)-l,2- dimethylpyrroIidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yI) oxy)-l,2,3j4- tetrahydronaphthalen-l-yI)urea

A solution of Example 26 (160 mg, 0.26 mmol) in MeOH (3 ml) and H ₂ 0 (0.5 ml) was treated with K2CO3 (70.6 mg, 0.51 mmol) and the reaction mixture was stirred at RT. The reaction mixture was partitioned between DCM and H ₂ 0 and the two phases were separated. The organic phase was washed with brine and the solvent was evaporated under reduced pressure. Purification by prep HPLC, eluting with 10-98%) MeCN/H ₂ 0, 0.1 % HC0 ₂ H in 3 injections followed by another prep HPLC, eluting with 10-98% MeCN/H ₂ 0, 0.1% NH ₄ OH in 2 injections afforded the title compound (66 mg, 44%).

LCMS (Method 3): Rt 3.17 min, m/z 585 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.26 (9H, s), 1.51 (3H, s), 1.78-2.33 (11H, m), 2.64 (1H, q, J = 8.6 Hz), 3.13-3.19 (1H, m), 4.41 (2H, d, J = 6.0 Hz), 4.95-5.03 (2H, m), 5.35 (1H, t, J = 4.0 Hz), 7.26-7.45 (6H, m), 7.75 (1H, dd, J = 9.8, 0.6 Hz), 8.45 (1H, d, J = 1.5 Hz), 8.51 (1H, br s), 9.59 (1H, s).

Example 28

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3,4- tetrahydronaphthaIen-l-yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate YYa (100 mg, 0.17 mmol) and Ν',Ν'-dimethylethane-

1,2-diamine (CAS: 108-00-9, 18 μΐ, 0.17 mmol) inDCM (2 ml) was treated with EDC.HC1 (32 mg, 0.17 mmol) and HOBt Hydrate (23 mg, 0.17 mmol). The reaction mixture was stirred at RT for 5 days. The reaction mixture was diluted with DCM and washed with H ₂ 0 and brine and the solvent was evaporated under reduced pressure. The residue was passed through a plug of silica, eluting with 0-5% 2N NH ₃ in MeOH/DCM followed by further purification by prep HPLC, eluting with 10-98% MeCN/H ₂ 0, 0.1% NH4OH to afford the title compound (41 mg, 38%).

LCMS (Method 3): Rt 2.62 min, m/z 669 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.31 (9H, s), 1.51 (3H, s), 1.79-2.29 (17H, m), 2.39 (2H, t, J = 6.0 Hz), 2.65 (1H, q, J = 8.5 Hz), 3.14-3.19 (1H, m), 3.35 (2H, q, J = 6.0 Hz), 4.96-5.02 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 7.27-7.43 (5H, m), 7.72-7.77 (2H, m), 8.19 (1H, br s), 8.46 (1H, d, J = 1.5 Hz), 8.57 (1H, t, J = 5.8 Hz), 9.88 (1H, s).

Example 29

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _» 4-tetrahydronaphthaIen-l-yl)ureido)-N-

(2-hydroxyethyl)pyrimidine-2-carboxamide

A solution of Intermediate YY (98 mg, 0.16 mmol) and 2-aminoethan-l-ol (CAS: 141-43-5, 9.9 μΐ, 0.16 mmol) in DCM (2 ml) was treated with EDC.HC1 (31.4 mg, 0.16 mmol) and HOBt Hydrate (22.1 mg, 0.16 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with H ₂ 0. The aqueous phase was extracted with DCM and the combined organic phases were washed with brine and the solvent was evaporated under reduced pressure. The residue was passed through a plug of silica, eluting with 0-10% 2N NH ₃ in MeOH/DCM followed by further purification by prep HPLC, eluting with 10-98% MeCN/H ₂ 0, 0.1% NH ₄ OH to afford the title compound (44 mg, 42%).

LCMS (Method 3): Rt 3.09 min, m/z 642 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.31 (9H, s), 1.51 (3H, s), 1.79-2.33 (11H, m), 2.65 (1H, q, J = 8.5 Hz), 3.14-3.19 (1H, m), 3.35 (2H, q, J = 6.0 Hz), 3.51 (2H, q, J = 6.0 Hz), 4.80 (1H, t, J = 5.3 Hz), 4.96-5.02 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 7.27-7.43 (5H, m), 7.72-7.76 (2H, m), 8.18 (1H, br s), 8.46 (1H, d, J = 1.5 Hz), 8.57 (1H, t, J = 6.0 Hz), 9.89 (1H, s).

Example 30

N-(4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrro lidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidin-2-yl)methanesulfonamide

A solution of Intermediate ZZ (51 mg, 0.19 mmol), in dioxane (2 ml) was treated with Intermediate OOa (81 mg, 0.19 mmol), Pd(OAc) ₂ (2.2 mg, 0.01 mmol), XantPhos (8.4 mg, 0.02 mmol) and Cs ₂ C0 ₃ (95 mg, 0.29 mmol). The reaction mixture was evacuated and purged with nitrogen (x 3) and then heated at 90 °C overnight. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were washed with H ₂ 0 and brine, dried with NaS0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP afforded the title compound (55 mg, 44%). LCMS (Method 3): Rt 2.92 min, m/z 648 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.25 (9H, s), 1.53 (3H, s), 1.79-2.31 (11H, m), 2.66 (1H, q, J = 8.5 Hz), 3.13-3.19 (1H, m), 4.99-5.05 (1H, m), 5.29 (1H, t, J = 3.8 Hz), 6.92 (1H, s), 7.21-7.37 (5H, m), 7.76 (1H, dd, J = 9.8, 0.8 Hz), 8.47-8.48 (1H, m), 8.59 (1H, br s), 9.38 (1H, br s), 10.76 (1H, br s) plus three protons not observed.

Example 31

l-(6-(tert-Butyl)-2-(4-methylpiperazin-l-yl)pyrimidin-4-y l)-3-((lS,4R)-4-((3-((S)-l,2- dimethylpyrrolidin-2-yI)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3 _? 4- tetrahydronaphthalen-l-yI)urea

A solution of Intermediate AB (50.0 mg, 0.19 mmol), in dioxane (4 ml) was treated with Intermediate OOa (62.0 mg, 0.15 mmol), Pd(dba) ₃ (6.8 mg, 0.01 mmol), XantPhos (5.7 mg, 0.02 mmol) and Cs ₂ C03 (84.8 mg, 0.26 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 100 °C for 6 h. The reaction mixture was cooled at RT, diluted with H ₂ 0 and extracted with EtOAc (x 2). The combined organic phases were washed with brine, dried with MgS0 ₄ and the solvent was removed under reduced pressure. The residue was purified by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM. This was further purified by prep HPLC (Gemini CI 8, 10-95% MeCN in H ₂ 0, 0.1%) HC0 ₂ H, 18 ml/min) and the fractions collected were basified with saturated NaHC0 ₃ solution. This was extracted with DCM and the organic phase was washed with brine, dried with MgS0 ₄ and the solvent was removed under reduced pressure to afford the title compound (19 mg, 20%).

LCMS (Method 3): Rt 2.70 min, m/z 653 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO): 1.18 (9H, s), 1.50 (3H, s), 1.78-2.33 (18H, m), 2.63 (1H, q, J = 8.5 Hz), 3.07-3.13 (1H, m), 4.93-4.98 (1H, m), 5.38 (1H, t, J = 4.8 Hz), 6.48 (1H, s), 7.30-7.45 (5H, m), 7.76 (1H, dd, J = 9.8, 0.6 Hz), 8.46 (1H, d, J = 1.6 Hz), 9.05 (1H, br s), 9.41 (1H, s), plus four protons not observed.

Example 32

4-(tert-Butyl)-N-(2-(dimethylamino)ethyI)-6-(3-((lS,4R)-4-(( 3-(l-methylcyclopropyl)- [l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3 ₅ 4-tetrahydronaphthaIeii-l- yl)ureido)pyrimidin

A solution of Intermediate AC (100 mg, 0.17 mmol) in methanol (2 ml) was treated withN',N'-dimethylethane-l,2-diamine (CAS: 108-00-9, 60 mg, 0.68 mmol). The reaction mixture was heated at 60 °C for 2 days. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was partitioned between DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM and organic was evaporated under reduced pressure. Purification by MDAP (Basic) afforded the title compound (44 mg, 41%).

LCMS (Method 3): Rt 3.23 min, m/z 626 [MH ⁺ ]. ¾ NMR (400 MHz, d- ₆ -DMSO):

0.93-0.95 (2H, m), 1.04-1.05 (2H, m), 1.31 (9H, s), 1.43 (3H, s), 1.92-2.33 (10H, m), 2.39 (2H, t, J = 6.6 Hz), 3.32-3.38 (2H, m, partially obscured by the water peak), 4.97-5.03 (1H, m), 5.63 (1H, t, J = 4.0 Hz), 7.29-7.45 (5H, m), 7.72-7.74 (2H, m), 8.10 (1H, d, J = 1.3 Hz), 8.25 (1H, br s), 8.57 (1H, t, J = 5.8 Hz), 9.89 (1H, s).

Example 33

4-(tert-Butyl)-N-(2-hydroxyethyl)-6-(3-((lS,4R)-4-((3-(morph oline-4-carbonyl)- [1 ,2,4] triazolo [4,3-a]py ridin-6-yl)oxy)-l ,2,3,4-tetrahydronaphthalen-l- yl)ureido)pyrimidine-2-carboxamide A solution of Intermediate AD (90 mg, 0.14 mmol) in methanol (10 ml) was treated with 2-aminoethanol (CAS: 141-43-5, 0.04 ml, 0.7 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure and purification by MDAP (Basic) afforded the title compound (44 mg, 47%).

LCMS (Method 3): Rt 3.75 min, m/z 658 [MH ⁺ ]. Ή NMR (400 MHz, d- ₆ -DMSO):

1.31 (9H, s), 1.88-2.33 (4H, m), 3.51 (2H, q, J = 5.6 Hz), 3.73 (6H, br s), 4.27 (2H, br s), 4.80 (1H, t, J = 5.2 Hz), 4.97-5.03 (1H, m), 5.50 (1H, t, J = 4.0 Hz), 7.29-7.43 (4H, m), 7.55 (1H, dd, J = 9.8, 2.2 Hz), 7.75 (1H, br s), 7.96 (1H, dd, J = 9.8, 0.7 Hz), 8.21 (1H, br s), 8.57 (1H, t, J = 5.9 Hz), 8.75 (1H, d, J = 1.6 Hz), 9.88 (1H, s), plus two protons obscured by solvent peak.

Example 34

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-2- methyIpyrroIidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)ox y)-l,2,3,4- tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate AE (37 mg, 0.06 mmol) in DCM (2 ml) was treated withN',N'-dimethylethane-l,2-diamine (CAS: 108-00-9, 0.5 ml). The reaction mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure. Purification by FCC, eluting with 0-8% 2N NH ₃ in MeOH/DCM, followed by further purification by reverse phase prep HPLC, eluting with 10-80% MeCN/H ₂ 0, 0.1% NH ₄ OH afforded the title compound mg, >100%).

LCMS (Method 3): Rt 2.57 min, m/z 655 [MH ⁺ ]. ^! H NMR (400 MHz, d- ₆ -DMSO): 1.31 (9H, s), 1.58 (3H, s), 1.65-2.12 (5H, m), 2.17 (6H, s), 2.22-2.33 (2H, m), 2.39 (2H, t, J = 6.6 Hz), 2.52-2.59 (1H, m), 2.78-2.85 (2H, m), 3.05-3.11 (1H, m), 4.96-5.02 (1H, m), 5.43 (1H, t, J = 4.0 Hz), 7.28-7.44 (5H, m), 7.70 (1H, dd, J = 9.9, 0.5 Hz), 7.76 (1H, s), 8.18 (1H, br s), 8.57 (1H, t, J = 5.8 Hz), 8.65 (1H, d, J = 1.5 Hz), 9.85 (1H, s), plus two protons obscured by solvent peak.

Example 35

l-(5-(tert-ButyI)-2-methoxypyridin-3-yI)-3-((lS,4R)-4-((3 -((S)-l-methylpyrroIidin-2- yl)-[l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yI)urea hydrochloride salt

HCl

A stirred solution of (lS,4R)-4-[3-((S)-l-methyl-pyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yloxy]-l,2,3,4-tetrahydro-na phthalen-l-ylamine (WO 2014/195402, 203 mg, 0.56 mmol) and DIPEA (0.29 ml, 0.67 mmol) in 2- methyltetrahydrofuran (2 ml) at 0 °C was dropwise added with a solution of Intermediate W (60 mg, 0.1 mmol) in 2-methyltetrahydrofuran (4 ml). The reaction mixture was warmed at RT, stirred for 3 hours and then quenched with H ₂ 0. The two phases were stirred for 3 hours and then the mixture was diluted with EtOAc and H ₂ 0. The two phases were separated and then the aqueous phase was extracted with EtOAc (x 2). The combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% MeOH/DCM afforded the title compound as a free base. The obtained solid was dissolved in MeCN (5 ml) and H ₂ 0 (5 ml) and aqueous 1M HCl solution (0.435 ml, 1 eq) was added. The mixture was lyophilised to afford the title compound as a hydrochloride salt (258 mg, 80%).

LCMS (Method 3): Rt 3.61 min, m/z 570 [MH ⁺ ]. ^r H NMR (400 MHz, d- ₆ -DMSO): 1.25 (9H, s), 1.81-2.04 (3H, m), 2.10-2.21 (4H, m), 2.30-2.43 (2H, br s), 2.65-2.86 (3H, m), 3.87 (3H, s), 4.87-4.94 (1H, m), 5.33 (0.2H, br s), 5.56 (0.8H, br s), 7.27-7.45 (6H, m), 7.68 (1H, d, J = 2.5 Hz), 7.84 (1H, d, J = 9.9 Hz), 8.05 (1H, s), 8.48 (1H, br s), 8.54 (1H, d, J = 2.3 Hz), plus two protons obscured by the solvent peak.

Example 36

Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yI)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthalen-l- yl)ureido)pyrimidine-2-carboxyIate

A mixture of Intermediate OOa (104 mg, 0.25 mmol), Intermediate Id (50 mg, 0.43 mmol), Xantphos (12 mg, 0.021 mmol), Pd ₂ (dba) ₃ (9.4 mg, 0.01 mmol) and Cs ₂ C0 ₃ (94 mg, 0.29 mmol) in dioxan (4.0 ml) was purged with argon and heated at 150 °C in the microwave for 30 mins. The mixture was diluted with DCM and washed with water, brine, passed through a phase separator and the filtrate evaporated. The residue was purified by FCC eluting with 0-5% 2M NH ₃ in MeOH / DCM followed by MDAP (basic) and by HPLC (X-Bridge CI 8, 10-98% MeCN in water, 0.1% NH ₄ OH). Lyophilization of the fractions containing the desired product afforded the title compound (26 mg).

LCMS (Method 3): Rt 3.69 min, m/z 627 [MH ⁺ ]. ^l U NMR (400MHz, d ₆ -DMSO):

1.18 (3H, t, J = 7.1 Hz), 1.29 (9H, s), 1.51 (3H, s), 1.77-2.28 (11H, m), 2.65 (1H, q, J = 68.8 Hz), 3.13 (1H, dt, J = 8.8, 4.0 Hz), 4.17-4.31 (2H, m), 4.96-5.04 (1H, m), 5.36 (1H, t, J = 4.0 Hz), 7.26-7.45 (5H, m), 7.71-7.79 (2H, m), 8.22 (1H, br s), 8.44 (1H, d, J = 1.5 Hz), 10.0 (1H, s).

Example 37

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((S)-2- methylpiperidin-l-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy )-l,2,3 ₅ 4- tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carboxamide A solution of Intermediate LL (165 mg, 0.28 mmol) and N,N- dimethylethylenediamine (30 μΐ, 0.28 mmol) in DCM (5 ml) was treated with HOBt.xH ₂ 0 (37.2 mg, 0.28 mmol) and EDC (52.8 mg, 0.28 mmol) and the mixture stirred at RT for 18 h. The RM was diluted with DCM and washed with water and brine, passed through a phase separator and evaporated. The residue was purified by HPLC (Kinetex C 18, 10-98% MeCN in H ₂ 0, 0.1% HC0 ₂ H, 18 ml/min) and the relevant fractions lyophilized to afford the title compound (118 mg, 64%»).

LCMS (Method 3): Rt 3.53 min, m/z 669 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 0.90 (3H, d, J = 6.3 Hz), 1.31 (9H, s), 1.40-2.30 (17H, m), 2.38 (2H, t, J = 6.6 Hz), 2.84- 2.93 (1H, m), 3.10-3.18 (1H, m), 4.96-5.04 (1H, m), 5.55 (1H, t, J = 3.9 Hz), 7.24-7.45 (5H, m), 7.64 (1H, d, J = 9.8 Hz), 7.69 (1H, d, J = 1.4 Hz), 7.72 (1H, br s), 8.32 (1H, br s), 8.57 (1H, t, H = 5.7 Hz), 9.90 (1H, s), plus two protons obscured by solvent peak.

Example 38

4-(tert-Butyl)-6-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo [4,3-a]pyridin-6-yI)oxy)-l,2,3,4-tetrahydronaphthalen-l-yl)u reido)-N- methylpyrimidine-2-carboxamide

A solution of Intermediate NN (80 mg, 0.21 mmol) and (lS,4R)-4-[3-((S)-l,2- dimethyl-pyrrolidin-2-yl)- [ 1 ,2,4] triazolo [4,3 -a]pyridin-6-yloxy]- 1 ,2,3 ,4-tetrahydro- naphthalen-l-ylamine (WO 2013/083604, 79 mg, 0.21 mmol) in dioxane (1 ml) was heated at 100 °C for 18 hours. The reaction mixture was cooled at RT, diluted with DCM and washed with H ₂ 0 (x2). The organic phase was passed through a phase separator and the solvent was removed under reduced pressure. Purification by HPLC (Kinetex C 18, 10-98% MeCN/H ₂ 0, 0.1% HC0 ₂ H, 18 ml/min) afforded the title compound (51 mg, 40%).

LCMS (Method 3): Rt 3.40 min, m/z 612 [MH ⁺ ] . ¾ NMR (400 MHz, d ₆ -DMSO): 1.32 (9H, s), 1.51 (3H, s), 1.77-2.31 (l lH, m), 2.65 (1H, q, J = 8.8 Hz), 2.80 (3H, d, J = 4.8 Hz), 3.13-3.21 (1H, m), 4.95-5.04 (1H, m), 5.36 (1H, t, J = 3.8 Hz), 7.26-7.33 (1H, m), 7.34-7.45 (4H, m), 7.70 (1H, br s), 7.76 (1H, dd, J = 9.8, 0.5 Hz), 8.30 (1H, br s), 8.47 (1H, d, J = 1.6 Hz), 8.62 (1H, q, J = 4.8 Hz), 9.91 (1H, s).

Example 39

1- (4-(tert-Butyl)-6-cyanopyridin-2-yl)-3-((lS,4R)-4-((3-(( )-l,2-dimethylpyrroIidin-

2- yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahyd ronaphthalen-l-yl)urea

A solution of Intermediate TT (170 mg, 0.40 mmol) in dioxane (5 ml) was treated with Intermediate AX (118 mg, 0.60 mmol), Pd(OAc) ₂ (18 mg, 0.10 mmol), XPhos (58 mg, 0.12 mmol) and Cs ₂ C0 ₃ (197 mg, 0.60 mmol). The reaction mixture was evacuated and purged with argon (x 3) and then heated at 70 °C under argon for 3 h. The reaction mixture was cooled to RT and the solvent was evaporated under reduced pressure. The residue was partitioned between H20 and DCM and the two phases were separated and the organic was evaporated under reduced pressure. The residue was purified by HPLC (Gemini CI 8, 20-60% MeCN in H ₂ 0, 0.1% HC0 ₂ H, 18 nuVmin). The collected fractions were applied to an SCX-2 cartridge, eluting with MeOH followed by 2M NH ₃ in MeOH and the solvent was evaporated under reduced pressure to afford the title compound (35 mg, 30%).

LCMS (Method 3): Rt 3.76 min, m/z 579 [MH ⁺ ]. Ή MR (300 MHz, CDC1 ₃ ): 1.27

(9H, s), 1.50 (3H, s), 1.75- 2.33 (13H, m), 4.94-4.99 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 7.28- 7.43 (5H, m), 7.69 (1H, d, J = 1.6 Hz), 7.73-7.77 (2H, m), 8.09 (1H, d, J = 1.5 Hz), 8.44 (1H, d, J = 1.6 Hz), 9.50 (1H, s).

Example 40

l-(6-(tert-Butyl)-2-methylpyrimidin-4-yl)-3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrroIidm-2-yI)-[l,2,4]triazoIo[4,3-a]pyridin-6-yI)o xy)-l,2,3,4- tetrahydronaphthalen-l-yI)urea

A mixture of Intermediate OOa (120 mg, 0.29 mmol), Intermediate PP (79 mg, 0.43 mmol), Xphos (41 mg, 0.086 mmol), Pd(OAc) ₂ (13 mg, 0.058 mmol) and Cs ₂ C0 ₃ (139 mg, 0.43 mmol) in dioxan (3.0 ml) was purged with argon. The mixture was heated at 90 °C for 5 h and stood overnight at RT. The mixture was filtered and the filtrate loaded onto a pre-conditioned 5 g SCX-2 cartridge and eluted with DCM/MeOH (1 :1) and MeOH and the basic components were then eluted with 2M N¾ in MeOH, MeOH and then DCM / MeOH (1 :1). The eluate was evaporated and the residue purified by HPLC (X-Bridge C18, 40-70% MeCN in water, 0.1% NH ₄ OH) to afford the title compound (15.4 mg, 9%).

LCMS (Method 3): Rt 3.27 min, m/z 569 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ -DMSO): 1.24 (9H, s), 1.50 (3H, s), 1.76-2.24 (11H, m), 2.39 (3H, s), 2.64 (1H, q, J = 8.8 Hz), 3.12 (1H, dt, J = 8.8, 3.8 Hz), 4.93-5.02 (1H, m), 5.36 (1H, t, J = 4.0 Hz), 7.27-7.46 (6H, m), 7.76 (1H, d, J = 9.8 Hz), 8.36 (1H, br s), 8.43 (1H, d, J = 1.6 Hz), 9.48 (1H, s).

Example 41

1- (6-(tert-ButyI)-2-ethylpyrimidin-4-yl)-3-((lS,4R)-4-((3-((S) -l,2-dimethylpyrrolidin-

2- yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)urea

The title compound (37.7 mg, 23%) was prepared starting from Intermediate OOa (120 mg, 0.29 mmol) and Intermediate QQ (85 mg, 0.43 mmol) using the procedure described to make Example 40.

LCMS (Method 3): Rt 3.62 min, m/z 583 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ -DMSO): 1.10 (3H, t, J = 7.6 Hz), 1.24 (9H, s), 1.50 (3H, s), 1.76-2.24 (11H, m), 2.59-2.71 (3H, m),

3.11 (1H, dt, J = 8.5, 3.5 Hz), 4.95-5.05 (1H, m), 5.36 (1H, t, J = 4.2 Hz), 7.24-7.45 (6H, m), 7.76 (1H, dd, J = 9.8, 0.6 Hz), 8.42 (1H, d, J = 1.5 Hz), 8.71 (1H, br s), 9.57 (1H, s).

Example 42

l-(6-(tert-Butyl)-2-isopropylpyrimidin-4-yl)-3-((lS,4R)-4 -((3-((S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3 ₅ 4- tetrahydronaphthalen-l-yl)urea

The title compound (52.2 mg, 31%) was prepared starting from Intermediate OOa (120 mg, 0.29 mmol) and Intermediate RR (91 mg, 0.43 mmol) using the procedure described to make Example 40.

LCMS (Method 3): Rt 4.00 min, m/z 597 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ -DMSO):

1.06 (3H, d, J = 6.9 Hz), 1.11 (3H, d, J = 6.9 Hz), 1.24 (9H, s), 1.51 (3H, s), 1.76-2.23 (11H, m), 2.64 (1H, q, J = 8.7 Hz), 2.87 (1H, septet, J = 6.9 Hz), 3.11 (1H, dt, J = 8.7, 3.4 Hz), 4.95-5.05 (1H, m), 5.37 (1H, t, J = 4.3 Hz), 7.18 (1H, br s), 7.25-7.45 (5H, m), 7.77 (1H, dd, J = 9.8, 0.5 Hz), 8.42 (1H, d, J = 1.5 Hz), 8.97 (1H, br s), 9.62 (1H, s).

Example 43

l-(6-(tert-Butyl)-2-(methoxymethyl)pyrimidin-4-yl)-3-((lS ,4R)-4-((3-((S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yI) oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea

The title compound (71.5 mg, 42%») was prepared starting from Intermediate OOa (120 mg, 0.29 mmol) and Intermediate SS (92 mg, 0.43 mmol) using the procedure described to make Example 40.

LCMS (Method 3): Rt 3.59 min, m/z 599 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ -DMSO): 1.25 (9H, s), 1.51 (3H, s), 1.77-2.26 (11H, m), 2.64 (1H, q, J = 8.8 Hz), 3.09-3.17 (1H, m), 3.25 (3H, s), 4.35 (1H, d, J = 14.3, Hz, AB system), 4.39 (1H, d, J = 14.3 Hz, AB system), 4.96-5.05 (1H, m), 5.36 (1H, t, J = 4.1 Hz), 7.25-7.46 (6H, m), 7.76 (1H, dd, J = 9.9, 0.5 Hz), 8.44 (1H, d, J = 1.5 Hz), 8.68 (1H, br s), 9.70 (1H, s).

Example 44

l-(4-(tert-Butyl)pyridin-2-yl)-3-((lS,4R)-4-((3-((S)-l,2- dimethylpyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridiii-6-yl)oxy)-l,2,3,4-tetrahydron aplithalen-l-yl)urea

The title compound (54 mg, 34%) was prepared starting from Intermediate OOa (120 mg, 0.29 mmol) and 4-(tert-butyl)-2-chloropyridine (73 mg, 0.43 mmol) using the procedure described to make Example 40.

LCMS (Method 3): Rt 3.27 min, m/z 554 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ -DMSO): 1.25 (9H, s), 1.51 (3H, s), 1.77-2.26 (11H, m), 2.64 (1H, q, J = 8.8 Hz), 3.11-3.18 (1H, m), 4.96-5.05 (1H, m), 5.36 (1H, t, J = 3.8 Hz), 6.97 (1H, dd, J = 5.5, 1.7 Hz), 7.25-7.47 (7H, m), 7.76 (1H, dd, J = 9.9, 0.5 Hz), 8.02 (1H, d, J = 5.5 Hz), 8.44 (1H, d, J = 1.5 Hz), 8.76 (1H, br d, J = 7.2 Hz), 9.18 (1H, br s).

Example 45

l-(6-(tert-Butyl)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-2- methylpiperidin-l-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phtlialen-l-yl)urea A solution of Intermediate BB (110 mg, 0.41 mmol) and (lS,4R)-4-[3-((S)-2- methyl-piperidin- 1 -yl)- [ 1 ,2,4]triazolo[4,3 -a]pyridin-6-yloxy]- 1 ,2,3 ,4-tetrahydro- naphthalen-l-ylamine (WO2014/194956, 153 mg, 0.41 mmol) in dioxan (3 ml) in a reaction tube was treated with (88 μΐ, 0.51 mmol) DIPEA and purged with argon. The tube was sealed and heated at 50 °C for 72 h. The RM was cooled at RT, diluted with EtOAc and washed with 1M NaOH solution, saturated NaHC0 ₃ solution, brine, dried with MgS0 ₄ and evaporated. The residue was purified by MDAP (basic) to afford the title compound as a cream solid (159 mg, 98%).

LCMS (Method 3): Rt 4.52 min, m/z 555 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.27 (9H, s), 1.44-2.24 (10H, m), 2.85-2.94 (1H, m), 3.12-3.20 (1H, m), 4.94-5.03 (1H, m), 5.56 (1H, t, J = 3.9 Hz), 7.22-7.45 (5H, m), 7.63-7.69 (2H, m), 7.72 (1H, d, J = 1.4 Hz), 8.19 (1H, br d, J = 8.3 Hz), 8.65 (1H, d, H = 1.2 Hz), 9.52 (1H, s) plus one proton obscured by solvent peak.

Example 46

l-(6-(tert-ButyI)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-l- methylpyrrolidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l,2,3,4-tetrahydron aphthalene-l-yl)urea hydrochloride

A stirred solution of Intermediate BB (90.6 mg, 0.334 mmol) in 2- methyltetrahydrofuran (3.5 mL) under argon was added with diisopropylamine (49.1 mg, 0.38 mmol) and the (lS,4R)-4-[3-((S)-l-methyl-pyrrolidin-2-yl)-[l,2,4]triazolo[ 4,3- a]pyridin-6-yloxy]-l,2,3,4-tetrahydro-naphthalen-l-ylamine (WO 2014/195402, 110 mg, 0.304 mmol) which gradually dissolved and a cream precipitate was formed overnight. The reaction mixture was stirred at 20 °C for 5 days then heated to 45°C overnight. The reaction mixture was quenched with water and partitioned with EtOAc (x 2). The combined organic layers were washed with IN NaOH, water and brine. The solvent was removed at reduced pressure to give a pale brown glassy material purified by FCC eluting 0-20% MeOH in EtOAc. This product was dissolved in MeCN (~5 mL) and IN HCl (0.15 mL) was added followed by water (5.5 mL) and lyophilised to afford the title compound (76.7 mg).

LCMS (Method 3): Rt 3.30 min, m/z 541 [M+H ⁺ ], sample assessed as ca. 98.8%.

'H NM (400 MHz, d ₆ DMSO): 1.27 (9H, s), 1.86-2.00 (1H, m), 2.01-2.31 (5H, m), 2.42 (2H, br s), 2.67-2.82 (2H, m), 2.91 (2H, s), 3.76 (1H, br s), 5.01 (1H, q, J = 8.4 Hz), 5.42 (0.7H, br s), 5.59-5.70 (1.3H, m), 7.29-7.36 (1H, m), 7.36-7.45 (4H, m), 7.68 (1H, s), 7.81 (1H, d, J = 9.9 Hz), 8.20-8.32 (1H, m), 8.53 (0.6H, br s), 8.66 (1H, d, J = 1.1 Hz), 8.87 (0.4H, br s), 9.51-9.65 (1H, m), 10.72 (1H, br s).

Example 47

l-(6-(ter^ButyI)pyrimidin-4-yl)-3-((lS,4R)-4-((3-((S)-l-i sopropylpyrrolidin-2-yl)-

[l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l,2,3,4-tetrahyd ronaphthalene-l-yI)urea hydrochloride.

A stirred solution of Intermediate BB (200 mg, 0.737 mmol) in dioxan (7 mL) under argon was added with diisopropylamine (108 mg, 0.838 mmol) and (lS,4R)-4-[3- ((S)- 1 -isopropyl-pyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yloxy]- 1 ,2,3 ,4- tetrahydro-naphthalen-l-ylamine (WO 2013/083604) (262 mg, 0.67 mmol) and the reaction mixture was heated to 60 °C for 2 days. The reaction mixture was quenched with water and partitioned with EtOAc (x 3). The combined organic layers were washed with IN NaOH, water and brine. The solvent was removed at reduced pressure and the residue was purified by FCC eluting with 0-20% MeOH/EtOAc, followed by a further purification by MDAP (acidic). The residue was dissolved in MeCN (6 mL), aqueous IN HCl solution (0.13 mL) and water (7 mL) and the solution was lyophilised to afford the title compound (54 mg, 13%).

LCMS (Method 3): Rt 3.43 min, m/z 569.4 [M+H ⁺ ], sample assessed as >99%. ^! H NMR (400 MHz, d ₆ DMSO): 1.14 (1H, d, J = 6.4 Hz), 1.20-1.26 (5H, m), 1.27 (9H, s), 1.84- 1.99 (1H, m), 2.00-2.41 (4H, m), 2.60-2.75 (1H, m), 3.04-3.16 (0.5H, m), 3.39-3.51 (2H, m), 3.65 (2H, br s), 4.95-5.06 (1H, m), 5.52-5.67 (1.5H, m), 5.92 (0.5H, br s), 7.29-7.36 (1H, m), 7.36-7.47 (3H, m), 7.67 (1H, s), 7.87 (1H, d, J = 9.9 Hz), 8.20-8.32 (1H, m), 8.55(1H, br s), 8.66 (1H, s), 8.92 (0.5H, s), 9.50-9.65 (1H, m), 10.43 (1H, br s), 12.02 (0.5H, s), plus 0.5 protons not observed.

Example 48

l-(6-(tert-Butyl)-2-(methylthio)pyrimidin-4-yl)-3-((lS,4R )-4-((3-((S)-l-

[l,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-l,2,3,4-tetrahyd ronaphthalen-l-yl)urea

A stirred solution of Intermediate AF (21 mg, 0.057 mmol) in dioxane (0.6 ml) was added diisopropylethylamine (13 μΐ,, 0.077 mmol) followed by (lS,4R)-4-[3-((S)-l- methyl-pyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yloxy]- 1 ,2,3 ,4-tetrahydro- naphthalen-l-ylamine (WO 2014/195402, 19 mg, 0.051 mmol). The mixture was stirred at 100 °C for 18 hours before adding (lS,4R)-4-[3-((S)-l-methyl-pyrrolidin-2-yl)- [ 1 ,2,4]triazolo [4,3 -a]pyridin-6-yloxy] - 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -ylamine (WO 2014/195402, 5 mg) and dioxane (0.3 mL). The heating was continued for 24 hours at 100 °C. The resulting reaction mixture was cooled at RT, partitioned between DCM/MeOH (19:1) and water and the two phases were separated. The aqueous layer was extracted with DCM (x 2). The combined organic layers were washed with brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-5% (2N NH ₃ in MeOH) in DCM gave a colourless glass which was taken up in MeCN/water and lyophilised to afford the title compound (7 mg). LCMS (Method 3): Rt = 3.95 min, m z 587 [M+H ⁺ ], sample assessed as ca. 97.8%. ¾NMR (400 MHz, d ₆ DMSO): 1.24 (9H, s), 1.83-2.26 (11H, m), 2.27-2.41 (4H, m), 3.08- 3.14 (1H, m), 3.98 (1H, t, J = 8.0 Hz), 4.93-5.02 (1H, m), 5.43 (1H, t, J = 4.1 Hz), 7.22- 7.45 (6H, m), 7.76 (1H, d, J = 9.9 Hz), 8.15-8.23 (2H, m), 9.59 (1H, s).

Example 49

l-(6-(tert-Butyl)-2-(methylthio)pyrimidin-4-yl)-3-((lS,4R )-4-((3-((S)-l,2- dimethylpyrroIidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridine-6-yl )oxy)-l,2,3 _> 4- tetrahy d ronaphthalen-l -y l)urea

A stirred solution of Intermediate AF (390 mg, 1.10 mmol) in dioxan (1.1 ml) was added with diisopropylethylamine (0.28 mL, 1.60 mmol) followed by (lS,4R)-4-[3-((S)- 1 ,2-dimethyl-pyrrolidin-2-yl)-[l ,2,4]triazolo[4,3-a]pyridin-6-yloxy]-l ,2,3,4-tetrahydro- naphthalen-l-ylamine (WO 2013/083604, 440 mg, 1.20 mmol) and the mixture was stirred at 100 °C for 24 hours. The resulting reaction mixture was partitioned with water/DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were washed with brine and dried with Na ₂ S0 ₄ . The solvent was removed under reduced pressure. Purification by FCC eluting 0-3.5% (2N NH ₃ in MeOH) in DCM, followed by a further purification by HPLC (Gemini CI 8 column, 18 mL/min eluting 10-98%MeCN/water + 0.1% HCOOH over 30 minutes) afforded the title compound as a formate salt. The residue was partitioned between saturated sodium bicarbonate solution and DCM. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined DCM layers were evaporated under reduced pressure. The residue was dissolved in MeCN/water and lyophilised to afford the title compound (43 mg, 68%).

LCMS (Method 3): Rt = 4.04 min, m/z 601 [M+H ⁺ ], sample assessed as >99%.. ¹ H NMR (400 MHz, d ₆ DMSO): 1.24 (9H, s), 1.50 (3H, s), 1.76-2.32 (11H, m), 2.31 (3H, s), 2.64 (1H, q, J = 8.7 Hz), 3.13 (1H, dt, J = 3.7, 8.5 Hz), 4.98 (1H, q, J = 5.5, 13.9 Hz), 5.36 (1H, t, J = 4.1 Hz), 7.23-7.46 (6H, m), 7.76 (1H, d, J = 9.9 Hz), 8.21 (1H, s), 8.43 (1H, d, J = 1.6 Hz), 9.59 (1H, s).

Example 50

1- (5-(tert-Butyl)-2-methylpyridin-3-yI)-3-((lS,4R)-4-((3-((S)- l,2-dimethylpyrrolidin-

2- yl)-[l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3 ₅ 4-tetrahydronaphthalen-l-yl)urea

The title compound (34 mg, 38%) was prepared from (lS,4R)-4-[3-((S)-l,2- dimethyl-pyn-olidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl oxy]-l,2,3,4-tetrahydro- naphthalen-l-ylamine (WO 2013/083604, 60 mg, 0.16 mmol) and Intermediate UU (45 mg, 0.16 mmol) using the procedure described to make Example 45.

LCMS (Method 3): Rt 2.60 min, m z 568 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.29 (9H, s), 1.52 (3H, s), 1.78-2.24 (11H, m), 2.36 (3H, s), 2.66 (1H, q, J = 8.5 Hz), 3.13- 3.20 (1H, m), 4.88-4.96 (1H, m), 5.36 (1H, t, J = 4.4 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.27- 7.46 (5H, m), 7.73-7.79 (2H, m), 8.12 (1H d, J = 2.2 Hz), 8.38 (1H, d, J = 2.2 Hz), 8.47 (1H, d, J = 1.6 Hz).

Example 51

l-(2-(tert-Butyl)-6-(hydroxymethyl)pyridin-4-yl)-3-((lS,4 R)-4-((3-((S)-l,2- dimethylpyrrolidin-2-yI)-[l,2,4]triazolo[4,3-a]pyridin-6-yI) oxy)-l,2,3,4- tetrahydronaphthalen-l-yl)urea

A solution of Intermediate OO (48 mg, 0.077 mmol) in dry THF (0.7 ml) was cooled in ice and treated with 2M LiAlH ₄ in THF (19 μΐ, 0.038 mmol). After 45 min stirring at 0-5°C a further aliquot of 2M LiAlH ₄ in THF (38 μΐ, 0.076 mmol) was added and stirring continued at RT. After 2.25 h the RM was cooled in ice and quenched cautiously with water. The mixture was partitioned between water and EtOAc and the two phases were separated. The aqueous phase was extracted with EtOAc (x2) and the combined organic layers extracted with 10% citric acid solution. The citric acid layer was basified with aqueous NaHC0 ₃ solution and extracted with DCM (x3). The combined DCM layers were dried (Na ₂ S0 ₄ ) and evaporated. Purification by FCC eluting with 0-6% 2M NH ₃ in MeOH / DCM afforded the title compound (13 mg, 29%).

LCMS (Method 3): Rt 2.45 min, m/z 584 [MH ⁺ ]. Ή NMR (400MHz, d ₆ -DMSO):

1.27 (9H, s), 1.51 (3H, s), 1.78-2.25 (11H, m), 2.66 (1H, q, J = 8.6 Hz), 3.12-3.20 (1H, m), 4.45 (2H, d, J = 5.8 Hz), 4.87-4.96 (1H, m), 5.24 (1H, t, J = 5.8 Hz), 5.35 (1H, t, J = 4.0 Hz), 6.81 (1H, br d, J = 8.6 Hz), 7.26-7.43 (7H, m), 7.76 (1H, dd, J = 9.9, 0.6 Hz), 8.46 (1H, d, J = 1.5 Hz), 8.80 (1H, s).

Example 52

l-(5-(tert-Butyl)-2-methoxypyridin-3-yl)-3-((lS,4R)-4-((3 -((S)-l,2- dimethylpyrrolidin-2-yl)- [1 ,2,4] triazolo [4,3-a] py ridin-6-yl)oxy)-l ,2,3j4- tetrahydronaphtha!en-l-yl)urea

A solution of Intermediate W (166 mg, 0.80 mmol) in 2-methyl THF (3 ml) was added to a solution of (lS,4R)-4-((3-((S)-l,2-dimethylpyrrolidin-2-yl)-[l,2,4]triaz olo[4,3- a]pyridin-6-yl)oxy)-l, 2,3, 4-tetrahydronaphthalen-l -amine (WO 2013/083604, 304 mg, 0.80 mmol) in 2-methyl THF (3 ml) and the reaction mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure and the residue was crystallised from DMSO to afford the title compound (115 mg, 24%). LCMS (Method 3): Rt 3.80 min, m/z 584 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.28 (9H, s), 1.52 (3H, s), 1.78-2.25 (11H, m), 2.66 (1H, q, J = 8.5 Hz), 3.13-3.21 (1H, m), 3.90 (3H, s), 4.87-4.95 (1H, m), 5.35 (1H, t, J = 4.4 Hz), 7.26-7.46 (6H, m), 7.71 (1H, d, J = 2.4 Hz), 7.76 (1H, dd, J = 9.8, 0.5 Hz), 8.05 (1H br s), 8.47 (1H, d, J = 1.6 Hz), 8.57 (1H, d, J = 2.4 Hz).

Example 53

6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethyIpyrrolid in-2-yI)-

[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yI)ureido)-N- methylpicolinamid

A solution of Intermediate WW (60 mg, 0.10 mmol) in DCM (1 ml) was treated with methylamine hydrochloride (10 mg, 0.15 mmol), HOBt.xH ₂ 0 (27 mg, 0.20 mmol), DIPEA (70 μΐ, 0.40 mmol) and finally with EDC (39 mg, 0.20 mmol) and the mixture stirred at RT for 18 h. The reaction mixture was partitioned between DCM and water and the two phases were separated. The aqueous layer extracted with DCM (x2) and the combined organic layers were washed with NaHC0 ₃ solution, brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (27 mg, 44%).

LCMS (Method 3): Rt 3.52 min, m/z 611 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.33 (9H, s), 1.51 (3H, s), 1.78-2.26 (11H, m), 2.65 (1H, q, J = 8.7 Hz), 2.84 (3H, d, J = 4.9 Hz), 3.13-3.20 (1H, m), 4.89-4.97 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 6.99 (1H, br d, J = 8.5 Hz), 7.26-7.43 (5H, m), 7.66 (1H, d, J = 1.9 Hz), 7.76 (1H, dd, J = 9.9, 0.5 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 1.6 Hz), 8.49 (1H, q, J = 4.9 Hz) 9.11 (1H, br s).

Example 54

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4 -((3-(methoxy-2- methylpropan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l ,2,3,4- tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate 7e (100 mg, 0.162 mmol) in MeOH (3 mL) was added to N,N-dimethylethylenediamine (72 mg, 0.813 mmol) and warmed to 50 °C for 18 hours. The reaction mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2), the combined DCM phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (63 mg, 59%).

LCMS (Method 3): Rt = 3.33 min, m/z 658 [M+H ⁺ ], sample assessed as ca. 99.1%.

¾NMR (400 MHz, d ₆ DMSO): 1.31 (9H, s), 1.53 (6H, s), 1.89-2.28 (4H, m), 2.17 (6H, s), 2.40 (2H, t, J = 6.6 Hz), 3.23 (3H, s), 3.36 (2H, q, J = 6.5 Hz), 3.67 (2H, s), 5.00 (1H, q, J = 8.4, 5.6 Hz), 5.54 (1H, t, J = 3.9 Hz), 7.27-7.47 (5H, m), 7.69-7.79 (2H, m), 8.22 (1H, br s), 8.28 (1H, s), 8.58 (1H, t, J = 5.8 Hz), 9.89 (1H, s).

Example 55

4-(teri-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-(3-methyloxetan-3-yl)-

[l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydr onaphthalen-l- yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate AH (100 mg, 0.167 mmol) in MeOH (3 mL) was added with N,N-dimethylethylenediamine (74 mg, 0.835 mmol) and warmed to 50 °C for 18 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined DCM phases were dried over solid MgS0 ₄ and purified by MDAP to afford the title compound (67 mg, 62%).

LCMS (Method 3): Rt = 3.07 min, m/z 642.3 [M+H ⁺ ], sample assessed as ca. 99.5%. ¾ NMR (400 MHz, d ₆ DMSO): 1.31 (9H, s), 1.78 (3H, s), 1.87-2.13 (3H, m), 2.17 (6H, s), 2.19-2.29 (1H, m), 2.50 (2H, t, J = 1.8 Hz), 3.35 (2H, q, J = 6.1 Hz), 4.82 (2H, d, J = 6.1 Hz), 4.99 (1H, q, J = 5.6 Hz), 5.12 (2H, q, J = 4.2 Hz), 5.58 (1H, t, J = 3.8 Hz), 7.27- 7.45 (5H, m), 7.74 (1H, s), 7.79 (1H, d, J = 9.9 Hz), 7.91 (1H, s), 8.21 (1H, br s), 8.53 (1H, t, J = 5.8 Hz), 9.86 (1H, br s).

Example 56

4-(teri-Butyl)-iV-(2-(dimethylamino)ethyI)-6-(3-((lS,4R)- 4-((3-((S)-l-methoxyethyl)- [l,2,4]triazoIo[4,3-a]pyridin-6-yl)oxy)-l,2,3j4-tetrahydrona phthalene-l- yl)ureido)pyrimidin-2-carboxamide

A stirred solution of Intermediate AJ (98 mg, 0.167 mmol) and N,N- dimethylamine ethanediamine (146 mg, 1.67 mmol) in DCM (3 mL) was stirred for 24 hours at RT and then the solvent was removed under reduced pressure. This residue was purified by MDAP to afford the title compound (82 mg, 77%).

LCMS (Method 3): Rt 3.18 min, m/z 630 [M+H ⁺ ], sample assessed as ca. 98.7%.

¾ NMR (400 MHz, d ₆ DMSO): 1.31 (9H, s), 1.66 (3H, d, J = 6.6 Hz), 1.87-2.31 (4H, m), 2.17 (6H, s), 2.39 (2H, t, J = 6.6 Hz), 3.23 (3H, s), 3.36 (2H, q, J = 6.2 Hz), 5.00 (1H, q, J

= 8.5 Hz), 5.17 (1H, q, J = 6.6 Hz), 5.53 (1H, t, J = 3.9 Hz), 7.27-7.49 (5H, m), 7.74 (1H, s), 7.78 (1H, d, J = 9.9 Hz), 8.17 (1H, s), 8.24 (1H, br s), 8.58 (1H, t, J = 5.7 Hz), 9.87 (1H, br s).

Example 57

l-(2-(tert-Butyl)-6-((2-morpholinoethoxy)methyl)pyrimidin -4-yl)-3-((lS,4R)-4-((3-(2- methoxy propan-2-yl)- [1 ,2,4] triazolo [4,3-a] pyridin-6-yI)oxy)-l,2,3,4- tetrahydronaphthaIen-l-yl)urea

A solution of Intermediate 12d (250 mg, 0.7.1 mmol), Intermediate AP (250 mg, 0.78 mmol), palladium(II)acetate (17 mg, 0.07 mmol), xantphos (81 mg. 0.14 mmol) and cesium carbonate (350 mg, 1.06 mmol) in dioxan (10 mL) was degassed by bubbling argon through the mixture under sonication for 10 minutes. The reaction mixture was stirred at 100 °C for 90 minutes then filtered through a pad of Celite®. The precipitate was washed with DCM and MeOH. The solvents were removed under reduced pressure and the crude mixture was purified by FCC eluting with 0-10% (2M NH ₃ in MeOH)/DCM followed by MDAP (basic) to afford the title compound (270 mg, 64%).

LCMS (Method 2): Rt = 2.73 min, m/z 672 [M+H ⁺ ], sample assessed as ca. 99%. Ή-NMR (400 MHz, DMSO): 1.27 (9H, s), 1.69 (6H, s), 1.85-2.26 (4H, m), 2.42 (4H, t, J = 4.4 Hz), 2.54 (2H, t, J = 5.8 Hz), 2.98 (3H, s), 3.56 (4H, t, J = 4.6 Hz), 3.63 (2H, t, J = 5.8 Hz), 4.45 (2H, s), 4.92 (1H, q, J = 8.7 Hz), 5.48 (1H, t, J = 4.1 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.26-7.44 (7H, m), 7.82 (1H, d, J = 9.9 Hz), 8.12 (1H, s), 8.84 (1H, s).

Example 58

4-(teri-ButyI)-6-(3-((lS,4R)-4-((3-(tert-butyl)-[l,2,4]triaz olo[4,3-a]pyridin-6-yI)oxy)- l,2,3,4-tetrahydronaphthalen-l-yl)ureido)- V-(2-(dimethylamino)ethyI)picolinamide

A solution of Intermediate AY (150 mg, 0.25 mmol) and N,N-dimethylethylene diamine (226 mg, 2.50 mmol) in ethanol (4 mL) was warmed to 80 °C for 2 days. The solvent was removed under reduced pressure and purification by FCC eluting with 0-10% (2M NH ₃ in MeOH)/DCM followed by MDAP (basic) afforded the title compound (75 mg, 48%).

LCMS (Method 3): Rt = 3.33 min, m/z 627 [M+H ⁺ ], sample assessed as ca. 99.5%. Ή-NMR (400 MHz, DMSO): 1.29 (9H, s), 1.53 (9H, s), 1.84-2.25 (4H, m), 2.14 (6H, s), 2.34 (2H, t, J = 6.3 Hz), 3.35 (2H, dd, J = 1.8, 6.1 Hz, partially obscured by the water peak), 4.96 (1H, q, J = 8.7 Hz), 5.64 (1H, t, J = 4.1 Hz), 7.25-7.48 (5H m), 7.58 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 1.7 Hz), 7.75 (1H, d, J = 9.9 Hz), 8.05 (1H, t, J = 5.6 Hz), 8.10 (1H, d, J = 1.6 Hz), 8.14 (1H, s), 9.08 (1H, s).

Example 59

4-(teri-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4 -((3-neopentyI- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3,4-tetrahydrona phthalen-l- yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate AI (100 mg, 0.167 mmol) in MeOH (3 mL) was added to N,N-dimethylethylenediamine (74 mg, 0.835 mmol) and warmed to 50 °C for 18 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined DCM phases were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (67 mg, 62%).

LCMS (Method 3): Rt = 3.44 min, m/z 642 [MH ⁺ ], sample assessed as ca. 99.5%. ¾ NMR (400 MHz, d ₆ DMSO): 1.98 (9H, s), 1.31 (9H, s), 1.89-2.29 (4H, m), 2.17 (6H, s), 2.38 (2H, t, J = 6.6 Hz), 3.03 (2H, q, J = 14.55 Hz), 3.39 (2H, q, J = 6.1 Hz, partially obscured by the water peak), 5.01 (1H, q, J = 8.7 Hz), 5.57 (1H, t, J = 3.9 Hz), 7.23-7.32 (2H, m), 7.32-7.46 (3H, m), 7.70 (1H, d, J = 9.8 Hz), 7.72 (1H, s), 8.31 (2H, br d, J = 1.3 Hz), 8.59 (1H, t, J = 7.5 Hz), 9.88 (1H, br s).

Example 60

4-(teri-Butyl)-N-(2-hydroxyethyI)-6-(3-((lS,4R)-4-((3-isobut yl-[l,2,4]triazolo[4,3- a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l-yl)ureido)pyrimidine-2- carboxamide

A solution of Intermediate AG (100 mg, 0.17 mmol) in MeOH (3 niL) was added with ethanolamine (52 mg, 0.85 mmol) and warmed to 55 °C for 8 hours. The reaction mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2) and the combined DCM phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP

(basic) afforded the title compound (56 mg, 55%).

LCMS (Method 3): Rt = 3.91 min, m/z 601 [M+H ⁺ ], sample assessed as ca. 98.8%.

¾ NMPv (400 MHz, d ₆ DMSO): 0.96 (6H, d, J = 6.6 Hz), 1.31 (9H, s), 1.88-2.31 (5H, m), 2.98 (2H, d, J = 6.8 Hz), 3.35 (2H, q, J = 5.8 Hz), 3.51 (2H, t, J = 5.8 Hz), 4.81 (1H, s), 5.00

(1H, q, J = 8.7 Hz), 5.57 (1H, t, J = 3.9 Hz), 7.23-7.45 (5H, m), 7.66-7.95 (2H, m), 8.23

(2H, s), 8.58 (1H, t, J = 5.9 Hz), 9.91 (1H, s).

Example 61

6-(tert-ButyI)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrrolid in-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3,4-tetrahydrona phthalen-l-yl)ureido)-N- (2-hydroxyethyl)picolinamide

A solution of Intermediate OO (55 mg, 0.09 mmol) in DCM (0.9 ml) was treated with ethanolamine (6.6 μΐ, 0.14 mmol), HOBt.xH ₂ 0 (18 mg, 0.14 mmol), DIPEA (40 μΐ, 0.23 mmol) and finally with EDC (26 mg, 0.14 mmol) and the mixture stirred at RT for 2 h. Further aliquots of ethanolamine (6.6 μΐ, 0.14 mmol) and EDC (26 mg, 0.14 mmol) were added along with DMF (0.5 ml) and the RM was warmed to 50 °C for 18 hours. Further aliquots of ethanolamine (6.6 μΐ, 0.14 mmol) and EDC (26 mg, 0.14 mmol) were added and stirring continued at 50°C for 5 h. The RM was partitioned between DCM and water and the two phases were separated. The aqueous layer was extracted with DCM (x2) and the combined organic layers were washed with NaHC0 ₃ solution, brine, dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (19 mg, 33%).

LCMS (Method 3): Rt 3.22 min, m/z 641 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.33 (9H, s), 1.51 (3H, s), 1.78-2.26 (11H, m), 2.65 (1H, q, J = 8.7 Hz), 3.13-3.20 (1H, m), 3.39 (2H, q, J = 5.8 Hz), 3.54 (2H t, J = 5.8 Hz), 4.83 (1H, br s), 4.89-4.97 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 7.11 (1H, br d, J = 8.5 Hz), 7.26-7.43 (5H, m), 7.69 (1H, d, J = 1.9 Hz), 7.76 (1H, dd, J = 9.9, 0.5 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 1.6 Hz), 8.53 (1H, t, J = 5.8 Hz) 9.24 (lH, br s).

Example 62

6-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-4-(3-((lS,4R)-4-(( 3-((S)-l,2- dimethylpyrrolidin-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl) oxy)-l,2,3 _» 4- tetrahydronaphthalen-l-yl)ureido)picolinamide

The title compound (9 mg, 15%) was prepared from N,N-dimethylethylenediamine (36μ1, 0.33 mmol) and Intermediate OO (55 mg, 0.09 mmol) using the procedure described to make Example 61.

LCMS (Method 3): Rt 2.72 min, m/z 668 [MH ⁺ ]. ¾ NMR (400MHz, d ₆ -DMSO): 1.33 (9H, s), 1.51 (3H, s), 1.78-2.26 (17H, m), 2.42 (2H, t, J = 6.5 Hz), 2.65 (1H, q, J = 8.7 Hz), 3.13-3.20 (1H, m), 3.38 (2H, q, J = 5.8 Hz), 4.89-4.97 (1H, m), 5.35 (1H, t, J = 4.0 Hz), 6.96 (1H, br d, J = 8.5 Hz), 7.26-7.43 (5H, m), 7.67 (1H, d, J = 1.9 Hz), 7.76 (1H, dd, J = 9.9, 0.5 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 1.6 Hz), 8.58 (1H, t, J = 5.8 Hz), 9.07 (lH, br s).

Example 63

l-(6-(tert-ButyI)-2-((2-morpholinoethoxy)methyl)pyrimidin -4-yl)-3-((lS,4R)-4-((3- (tert-butyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3,4 -tetrahydronaphthalen-l- yl)urea

A solution of Intermediate EE (136 mg, 0.22 mmol) in 2-methyltetrahydrofuran (5 ml) was treated with K ₂ C0 ₃ (91 mg, 0.66 mmol) and 2-morpholinoethanol (CAS: 622- 40-2, 80 μΐ, 0.66 mmol). The reaction mixture was heated at 70 °C for 5 hours and then another aliquot of morpholinoethanol (80 μΐ, 0.66 mmol) was added. The reaction mixture was heated at 90 °C for 5 days. The reaction mixture was cooled at RT and then treated with sodium hydride (60% in mineral oil, 10 mg, 0.26 mmol). The resulting mixture was heated at 80 °C for 18 hours. The reaction mixture was cooled at RT and then treated another aliquot of sodium hydride (60% in mineral oil, 10 mg, 0.26 mmol). The resulting mixture was heated at 80 °C for 18 hours, cooled at RT and quenched with H ₂ 0. The product was extracted with EtOAc and the solvent was removed under reduced pressure. Purification by MDAP (basic), followed by HPLC (Kinetex CI 8, 5-50% MeCN in H ₂ 0, 0.1 % HC0 ₂ H, 18 ml/min) afforded the title compound as formate salt. The residue was partitioned between 2-methyltetrahydrofuran and saturated aqueous NaHC0 ₃ solution and the two phases were separated. The solvent was removed under reduced pressure. The residue was partitioned between DCM and an aqueous 1M NaOH solution and the two phases were separated. The solvent was removed under reduced pressure to afford the title compound as a free base (8 mg, 5%).

LCMS (Method 3): Rt 3.27 min, m/z 657 [MH ⁺ ]. ¾ NMR (400 MHz, CDC1 ₃ ): 1.29 (9H, s), 1.59 (9H, s), 2.12-2.27 (3H, m), 2.34-2.42 (7H, m), 3.59-3.64 (6H, m), 4.50 (1H, d, J = 14.6 Hz, AB system), 4.55 (1H, d, J = 14.6 Hz, AB system), 5.19-5.25 (2H, m), 6.73 (1H, s), 7.16 (1H, dd, J = 9.9, 2.0 Hz), 7.28-7.38 (3H, m), 7.54-7.57 (1H, m), 7.77 (1H, d, J = 9.9 Hz), 7.82 (1H, d, J = 1.3 Hz), 8.38 (1H, br s), 9.83 (1H, br s).

Example 64

4-(tert-ButyI)-6-(3-((lS,4R)-4-((3-cyclopentyl-[l,2,4]triazo Io[4,3-a]pyridin-6-yl)oxy)- l,2,3 _» 4-tetrahydronaphthalen-l-yl)ureido)-N-(2-(dimethyIamin o)ethyl)pyrimidine-2- carboxamide

A solution of Intermediate KK (90 mg, 0.15 mmol) in methanol (2 ml) was treated with N V-dimethylethylenediamine (91 μΐ, 1.5 mmol). The reaction mixture was heated at 55 °C for 18 hours, cooled at RT and the solvent was removed under reduced pressure. Purification by MD AP (basic) afforded the title compound (70 mg, 60%).

LCMS (Method 3): Rt 3.92 min, m/z 613 [MH ⁺ ]. 1H NMR (400 MHz, d- ₆ -DMSO): 1.39 (9H, s), 1.66-2.22 (12H, m), 3.30-3.37 (2H, m), 3.51 (2H, br s), 3.62 (1H, quintet, J = 7.9 Hz), 4.80 (1H, br s), 4.98-5.04 (1H, m), 5.57 (1H, t, J = 4.0 Hz), 7.25-7.43 (5H, m), 7.69 (1H, dd, J = 9.8, 0.6 Hz), 7.74 (1H, br s), 8.20 (1H, d, J = 1.3 Hz), 8.25 (1H, br s), 8.57 (1H, t, J = 5.8 Hz), 9.84 (1H, br s).

Examples 65-211

a procedure I (Examples 65-85, 89-102, 104-109, 111-112, 114-125, 128-134, 136- 143, 145-197 and 199-211)

A solution of Intermediate (Table 1, 1 eq) and the relevant amine (Reagent, Table 1, 2-15 eq) in suitable solvent such as MeOH (3-5 ml) or EtOH (3-5 ml) was heated to a range of temperature, usually between 50 °C and 80 °C for 18 h. After cooling the mixture was evaporated and the residue was purified by FCC eluting with 0-10% (2M NH3 in MeOH)/DCM to afford the title compound (10% - 90%). Where necessary further purification by, for example, trituration, crystallisation, HPLC, MDAP or SFC could be undertaken.

a. procedure II (Examples 86-88, 113 and 135)

A solution of Intermediate (Table 1, 1 eq) in tetrahydrofuran was treated with the relevant amine (Reagent, Table 1, 1-10 eq). The reaction mixture was heated at 60 °C for 18 hours. The reaction mixture was cooled at RT and diluted with DCM and H ₂ 0. The two phases were separated and the aqueous phase was extracted with DCM (x 2). The combined organic phases were dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-10% (2M NH3 in MeOH)/DCM or MDAP (basic) afforded the title compound (40% - 50%). Where necessary further purification by, for example, trituration, crystallisation, HPLC, MDAP or SFC could be undertaken.

b. procedure III (Examples 103, 110 and 126-127)

A solution of Intermediate (Table 1, 1 eq), HOBt (1.2 eq) and EDC (1.2 eq) in DCM (3-5 ml) was treated with the relevant acid (Reagent, Table 1, 1.2 eq). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and H ₂ 0 and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (10% - 50%). Where necessary further purification by, for example, trituration, crystallisation, HPLC, MDAP or SFC could be undertaken.

c. procedure IV (Example 144)

A solution of the relevant alcohol (Reagent, Table 1, 2 eq) in tetrahydrofuran (4 ml) under nitrogen was treated with NaH (60% in mineral oil, 2 eq). The reaction mixture was stirred for 1 hour and a solution of Intermediate (Table 1, 1 eq) in tetrahydrofuran (2 ml) was added. The reaction mixture was stirred at RT for 1 hour and partitioned between H ₂ 0 and EtOAc. The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried with MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting with 0-10% (2M NH3 in MeOH)/DCM afforded the title compound (3%).

d. procedure V (Example 198)

A solution of Intermediate (Table 1, 1 eq) in MeOH (3 ml) and H ₂ 0 (0.5 ml) was treated with K ₂ C0 ₃ . The reaction mixture was stirred at RT for 2 hours and diluted with H ₂ 0 and DCM. The two phases were separated and the aqueous phase was extracted with DCM (x 3). The combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by MDAP (basic) afforded the title compound (69%).

Table 1

Example 212

N-(6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrro lidin-2-yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yI)oxy)-l,2,3 _» 4-tetrahydronaphthaIen-l- yl)ureido)pyridin-2-yl)methanesulfonamide

A solution of Intermediate AT (322 mg, 1.23 mmol), Intermediate OOa (520 mg,

1.23 mmol), XPhos (59 mg, 0.123 mmol) in previously degassed dioxane (5 ml) was treated with Cs ₂ C0 ₃ (601 mg, 1.85 mmol) and Pd(OAc) ₂ (14 mg, 0.062 mmol). The reaction mixture was degassed for a few minutes with argon and heated at 110 °C for 24 hours. The reaction mixture was cooled at RT, diluted with DCM and filtered through a pad of Celite®. The solvent was removed under reduced pressure and the residue was dissolved in dioxane (5 ml). This solution was added with Intermediate AT (322 mg, 1.23 mmol), XPhos (59 mg, 0.123 mmol), Cs ₂ C0 ₃ (601 mg, 1.85 mmol) and Pd(OAc) ₂ (14 mg, 0.062 mmol) and the reaction mixture was heated at 95 °C for 1 hour. Other aliquots of XPhos (59 mg, 0.123 mmol) and Pd(OAc) ₂ (14 mg, 0.062 mmol) were added and the reaction mixture was stirred at 95 °C for 1 hour. The reaction mixture was partitioned between DCM and H ₂ 0 and the two phases were separated. The organic phases was dried with Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM, followed by a further purification by HPLC (Waters CI 8, 15-80% MeCN in H ₂ 0, 0.1% NH ₄ OH, 18 ml/min) afforded the title compound (191 mg, 23%).

LCMS (Method 3): Rt 3.10 min, m/z 646 [MH ⁺ ]. ^! H NMR (400 MHz, d- ₆ -DMSO): 1.28 (9H, s), 1.53 (3H, s), 1.80-2.23 (11H, m), 2.68 (1H, q, J = 8.8 Hz), 3.12-3.17 (1H, m),

3.24 (3H, br s), 4.89-4.95 (1H, m), 5.35 (1H, t, J = 4.4 Hz), 6.66 (1H, d, J = 8.2 Hz), 6.95 (1H, s), 7.04 (1H, s), 7.25-7.42 (6H, m), 7.70 (1H, dd, J = 9.8, 0.8 Hz), 8.46-8.47 (1H, m), 8.75 (1H, br s). Example 213

N-(6-(tert-Butyl)-4-(3-((lS,4R)-4-((3-((S)-l,2-dimethylpyrro lidin-2-yl)-

[l,2,4]triazolo[4,3-a]pyridm-6-yl)oxy)-l,2,3,4-tetrahydro naphthalen-l- yl)ureido)pyridin-2-yl)ethanesulfonamide

A solution of Intermediate AU (126 mg, 0.46 mmol), Intermediate OOa (193 mg, 0.46 mmol), XPhos (22 mg, 0.46 mmol) in previously degassed dioxane (4 ml) was treated with Cs ₂ C0 ₃ (225 mg, 0.69 mmol) and Pd(OAc) ₂ (5 mg, 0.023 mmol). The reaction mixture was degassed for a few minutes with argon and heated at 110 °C for 1 hour. The reaction mixture was cooled at RT, diluted with H ₂ 0 and extracted with DCM (x 3). The combined organic phases were dried with MgS04 and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (120 mg, 40%).

LCMS (Method 3): Rt 3.19 min, m/z 661 [MH ⁺ ]. ¾NMR (400 MHz, d- ₆ -DMSO): 1.21-1.25 (12H, m), 1.51 (3H, s), 1.79-2.22 (11H, m), 2.66 (1H, q, J = 8.8 Hz), 3.14-3.19 (1H, m), 3.55 (2H, br s), 4.88-4.93 (1H, m), 5.35 (1H, t, J = 4.1 Hz), 6.80 (1H, br s), 6.91 (1H, br s), 7.05 (1H, br s), 7.27-7.40 (5H, m), 7.76 (1H, dd, J = 9.9, 0.6 Hz), 8.46 (1H, d, J = 1.5 Hz), 8.87 (1H, br s), 10.2 (1H, br s).

Example 214

4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4 -((3-((R)-4- methylmorpholin-3-yl)- [1,2,4] triazolo [4,3-a] pyridin-6-yl)oxy)-l ,2,3,4- tetrahydronaphthalen-l-yI)ureido)pyrimidine-2-carboxamide a. (S)-N'-(5-Fluoropyridin-2-yI)-4-methylmorphoIine-3-carbohydr azide

(Intermediate 214a)

A solution of (S)-4-methylmorpholine-3-carboxylic acid (16.2 g, 111.7 mmol) in DCM (250 ml) was treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (17.2 g, 89.6 mmol), hydroxybenzotriazole (1.37 g, 10.1 mmol) and (5- fluoro-2-pyridyl)hydrazine (11.4 g, 89.7 mmol). The reaction mixture was stirred at 20 °C for 4 hours then diluted with 2-methyltetrahyrofuran. The organic layer was washed with 2N citric acid solution (x2) and water. The combined citric acid layers were washed with Et ₂ 0, basified with solid K ₂ C0 ₃ and extracted with DCM (x2). The combined DCM layers were dried over solid Na ₂ S0 ₄ and the solvent was removed under reduced pressure. Purification by FCC, eluting 10% acetone in DCM followed 10% (2M NH ₃ in MeOH)/DCM to afford the title compound (7.6g, 33%).

lH NMR (300 MHz, CDC1 ₃ ): 2.17 (3H, s), 2.38 (1H, dt, J = 11.4, 3.5 Hz), 2.82 (1H, dt, J = 11.9, 2.3 Hz), 2.96 (1H, dd, J = 3.9, 9.9 Hz), 3.54 (1H, dd, J = 9.9, 11.3 Hz), 3.65 (1H, dt, J = 2.4, 11.3 Hz), 3.88 (1H, d, J = 11.5 Hz), 4.04 (1H, dq, J = 0.9, 3.9, 11.34 Hz), 6.62 (1H, dd, J = 3.4, 9.0 Hz), 6.67 (1H, s), 7.29 (1H, quintet, J = 2.9, 7.8, 8.97 Hz), 8.03 (1H, d, J = 2.9 Hz), 8.64 (1H, br s).

b. (R)-3-(6-Fluoro~ [1,2,4] triazolo [4,3-a] pyridin-3-yl)-4-methylmorpholine (Intermediate 214b)

A solution of Intermediate 214a (6.5 g, 25.6 mmol) in 2-methyltetrahydrofuran (100 mL) was treated with triphenylphosphine (13.4 g, 51.2 mmol), triethylamine (10.3 g, 102.4 mmol) and cooled to 0 °C before hexachloroethane (12.1 g, 51.2 mmol) was slowly added. The reaction mixture was allowed to warm to rt over 1 hour, exotherming to 32°C. The reaction mixture was washed with water, then extracted into IN HC1 solution. The acidic layer was washed with Et ₂ 0, basified with solid Na ₂ S0 ₄ and extracted with DCM (x2). The combined DCM phases were dried over Na ₂ S0 ₄ and the solvent was removed under reduced pressure to afford the title compound (4.20 g, 70%).

¾ NMR (300 MHz, CDC1 ₃ ): 2.11 (3H, s), 2.52 (1H, dt, J = 3.4, 11.7 Hz), 2.94 (1H, dt, J = 1.9, 11.8 Hz), 3.66 (1H, t, J = 11.1 Hz), 3.81 (1H, dt, J = 2.4, 11.6 Hz), 3.92-4.01 (2H, m), 4.14 (1H, dd, J = 3.8, 10.8 Hz), 7.21 (1H, ddd, J = 2.3, 7.5 Hz), 7.75 (1H, dq, J = 0.7, 5.0 Hz), 8.89 (1H, t, J = 2.7 Hz).

c. (lS,4R)-4-((3-((R)-4-Methylmorpholin-3-yl)-[l,2,4]triazolo[4 ,3-a]pyridin-6- yl)oxy)-l,2,3,4-tetrahydronaphthalen-l-amine (Intermediate 214c)

A solution of Intermediate 214b (4.25 g, 18.0 mmol), (lR,4S)-4-amino-l,2,3,4- tetrahydronaphthalen-l-ol (2.93 g, 18.0 mmol) and 18-crown-6 ether (2.36 g, 9.0 mmol) in 2-methyltetrahydrofuran (30 mL) was degassed for 10 minutes under sonication bubbling argon through the mixture, then cooled to 0 °C and potassium tert-butoxide (2.4 g, 21.6 mmol) was added. The reaction mixture was allowed to warm to 20 °C over 3 hours with stirring. The reaction mixture was diluted with 2-methyltetrahydrofuran and washed with water, then dried over solid Na ₂ S0 ₄ . The solvent removed under reduced pressure and purification by FCC, eluting with 0-10% 2N NH ₃ in MeOH/DCM afforded the title compound (5.2 g, 70%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.88-2.00 (1H, m), 2.02-2.11 (2H, m), 2.12 (3H, s), 2.33-2.43 (1H, m), 2.50 (1H, dt, J = 3.4, 11.8 Hz), 2.89 (1H, d, J = 11.9 Hz), 3.62 (1H, t, J = 11.1 Hz), 3.68 (1H, dt, J = 2.3, 11.4 Hz), 3.92 (1H, dd, J = 3.7, 7.3 Hz), 3.97 (1H, s), 4.00 (1H, dd, J = 5.2, 8.1 Hz), 4.09 (1H, dd, J = 3.8, 10.8 Hz), 5.24 (1H, t, J = 4.4 Hz), 7.14 (1H, dd, J = 2.2, 9.9 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.34 (1H, d, J = 6.5 Hz), 7.40 (1H, dt, J = 1.4, 7.5 Hz), 7.61 (1H, d, J = 7.7 Hz), 7.68 (1H, d, J = 9.9 Hz), 8.44 (1H, s).

d. l-((lS,4R)-4-((3-((R)-4-Methylmorpholin-3-yl)-[l,2,4]triazol o[4,3-a]pyridin-6- yl)oxy)-l ,2,3 _> 4-tetrahydronaphthaIen-l-yI)urea (Intermediate 214d)

A solution of triphosgene (1.72 g, 5.79 mmol) in DCM (25 mL) under nitrogen was cooled to -10°C and a solution of Intermediate 214c (2.0 g, 5.27 mmol) and triethylamine ( 3.0 mL, 21.1 mmol) in DCM (25mL) was dropwise added at or below - 10°C. This solution was stirred at 0°C for one hour before a solution of NH ₃ in MeOH (2N, 80 mL, 158 mmol) pre-cooled to 0°C was added and the reaction mixture was allowed to warm to 20°C. The mixture was partitioned between water and DCM and the two phases were separated. The aqueous phase was extracted with DCM (x 2), the combined DCM layers were dried over solid MgS0 ₄ and the solvent was removed under reduced pressure. Purification by FCC eluting 0 to 10% (2N NH ₃ in MeOH) in DCM afforded the title compound (1.42 g, 60%).

¾ NMR (300 MHz, CDC1 ₃ ): 1.99-2.32 (3H, m), 2.14 (3H, s), 2.28-2.40 (1H, m), 2.51 (1H, dt, J = 3.3, 11.8 Hz), 2.91 (1H, d, J = 11.7 Hz), 3.64 (1H, t, J = 11.1 Hz), 3.70 (1H. dt, J = 2.0, 11.7 Hz), 3.88-4.01 (2H, m), 4.08 (1H, dd, J = 3.7, 10.7 Hz), 4.53 (2H, s), 5.07 (2H, s), 5.21 (1H, t, J = 4.4 Hz), 7.09 (1H, dd, J = 2.2, 9.9 Hz), 7.27-7.41 (3H, m), 7.51 (1H, d, J = 7.4 Hz), 7.64 (1H, d, J = 9.9 Hz), 8.48 (1H, s).

e. Ethyl 4-(tert-butyl)-6-(3-((lS,4R)-4-((3-((R)-4-methylmorpholin-3- yl)- [l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-l,2,3 _? 4-tetrahydronaphthalen-l- yl)ureido)pyrimidine-2-carboxylate (Intermediate 214e)

A solution of Intermediate 214d (710 mg, 1.70 mmol), Intermediate Id (408 mg, 1.70 mmol), palladium(II)acetate (190 mg, 0.85 mmol), Xantphos (98 mg, 0.17 mmol) and cesium carbonate (776 mg, 0.17 mmol) in dioxan (20 mL) was degassed by bubbling argon through the mixture for 5 minutes under sonication and the reaction mixture was heated to 90 °C for 20 hours. The reaction mixture was filtered through a pad of Celite® washing the precipitate with EtO Ac. The solvents were removed under reduced pressure. Purification by FCC eluting with 0-10% IMS in EtOAc afforded the title compound (610 mg, 57%).

Ή NMR (300 MHz, CDC1 ₃ ): 1.26 (3H, t, J = 7.2 Hz), 1.36 (9H, s), 1.39-1.44 (1H, m), 2.05 (3H, s), 2.07-2.59 (5H, m), 2.91 (1H, d, J = 11.7 Hz), 3.63-3.78 (2H, m), 3.89- 4.01 (1H, m), 4.08-4.32 (2H, m), 4.12 (2H, q, J = 7.2 Hz), 5.17-5.28 (1H, m), 6.87 (1H, br s), 7.11 (1H, dd, J = 2.0, 9.9 Hz), 7.28-7.42 (2H, m), 7.55 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 7.8 Hz), 8.06 (1H, s), 8.53 (1H, s), 9.77 (1H, br s).

f. 4-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-6-(3-((lS,4R)-4-(( 3-((R)-4- methylmorpholin-3-yI)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)oxy )-l,2,3,4- tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carboxamide (Example 214)

A solution of Intermediate 214e (100 mg, 0.17 mmol) in MeOH (3 mL) was added with ethanolamine (52 mg, 0.85 mmol) and warmed to 55°C for 18 hours. The solvent was removed under reduced pressure and purified by MDAP followed by FCC eluting 0 - 10% (2M NH ₃ in MeOH)/DCM afforded the title compound (16 mg, 14%).

LCMS (Method 3): Rt 4.20 min, m/z 671 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ DMSO): 1.31 (9H, s), 1.88-2.45 (7H, m), 1.99 (3H, s), 2.17 (6H, s), 2.90 (1H, d, J = 11.8 Hz), 3.34- 3.39 (2H, m, partially obscured by the water peak), 3.69 (1H, dt, J = 11.9, 2.2 Hz), 3.74- 3.82 (2H, m), 3.86 (1H, d, J = 11.2 Hz), 3.98 (1H, dd, J = 4.4, 9.4 Hz), 5.01 (1H, q, J = 4.8 Hz), 5.51 (1H, t, J= 3.7 Hz), 7.26-7.45 (5H, m), 7.70-7.79 (2H, m), 8.25 (1H, br s), 8.53 (1H, d, J = 1.5 Hz), 8.58 (1H, t, J = 5.7 Hz), 9.87 (1H, br s).

Example 215

4-(tert-Butyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-6- (3-((lS,4R)-4-((3-((R)- 4-methylmorpholiu-3-yl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)o xy)-l,2,3,4- tetrahydronaphthalen-l-yl)ureido)pyrimidine-2-carboxamide

A solution of Intermediate 214e (102 mg, 0.162 mmol) in IMS (3 mL) was added with 2-[(2-aminoethyl)(methyl)amino]ethanol (190 mg, 0.50 mmol) and warmed to 55 °C for 18 hours. The solvent was removed under reduced pressure and purified by HPLC (Kinetex CI 8, 10-95% MeCN in H ₂ 0, 0.1% HC0 ₂ H, 18 ml/min). The required fractions were evaporated under reduced pressure and the residue was dissolved in saturated bicarbonate solution. The aqueous phase was extracted with DCM (x 2) and the combined organic layers were evaporated under reduced pressure. Final purification by MD AP (basic) afforded the title compound (16 mg, 14%).

LCMS (Method 3): Rt 2.69 min, m/z 701 [MH ⁺ ]. ¾ NMR (400 MHz, d ₆ DMSO): 1.32 (9H, s), 2.00 (3H, s), 2.03-2.19 (2H, m), 2.21-2.34 (4H, m), 2.40 (1H, dt, J = 11.5, 3.2 Hz), 2.47 (2H, t, J = 7.0 Hz), 2.52-2.56 (2H, m), 2.90 (1H, d, J = 11.7 Hz), 3.35 (4H, q, J = 6.3 Hz), 3.48 (2H, t, J = 6.5 Hz), 3.69 (1H, dt, J = 2.2, 11.1 Hz), 3.74-3.82 (2H, m), 3.86 (1H, d, J = 10.9 Hz), 3.98 (1H, dd, J = 4.3, 9.3 Hz), 5.01 (1H, q, J = 8.9 Hz), 5.51 (1H, t, J = 3.8 Hz), 7.26-7.46 (4H, m), 7.69-7.80 (2H, m), 8.19 (1H, s), 8.27 (1H, br s), 8.53 (1H, d, J = 1.4 Hz), 8.61 (1H, t, J = 5.6 Hz), 9.90 (1H, s).

Biological Assays

P38alpha enzyme inhibition assay

The inhibitory activity of compounds was determined using an Alphascreen® (Perkin Elmer) based kinase activity assay. Kinase reactions consisted of 25mM HEPES pH 7.5, lOmM MgCl ₂ , ΙΟΟμΜ Na ₃ V0 ₄ , 2mM DTT, 0.05mg/ml Tween 20, ΙΟΟρΜ p38alpha (Invitrogen, PV3304), 1% DMSO and 03μ§/πά ATF-2 fusion protein (New England Biolabs, 9224). Compounds were incubated under these conditions for 2 hours, at 25°C, prior to the initiation of the kinase activity by the addition of the 250μΜ ATP. Reaction volumes were 20uL. After lhr at 25°C reactions were stopped by the adding lOuL of 25mM HEPES pH 7.5 containing 62.5mM EDTA, 0.05% Triton X-100, 10% BSA and 0.83ng/uL anti- phospho-ATF2 antibody (Abeam, ab28812). Detection was performed by measuring luminescence following the addition of Alphascreen Donor beads (Perkin Elmer 6765300) and Protein A Alphascreen Acceptor beads (Perkin Elmer 6760137), both at a final concentration of 20ug/ml. IC ₅₀ values were determined from concentration- response curves.

Results are shown in the following Table:

In the table above, p38a potencies (IC ₅₀ values) are indicated as follows: 1-10 nM

'+'; <lnM '++'

LPS-stimulated PBMC TNFa release assay

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from healthy human volunteer blood using a standard density gradient centrifugation technique. Citrated blood was placed onto Histopaque™ and centrifuged. The PBMCs were removed from the density gradient interface and washed in phosphate buffered saline (PBS). The PBMCs were suspended in RPMI 1640 medium (without serum), dispensed into a 96-well plate and incubated at 37°C for 3h in a humidified incubator. After incubation, the medium was replaced (with medium containing 1% foetal bovine serum) and the plate incubated at 37°C, for lh, in the presence of test compound or the appropriate vehicle. LPS (lOng/ml), or an appropriate vehicle control, was then added to the cells and the plate returned to the incubator for 18h. Cell-free supematants were removed and assayed for TNFa levels using MSD plates on the Sector Imager 6000 (MesoScale).

A dose response curve to each test compound was performed and the effect of compound in each experiment was expressed as a percentage inhibition of the control TNFa release. Dose response curves were plotted and compound potency (IC ₅₀ ) was determined. Compounds were tested in at least three separate experiments.

Results are shown in the following Table:

In the table above, human PBMC potencies (IC ₅₀ values) are indicated as follows:

>5 nM '+'; 1-5 nM '++'; <lnM '+++'

Anti-inflammatory activity of P38alpha inhibitors in a LPS-challenge model in rat

Twelve hours after compound/vehicle administration, rats are challenged intratracheally with LPS. Four hours later, rats are sacrificed, bronchoalveolar lavage fluid (BALF) collected and the total cell number and neutrophil numbers determined. Anti-inflammatory activity is represented by a reduction in the number of neutrophils as compared to a vehicle- treated control group.

Solubility Assays

Kinetic solubility

Using a 10 μΜ stock solution of each test and control compound (hydrocortisone, reserpine) in 100% DMSO, dilutions were prepared to a theoretical concentration of 200 μΜ in both 0.1 M potassium phosphate buffer containing 0.8% NaCl (PBS), pH 7.4 (2% DMSO final), and in 100% DMSO. An aliquot of the 200 μΜ DMSO solution was then further diluted to 10 μΜ and all dilutions (n=2, in 96-well plates) allowed to equilibrate at RT on an orbital shaker for two hours. The PBS dilutions were filtered using a Multiscreen HTS solubility filter plate (Millipore) and filtrate was analysed by LC-UV with confirmation of the peak of interest by mass spectrometry. The concentration of compound in PBS filtrate was determined by comparing the UV absorbance peak with that of the two DMSO dilutions as calibration standards.

The effective range of the assay is 10-200 μΜ and compounds returning values close to the upper limit may have much higher solubilities.