Wild type kit inhibitors

Abstract

Disclosed is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are defined herein. Compounds of Formula (I) are useful for inhibiting wild type c-kit kinase and for treating disorders and diseases mediated by wild type c-kit kinase in humans or non-humans.

Description

Atty. Dkt. No.: 134108-861202024-8061 PCTWILD TYPE KIT INHIBITORSRELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 734,589, filed on December 16, 2024, the entire teachings of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The disclosure relates to novel compounds and their use as selective inhibitors of wild type c-kit kinase, a cell surface receptor that acts as the master survival and functional regulator of mast cells.BACKGROUND OF THE INVENTION

[0003] Mast cells are a part of the immune system. They are a main driver of allergic inflammatory responses and are present throughout the body in connective and vascularized tissues, most prominently along surface boundaries with exposure to the external environment: in the skin, the respiratory tract and the gastrointestinal tract. Dysfunctional mast cell activity has been implicated in the pathophysiology of a broad range of allergic and other inflammatory disorders including urticaria, asthma and gastrointestinal disorders.

[0004] For many who suffer from allergic conditions, inhibition of mast cell derived mediators, including histamines, leukotrienes, and prostaglandins, has resulted in insufficient therapeutic benefit to-date given that many mast cell-driven disorders involve multiple pro- inflammatory mediators. One such mast-cell driven disorder is chronic urticaria, which is defined as the occurrence of wheals, angioedema, or both for more than 6 weeks. The international urticaria guideline classifies the disease as chronic spontaneous urticaria (CSU, also called chronic idiopathic urticaria), without a definite eliciting factor involved, or as chronic inducible urticaria (CIndU), where defined and definite eliciting factors reproducibly trigger signs and symptoms and are required for their occurrence. The point prevalence of chronic urticaria is approximately 0.5% to 1%. Chronic urticaria is unpredictable in its course and duration, and it may persist for several years in many patients. Chronic urticaria is a disabling condition that leads to substantial deterioration in quality of life. Furthermore, psychosocial factors, such as anxiety, depression, somatization, interpersonal sensitivity, insomnia, and stressful life events, are present in many of the patients with chronic urticaria. In addition, care of patients with chronic urticaria is time-consuming and costly. No curative treatment exists for1ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTchronic urticaria, and all currently recommended treatment options are intended only to control and prevent the symptoms of chronic urticaria.

[0005] Wild-type c-kit plays a central role in mast cell survival, proliferation, and activation.Recently in clinical trials, c-kit inhibition has shown positive responses in mast cell mediated diseases. For example, c-kit inhibition in chronic inducible urticaria and chronic spontaneous urticaria has been shown to be an effective treatment in a phase I trial (inducible) and phase 1 and 2 (spontaneous) using a monoclonal antibody, and a c-kit small molecule inhibitor has also shown modulation of tryptase, a mast cell mediator, in normal healthy volunteers and in a phase 1 trial of chronic inducible urticaria the inhibitor has been shown to be an effective treatment. There is need for treatments to target mast cells directly through highly selective inhibition of c- kit to achieve broad symptomatic relief across a range of mast cell mediated diseases.SUMMARY OF THE INVENTION

[0006] Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which are useful for inhibiting wild type c-kit kinase and for treating diseases or disorders mediated by wild type c-kit kinase. The compounds of the disclosure or pharmaceutically acceptable salts thereof are potent inhibitors of c-kit kinase (see Table 2 in Example 113). Some compounds of the disclosure are orally bioavailable, selective over other kinases such FLT3, CSF1R and PDGFRB and have minimal CNS penetration to reduce CNS side effects. Some compounds have better PDGFRA selectivity. Certain compounds of the disclosure do not form glutathione adducts. Some compounds do not cause inhibition of cytochrome P450 (CYP) enzymes. Some compounds of the disclosure cause low CYP induction.

[0007] One embodiment of the disclosure is a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C1-6alkyl, deuterated C1-6alkyl, and C3-6cycloalkyl, wherein said C1-6alkyl and deuterated C1-6alkyl are optionally substituted with C3-6cycloalkyl;ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTeach R2is independently selected from C1-3alkyl, C1-3haloalkyl, halogen, CN, and C3-4cycloalkyl;R3and R4are each independently selected from hydrogen and C1-4alkyl; R5is selected from C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, hydroxymethyl, C2-6hydroxyalkyl, C2-6hydroxyhaloalkyl, S(O)C1-3alkyl, S(O)(NH)C1-3alkyl, and C(O)NH(C1-3alkyl), wherein:C1-6alkyl and C1-6haloalkyl represented by R5are each optionally substituted with R5aselected from C1-4hydroxyalkoxy, S(O)C1-3alkyl, S(O)(NH)C1-3alkyl, C(O)NH(C1-3alkyl), C(O)(C1-3alkyl), P(O)(C1-6alkyl)2, N(C1-3alkyl)(C1-3hydroxyalkyl), N(C1-3alkyl)2, and C1-5alkoxy;wherein C1-5alkoxy represented by R5ais optionally substituted with NH(C1-3alkyl) or N(C1-3alkyl)2; andC2-6hydroxyalkyl and C2-6hydroxyhaloalkyl represented by R5are each optionally substituted with two C1-5alkoxy or R5bselected from OH, CN, C1-5alkoxy, C1-5alkoxyC1-5alkoxy, C(O)NH(C1-3alkyl), C(O)O(C1-3alkyl), NH(C1-6alkyl), N(C1-6alkyl)2, N(C1-6haloalkyl)2, and NH(C1-6haloalkyl); andn is 1 or 2.

[0008] Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the composition is for treating a disease or disorder mediated by wild type c-kit kinase. In another aspect, the composition is for inhibiting wild type c-kit kinase.

[0009] Another embodiment of the disclosure is a method of treating a subject suffering from a disease or disorder mediated by wild type c-kit kinase. The method comprises administering to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0010] Another embodiment of the disclosure is a method of inhibiting wild type c-kit kinase in a subject in need thereof. The method comprises administering to the subject in need thereof an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically3ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTacceptable excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0011] Another embodiment of tire disclosure is tire use of a compound of tire disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in the manufacture of a medicament for tire treatment of medical condition mediated by wild type c-kit kinase.

[0012] Another embodiment of the disclosure is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in the manufacture of a medicament for inhibiting wild type c-kit kinase in a subject in need thereof.

[0013] In yet another embodiment, tire disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for tire treatment of a medical condition mediated by wild type c-kit kinase.

[0014] Also included in the disclosure is a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for inhibiting wild type c-kit kinase in a subject in need thereof.DETAILED DESCRIPTION OF THE INVENTION

[0015] An object of this disclosure is to provide novel compounds and compositions with highly selective, potent activity against wild type c-kit kinase for the safe and effective treatment of mast cell associated disease in a subject. For example, the IC50 values for inhibition of phospho kit provided in Table 2 of Example 113 demonstrate that these compounds are potent inhibitors of c-kit. The term “KIT”, “kit” or “c-kit” refers to a human tyrosine kinase that may be referred to as mast / stem cell growth factor receptor (SCFR), proto-oncogene c-kit, tyrosineprotein kinase kit or CD117.

[0016] In treating these mast cell associated diseases, especially chronic disorders such as urticaria and asthma, any new therapy should be well-tolerated. The compounds of the disclosure or a pharmaceutically acceptable salt thereof aim to provide treatments having desirable efficacy, safety, and pharmaceutical properties for tire treatment of c-kit mediated diseases. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt 4ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTthereof are orally administered. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof are selective inhibitors of c-kit kinase. Selective inhibitors selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target, which leads to an increased probability of clinical success in comparison with a non-selective inhibitors. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof have low CNS penetration, which is a desirable property for reducing and minimizing side effects of chronic treatment. Compounds with low CNS penetration often have high levels or active transport out of the brain, i.e., high efflux ratios from the CNS. Some compounds of the disclosure have the advantage of not forming glutathione adducts. Some compounds of the disclosure are beneficial with respect to cytochrome P450, e.g.,some compounds do not inhibit CYP and some compounds have low CYP induction.

[0017] Compounds of the disclosure or a pharmaceutically acceptable salt thereof are selective c-kit inhibitors. As used herein, a “selective c-kit inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that has the ability to selectively inhibit c-kit kinase over other targets. More specifically, a selective c-kit inhibitor has the ability to selectively inhibit c-kit over another kinase. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof are selective for c-kit over FLT3 kinase, CSF1R kinase and PDGFR kinase. A selective c-kit inhibitor has the ability to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. The ability to selectively target c-kit with a compound of tire disclosure or pharmaceutically acceptable salt thereof provides advantages in terms of improved potency, less off-target activity and an increased probability of clinical success in comparison with a non- selective compound or salt.

[0018] Some compounds of the disclosure or a pharmaceutically acceptable salt thereof are inhibitors of KIT exon 9 and / or 11. Mutations in exon 9 and 11 of KIT are primary driver mutations in -10% of gastrointestinal tumors, and high dose imatinib, a KIT ex9 / ll inhibitor, has been shown to be an effective treatment option.

[0019] A first aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are as described above.

[0020] A second aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is C1-3alkyl, deuterated C1-3alkyl, or C3-6cycloalkyl, and tire remainder of the variables are as described for Formula (I) in the first aspect.5ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT10021] A third aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is methyl, -CD3, ethyl or cyclopropyl and the remainder of the variables are as described for Formula (I) in the first aspect.

[0022] A fourth aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein each R2is independently C1-3alkyl, halogen or CN and tire remainder of the variables are as described for Formula (I) in tire first aspect, the second aspect or the third aspect.

[0023] A fifth aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein each R2is independently methyl, fluoro, chloro or CN and the remainder of die variables are as described for Formula (I) or die first aspect, die second aspect or die third aspect.

[0024] A sixth aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt diereof, wherein n is 1 and R2is Cualkyl or halogen and the remainder of the variables are as described for Formula (I) in the first aspect, die second aspect, or the third aspect.

[0025] A seventh aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 and R2is methyl or chloro and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or the third aspect.

[0026] An eighth aspect of die disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 2 and wherein each R2is independently C1-3alkyl, halogen or CN and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or the third aspect.

[0027] A nineth aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 2 and each R2is independently mediyl, fluoro, chloro or CN and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or die third aspect.

[0028] A tenth aspect of die disclosure is a compound represented by Formula (I) or a pharmaceudcally acceptable salt thereof, wherein n is 2; one of R2is mediyl and die other R2is fluoro or CN; or one of R2is chloro and die other R2is fluoro; and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or die diird aspect.

[0029] An eleventh aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt diereof, wherein n is 2; one of R2is methyl and the odier R2is 6ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTfluoro or CN and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or the third aspect.

[0030] A twelfth aspect of the disclosure is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 2; one of R2is chloro and tire other R2is fluoro and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, or the third aspect.

[0031] A thirteenth aspect of tire disclosure is a compound represented by Formula (II) or (III):or a pharmaceutically acceptable salt thereof. The variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, tire fifth aspect, the sixth aspect, the seventh aspect, tire eighth aspect, the nineth aspect, tire tenth aspect, the eleventh aspect or the twelfth aspect.

[0032] A fourteenth aspect of the disclosure is a compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently selected from hydrogen and methyl and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, the fifth aspect, the sixth aspect, the seventh aspect, the eighth aspect, the nineth aspect, the tenth aspect, the eleventh aspect, the twelfth aspect or the thirteenth aspect.

[0033] A fifteenth aspect of the disclosure is a compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R3and R4are both hydrogen and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, the fifth aspect, the sixth aspect, the seventh aspect, the eighth aspect, the nineth aspect, the tenth aspect, the eleventh aspect, the twelfth aspect or the thirteenth aspect.

[0034] A sixteenth aspect of the disclosure is a compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein one of R3and R4is hydrogen and the other of R3and R4is methyl and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, the fifth aspect, the sixth7ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTaspect, the seventh aspect, the eighth aspect, the nineth aspect, the tenth aspect, the eleventh aspect, the twelfth aspect or the thirteenth aspect.

[0035] A seventeenth aspect of tire disclosure is a compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R5is Ci.3alkyl, deuterated Ci-3alkyl, Ci.3haloalkyl, C2-6hydroxyhaloalkyl, or C2-6hydroxyalkyl, wherein:C1-3alkyl and C1-3haloalkyl represented by R5are each optionally substituted with R5aselected from C1-4hydroxyalkoxy, S(O)C1-3alkyl, S(O)(NH)C1-3alkyl, C(O)NH(C1-3alkyl), C(O)(C1-3alkyl), P(O)(C1-3alkyl)2, N(C1-3alkyl)(C1-3hydroxyalkyl), N(C1-3alkyl)2and C1-5alkoxy, wherein C1-5alkoxy represented by R5ais optionally substituted with NH(C1-3alkyl) or N(C1-3alkyl)2; and andC2-6hydroxyalkyl and C2-6hydroxyhaloalkyl represented by R5are each optionally substituted with two C1-3alkoxy or R5bselected from OH, CN, C1-3alkoxy, C1-3alkoxyC1-3alkoxy, C(O)NH(C1-3alkyl), C(O)O(C1-3alkyl), NH(C1-3alkyl), N(C1-3alkyl)2, N(C1-3haloalkyl)2and NH(C1-3haloalkyl), and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, the fifth aspect, the sixth aspect, the seventh aspect, the eighth aspect, the nineth aspect, the tenth aspect, the eleventh aspect, the twelfth aspect, the thirteenth aspect, the fourteenth aspect, the fifteenth aspect or the sixteenth aspect.

[0036] An eighteenth aspect of the disclosure is a compound represented by Formula (I), (II) or (111) or a pharmaceutically acceptable salt thereof, wherein R5is methyl, -CD3, -CH2CHF2, -V-OH CH2CH(OH)-CH3, / , -CH(CH3)CH(OH)(CH3), HO HoHO. -CH2C(OH)(CH3)2, -CH2CH(OH)CH2CH3, -CH2CH(OH)CF3,- HO'^X^'5CH2CH(OH)CHF2, -CH2C(OH)(CH3)CH2OH, * OHCH2CH(OH)CH(OH)CH3, -CH2CH(OH)C(OH)(CH3)2OH CH2CH(OH)CH2CH(OH)(CH3), OHME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT-CH2C(OH)(CH3)CH2OCH2CH3, — / CH(CH3)CH(OH)CH2OCH3, / , / CH2C(OH)(CH3)CH(CH3)OCH3, ° OH, -CH2CH(OH)CH2OCH3.CH2C(OH)(CH3)CH2OCH2CH2OCH3, CH2C(OH)(CH2-OCH3)2, -CH2CH(OH)CH2OCH2CH2OCH3,ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTOH, -CH2CH2OCH2CH2OH, -CH2OCH2CH2OH, - CH2CH2OCH2C(CH3)2OH, -CH2S(O)CH3, -CH2S(O)(NH)CH3, -CH2CH2S(O)(NH)CH3, -CH2C(O)NHCH3, -CH2C(OH)(CH3)C(O)NH(CH3),CH2C(OH)(CH3)C(O)NH(CH2CH3), CH2C(OH)(CH3)C(O)OCH3, -CH2C(O)(CH2CH3), -CH(CH3)C(O)(CH3), -CH2P(O)(CH3)2, - CH2CH2OCH2CH2N(CH3)2, -CH2CH2N(CH3)CH2CH2(OH), -CH2CH(OH)CH2N(CH3)2, - —CH2C(OH)(CH3)CH2N(CH3)2, OH OH;and - CH2C(OH)(CH3)CH2NHCH2CF3, and the remainder of the variables are as described for Formula (I) in the first aspect, the second aspect, the third aspect, the fourth aspect, the fifth aspect, the sixth aspect, the seventh aspect, the eighth aspect, the nineth aspect, the tenth aspect, the eleventh aspect, the twelfth aspect, the thirteenth aspect, the fourteenth aspect, the fifteenth aspect or the sixteenth aspect.

[0037] A nineteenth aspect of the disclosure is a compound represented by Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:R1is cyclopropyl;R2aand R2bare each independently methyl, fluoro or chloro; andR5is C2-4hydroxyalkyl.10ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0038] A twentieth aspect of the disclosure is a compound represented by Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R2ais chloro or methyl and R2bis fluoro and the remainder of the variables are as described for Formula (IV) in the nineteenth aspect.

[0039] A twenty-first aspect of the disclosure is a compound represented by Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R5is -CH2C(OH)(CH3)2 and the remainder of the variables are as described for Formula (IV) in the nineteenth aspect or the twentieth aspect.

[0040] A twenty-second aspect of the disclosure is a compound shown below in Table 1 and in the Exemplification. Pharmaceutically acceptable salts thereof and the corresponding neutral form are included in the disclosure. < H / = / \ f / Table 1Example Scheme number Structure number zR--NYN A-N1 4HO,N2 4A H U UN,nJor3 4H0JG 1 N xN~< I"fj UNHOZME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number4 4FR / j-NfY if J, N5 / \ 1 3N=N H JN1 A6 4^OH7 5 / HN-N.8 3HO—rS NN, N9 5r'ON-7^ / ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number10 3 + FGIy \ HO*X ox / 4 u. z- ti "z Z ',z Y11 5TZN\ " K12 Y'z zI I 4FZZ- \ *y LX o13 YA Y^ 5 HO-7r\14 415 zr--JOa> C( ’:>50^DDrN<>16 OHNc ^-rNrx HX NN^ \7 3■'~" F13ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number17 7\ O / o$Xi R18 AN, K 14 5 + FGI o tHHN^_ / / 44I A< X' z II19 4N=NNX / HO N-^orN=N20 9- / 7Y iNfjHO_ / o—^1 > T\°* / X'N'<V-== — \ / 21 / OHN- / MNH4 >=\_ / N=N''F VME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber numberH N=N"°_rOH N= / or22 \Z“ 5\ o-1o W Hi / *. N=N°__ J I1zz z- OxH N=^FA r-Nx5V(\-H^=t r N N=N° _ J OH N / \ Jj _or ''' N> A23 F / ^NV^ ^-0 \ 5VVN H'X_ - 0c.)_ >= N=N / OH N= / Yhl^ N H F Z IIy2-- z2ZzA\ / / A U QN=N>24 J AnA -N7 5 25 7 26 3r" NH O'Z^0\ / ^N'N,N=N.or <r r v--yA v^ *27 ^NF4 ^==X / )Hc'^r’zy^ rV\^,N=N,ncr X0FME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number28 3 + FGIr-XN\H Xcf0-7J°vIz.29. AX 3 + FGI! — \ / NHO O'"ZIx^-NN=N / bn N= / xx > A==yANy TIz-. N_30 r-NFz 5J 1 / 7-\N=NNY1 OH N= / XXF31 3N-\(32 4r-'KH / ?=r'Nv--\ / N=N*IH 6H N= / orJQ-V-V33 HF^ / y" N'V^ yyN..,N=N. 4OH °H N~FME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber number XQ HN= / VNor34 4H OH 6HN~ j^y^N'NA7F35 5 O. NJ's-7 / r~-Nvfx)N / >"N\N=NN / / oH N36 7ANt / >'■'N\N=N / OH N= / AJT^'SFr-NHO^l’y / A'N 7N=N>'oh Norryvx37 4HFHoO<~N, XV^ / / rN> _ _ ZN=N>' OH N- / ^ / T JQXN'N^Fr-NHN., P d N=N38 / S. / " N;y" r YNy=x / 5 + FGI VN Y- / NME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber numberHO / OHN= / A 1.or — x-A ’39 F 4X\o / OV'NAVF Z*'Ai; VZ40 75\z. / £z \° Tza z-.-dz441 4rf % N -N42 N^J^XX, XXF5no'K / V XXv- Hk N=NH0COH N^ XX43 5H°? OH N= / JQA-N>7ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber number 44 V " A HN=N>5,z!I.45 V 4cw IZOP fl rd zV / \TT~46 ^z i? <. Or° Y - 5 + FGI i‘- °'N-< / 1IzN=\Hz~-ZN'47 X5%R^ 5 + FGIC- O-T^on; / 48 5poHN-N49 4».yxu X^'N'N^ 3ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber number r".500H^ZH-NHK5N-NAyCr'U'51 LJ 50HCi AAFCRCj Yho'^7' C / ’52 5BOA Y53 5r% N=\54 / °'~^'° 'OHNNSN 4 > Qikr / O^-O / ~<OHNME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber numberNAL. N— <jJN ORN NA55.0^- - 0 OH if H 1 N— <1 4 XXf X Xz-N 1 / - ■ / 0~^'0 'OHN\ JlN / V''N N=N6H NorUXCOX i MA ^ — \A HFN, / 7 / X'''N\_--XN=Nn / oh norF56 r-N 5_ A 1 MA^^ jfXA HN 'y — / Xx'N\^N=: N6HorO")FN' 2 / ^ / V''NN---Xn==n>N / OH NFOH O / X 1%No57 '~NO rN5+ FGI \ ft 4 ■H / r-'NkN=NN Z iHor;HF7 —555S^ f r" NN=NOHN= / V-N ^ Xy-^. N.^58 5t Hy — N=NN- OH N= / ORy=y< V'vk arX }FN=NN / °H NFME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number1 y N MU / OH N— ' / y N \ / 59 5) / JT pzz -k60 4Xci!z-zSli1I T61 4OH bHOHN-N D0 1 H N-4-D62 N j| N 1 ^1 5V OH'x / JTx)NZ6HN-or y" ykrkZ'- 63 x / Zv) 3 + FGINZOHN= / VNNZ& H64 < / J!x) 3 + FGINzOHNNt= / / / (y. / / / r-N N=NME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTExample Scheme Structurenumber number65 3+ FGIY^ o- AHN=N.66 O A A MH N A- 17JA MA^^. \ \\\ A A 4A / \ / / ( A AW A Q67 << J? 4n o G 7 A Z ii. A t ' 468 5A 15^1 A AA u XXFAO A\c-. A' J69 A 5(A r A ^orx n XXF» 11 \ ^N- JA i / ~°oh / —C> OHME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCT Example Scheme number Structure numberT 1.. V- X L i AA- 70... G / w*( *• ■.- A / "v: S:"......, X. K 5. Xv XK v.r> '0JfAN H / / < OH N ’ -^ VN / N=N- or AA.7 J! / T\1 0!f4AN H' A c- OH N- _7' ^ / VN^x / N=N- Fr-^N,: N D JAVAT72 \ / -N: '' - A ' J 5'"-X f-AHO )<2N' N\=NZNAH / N~O“FVT^d / \ Z / N 7N,*N.N- -"73 HX? H / °r / ^=\ FIN — \ — r 5f N ~V / -Fy ^NH,zOH _ y'J l \ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCT Example Scheme number Structure number74 5 YVN.N / )° / — / N' / / / V \^NS / 75 5Cii\XY76 4h 1 t.^ Y'A-, ■77 4OH N~~x.. p / >bHME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme number Structure number 78 4 HQ bHOH KMtN Ny=N0=^N-0~F, N. „M 'N / N- N"79 5A / IZCo^ \ ' N / A / N Z\OH = / N^ / NNN' NV=N / — C, N ' zN. / N; * / ' )=N80NOR =54 / N\H / NA y~^ / -Foh / — / N81 5ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCTExample Scheme number Structure numberX / HHOQ\H N= / orPOMA82 5 Xz'N'V^ r yN, N=NH5z:0, < OH N= / P^P^jP'N'N'~z< N■ - 6y ’- X / Hy / -N^v \^ r >-Nx,N=N.H0X OH N- ■ / .ORVN83 \ f Fjf; z=< 5)21 •sN=NH0< OH N= / Fri X -z- z184 6<-NvJP) H^o^-xnx^Nz,!^ r yNx^vA. N- °AOHN=^ or VN U^jT^NF85 ^-*N 4JP HN f=N.rv0'OHN= / XJX FNME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCT Example Scheme number Structure numberN'-KH L -N“ / —T86or / O^o0H£ 4y£ / "'F / — N J. — 7 N0H... / 87 4? SHN=N.AMN-,... 0 ' T\:NN -!jTHQ,N'"88 7FHN-'7i iF" VF, NM-Z\N'y=N<N=\= / N~O^SN. / C£NN''II'N''Z~^89 5N? \<= / V^A<N-Q A-7-^y ^NQHNME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber numberX / =( -N. zA / — \\,N'N>' f90 / I 5o % X?H / =(WNZ~(, NZ / WAZZ'o91 4 / 7^VZTo^, N,N N z II\=Nzz- N= HN_£J_Fd _ _r V; _~ \ / ' / N. ZA_, N CI N'ZW92 NxOH _ _ / Klf=\ 5 O=< / / WCI / ,,, OH / N[l ] H N=Njt, N— <-7XlNOH93 4H N=NU x rN94 [intentionally omitted]ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme Structurenumber numberN=Nf 1 R A <N~95 I Io o A " " A a rV 7A'O II II 1I Z Yj A>N| c o 1> z I I I z z, oOH CKZM / zA A (Yv rZI ZI ZI96 45 cy xzA A A97 498 4ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Example Scheme number Structure number 99 4Y Y\ Jz”o oxz xz^ YzFz r z r J ( A) z z _ _ry100 V r(= z 4ZI ZI X Z X ZoY Y z z Z zX X ''z z1 1101 4102 4ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCTExample Scheme number Structure numbers: A H U >»“106 u I zkK 4Z™K J... - » 'Git107 7HOyN / N-N, A zl A. zX108 1 1 i:r 4U- HdN=N D109 5N-JHO— i —1 / ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCTExample Scheme Structurenumber numberA,1 A °no N. if ^4 ' F 7HOS / N"JtN-N. pX X N A 'N~hYXN D D1111 OfPJl A N A / 4D 50HuN°1 \ / NXx / TOHHN=N DJXXN.^ AM-NXDzx X lM YXX Dor1r< A N=N D1120H N5o1 \ A- OH

[0041] As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit / risk ratio.

[0042] Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts,34ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTalkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0043] The following abbreviations and terms have the indicated meanings throughout:

[0044] The term “alkyl” used alone or as part of a large moiety, such as alkoxy, haloalkyl, hydroxyhaloalkyl or hydroxyalkyl and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl typically has 1 to 6 carbon atoms (Ci-e alkyl) (i.e., 1, 2, 3, 4, 5 or 6), alternatively, 1 to 4 carbon atoms (Cu alkyl) (i.e., 1, 2, 3, or 4), alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (i.e., 1, 2 or 3). Examples include methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, and the like.

[0045] The term “alkoxy” used alone or as part of a large moiety, such as alkoxyalkoxy, hydroxy alkoxy, and the like, means a saturated aliphatic straight-chain or branched monovalent radical composed of an alkyl group bonded to oxygen. Unless otherwise specified, an alkoxy group typically has 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms and an oxygen atom (Ci-ealkoxy), alternatively, 1 to 5 (i.e., 1, 2, 3, 4 or 5) carbon atom and an oxygen atom (CM alkoxy), alternatively, 1 to 4 (i.e., 1, 2, 3, or 4) carbon atom and an oxygen atom (CM alkoxy), alternatively, 1 to 3 (i.e., 1, 2, or 3) carbon atom and an oxygen atom (C1-3 alkoxy). Examples of alkoxy include methoxy, ethoxy, and the like.

[0046] The term “cycloalkyl” means a saturated aliphatic monocyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 6 (i.e., 3, 4, 5, or 6) ring carbon atoms (C3-6 cycloalkyl), alternatively, 3 to 5 (i.e., 3, 4, or 5) ring carbon atoms (C3-5 cycloalkyl), alternatively, 3 to 4 carbon atoms (C3-4 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, and the like.

[0047] The term “haloalkyl”, used alone or as part of a large moiety, such as hydroxyhaloalkyl, means an alkyl group wherein at least one hydrogen substituent is replaced by a halogen group. Unless otherwise specified, a haloalkyl group typically has 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms (Ci-ehaloalkyl), alternatively, 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms (Ci- draloalkyl), alternatively, 1 to 3 carbon atoms (Cuhaloalkyl) (i.e., 1, 2 or 3). Examples include trifluoromethyl, trifluoroethyl, difluoroethyl, and the like.

[0048] The term “halogen” or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl) or bromine or bromo (Br).

[0049] The term “hydroxy” means OH.35ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT10050] The term “hydroxyalkoxy” means an alkoxy group wherein at least one hydrogen substituent is replaced by a hydroxy group. For example, a “Ci-4hydroxyalkoxy” means -OCi.4alkyl, wherein the Ci-4alkyl is substituted with a hydroxyl group. Examples of hydroxyalkoxy include -OCH2CH2OH, -OCH2C(CH3)2OH and the like.

[0051] The term “Ci.xalkoxyCi.xxalkoxy” means a Ci-salkoxy group wherein at least one hydrogen substituent of the Ci.^alkoxy group is replaced by an Ci.xalkoxy group. For example, Ci-salkoxyCi-salkoxy group means a Ci-salkoxy group wherein at least one hydrogen substituent of the Ci-salkoxy group is substituted with a Ci-salkoxy group. Examples of Ci-salkoxyCi- jalkoxy include -OCH2CH2OCH3 and the like.

[0052] The term “hydroxyalkyl” means a saturated aliphatic straight-chain or branched monovalent radical composed of an alkyl group substituted with a hydroxy group. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.

[0053] The term “hydroxyhaloalkyl” means a haloalkyl substituted with a hydroxy group.Examples include difluorohydroxypropyl, dichlorohydroxypropyl, and the like.

[0054] The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).

[0055] If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted.

[0056] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0057] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “7?” or “5”) or structure (e.g., the configuration is indicated by “wedge”36ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTbonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.

[0058] ‘Enrichment of tire indicated configuration relative to tire opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0059] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “5” orthe name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0060] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.

[0061] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0062] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0063] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the37ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTencompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0064] When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above.

[0065] The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment. A deuterated group such as a “deuterated alkyl” has hydrogen atoms at one or more positions replaced or enriched with deuterium.

[0066] The c-kit kinase inhibitors described herein are useful for treating diseases and disorders mediated by wild type c-kit. In some aspects c-kit mediated diseases and disorders include mast cell related disorder, an eosinophil related disorder, cancer, asthma, an inflammatory condition, rheumatoid arthritis, an allergic inflammation, inflammatory bowel disease, a gastrointestinal disorder, and fibrosis.

[0067] Wild-type KIT plays a central role in mast cell survival, proliferation, and activation.Specifically, inhibitors of c-kit are useful for the inhibition and / or depletion of mast cells and thus are useful for treating mast cell related disorders. As used herein, the term "mast cell related disorder" or "mast cell related disorders" or “mast cell mediated disorder” or “mast cell mediated disorders” refers to disorders where mast cell activity contributes to the pathology and / or mast cells are found in abnormal amounts, such as above-normal amounts or below-normal amounts, in various parts of the body. For example, mast cell related disorders can exhibit accumulation of pathological mast cells and / or can be characterized by mast cells that are aberrantly activated in potentially any or all organs and tissues and / or aberrant release of one or more mast cell mediators such as inflammatory mediators. Non-limiting examples of inflammatory mediators released by mast cells include any of (i) granule-associated mediators, including histamine, serotonin (5-hydroxytryptamine), and a variety of proteases such as tryptase and chymase) and peptidases; (ii) eicosanoids such as prostaglandin D2 (PGD2) and leukotriene C4 (LTC4); and (iii) cytokines including interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, granulocyte- 38ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTmacrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor a (TNFa), and chemokines including CCL-2, CCL-3, CCL-5, and CXCL8.

[0068] Compounds of the disclosure or a pharmaceutically acceptable salt thereof are useful for treating chronic urticaria. Chronic urticaria includes chronic spontaneous urticaria (CSU), chronic idiopathic urticaria and chronic induced urticaria (i.e., chronic inducible urticaria (CIndU). In certain aspects, the mast cell related disorder is CSU. In certain aspects, the mast cell related disorder is CIndU. Chronic inducible urticarias are forms of urticaria that have an attributable trigger associated with them, typically resulting in inflammation of the skin characterized by wheals (hives) or angioedema. Complications of both CSU and CIndU include swelling / hives in inopportune sites (mouth, airway, genitals) and anaphylaxis. Sleep disruption, stress, & anxiety due to severe itching are major contributors to disease burden. In a specific aspect, the chronic inducible urticaria is cold urticaria (ColdU). People afflicted with cold urticaria experience symptoms like itching, burning wheals and angioedema when their skin is exposed to temperatures below skin temperature. In another aspect, the chronic inducible urticaria is symptomatic dermographism (SD). Symptomatic dermographism is characterized by the development of a wheal and flare reaction in response to stroking, scratching or rubbing of the skin and usually occurs within minutes of the inciting stimulus. In another aspect, the chronic inducible urticaria is cholinergic urticaria. Cholinergic urticaria is triggered by the body’s sweating response to active or passive body warming and is characterized by small (1-4 mm) wheals surrounded by bright red flares. Common triggers include exercise, hot baths / showers, fever, occlusive dressings, eating spicy foods and emotional stress. In another aspect, the chronic inducible urticaria is heat urticaria. In another specific embodiment, the chronic inducible urticaria is delayed pressure urticaria. In another aspect, the chronic inducible urticaria is solar urticaria. In another specific embodiment, the chronic inducible urticaria is vibratory urticaria. In another aspect, the chronic inducible urticaria is contact urticaria. In one aspect, the vibratory urticaria is characterized by a missense mutation in EMR2. In another aspect, the chronic inducible urticaria is aquagenic urticaria.

[0069] Other mast cell related disorders and diseases that compounds of the disclosure or a pharmaceutically acceptable salt thereof are useful for treating include: dermatosis, including: atopic dermatitis and allergic contact dermatitis; idiopathic angioedema; idiopathic anaphylaxis; asthma, including allergic asthma; hereditary alpha tryptasemia (HAT); idiopathic mast cell activation syndrome (MCAS); monoclonal MCAS; neurofibromatosis; idiopathic pulmonary fibrosis; bullous pemphigoid; and prurigo nodularis.39ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT10070] Additional diseases with mast cell involvement that compounds of the disclosure or a pharmaceutically acceptable salt thereof are useful for treating include: age-related macular degeneration; allergic conjunctivitis; allergic rhinitis; non-allergic rhinitis; alpha-1 antitrypsin deficiency; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); bronchiectasis; Celiac disease; chronic graft verse host disease; chronic rhinosinusitis with nasal polyps; allergic fungal rhinosinusitis; aspirin-exacerbated respiratory disease; allergic broncho pulmonary aspergillosis; colorectal cancer; dermatitis herpetiformis; irritable bowel syndrome (IBS), including diarrheaprominent IBS; fibromyalgia; fibrosis, including hepatic fibrosis, pulmonary, and cardiac fibrosis; food allergies, including IgE-mediated food allergies and peanut allergies; insect venom allergy; drug allergy; insulin-dependent diabetes mellitus; mast cell activation syndrome (MCAS), mast cell leukemia; migraine; multiple sclerosis; Parkinson’s disease; psoriasis; and rheumatoid arthritis.

[0071] Other diseases modulated by c-kit that compounds of the disclosure or a pharmaceutically acceptable salt thereof are useful for treating include: pulmonary arterial hypertension (PAH); inflammatory bowel disease (IBD), cholestatic pruritis; uremic pruritis; chronic pruritis of unknown origin; pulmonary fibrosis; scleroderma; dermatosis; dermatitis herpetiformis; melanoma; gastrointestinal stromal tumor; mast cell tumor; anaphylactic syndrome; idiopathic anaphylaxis; diabetes, type I or type II, eosinophilic esophagitis (EoE); eosinophilic gastritis & duodenitis; interstitial cystitis / bladder pain syndrome, chronic prostatitis I chronic pelvic pain syndrome; endometriosis; and mastocytosis, including cutaneous mastocytosis and systemic mastocytosis.

[0072] Compounds of tire disclosure or a pharmaceutically acceptable salt thereof are useful for treating chronic urticaria, allergic asthma, hereditary alpha tryptasemia (HAT), allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis with nasal polyps and idiopathic mast cell activation syndrome (MCAS).

[0073] Compounds of the disclosure or a pharmaceutically acceptable salt thereof are useful for treating gastrointestinal stromal tumor (GIST). GISTs are the most common malignant subepithelial lesions of the gastrointestinal tract, and the most common symptoms of GISTs are gastrointestinal bleeding, acute melena (dark feces containing blood), hematemesis (vomiting of blood) with anemia, weakness, and abdominal pain and distension. Nearly 80% of metastatic GISTs have a primary activating mutation in either the extracellular region (exon 9) or the juxtamembrane (JM) domain (exon 11) of KIT. Imatinib is a standard therapy used to treat40ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTGIST. Side effects of imatinib include mild stomach upset, diarrhea, muscle pain, and skin rashes. There is a need for new therapies for the treatment of GIST.

[0074] Compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered in combination with another agent. In one aspect, compounds of the disclosure are administered in combination with one or more antihistamine agents such as loratadine, cetirizine, fexofenadine, cimetidine, famotidine or diphenhydramine. In another aspect, compounds of the disclosure or a pharmaceutically acceptable salt thereof are administered in combination with one or more asthma agents such as montelukast and zafirlukast.

[0075] In another aspect, compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered in combination with one or more other agents that are used in the treatment of urticaria. For example, compounds of the disclosure or a pharmaceutically acceptable salt thereof are administered in combination with omalizumab,dupilumab, reslizumab, mepolizumab, and benralizumab. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered with novel anti- IgE monoclonal antibodies such as ligelizumab and UB-221. Compounds of the disclosure or a pharmaceutically acceptable salt thereof can also be administered with a monoclonal antibody to Siglec-8 (AK002), Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), a spleen tyrosine kinase inhibitor, and dupilumab. The compound of the disclosure or a pharmaceutically acceptable salt thereof and agent can be co-administered or administered in alternating regimen. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered with antihistamines. Examples of antihistamine agents include Classic Hl antihistamines with sedation as a side effect including chlorpheniramine, hydroxyzine, and diphenhydramine, nonsedating second generation Hl antihistamines including loratadine, cetirizine, terfenadine, and mizolastine, second generation Hl antihistamine derivatives including desloratadine, levocetirizine, and fexofenadine, and H2 antihistamines including cimetidine, ranitidine, famotidine and nizatadine. Other antihistamine agents include bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and rupatadine. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof can be administered in combination with an MRGPRX2 inhibitor. Examples of MRGPRX2 inhibitors are EP-262 and EVO-756.

[0076] In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof are administered to a subject in need thereof. In some aspects, compounds of the disclosure or a pharmaceutically acceptable salt thereof are administered as a pharmaceutical41ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTformulation, wherein the compound or a pharmaceutically acceptable salt thereof is combined with one or more pharmaceutically acceptable excipients. Thus, in some aspects, disclosed herein are compositions comprising at least one entity chosen from compounds of Formula I or a pharmaceutically acceptable salt thereof and optionally further comprising at least one pharmaceutically acceptable excipient.

[0077] The compounds of the disclosure or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

[0078] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0079] Examples of pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0080] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.42ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0081] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0082] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0083] Suspensions, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0084] Ointments, pastes, creams and gels may contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0085] Powders and sprays can contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.43ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0086] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with an excipient material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of the compound of the disclosure or a pharmaceutically acceptable salt thereof that can be combined with an excipient material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0087] Dosage forms for the topical or transdermal administration of a compound of the disclosure or pharmaceutically acceptable salts thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers, or propellants that may be required.

[0088] When the compounds of the disclosure or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable excipient.

[0089] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

[0090] Actual dosage levels of tire active ingredients in the pharmaceutical compositions of the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0091] The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day. The precise amount of a compound or a pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, tire type, and severity of the disease or condition, and on the characteristics of tire subject, such as general tire route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and / or materials used in 44ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcombination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003). A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the compounds of the disclosure or a pharmaceutically acceptable salt thereof employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until tire desired effect is achieved.

[0092] In general, a suitable daily dose of a compound of the disclosure or a pharmaceutically acceptable salt thereof will be that amount of the compound or a pharmaceutically acceptable salt thereof that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0093] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.

[0094] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[0095] “Pharmaceutically acceptable excipient” refers to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be45ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTincluded in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0096] A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, tire patient is a human. In one aspect, the patient is an adult human.

[0097] The compounds of tire disclosure or a pharmaceutically acceptable salt thereof can be prepared according to the following general synthetic methods.

[0098] General Synthetic Methods

[0099] Scheme 146ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTR1-LG R1-B(ORB)2R1-LG R1-B(ORB)2(VII) (V)(R2)n(VIII)

[0100] LG is a leaving group, typically a halo, mesylate or tosylate.

[0101] B(ORB)2is a boronic acid or boron pinacol ester.

[0102] The aryl nitrile compound (II) may be treated with an azide source, such as Bu₃SnN₃or TMSN3, optionally in the presence of Bu₂SnO, at elevated temperature and optionally under flow chemistry conditions, to provide the tetrazole (III).

[0103] The tetrazole (III) may be alkylated with R'LG, in the presence of a base, optionally under flow chemistry conditions, to give the compound (IV).

[0104] Alternatively, the tetrazole (III) may be alkylated by boronic acid or pinacol ester, R1- B(ORB)2, under Chan-Lam type coupling conditions, optionally under flow chemistry conditions, to give compound (IV).

[0105] Compound (VII) may be obtained by the nitration of compound (IV) using potassium nitrate for example, optionally under flow chemistry conditions.

[0106] Alternatively, compound (VII) may be obtained from aryl nitrile (V), via compound (VI), according to tire methods described for the preparation of (IV) from compound (II), described above.ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0107] The nitroaryl (VII) can be reduced using Fe under acidic conditions in an alcoholic solvent, or in the presence of tetrahydroxyboron with 4,4’-bipyridine at rt, optionally under flow chemistry conditions, to give the compound (VIII).

[0108] Scheme 2R1LG R1B(ORB)2(R2)n(XI)

[0109] PG is a N protecting group, typically Boc.

[0110] Compound (VIII) may be obtained from compound (IX), via compound (X) and (XI), following the steps described in Scheme 1, for the preparation of compound (VIII) from compound (V). The PG may be removed upon treatment with acid.

[0111] Scheme 3(VIII)

[0112] Compound (XIII) may be obtained from aniline (VIII) and chloride (XII), in the presence of Me₃Al, LiHMDS or TsOH in a suitable solvent at between rt and 100°C.ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0113] Compound (XV) may be obtained from bromide (XIII) and alkyne (XIV), via a Sonogashira type coupling reaction, optionally in the absence of a copper co-catalyst.

[0114] Compound (I) may be obtained by an alkylation reaction of compound (XV) with R5- LG in the presence of an acid or base.

[0115] Alternatively, compound (I) may be obtained by reaction of compound (XV) with R5- OH under Mitsunobu type reaction conditions.

[0116] Optionally, compound (I) may also be prepared according to Scheme 3 followed by further functional group interconversions (FGI), for example reduction to an alcohol and deprotection.

[0117] Scheme 4(XV)

[0118] In Scheme 4, R5is C2-6hydroxyalkyl, wherein Cj-ehydroxyalkyl represented by R5is optionally substituted with two Ci-salkoxy or R5bselected from OH, Ci-salkoxy, Ci-salkoxyCi. salkoxy, C(O)NH(Ci-jalkyl), C(O)O(Ci-3alkyl), compound (I) may be obtained by reaction of compound (XV) with oxirane (XVI), in the presence of an inorganic base.

[0119] Scheme 5

[0120] Compound (I) may be obtained from bromide (XIII) and alkyne (XIV), via a Sonogashira type coupling reaction, optionally in the absence of a copper co-catalyst.

[0121] Optionally, compound (I) may also be prepared according to Scheme 5 followed by further functional group interconversions (FGI), for example N-H insertion, reduction to an alcohol and deprotection.

[0122] Scheme 649ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0123] Compound (XVI) may be obtained from bromide (XIII) and ethynyl(trimethyl) silane,via a Sonogashira type reaction.

[0124] Compound (I) may be obtained from alkyne (XVI) and bromopyrazole (XVII), via a Sonogashira type reaction, optionally in the absence of a copper co-catalyst.

[0125] Scheme 7

[0126] R5is H, methyl or ethyl.

[0127] Rxis C1-C5 alkyl.

[0128] RNis independently H, Ci-Ce alkyl or C₁₋₆haloalkyl.

[0129] Wherein R5is C₂₋₆hydroxyalkyl, wherein C₂₋₆hydroxyalkyl represented by R⁵ isoptionally substituted with R5bselected from NH(C₁₋₃alkyl), N(Ci-6alkyl)2, N(Ci-6haloalkyl)2, andME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTNH(C1-6haloalkyl), compound (I) may be obtained from compound (XIX) by reaction with NH(RN)2in the presence of an organic base.

[0130] Wherein Ci-ehydroxyalkyl represented by R5is optionally substituted with RSbthat is Ci-salkoxy or Ci-salkoxyCi-salkoxy, compound (I) may be obtained from compound (XIX) by reaction with RXOH or RxONa in the presence of an inorganic base.

[0131] Wherein R5is Cz-shydroxyalky 1 represented by R5is optionally substituted with R5bis CN, compound (I) may be obtained from compound (XIX) and NaCN or TMSCN in the presence of TBAF.

[0132] Compounds (II), (V), (IX), (XII), (XIV), (XVI), (XVII) and (XVIII) are commercially available, or may be obtained as described in the Examples section below.

[0133] Compounds (I) to (XIX) may be converted to alternative compounds (I) to (XIX) by chemical transformations. Examples of these transformations include, but are not limited to: alkylation of an alkyl alcohol to give an ether, reduction of a ketone to provide a secondary alcohol, and Grignard reaction of a ketone to provide a tertiary alcohol.

[0134] Rhodium catalyzed reaction of an alkyl sulfone and amide to provide an imino sulfanone.

[0135] It will be appreciated by those skilled in tire art, that it may be necessary to utilize a suitable protecting group strategy for tire preparation of compounds of Formula (I). Typical protecting groups may comprise, a carbamate, preferably a Boc group, for the protection of primary or secondary aliphatic amines, and an acetyl or TBS group for the protection of alcohols.

[0136] It will be appreciated that it may be necessary and / or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0137] Compounds that contain one or more stereocenters may be separated into their separate steroisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Examples below.

[0138] The invention is illustrated by the following examples, which are not intended to be limiting in any way.

[0139] EXEMPLIFICATION

[0140] Abbreviations51ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100141] Abbreviations and acronyms used herein include the following:AcOH means acetic acid;AlMe3 means trimethylaluminium;Aq. means aqueous;Boc means tert-butoxy carbonyl;Brettphos means 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l,l'- biphenyl;BrettPhos Pd G3 means l(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1, 1 '-biphenyl)-2-(2'- amino- 1, T -biphenyl)lpalladium(II) methanesulfonate;BrettPhos Pd G4 means dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2- yl)phenyl] phenyl]phosphane;methanesulfonic acid; N-methyl-2- phenylaniline;palladiumBu3SnN3 means azido(tributyl)stannane;Bu2SnO means dibutyl(oxo)tin;CD3I means Iodomethane-d3CuI means copper(I) iodideCH3ONa means sodium methoxideCu(OAc)2 means copper (II) acetated means doublet;dd means doublet of doublets;ddd means doublet of doublet of doublets;ddt means doublet of doublet of triplets;dq means doublet of quartets;dt means doublet of triplets;DCE means 1,2-dichloroethane;DCM means dichloromethane;DEA means diethylamineDIAD means diisopropyl azodicarboxylate;DIPEA means N-ethyldiisopropylamine or N, N-diisopropylethylamine; DMA means N, N-Dimethylacetamide;DMAP means N, N-dimethylpyridin-4-amine;DMF means N, N-dimethylformamide;DMSO means Dimethylsulfoxide;DMSO-de means trideuterio(trideuteriomethylsulfinyl)methane;52ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061PCTEDCI means l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide;EtOAc means ethyl acetate;EtOH means ethanol;FA means formic acid;Fe means ironHATU means l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;HPLC means high performance liquid chromatography;IPA means 2-propanol;LG means leaving group;LCMS means liquid chromatography mass spectrometry;LiHMDS means Lithium bis(trimethylsilyl)amidem means multiplet;MBTE means Methyl tert butyl etherMeCN means acetonitrile;Mel means iodomethane;MeOH means methanol;MS m / z means mass spectrum peak;NaBH4 means sodium borohydrideNaCN means sodium cyanideN2 means nitrogen gasNMR means nuclear magnetic resonance;Na2SO4 means sodium sulfateNH4CI means ammonium chlorideNH4HCO3 means ammonium bicarbonatePE means petroleum ether;Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium (0);Pdtdppf )C F means [1,1’ -bis(diphenylphosphino)ferrocene]dichloropalladium(II); q means quartet;rt means room temperature;s means singlet;sat. means saturated;SFC means supercritical fluid chromatography;t means triplet;td means triplet of doublets;53ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTtq means triplet of quartets;tt means triplet of triplets;T3P® means 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBAF means tetrabutylammonium fluoride;TBDMS means tert-Butyldimethylsilane;TEA means triethylamine;TFA means trifluoroacetic acid;THF means tetrahydrofuran;THP means tetrahydropyran;TLC means thin layer chromatography;TMEDA means N, N, N’, N’-TetramethylethylenediamineTMSN3 means trimethylsilyl azideTsCl p-Toluenesulfonyl chlorideTsOH means p-Toluenesulfonic acidTsCl p-Toluenesulfonyl chlorideXantphos means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;XPhos means dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; XPhos Pd G3 means dicyclohexyl-[2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphane;methanesulfonate;palladium;2-phenylaniline.

[0142] HPLC ConditionsMethod A: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min.Method B: Column: Xselect CSH C18 OBD Column 30*150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min.Method C: Column: Xselect CSH C18 OBD Column 19*250mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 30 mL / min.

[0143] Chiral HPLC ConditionsMethod 1: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min.Method 2: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min.54ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTMethod 3: Column: CHIRALPAK ID, 2*25 cm, 5 gm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH), Mobile Phase B: EtOH: DCM = 1:1; Flow rate: 20 mL / min.

[0144] Intermediate 1

[0145] 4-ethynyl-3-methyl- 1 H-pyrazole

[0146]

[0147] A mixture of 4-iodo-3-methyl-l H-pyrazole (5 g, 24.0 mmol), tributyl(ethynyl)stannane (15.1 g, 48.0 mmol), Pd(PPh3)4 (2.77 g, 2.40 mmol) and TEA (7.28 g, 72.0 mmol) in dioxane (30 mL) was stirred at 80°C for 3 h under Nz. The resulting solution was extracted with EtOAc (3x150 mL). The organic layer was dried with Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 20: 1) to afford the title compound (2 g) as a yellow oil. LCMS m / z = 107 [M+H]+

[0148] Intermediate 2

[0149] 1 -(4-ethynyl- 1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

[0150]

[0151] A mixture of 4-ethynyl- 1 H-pyrazole (200 mg, 2.17 mmol), 2,2-dimethyloxirane (312 mg, 4.34 mmol) and Cs2CO3 (1423 mg, 4.34 mmol) in DMF (5 mL) was stirred at 100 °C for 12 h. The resulting solution was extracted with EtOAc (3x10 mL) and the combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column with DCM / MeOH (20 / 1) to give the title compound (120 mg, 33.7%) as a light yellow solid. LCMS m / z = 165 [M+H]+

[0152] Intermediate 3

[0153] l-(4-ethynyl-lH-pyrazol-l-yl)butan-2-one

[00154] O

[0155] The title compound was obtained, 120 mg, 37%, as a yellow solid, from 4-ethynyl-1H-pyrazole and l-bromobutan-2-one, following a similar procedure to that described in Intermediate 2, except K2CO3was used. LCMS m / z = 163 [M+H]+ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0156] Intermediate 4A

[0157] (R)-4-(4-etliynyl-lH-pyrazol-l-yl)-3-hydroxy-3-metliylbutanenitrile or (S)-4-(4- ethynyl- lH-pyrazol-l-yl)-3-hydroxy-3-metliylbutanenitrile or (S)-l-(4-((8-((4-fhioro-2-methyl- 5-(2-inethyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)- 2,3-dimethylbutane-2,3-diol

[0158] And Intermediate 4B

[0159] (S)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile or (S)-4-(4- ethynyl-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile or (R)-L(4-((8-((4-fluoro-2-methyl- 5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)- 2,3-dimethylbutane-2,3-diol

[0160] Step 1: Synthesis of4-ethynyl-l-((2-methyloxiran-2-yl)methyl)-lH-pyrazole

[0161] To a solution of 4-ethynyl-lH-pyrazole (20.0 g, 217 mmol) in 2-(chloromethyl)-2- methyloxirane (160 mL) was added TEA (43.9 g, 434 mmol) and the reaction mixture was stirred at 75 °C for 3 h. The mixture was added dropwise into H2O (200 mL), the mixture was extracted with EtOAc (50.0 mL x 3) and the organic phase was dried over NajSCU and concentrated in vacuo to give the title compound (33.0 g, 62.8%) as a brown oil. LCMS m / z = 163 [M+H]+

[0162] Step 2: Synthesis of (R)-4-(4-ethynyl-l H-pyrazol-l-yl)-3-hydroxy-3- methylbutanenitrile or (S)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile

[0163] To a solution of 4-ethynyl-1-((2-methyloxiran-2-yl)methyl)-1H-pyrazole (33.0 g, 203 mmol) in DMF (330 mL) and H2O (70.0 mL) was added NaCN (20.5 g, 419 mmol) portion wise. The mixture was warmed slowly to 50 °C, then stirred for 2 h. The reaction mixture was quenched with H2O (2 L) at rt and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) to give 4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-3-56ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTmethylbutanenitrile (28.0 g, 66.9%) as a yellow oil. This was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [CO2-i-PrOH (0.1%NH3H2O)]; B%: 15%, isocratic elution mode) to give Peak 1, Intermediate 4A, as a white solid, 2.1 g and Peak 2, Intermediate 4B, 2.2 g, as a white solid.

[0164] Intermediate 4A: 1H NMR (400 MHz, CDC13) 57.69 - 7.66 (m, 2H), 4.28 - 4.16 (m, 2H), 3.05 (s, 1H), 2.51 - 2.26 (m, 2H), 1.41 (s, 1H).

[0165] Intermediate 4B: 'H NMR: (400 MHz, CDC13)7.70 - 7.66 (m, 2H), 4.33 - 4.17 (m, 2H), 3.05 (s, 1H), 2.51 - 2.25 (m, 2H), 1.41 (s, 1H).

[0166] Intermediate 5

[0167] 3-(4-ethynyl-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide

[0168] Step 1: Synthesis of methyl 3-(4-ethynyl-lH-pyrazol-l-yl)-2-hydroxy-2- methylpropanoate

[0169] A mixture of 4-ethynyl-lH-pyrazole (2 g, 21.7 mmol), methyl 2-methyloxirane-2- carboxylate (2.51 g, 21.7 mmol) and K2CO3(8.99 g, 65.1 mmol) in DMF (20 mL) was stirred at 50°C for 2 h under N2. The resulting solution was extracted with DCM (3x150 mL). The combined organic extracts were dried with Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 20: 1) to afford the title compound (1.3 g) as an off-white oil. LCMS m / z = 209 [M+H]+

[0170] Step 2: Synthesis of 3-(4-ethynyl-lH-pyrazol-l-yl)-2-hydroxy-N,2- dimelhylpropanamide

[0171] LiHMDS (6.24 mL, 6.24 mmol, IM) was added to methyl 3-(4-ethynyl-lH-pyrazol- l-yl)-2-hydroxy-2-methylpropanoate (1.3 g, 6.24 mmol) and MeNH2. HCl (837 mg, 12.4 mmol) in toluene (15 mL) at 0°C under N2. The reaction mixture was stirred at rt for 16 h. The resulting solution was extracted with DCM (3x100 mL) and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=20:l) to afford tire title compound, 260 mg as a yellow oil.LCMS m / z = 208 [M+H]+

[0172] Intermediate 6ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0173] methyl (S)-3-(4-ethynyl-l H-pyrazol- l-yl)-2-hydroxy-2-methylpropanoate or methyl (R)-3-(4-ethynyl-lH-pyrazol-l-yl)-2-hydroxy-2-methylpropanoate

[0174] The compound from Intermediate 5, step 1 was purified by prep-HPLC (column:XPT C18250 * 70 * 7 um; mobile phase: [water ( NH4HCO3) - MeCN]; gradient: 15% - 45% B over 20 mins) to give a yellow oil (6.00 g, 26.7%). The product was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 um); mobile phase: [COz-i-PrOH (0.1% NH3H2O)]; B%: 12%, isocratic elution mode) to give Peak 1, the title compound (2.32 g, 38.6%) and Peak 2 (2.42 g, 40.2%) as a yellow oil. LCMS m / z = 209 [M+H]+

[0175] Intermediate 7

[0176] 5-(4-methyl-3-nitrophenyl)-2H-tetrazole

[0177] A mixture of 4-methyl-3-nitrobenzonitrile (25 g, 154 mmol) and TMSN3 (35.53 g, 308 mmol) in DMF (100 mL) was stirred at 100°C for 16 h. The residue was diluted with H2O (100 mL), tire precipitated solids were filtered off and washed with n-Hexane (3x10 L) to afford tire title compound (30.4 g, 95.8%) as alight yellow solid. LCMS: m / z = 206 [M+H]+.

[0178] Intermediate 8

[0179] 5-(4-chloro-2-fhioro-5-nitrophenyl)-2H-tetrazole

[0180] To a mixture of 4-chloro-2-fluoro-5-nitrobenzonitrile (10 g, 49.8 mmol) in toluene (50 mL) was added BuzSnO (24.7 g, 99.6 mmol) and TMSN3 (11.4 g, 99.6 mmol) at 0°C and the reaction mixture was stirred at 100°C for 16 h under Nz. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column (100:0 to 90:10, DCM: MeOH) to give the title compound (10 g, 82.6%) as a yellow oil. LCMS m / z = 242 [M+H]+ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0181] Intermediate 9

[0182] 5-(2-fluoro-4-methyl-5-nitropheriyl)-2H-tetrazoleN=N o2N^^ AN'NHT JL

[0183] TMSN3 (29.2 g, 253 mmol) followed by Bu2SnO (23.6 g, 94.9 mmol) were added slowly to a solution of 2-fluoro-4-methyl-5-nitrobenzonitrile (11.4 g, 63.3 mmol) in toluene (150 mL) and the reaction mixture was stirred at 100°C for 2 h. The mixture was cooled to rt, concentrated in vacuo, then azeotroped with MeOH to afford the title compound as a yellow oil. LCMS m / z = 224 [M+H]+

[0184] Intermediate 10

[0185] 4 -fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)aniline

[0186] Step 1: Synthesis of 5-(2-fluoro-4-methyl-5-nitrophenyl)-2-methyl-2H-tetrazole

[0187] Mel (3.80 g, 26.8 mmol) was added dropwise to Intermediate 9 (2 g, 8.96 mmol) and K2CO3 (2.47 g, 17.9 mmol) in DMF (20 mL) and the reaction mixture was stirred at 25°C for 16 h under N2. The resulting solution was extracted with EtOAc (3x150 mL) and the combined organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 20: 1) to afford tire title compound (900 mg) as a yellow oil. LCMS m / z = 238 [M+H]+

[0188] Step 2: Synthesis of4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)aniline

[0189] A mixture of 5-(2-fluoro-4-methyl-5-nitrophenyl)-2-methyl-2H-tetrazole (900 mg, 3.79 mmol) and Fe (423 mg, 7.58 mmol) in NH4Cl: EtOH =1:4 (16 mL) was stirred at 80°C for 3h under N2. The resulting solution was extracted with EtOAc (3x80 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by Prep-TLC (DCM: MeOH= 20: 1) to afford tire title compound (380 mg) as a yellow oil. LCMS m / z = 208 [M+H]+

[0190] Intermediate 11

[0191] 5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline59ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTN=N Fe, AcOH Step 2

[0192] Step 1: Synthesis of2-ethyl-5-(2-fluoro-4-methyl-5-nitrophenyl)-2H-tetrazole

[0193] Na2CO3 (30.2 g, 285 mmol) and ethyl iodide (37.0 g, 238 mmol) were added to a solution of Intermediate 9 (53.0 g, 238 mmol) in DMF (1 L) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into H2O ( 1 L), the aqueous layer was extracted with EtOAc (500 mL x 3), the combined organic layer was washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EtOAc = 50 / 1 -10 / 1) to give the title compound, as a yellow solid. 12 g, 20%. LCMS m / z = 252 [M+H]+

[0194] Step 2: Synthesis of 5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0195] H2O (35 mL), EtOH (70 mL) and AcOH (52 mL) were added to 2-ethyl-5-(2-fluoro- 4-methyl-5-nitrophenyl)-2H-tetrazole (11.5 g, 45.8 mmol). Fe (11.5 g, 206 mmol) was added slowly and tire reaction mixture stirred at 50 °C for 1 h. The resulting reaction mixture was filtered, and tire pH of the filtrate adjusted to pH 8-9 with Na2CO3. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound, 9.9 g, as an off-white solid. LCMS m / z = 222 [M+H]+

[0196] Intermediate 12

[0197] 4 -amino-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0198] Step 1: Synthesis of 5-(2-fluoro-4-methylphenyl)-2H-tetrazole

[0199] A solution of 2-fluoro-4-methylbenzonitrile (900 g, 6.66 mol) and n-Bu2Sn(OAc)2 was pumped by Pump 1 (51.13 mL / min) to flow reactor 1 (FLR1, PFA, Coils reactor, 6.350(1 / 4”) mm, 317 mL, 65 °C) atrt. A solution of TMSN3 (1.53 Kg, 13.3 mol) in toluene (9L) was pumped by Pump 2 (51.13 mL / min) to flow reactor 1 at rt. The reaction liquid wasME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcirculated in flow reactor 1 at 65 °C for 14 h under N2. The mixture was cooled to rt and diluted with H2O (315 mL). The resulting mixture was filtered and the filter cake washed with toluene ( 100 mL x 3), then dried in vacuo to afford the title compound, 1 Kg, 84%.

[0200] Step 2: Synthesis of2-cyclopropyl-5- 2-fluoro-4-methylphenyl)-2H-tetrazole

[0201] Cyclopropyl boronic acid (217 g, 2.53 mol), CH₃ONa (91.0 g, 1.68 mol), Cu(OAc)2(153 g, 842 mmol) and TMEDA (489 g, 4.21 mol) were added consecutively to a solution of 5-(2- fhroro-4-methylphenyl)-2H-tetrazole (150 g, 842 mmol) in dioxan (1.35 L) at rt. O2was injected into the reaction solution and the mixture stirred at 80°C for 12 h. Further cyclopropyl boronic acid (36.2 g, 421 mmol) was added and the reaction stirred for 12 h. Further cyclopropyl boronic acid (36.2 g, 421 mmol) was added and the reaction stirred for 12 h at 80°C. The cooled mixture was diluted with EtOAc (1.8 L), the mixture stirred for 30 min, then filtered. The filter cake was suspended in EtOAc (1.3 L) and filtered. The filtrates were combined, H2O (1.80 L) added and the mixture stirred for 30 mins. The mixture was extracted with EtOAc (1.8 L) and the organic layers were washed sequentially with 1M NaOH (1.80 L), 1M HCl (1.80 L) and brine (1.8 L), then concentrated in vacuo. The resulting residue was stirred in EtOH (2.1 L) at 60°C for 30 min, water (120 mL) slowly added and the mixture stirred at rt for 1 h. The resulting solid was filtered off and dried to give the title compound, 610 g, 47% as a yellow solid.

[0202] Step 3: Synthesis of 2-cyclopropyl-5-(2-fluoro-4-methyl-5-nitrophenyl)-2H-tetrazole

[0203] A solution of 2-cyclopropyl-5-(2-fluoro-4-methylphenyl)-2H-tetrazole (610 g, 2.8 mol) in H2SO4 (2.44 L) was pumped by Pump 1 (6.87 mL / min) to flow reactor 1 (FLR1, PFA, Coils reactor, 3.175(1 / 8”) mm, 68.06 mL, 25 °C) at rt. A solution of KNO₃ (565 g, 5.6 mol) in H2SO4(2.44 mL) was pumped by Pump 2 (6.75 mL / min) to flow reactor 1 at rt. The pumps were started synchronously and the mixture collected in a bottle for 2 h. The mixture was quenched with ice water (6 L) at 0°C and the mixture filtered. The filter cake was washed with water (2 L) and dried in vacuo to give the title compound, 540 g, 70.8%. LCMS m / z = 264 [M+H]+

[0204] Step 4: Synthesis of2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methyl-4-nitrobenzonitrile

[0205] A mixture of 2-cyclopropyl-5-(2-fluoro-4-methyl-5-nitrophenyl)-2H-tetrazole (514 g, 1.95 mol) in DMSO (2.57 L) was degassed and purged with N2at rt. KCN (190 g, 2.92 mol) was added and the reaction mixture stirred at rt for 3 h. The mixture was poured into saturated aq. NaHCO₃ (7.70 L), then extracted with EtOAc (2.50 L x 3). The combined organic layer was washed with brine (2.50 L x 2), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO®; SepaFlash® Silica Flash Column, Eluent of 0 - 30% EtOAc / PE) and the product purified by prep-HPLC (column: Welch Ultimate XB-CN61ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT250*70*10um; mobile phase: [Hexane - EtOH]; B%: 22%, isocratic elution mode) to give the title compound as a yellow solid, 111 g, 20.8%. LCMS m / z = 271 [M+H]+

[0206] Step 5: Synthesis of 4-amino-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0207] A solution of 2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methyl-4-nitrobenzonitrile (110 g, 407 mmol) and 4-bipyridine (0.32 g) in DMF (555 mL) was pumped by Pump 1 (4.5 mL / min) to flow reactor 1 (FLR1, PFA, Coils reactor, 3.175(1 / 8”) mm, 136.12 mL, 0 °C) atrt. A solution of B2(OH)2(164 g, 1.83 mol) in DMF (1110 mL) was pumped by Pump 2 (9 mL / min) to flow reactor 1. The pumps were started synchronously and the mixture collected for 10 mins. The mixture was poured into water (6 L), stirred for 30 mins then filtered. The filter cake was washed with water (1 L x 2) then dried in vacuo to afford the title compound (103 g, 79.1% ) as a yellow solid. LCMS m / z = 241 [M+H]+

[0208] Intermediate 13

[0209] 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoroanilineTMSN3Step 1

[0211] The title compound was obtained as a solid, from 4-chloro-2-fluorobenzonitrile, following a similar 4 step procedure to that described in Intermediate 12, steps 1 to 3 and step 5. LCMS m / z = 254 [M+H]+.

[0212] Intermediate 14

[0213] 5-bromo-N-(2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-2,7- naphthyridin- 1 -amine62ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTNA Fe / NH4CI NA EtOH / H2O Step 2Step 3

[0214] Steps 1 and 2: Synthesis of2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5-yl)aniline

[0215] The title compound was obtained as a brown solid, 3 g, from Intermediate 8 and Mel, following a similar 2 step procedure to that described in Intermediate 10.

[0216] Step 3: Synthesis of 5-bromo-N-(2-chloro-4-fluoro-5- 2-methyl-2H-tetrazol-5- yl)phenyl)-2,7-naphthyridin-l -amine

[0217] To a mixture of 2-chloro-4-fluoro-5-(2-inethyl-2H-tetrazol-5-yl)aniline (2 g, 8.78 mmol) and 5-bromo-l-chloro-2,7-naphthyridine (2.34 g, 9.65 mmol) in toluene (20 mL) was added Me₃Al (10 mL) at 0°C under N₂. The reaction mixture was heated at 100°C for 16 h. The mixture was quenched with HC1 (IM) and concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH, Gradient: 0% B to 10% B in 50 min) to give the title compound (3.2 g, 83.9%) as a yellow oil. LCMS m / z = 434 [M+H]+

[0218] Intermediate 15

[0219] 5-bromo-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-2,7- naphthyridin- 1 -amine

[0222] Step 1: Synthesis of4-fluoro-2-methyl-5-(2H-tetrazol-5-yl)anilineME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0223] To a stirred solution of 5-amino-2-fluoro-4-methylbenzonitrile (500 mg, 3.32 mmol) in DMF (5 ml) was added Bu3SnN3(3.30 g, 9.95 mmol) and the reaction mixture was stirred at 100°C for 12 h. The mixture was diluted with EtOAc (50 mL) and water (50 mL). The water phase was extracted with EtOAc (3 x 20 mL) and the combined organic phase was washed with brine (30 mL). The organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified by prep-TLC with PE: EtOAc= 3: 1 to give the title compound, 330 mg, 51% as a white solid. LCMS: m / z = 194 [M+H]+.[00224J Step 2: Synthesis of5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0225] A mixture of 4-fluoro-2-methyl-5-(2H-tetrazol-5-yl)aniline (300 mg, 1.55 mmol), K2CO3 (641 mg, 4.65 mmol), [CuOH(TMEDA)]2C12 (143 mg, 310 pmol) and cyclopropylboronic acid (266 mg, 3.10 mmol) in DCE (10 mL) was stirred at 60°C for 24h under O2 and then cooled to rt. The mixture was filtered and the filter cake was washed with a solution of DCM: MeOH = 10: 1. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column with PE: EtOAc= 2: 1 to give the title compound (60 mg, 17%) as a yellow solid. LCMS m / z = 234 [M+H]+[002261 Step 3: Synthesis of 5-bromo-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)-2, 7-naphthyridin-l -amine

[0227] A mixture of 5-bromo-l-chloro-2,7-naphthyridine (120 g, 493 mmol) and 5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline (121 g, 517 mmol) in THF (1.2 L) was degassed and purged with N2. The mixture was cooled to -75 °C, then LiHMDS (1 M, 986 mL) was added dropwise. The mixture was allowed to warm to 25 °C and stirred for 16 h. The mixture was poured into NH4CI (aq. 3.60 L) and the mixture diluted with EtOAc (1.2 L). The mixture was filtered, and the solid dried in vacuo. The crude product was triturated with H2O (200 mL) at rt for 0.5 h, filtered, the solid washed with water and dried in vacuo to afford the title compound as a yellow solid, 257 g, 75%. LCMS m / z = 444 [M+H]+

[0228] Intermediate 16

[0229] 5-bromo-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)-2,7- naphthyridin- 1 -amineME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0230] The title compound was obtained as a yellow solid, 800 mg, 88.6%, from 5-bromo-l- chloro-2,7-naphthyridine and Intermediate 13, following a similar procedure to that described in Intermediate 17, step 3. LCMS m / z = 462 [M+H]+

[0231] Intermediate 17

[0232] 5-bromo-N-(4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)-2,7- naphthyridin- 1 -amineMeCDs Fe / NH4CI, EtOH / H2O step 1 'CD3step 2step 3

[0233] Step 1: Synthesis of5-(2-fluoro-4-methyl-5-nitrophenyl)-2-(methyl-d3)-2H-tetrazole

[0234] To a solution of Intermediate 9 (350 mg, 1.57 mmol), in DMF (5 mL), was added NaH (75 mg, 3.14 mmol) at 0°C and the resulting mixture was stirred for 0.5 h. MeCD3(220 mg, 3.14 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction was quenched with water and extracted with DCM. The combined organic extracts were evaporated under reduced pressure to give the title compound as a white solid, 260 mg, 68.9%. LCMS m / z = 241 [M+H]+

[0235] Step 2: Synthesis of4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)aniline

[0236] A mixture of 5-(2-fluoro-4-methyl-5-nitrophenyl)-2-(methyl-d3)-2H-tetrazole (260 mg, 1.07 mmol) and Fe (56 mg, 0.1 mmol) in NH4C1 (aq): EtOH (5 mL, 1: 4) was stirred at 80°C for 1 h. The solids were filtered off and the filtrate was concentrated in vacuo to give the title compound, 200 mg (89%) as an off-white solid. LCMS: m / z = 211 [M+H]+.

[0237] Step 3: Synthesis of 5-bromo-N-(4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)-2,7-naphthyridin-l-amine

[0238] LiHMDS (147 mg, 0.95 mmol) was added to a mixture of 4-fhioro-2-methyl-5-(2- (methyl-d3)-2H-tetrazol-5-yl)aniline (200 mg, 0.95 mmol) and 5-bromo-l-chloro-2,7- naphthyridine (230 mg, 0.95 mmol) in toluene (5 mL) at 0°C under N2. The resulting mixture was stirred at rt for 12 h under N2. The mixture was extracted with EtOAc (50 mL x 3) and theME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcombined organic extracts washed with brine (20 mL x 2), dried with anhydrous Na2SO4and concentrated in vacuo to give the title compound, 200 mg (50.5%) as an off-white solid. LCMS: m / z = 417 [M+H]+.

[0239] Intermediate 18

[0240] 4-((5-bromo-2,7-naphthyridin-l-yl)amino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5- methylbenzonitrile

[0241] LiHMDS (3.06 mL, 3.06 mmol, 1 M) was added dropwise to 5-bromo-l-chloro-2,7- naphthyridine (250 mg, 1.02 mmol) and Intermediate 12 (245 mg, 1.02 mmol) in toluene (10 mL) and THF (10 mL) at 0°C. The mixture was stirred at 25°C for 16 h under N2 then diluted with EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic phase was washed with brine. The organic layer was dried with Anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by prep-TLC with PE: EtOAc = 25: 1 to give the title compound (222 mg, 48.6 %) as a yellow solid. LCMS m / z = 449 [M+H]+

[0242] Intermediate 19

[0243] 5-((lH-pyrazol-4-yl)ethynyl)-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)-2,7-naphthyridin-l-amine

[0244] 4-Ethynyl-lH-pyrazole (30.7 g, 334 mmol) was added to a solution of Intermediate 15 (100 g, 223 mmol) in dioxane (1.86 L). Cui (1.70 g, 8.90 mmol) then TEA (90.1 g, 890 mmol) were added and the mixture degassed and purged with N2. Pd(PPh3)4 (5.14 g, 4.45 mmol) was added and the reaction mixture was stirred at 100 °C for 16 h under N2. The cooled mixture was filtered and the solid washed with dioxane (300 mL). The solid was dried in vacuo to give the title compound as a yellow solid, 100 g, crude. LCMS m / z = 452 [M+H]+66ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0245] Intermediate 20

[0246] 5-((lH-pyrazol-4-yl)ethynyl)-N-(5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)-2,7-naphthyridin-l-amine

[0247] Step 1: Synthesis of 5-bromo-N-( 5-( 2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl) -2, 7-naphthyridin-l -amine

[0248] The title compound was obtained as a white solid, 900 mg, 93.4%, from Intermediate 11 and 5-bromo-l-chloro-2,7-naphthyridine following a similar procedure to that described in Intermediate 17, step 3. LCMS m / z = 428 [M+H]+

[0249] Step 2: Synthesis of 5-((1H-pyrazol-4-yl)ethynyl)-N-(5-(2-ethyl-2H-tetrazol-5-yl)-4- fluoro-2-methylphenyl)-2, 7-naphthyridin-l -amine

[0250] A mixture of 5-bromo-N-(5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-2,7- naphthyri din- 1 -amine (500 mg, 1.16 mmol), 4-ethynyl-lH-pyrazole (213 mg, 2.32 mmol), Cui (66.2 mg, 348 pmol), TEA (469 mg, 4.64 mmol) and Pd(PPh3)4 (134 mg, 116 pmol) in THF (5 mL) was stirred at 80°C for 12 h under N2. Water (60 mL) was added and the resulting solution was extracted with EtOAc (3x50 mL). The organic layer was dried with Anhydrous Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column with DCM: MeOH= 16: 1 to give the title compound (320 mg, 62.8%) as a white solid. LCMS m / z = 440 [M+H]+

[0251] Intermediate 21

[0252] 5-((lH-pyrazol-4-yl)ethynyl)-N-(4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)-2,7-naphthyridin- 1 -amine

[0253] Step 7: Synthesis of 5-bromo-N-(4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)-2, 7-naphthyridin-l -amine

[0254] A mixture of Intermediate 10 (380 mg, 1.83 mmol), 5-bromo-l-chloro-2,7- naphthyridine (445 mg, 1.83 mmol) and TsOH (377 mg, 2.19 mmol) in IPA (10 mL) was stirred at 100°C for 3 h under Nz. The resulting solution was extracted with EtOAc (3x80 mL) and the 67ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcombined organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 15: 1) to afford the title compound (200 mg) as a yellow solid. LCMS m / z = 414 [M+H]+

[0255] Step 2: Synthesis of 5-(( 1 H-pyrazol-4-yl)ethynyl)-N-(4-fluoro-2-methyl-5-(2-methyl- 2H-tetrazol-5-yl)phenyl)-2,7-naphthyridin-l -amine

[0256] A mixture of 5-bromo-N-(4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)- 2,7-naphthyridin-l -amine (200 mg, 482 pmol), 4-ethynyl-lH-pyrazole (132 mg, 1.44mmol), P(Cy₃)Pd G3 (62.6 mg, 96.4 pmol), tricyclohexylphosphanium tetrafluoroborate (35.4 mg, 96.4 pmol) and K2CO3 (265 mg, 1.92 mmol) in MeCN (10 mL) was stirred at 75°C for 16 h under N2. The resulting solution was extracted with EtOAc (3x80 mL) and the combined organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC (DCM: MeOH= 15: 1) to afford the title compound (140 mg) as a yellow solid. LCMS m / z = 426 [M+H]+

[0257] Intermediate 22

[0258] 5-((lH-pyrazol-4-yl)ethynyl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-2,7- naphthyridin- 1 -amineN=N

[0259] The title compound was obtained as a yellow oil, 150 mg, 52.6%, from 2-methyl-5- (2-methyl-2H-l,2,3,4-tetrazol-5-yl)aniline, 5-bromo-l-chloro-2,7-naphthyridine and 4-ethynyl- IH-pyrazole, following a similar 2 step procedure to that described in Intermediate 20. LCMS: m / z = 408 [M+H]+.

[0260] Intermediate 23

[0261] 5-((lH-pyrazol-4-yl)ethynyl)-N-(2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5- yl)phenyl)-2,7-naphthyridin- 1 -amineME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0262] The title compound was obtained as a yellow oil, 100 mg, 39%, from Intermediate 14 and 4-ethynyl-lH-pyrazole, following a similar procedure to that described in Intermediate 20, step 2. LCMS m / z = 446 [M+H]+

[0263] Intermediate 24

[0264] 2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methyl-4-((5-((3-methyl-lH-pyrazol-4- yl)ethynyl)-2,7-naphtlryridin-l-yl)amino)benzonitrile

[0265] The title compound was obtained as a yellow solid, 800 mg, from 5-bromo-l-chloro- 2,7-naphthyridine, Intermediate 12 and Intermediate 1, following a similar 2 step procedure to that described in Intermediate 20. LCMS: m / z = 473 [M+H]+

[0266] Intermediate 25

[0267] 5-((lH-pyrazol-4-yl)ethynyl)-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)-2,7-naphthyridin-l-amine

[0268] To a mixture of Intermediate 16 (800 mg, 1.30 mmol) and 4-ethynyl-lH-pyrazole (240 mg, 1.95 mmol) in DMF (10 mL) was added Pd(PPh3)2C12 (121.6 mg, 174 pmol), TEA (524 mg, 5.20 mmol) and Cui (66 mg, 347 pmol) and tire reaction mixture was stirred at 80°C for 16 h. The resulting mixture was extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH; Gradient: 0% B to 10% B in 30 min) to give the title compound (400 mg, 48.8%) as a yellow oil. LCMS m / z = 472 [M+H]+

[0269] Intermediate 26

[0270] N-(4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-5-((3-methyl-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine69ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0271] The title compound was obtained as a yellow oil, 200 mg, 62.7%, from Intermediate 21, step 1 and Intermediate 1, following a similar procedure to that described in Intermediate 25. LCMS m / z = 440 [M+H]+

[0272] Intermediate 27

[0273] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((3-methyl-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine

[0274] Intermediate 1 (650 mg, 6.12 mmol), Intermediate 15 (2.24 g, 5.10 mmol), Cui (96.8 mg, 510 pmol), Pd(PPh3)4 (589 mg, 510 pmol) and TEA (1.06 mL, 7.65 mmol) in CH3CN (80 mL) was stirred at 80°C for 3 h under N2. The reaction mixture was allowed to cooled to room temperature and diluted with 20 mL of water. The resulting solution was extracted with EtOAc (2X80mL) and the organic layer washed with saturated brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified by prep-TLC (DCM: MeOH= 30: 1) to furnish the title compound (1.422 g, yield: 59.9 %) as a yellow solid. LCMS: m / z = 466.30 [M+H],

[0275] Example 1

[0276] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol

[0277] 2,2-Dimethyloxirane (16.0 g, 222 mmol) was added portion wise, followed by NaOH (13.3 g, 332 mmol) to a solution of Intermediate 19 (100 g, 222 mmol) in MeOH (1 L) and the mixture stirred at 60 °C for 20 h. The cooled mixture was diluted with HzO (3 L), then filtered and the filter cake washed with H2O (500 mL). The solid was suspended in DCM (3 L), the mixture 70ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTfiltered and the solids washed with DCM (500 mL). The filtrate was concentrated in vacuo and the residue purified by prep-HPLC (column: Phenomenex luna Cig (250*70mm, 10 urn); mobile phase: [water (NH₄HCO₃)-MeCN]; gradient 35%-65% B over 22 min). The product containing fractions were concentrated in vacuo to remove MeCN, then filtered, washing through with H₂O (200 mL). The filter cake was dissolved in DCM (400 mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give the title compound, crude, 50 g.

[0278] The crude product was combined with a second batch (18 g). To the combined crude compound in DCM (340 mL) and MeOH (68 mL) was added modified silica gel (135.0 g) and depalladium resin (135.0 g) and the mixture stirred at rt for 16 h. The mixture was filtered through Celite®, washing through with DCM (500 mL). The filtrate was concentrated in vacuo, to give a yellow solid, 56 g. LCMS m / z = 524 [M+H]⁺ (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.17 - 8.10 (m, 2H), 7.99 (d, 1H), 7.83 (s, 1H), 7.41 (d, 1H), 7.31 (d, 1H), 4.78 (s, 1H), 4.48 (tt, 1H), 4.07 (s, 2H), 2.26 (s, 3H), 1.44 - 1.35 (m, 2H), 1.32 - 1.24 (m, 2H), 1.08 (s, 6H).

[0279] Example 2

[0280] (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)propan-2-ol

[0281] Cs₂CO₃ (172 mg, 530 pmol) was added to Intermediate 19 (120 mg, 265 pmol) and (2R)-2-methyloxirane (15.3 mg, 265 pmol) in DMF (10 mL) and the reaction mixture was heated at 80°C for 5 h. The mixture was concentrated in vacuo and the crude product was purified by prep-TLC with DCM: MeOH= 20: 1. The residue was purified by Prep-HPLC: (Method A, Gradient: 28% B to 58% B in 8 min) to afford the title compound (56 mg, 41.4%) as a yellow solid. LCMS: m / z = 510 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.74 - 9.63 (m, 2H), 8.83 (s, 1H), 8.20 - 8.14 (m, 2H), 8.00 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.00 (d, 1H), 4.49 (tt, 1H), 4.04 (tp, 3H), 2.26 (s, 3H), 1.40 (q, 2H), 1.29 (td, 2H), 1.06 (d, 3H).

[0282] Example 3

[0283] (2R,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-ol or (2S,3R)-3- (4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-71ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTyl)ethynyl)- 1 H-pyrazol- l-yl)butan-2-ol

[0284] NaH (21.2 mg, 530 pmol) was added to Intermediate 19 (120 mg, 265 pmol) and trans 2,3-dimethyloxirane (38.2 mg, 530 pmol) in DMF (5 mL) and the reaction mixture was heated at 80°C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1 and the product further purified by Prep-HPLC (Method A, Gradient (B%): 35% B to 53% B in 7min) to give rel-(2R,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro- 2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-l H-pyrazol- l-yl)butan-2-ol, 100 mg. This was further purified by Prep-Chiral-HPLC (Method 2, Gradient 60% B isocratic) to give Peak 1, 35.2 mg as a yellow solid, and Peak 2, the title compound, 34.5 mg. LCMS: m / z = 524 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.62 (s, 1H), 8.82 (s, 1H), 8.27 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.02 (d, 1H), 4.49 (tt, 1H), 4.18 (p, 1H), 3.85 (h, 1H), 2.26 (s, 3H), 1.47 (d, 3H), 1.44 - 1.33 (m, 2H), 1.33 - 1.21 (m, 2H), 0.90 (d, 3H).

[0285] Example 4

[0286] (2R,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)butan-2-ol or (2S,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTyl)ethynyl)- 1 H-pyrazol- l-yl)butan-2-ol

[0287] Rel-(2R,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-ol was obtained, 50 mg, as a yellow solid, from Intermediate 19 and cis-2,3-dimethyloxirane, following a similar procedure to that described in Example 3. This was further purified by Prep-Chiral-HPLC:Column: CHIRALPAK-ID-34.6*50mm, 3.0um; Mobile Phase A: Hex (0.2% DEA): (EtOH:DCM=l:l)=60: 40; Gradient: isocratic, to give Peak 1, 11.3 mg as a yellow solid and Peak 2, the title compound, 13.7 mg. LCMS: m / z = 524 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.62 (s, 1H), 8.82 (s, 1H), 8.22 - 8.14 (m, 2H), 7.99 (d, 1H), 7.81 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 4.91 (d, 1H), 4.49 (tt, 1H), 4.25 (p, 1H), 3.88 (h, 1H), 2.26 (s, 3H), 1.40 (dd, 5H), 1.36 - 1.21 (m, 2H), 1.01 (d, 3H).

[0288] Example 5

[0289] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l-(2,2- difluoroethyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine

[0290] K2CO3 (36.5 mg, 265 pmol) was added to Intermediate 19 (80 mg, 177 nmol) and 2- bro mo- 1,1 -difluoroethane (30.7 mg, 212 pmol) in DMF (5 mL) and the reaction mixture was heated at 80°C for 16 h. The mixture was concentrated in vacuo and the crude product was purified by prep TLC with DCM: MeOH= 20: 1. The product was further purified by Prep- HPLC (Method A, 36% B to 61% B in 8 min), to afford the title compound (23.4 mg, 25.6 %) as an off-white solid. LCMS: m / z = 516 [M+H]+. NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H),73ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT9.63 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.15 (d, 1H), 8.03 - 7.93 (m, 2H), 7.42 (d, 1H), 7.31 (d, 1H), 6.42 (t, 1H), 4.70 (td, 2H), 4.49 (tt, 1H), 2.26 (s, 3H), 1.45 - 1.33 (m, 2H), 1.36 - 1.21 (m, 2H).

[0291] Example 6

[0292] (R)-l-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)propan-2-ol

[0293]

[0294] The title compound was obtained as a yellow solid, 27.7 mg, 30.6%, from Intermediate 25 and (2R)-2-methyloxirane, following a similar procedure to that described in Example 2. LCMS: m / z = 530 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.74 (s, 1H), 8.84 (s, 1H), 8.32 - 8.01 (m, 3H), 7.94 -7.65 (m, 2H), 7.38 (d, 1H), 4.98 (d, 1H), 4.65 -4.40 (m, 1H), 4.22 - 3.85 (m, 3H), 1.49 - 1.36 (m, 2H), 1.33 - 1.27 (m, 2H), 1.06 (d, 3H).

[0295] Example 7

[0296] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l-methyl-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine

[0297] To a mixture of 4-ethynyl-l -methyl- IH-pyrazole (120 mg, 1.13 mmol) and Intermediate 15 (398 mg, 904 pmol) in MeCN (10 mL) was added Pd(PPh₃)₄ (65.2 mg, 56.5 pmol), Cui (23.0 mg, 226 pmol) and TEA (246 mg, 2.26 mmol) and the reaction mixture was stirred at rt for 10 min. The mixture was heated at 80°C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Method A, Gradient: 31% B to 56% B in 7 min) to give the title compound (69.9 mg, 13.2%) as an off-white solid. LCMS: m / z = 466.15 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.62 (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H),74ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT7.33 - 7.27 (m, 1H), 4.58 -4.40 (m, 1H), 3.89 (s, 3H), 2.26 (s, 3H), 1.45 - 1.35 (m, 2H), 1.32 - 1.24 (m, 2H).

[0298] Example 8

[0299] 2-(2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7 -naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)ethoxy )ethan- 1 -olN=N f N- N=N N L N' N'•0

[0300] DIAD (89.2 mg, 442 pinol) was added to Intermediate 19 (100 mg, 221 pmol), 2-(2- hydroxyethoxy)ethan-l-ol (46.9 mg, 442 pmol) and PPh3(144 mg, 552 pinol) in THF (5 mL) at 0°C and the reaction mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo and the residue was purified by prep-TLC with DCM: MeOH= 10: 1. The crude product was purified by Prep-HPLC (Method A, Gradient: 28% B to 53% B in 7 min) to afford the title compound (8.5 mg, 7.14 %) as an off-white solid. LCMS: m / z = 540 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.27 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.86 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 4.64 (t, 1H), 4.49 (tt, 1H), 4.32 (t, 2H), 3.80 (t, 2H), 3.46 (dq, 4H), 2.26 (s, 3H), 1.40 (q, 2H), 1.32 - 1.21 (m, 2H).

[0301] Example 9N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-mediylphenyl)-5-((l-(2-(2- (dimethylamino)ethoxy)ethyl)- 1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin- 1 -amineN=N N=N L i

[0302] Step 1: Synthesis of2-(2-( 4-ethynyl-lH-pyrawl-l-yl)ethoxy)-N, N-dimethylethan-l- amine

[0303] A mixture of 4-ethynyl-lH-pyrazole (200 mg, 2.17 mmol), 2-(2- (dimethylamino)ethoxy)ethan-l-ol (578 mg, 4.34 mmol) and (tributylphosphoranylidene)acetonitrile solution (483 mg, 2.17 mmol) in toluene (10 mL) was stirred for 16 h at 120°C under N₂. The mixture was poured into H? O (40 mL), extracted withME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTEtOAc (20 mL x 3), the combined organic extracts washed with brine (30 mL) and concentrated in vacuo. The residue was purified by Prep-TLC (DCM: MeOH= 10: 1) to give the title compound (200 mg, 44.5%) as a yellow oil. LCMS m / z = 208 [M+H]+

[0304] Step 2: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-((l -(2-( 2-( dimethylamino)ethoxy)ethyl)-lH-pyrazol-4-yl)ethynyl)-2, 7-naphthyridin-l -amine

[0305] A mixture of Intermediate 15 (106 mg, 241 pmol), TEA (72.9 mg, 722 pmol), Cui (4.57 mg, 24.1 pmol) and Pd(PPh₃)₂Cl₂ (13.6 mg, 24.1 μmol) in DMF (2 mL) was stirred for 16 h at 80°C under N₂. The mixture was poured into H2O (40 mL), extracted with EtOAc (20 mL x 3), the combined organic extracts washed with brine (30 mL) and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH=10:l) and the crude product was purified by Prep-HPLC (Method A, Gradient: 31% B to 56% B in 8 min) to give the title compound (90.2 mg, 66.3%) as a yellow solid. LCMS: m / z = 567 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.77 - 9.72 (m, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.29 - 8.25 (m, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.43 (d, 1H), 7.33 - 7.27 (m, 1H), 4.54 - 4.43 (m, 1H), 4.35 - 4.28 (m, 2H), 3.81 - 3.75 (m, 2H), 3.51 - 3.44 (m, 2H), 2.39 - 2.32 (m, 2H), 2.26 (s, 3H), 2.11 (s, 6H), 1.45 - 1.33 (m, 2H), 1.33 - 1.20 (m, 2H).

[0306] Example 10

[0307] 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methoxy)ethan-l-ol

[0308] Step 1: Synthesis of2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methoxy)ethyl acetate

[0309] TsOH (38.0 mg, 221 pmol) was added to (2-(acetyloxy)ethoxy)methyl acetate (155 mg, 884 pmol) and Intermediate 19 (200 mg, 442 pmol) in toluene (10 mL) and the reaction mixture was heated at 100°C for 16 h. The mixture was concentrated in vacuo and the crude product was purified by prep-TLC with DCM: MeOH= 20:1 to afford the title compound (55 mg, 22%) as a yellow solid. LCMS m / z = 568 [M+H]+76ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0310] Step 2: Synthesis of2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2.7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methoxy)ethan-l-ol

[0311] NH₃·H₂O (0.2 mL) was added to 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluoro-2-methy lphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)methoxy)ethyl acetate (50 mg, 88.0 pmol) in MeOH (4 mL) and the reaction mixture was stirred at rt for 3 h.The mixture was concentrated in vacuo. The residue was purified by prep SFC (Column:GreenSep Basic 3*15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA (20mM NH3);Flow rate: 75 mL / min; Gradient: isocratic 39% B) to afford the title compound (8.9 mg, 19.2 %) as a light yellow solid. LCMS: m / z = 526 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 69.76 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.46 (d, 1H), 8.15 (d, 1H), 8.00 - 7.95 (m, 2H), 7.42 (d, 1H), 7.32 (dd, 1H), 5.50 (s, 2H), 4.75 - 4.67 (m, 1H), 4.49 (tt, 1H), 3.49 - 3.46 (m, 4H), 2.26 (s, 3H), 1.45 - 1.37 (m, 2H), 1.37 - 1.21 (m, 2H).

[0312] Example 11

[0313] l-(2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)ethoxy)-2-methylpropan-2-ol

[0314] Step 1: Synthesis of l-(2-(4-ethynyl-lH-pyrazol-l-yl)ethoxy)-2-rnethylpropan-2-ol

[0315] The title compound was obtained as a colorless oil, 50 mg, 44.2%, from 4-ethynyl- IH-pyrazole and l-(2-hydroxyethoxy)-2-methylpropan-2-ol, following a similar procedure to that described in Example 9, step 1. LCMS: m / z =110 [M+H]+.

[0316] Step 2: Synthesis of J-(2-(4-((8-((5-(2-cyclopropyI-2H-tetrazol-5-yI)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)ethoxy)-2-methylpropan-2- ol

[0317] A mixture of Intermediate 15 (63.4 mg, 0.144 mmol), XantPhos (6.53 mg, 0.014 mmol), Pd2(dba)3(137 mg, 0.144 mmol) andCs₂CO₃ (46.8 mg, 0.288 mmol) in dioxane was stirred at 100°C for 2 h. The reaction was evaporated in vacuo and the residue was purified by Prep-TLC (DCM: MeOH= 20: 1). The crude compound was purified by Prep-HPLC (Method A, Gradient: 31% B to 56% B in 8 min) to afford the title compound (12.9 mg, 15.7 %) as a light yellow solid. LCMS: m / z =568 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s,77ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT1H), 8.26 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1 H), 7.86 (s, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 4.49 (tt, 1H), 4.37 - 4.28 (m, 3H), 3.80 (t, 2H), 3.16 (s, 2H), 2.26 (s, 3H), 1.40 (q, 2H), 1.35 - 1.21 (m, 2H), 1.02 (s, 6H).

[0318] Example 12

[0319] 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diolF

[0320] The title compound was obtained as a yellow solid, 16.6 mg, 17.3%, from Intermediate 19 and (2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 2. LCMS: m / z = 540 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.59 (s, 1H), 8.83 (s, 1H), 8.17 - 8.10 (m, 2H), 7.99 (d, 1H), 7.82 (s, 1H), 7.41 (d, 1H), 7.31 (d, 1H), 4.82 (t, 1H), 4.69 (s, 1H), 4.48 (tt, 1H), 4.19 -4.06 (m, 2H), 3.26 - 3.16 (m, 2H), 2.26 (s, 3H), 1.39 (q, 2H), 1.36 - 1.21 (m, 2H), 0.97 (s, 3H).

[0321] Example 13

[0322] 2-((2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)ethyl)(methyl)amino)ethan- 1 -ol

[0323] The title compound was obtained as a white solid, from 4-ethynyl-lH-pyrazole, 2-((2- hydroxyethyl)(methyl)amino)ethan-l-ol and Intermediate 15, following a similar 2 step procedure to that described in Example 11. LCMS: m / z = 553 [M+H]+;XH NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 4.53 - 4.45 (m, 1H), 4.38 - 4.32 (m, 1H), 4.27 - 4.18 (m, 2H), 3.46 - 3.37 (m, 2H), 2.83 - 2.75 (m, 2H), 2.49 - 2.42 (m, 2H), 2.28 - 2.20 (d, 6H), 1.45 - 1.32 (m, 2H), 1.35 - 1.21 (m, 2H).

[0324] Example 1478ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0325] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butane-2,3-diol

[0326] A mixture of Intermediate 19 (60 mg, 132 pmol), l-(oxiran-2-yl)ethan-l-ol (17.4 mg, 198 pmol) and Cs2CO3(86.0 mg, 264 pmol) in DMF (2 mL) was stirred for 6 h at 25 °C. The mixture was concentrated and the crude product was purified by Prep-HPLC (Method B, Gradient: 22% B to 35% B in 7 min) to give the title compound (24.0 mg, 33.7%) as a yellow solid. LCMS: m / z = 540 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.21 - 8.11 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.04 (d, 1H), 4.78 (d, 1H), 4.54 - 4.44 (m, 1H), 4.48 - 4.33 (m, 1H), 4.11 -3.95 (m, 1H), 3.71 - 3.43 (m, 2H), 2.26 (s, 3H), 1.44 - 1.36 (m, 2H), 1.37 - 1.21 (m, 2H), 1.15 -1.06 (m, 3H).

[0327] Example 15

[0328] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l-(methyl-d3)- 1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin- 1 -amine

[0329] Step 1: Synthesis of4-ethynyl-l-(methyl-d3)-lH-pyrazole

[0330] The title compound was obtained as a colorless oil, from 4-ethynyl-lH-pyrazole and CD3I, following a similar procedure to that described in Intermediate 10, step 1.

[0331] Step 2: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-((l- methyl-d3)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l -amine

[0332] The title compound was obtained as a white solid, 10.4 mg, 19.5%, from Intermediate 15 and 4-ethynyl-l-(methyl-d3)-lH-pyrazole, following a similar procedure to that described in Example 11, step 2. The crude compound was purified by Prep-HPLC (Method B, Gradient: 23% B to 51% B in 7 min). LCMS: m / z =469 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 4.49 (tt, 1H), 2.26 (s, 3H), 1.44 - 1.32 (m, 2H), 1.35 - 1.21 (m, 2H).ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0333] Example 16

[0334] 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1-yl)- 1,1,1 -trifluoropropan-2-ol

[0335] A mixture of Intermediate 19 (100 mg, 221 pmol), 3-bromo- 1,1,1 -trifluoropropan-2- ol (85.2 mg, 442 pmol) and K2CO3 (91.6 mg, 663 pmol) in DMF (5 mL) were heated at 50°C for 1 day. The solution was filtered. The filtrate was purified by Prep-HPLC (Method A, Gradient:33% B to 60% B in 7 min) to give the title compound as a yellow solid, (57.1 mg, 45.4%).LCMS: m / z = 546 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.60 (s, 1H), 8.96 (s, 1H), 8.31 (s, 1H), 8.18 (d, 1H), 8.05 - 7.75 (m, 2H), 7.55 - 7.25 (m, 1H), 7.30 (d, 1H), 6.73 (d, 1H), 4.60 - 4.38 (m, 3H), 4.25 -4.15 (m, 1H), 2.26 (s, 3H), 1.42-1.36 (m, 2H), 1.31-1.21 (m, 2H).

[0336] Example 17

[0337] (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)-2-methylpropan-2-ol or (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-y l)ethynyl)-l H-pyrazol- l-yl)-3-(2-medroxyethoxy)-2-methylpropan-2-ol

[0338] And

[0339] Example 40

[0340] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)-2-methylpropan-2-ol or (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)-2-methylpropan-2-ol80ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0341] Step 1: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-((l-((2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l -amine

[0342] A mixture of Intermediate 19 (1.5 g, 3.32 mmol), 2-(chloromethyl)-2-methyloxirane (707 mg, 6.64 mmol) and Cs₂CO₃ (3.24 g, 9.95 mmol) in DMF (20 mL) was stirred at rt for 16 h. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE: EtOAc; Gradient: 0% B to 50% B), to give the title compound (750 mg, 43.3%) as a brown oil. LCMS m / z = 522 [M+H]+

[0343] Step 2: Synthesis of(R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)-2- methylpropan-2-ol and (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)-2- methylpropan-2-ol

[0344] To a mixture of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5- (( 1 -((2-methyloxiran-2-yl)methyl)- 1 H-pyrazol-4-yl)ethynyl)-2,7 -naphthyridin- 1 -amine (100 mg, 191 pmol) and 2-methoxyethan-1-ol (29.0 mg, 382 pmol) in DMF (10 mL) was added NaH (13.7 mg, 573 prnol) at 0°C and the reaction mixture was stirred at rt for 2 h. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH; Gradient: 0% B to 10% B in 30 min). The product was purified by Prep-HPLC (Column: XBridge Shield RP1881ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTOBD Column, 19*250 mm, 5p,m; Mobile Phase A: water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 30% B to 47% B in 9 min) to give l-(4-((8-((5-(2-cyclopropyl- 2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l- yl)-3-(2-methoxyethoxy)-2-methylpropan-2-ol. This was further purified by Prep-HPLC (Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: IPA: DCM; Flow rate: 20 mL / min; Gradient: isocratic 45) to give Peak 1, Example 17, (2 mg, 3.94%) as a yellow solid. LCMS: m / z = 598 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.74 (s,1H), 9.62 (s, 1H), 8.83 (d, 1H), 8.17 - 8.08 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.34 - 7.28 (m, 1H), 4.94 (d, 1H), 4.52 - 4.40 (m, 1H), 4.13 (d, 2H), 3.65 - 3.56 (m, 2H), 3.55 - 3.40 (m, 2H), 3.49 (t, 3H), 3.17 (d, 2H), 2.26 (s, 3H), 1.43 - 1.37 (m, 2H), 1.32 - 1.25 (m, 2H), 1.01 (d, 3H).

[0345] Further elution provided Peak 2, Example 40, 2.2 mg, 4.3% as a yellow solid.LCMS: m / z = 598 [M+H]+; H NMR (400 MHz, DMSO-d6) δ9.74 (s, 1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.17 - 8.11 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H),4.93 (s, 1H), 4.52 - 4.42 (m, 1H), 4.13 (d, 2H), 3.60 - 3.51 (m, 2H), 3.49 (t, 2H), 3.25 (s, 3H), 3.21 (s, 2H), 2.26 (s, 3H), 1.42 - 1.36 (m, 2H), 1.31 - 1.26 (m, 2H), 1.02 (s, 3H).

[0346] Example 18

[0347] ((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methyl)(imino)(methyl)-X6-sulfanone

[0348] Step 1: Synthesis of4-ethynyl-l-((methylthio)methyl)-lH-pyrazole

[0349] The title compound was obtained as a yellow solid, 1 g, 30% from (chloromethyl)(methyl)sulfane and 4-ethynyl-lH-pyrazole, following a similar procedure to that described in Example 15, step 1. LCMS m / z = 153 [M+H]+

[0350] Step 2: Synthesis of4-ethynyl-l-((methylsulfinyl)methyl)-lH-pyrazoleME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0351] m-CPBA (270 mg, 1.57 mmol) was added to 4-ethynyl-l-((methylthio)methyl)-lH- pyrazole (240 mg, 1.57 mmol) in DCM at -60°C and the solution was stirred for 30 min at this temperature and then allowed to warm to rt. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCOs (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over anhydrous NajSCL, filtered and evaporated under reduced pressure. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1, to afford the title compound (220 mg, 83.3 %) as a yellow solid. LCMS m / z = 169 [M+H]+

[0352] Step 3: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-((l-((methylsulfinyl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l -amine

[0353] The title compound was obtained as a white solid, 12 mg, 4.8%, from 4-ethynyl-1- ((methylsulfinyl)methyl)-lH-pyrazole and Intermediate 15, following a similar procedure to that described in Example 11, step 2. LCMS: m / z = 528 [M+H]+1H NMR (400 MHz, DMSO-de) 5 9.76 (s, 1H), 9.63 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 8.15 (d, 1H), 8.06 - 7.96 (m, 2H), 7.42 (d, 1H), 7.33 (d, 1H), 5.57 (d, 1H), 5.35 (d, 1H), 4.49 (tt, 1H), 2.57 (s, 3H), 2.26 (s, 3H), 1.45 - 1.32 (m, 2H), 1.35 - 1.21 (m, 2H).

[0354] Step 4: Synthesis ofN-(((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methyl)(methyl)(oxo)-2.6- sulfaneylidene)-2,2,2-trifluoroacelamide

[0355] A mixture of Rh2(OAc)4(49.9 mg, 113 pmol), trifluoroacetamide (85.6 mg, 758 pmol), MgO (60.4 mg, 1.51 mmol), (diacetoxyiodo)benzene (122 mg, 379 pmol) and N-(5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l-((methylsulfinyl)methyl)-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine (200 mg, 379 pmol) in DCM (15 mL) was stirred at rt for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1, to afford the title compound (30 mg, 12.3 %) as a yellow solid. LCMS m / z = 639 [M+H]+

[0356] Step 5: Synthesis of(( 4-( ( 8-( (5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)methyl)(imino)(methyl)- 76 -sulfa none

[0357] K2CO3 (3.22 mg, 23.4 pmol) was added to N-(((4-((8-((5-(2-cyclopropyl-2H-tetrazol- 5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l- yl)methyl)(methyl)(oxo)-X6-sulfaneylidene)-2,2,2-trifluoroacetamide (30 mg, 46.9 pmol) in MeOH (3 mL) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted83ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTwith EtOAc (30 mL), washed with water (30 mL x 3) and saturated brine (30 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Prep-HPLC (Method A, Gradient: 54%B to 79%B in 10 min) to afford the title compound (3.2 mg, 12.5 %) as a yellow solid. LCMS: m / z = 543 [M+H]+; 'H NMR (400 MHz, DMSO-de) 59.76 (s, 1H), 9.64 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H), 8.15 (d, 1H), 8.05 -7.96 (m, 2H), 7.42 (d, 1H), 7.32 (d, 1H), 5.69 (d, 1H), 5.50 (d, 1H), 4.49 (tt, 1H), 4.01 (s, 1H), 2.92 (s, 3H), 2.26 (s, 3H), 1.44 - 1.33 (m, 2H), 1.33 - 1.21 (m, 2H).

[0358] Example 19

[0359] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-3-methylbutane-2,3-diol or (R)-l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-methylbutane-2,3-diol

[0360] A mixture of Intermediate 19 (280 mg, 620 pmol), 2-(oxiran-2-yl)propan-2-ol (189.6 mg, 1.86 mmol) and K2CO3 (171.2 mg, 1.24 mmol) in DMF (10 mL) was stirred at 25°C for 2 h under N2. The resulting solution was extracted with DCM (3 x 60 mL) and the combined organic layers were dried over Na2SO4and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 15: 1) to afford l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methylbutane-2,3-diol. This was further purified by prep chiral HPLC (Method 3, Gradient: 60% B isocratic) to afford Peak 1, 81.3 mg as a yellow solid and Peak 2, the title compound, 75.1 mg, as a yellow solid. LCMS: m / z = 554 [M+23]+; 1H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.27 - 8.13 (m, 2H), 8.00 (d, 1H), 7.84 (s, 1H), 7.37 (dd, 2H), 5.06 (d, 1H), 4.62 - 4.39 (m, 3H), 3.95 (dd, 1H), 3.66 -3.50 (m, 1H), 2.26 (s, 3H), 1.40 (q, 2H), 1.29 (dt, 2H), 1.12 (d, 6H).84ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0361] Example 20

[0362] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)-3-etlroxy-2-methylpropan-2-ol or (R)- 1 -(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxy-2-methylpropan-2-ol

[0363] A mixture of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l- ((2-methyloxiran-2-yl)methyl)- 1 H-pyrazol -4-yl)ethynyl)-2,7-naphthyridin- 1 -amine (Example 17, step 1, 100 mg, 191 pmol) and sodium ethoxide (38.9 mg, 573 pmol) in EtOH (10 mL) was stirred at rt for 3 h. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH; Gradient: 0% B to 10% B in 30 min) and the product was further purified by Prep-HPLC (Method A, Gradient (B%): 35% B to 60% B in 7 min) to give l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-ethoxy-2-methylpropan-2-ol. This was purified by Prep-HPLC (Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: Hex: (MeOH: DCM=1: 2)=5: 6; Flow rate: 20 mL / min; Gradient (B%): isocratic 55) to give Peak 1, (21.5 mg, 42.6%) as a yellow solid and Peak 2, the title compound, (19.6 mg, 39.0%) as a yellow solid. LCMS: m / z = 568 [M+H]+;1H NMR (400 MHz, DMSO-tfe) 59.74 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.17 - 8.09 (m, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.91 (s, 1H), 4.49 (m, 1H), 4.13 (s, 2H), 3.47 (m, 2H), 3.17 (s, 2H), 2.26 (s, 3H), 1.39 (m, 2H), 1.31 - 1.26 (m, 2H), 1.14 (t, 3H), 1.01 (s, 3H).

[0364] Example 2185ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0365] methyl 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-2- methylpropanoate

[0366] The title compound was obtained as a yellow solid, 2.2 mg, 6%, from Intermediate 19 and methyl 2-methyloxirane-2-carboxylate, following a similar procedure to that described in Example 5. LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 69.81 - 9.72 (m, 1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.19 - 8.11 (m, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.31 (dd, 1H), 5.83 (s, 1H), 4.49 (tt, 1H), 4.44 - 4.24 (m, 2H), 3.67 (s, 3H), 2.26 (s, 3H), 1.43 - 1.37 (m, 2H), 1.33 - 1.26 (m, 5H).

[0367] Example 22

[0368] (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol or (S)-l-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol

[0369] And Example 23

[0370] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol or (R)-l-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol86ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0371] Step 1: Synthesis of l-((2-ethyloxiran-2-yl)methyl)-4-ethynyl-lH-pyrazole

[0372] The title compound was obtained as a light-yellow oil, 220 mg, 38.4%, from 4- ethynyl-lH-pyrazole and 2-(chloromethyl)-2-ethyloxirane, following a similar procedure to that described in Intermediate 11, step 1. LCMS m / z = 177 [M+H]+

[0373] Step 2: Synthesis of l-(4-ethynyl-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol

[0374] MeONa (66.9 mg, 1.24 mmol) was added to l-((2-ethyloxiran-2-yl)methyl)-4- ethynyl-lH-pyrazole (220 mg, 1.24 mmol) in MeCN (10 mL) and the reaction mixture was heated at 60°C for 16 h. The mixture was concentrated in vacuo and the crude product was purified by prep-TLC with DCM: MeOH= 30: 1, to afford the title compound (180 mg, 69.7 %) as a light-yellow oil. LCMS m / z = 209 [M+H]+

[0375] Step 3: Synthesis ofl-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan- 2-ol

[0376] A mixture of Cui (16.4 mg, 86.4 junol), Pd(PPh3)4(99.8 mg, 86.4 jimol), TEA (173 mg, 1.72 mmol), l-(4-ethynyl-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol (180 mg, 864 pmol) and Intermediate 15 (380 mg, 864 pmol) in MeCN (10 mL) was heated at 80°C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1, to afford the title compound (160 mg, 32.6 %) as a yellow solid. LCMS m / z = 568 [M+H]+

[0377] Step 4: Synthesis of(R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyraz.ol-l-yl)-2-(methoxymethyl)butan-ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT2-ol and (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2.7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol

[0378] l-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-(methoxymethyl)butan-2-ol (160 mg, 281 pinol) was further purified by Prep-Chiral-HPLC (Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient: 20% B isocratic in 23 min) to give Peak 1, Example 22, 70.8 mg, as a yellow solid and Peak 2, Example 23, 67.2 mg, as a yellow solid.

[0379] Example 22, LCMS: m / z = 568 [M+H]+; Chiral-HPLC: (ES, m / z): R = 2.958 min; 1H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.65 (s, 1H), 8.84 (s, 1H), 8.14 (d, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 4.74 (s, 1H), 4.49 (tt, 1H), 4.20 - 4.08 (m, 2H), 3.28 (s, 3H), 3.15 (d, 1H), 3.05 (d, 1H), 2.26 (s, 3H), 1.47 - 1.34 (m, 3H), 1.29 (qd, 3H), 0.85 (t, 3H).

[0380] Example 23, LCMS: m / z = 568 [M+H]+; Chiral-HPLC: (ES, m / z): R = 3.959 min; 1H NMR (400 MHz, DMSO-ds) 59.74 (s, 1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.14 - 8.09 (m, 2H), 8.00 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.79 (s, 1H), 4.49 (tt, 1H), 4.20 - 4.08 (m, 2H), 3.28 (s, 3H), 3.15 (d, 1H), 3.05 (d, 1H), 2.26 (s, 3H), 1.41 - 1.29 (m, 6H), 0.85 (t, 3H).

[0381] Example 24

[0382] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-olstep 4

[0383] Step 1: Synthesis of(Z)-l-(but-2-en-l-yl)-4-ethynyl-lH-pyrazole

[0384] The title compound was obtained as an off-white solid, 1.4 g, 44%, from 4-ethynyl- IH-pyrazole and (2Z)-l-bromobut-2-ene, following a similar procedure to that described in Intermediate 2. LCMS m / z = 147 [M+H]+

[0385] Step 2: Synthesis of4-ethynyl-l-((3-methyloxiran-2-yl)methyl)-lH-pyrazoleME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0386] m-CPBA (4.95 g, 28.7 mmol) was added to (Z)-l-(but-2-en-l-yl)-4-ethynyl-lH- pyrazole (1.4 g, 9.57 mmol) in DCM (15 mL) at 0°C and the reaction mixture was stirred at 20°C for 16 h under N2. The resulting solution was extracted with EtOAc (3 x 150 mL). The organic layer was dried with anhydrous Na2SO4and concentrated in vacuo. The residue was purified by Prep-TLC (DCM: MeOH= 20: 1) to afford the title compound (1 g, 64.1%) as an off-white solid. LCMS: m / z = 163 [M+H]+.

[0387] Step 3: Synthesis of 3-ethoxy-l-(4-ethynyl-lH-pyrazol-l-yl)butan-2-ol

[0388] A mixture of 4-ethynyl-l-((3-methyloxiran-2-yl)methyl)-lH-pyrazole (1 g, 6.16 mmol) and sodium ethoxide (628 mg, 18.48 mmol) in EtOH (15 mL) was stirred at 80°C for 16 h under N2. The resulting solution was extracted with EtOAc (3x150 mL) and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to afford tire title compound (220 mg) as a yellow solid. LCMS m / z = 209 [M+H]+

[0389] Step 4: Synthesis ofl-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol

[0390] The title compound was obtained as an off-white solid, 140 mg, 47%, from 3-ethoxy- l-(4-ethynyl-lH-pyrazol-l-yl)butan-2-ol and Intermediate 15, following a similar procedure to that described in Example 11, step 2. LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO- d6) 89.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.25 - 8.12 (m, 2H), 8.00 (d, 1H), 7.85 (d, 1H), 7.48 - 7.18 (m, 2H), 5.10 (dd, 1H), 4.49 (tt, 1H), 4.37 - 4.00 (m, 2H), 3.89 - 3.80 (m, OH), 3.69 (dtd, 1H), 3.55 (dqd, 1H), 3.42 (dt, 1H), 3.27 (p, 1H), 2.26 (s, 3H), 1.45 - 1.35 (m, 2H), 1.33 - 1.23 (m, 2H), 1.18 - 1.06 (m, 6H).

[0391] Example 25

[0392] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-3-(dimethylamino)propan-2-ol

[0393] Step 1: Synthesis of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-Jluoro-2-methylphenyl)- 5-((l-( oxiran-2-ylmethyl)-lH-pyrazol-4-yl)ethynyl)-2, 7-naphthyridin-l -amineME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0394] The title compound was obtained as a white solid, 100 mg, 68.9%, from 2- (chloromethyl)oxirane and Intermediate 19, following a similar procedure to that described in Example 2.

[0395] Step 2: Synthesis ofl-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3- ( dimethylamino)propan-2-ol

[0396] A mixture of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l- (oxiran-2-ylmethyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine (100 mg, 197 pmol), dimethylamine (35.5 mg, 788 pmol) and DIEA (45.7 mg, 354 pmol) in EtOH (2 mL) was stirred at 80°C for 3 h under N2. Water (30 mL) was added and the resulting solution was extracted with EtOAc (3x20 mL). The organic layer was dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by prep-TLC with DCM: MeOH= 12: 1 and the product further purified by prep-HPLC: (Method A, Gradient: 27% B to 52% B in 8 min) to give the title compound (1.4 mg, 1.29%) as a white solid. LCMS: m / z = 553 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.98 (d, 1H), 4.49 (t, 1H), 4.26 (d, 1H), 4.02 (d, 1H), 3.94 (s, 1H), 2.28 - 2.20 (m, 5H), 2.19 (s, 6H), 1.44 - 1.32 (m, 2H), 1.35 - 1.21 (m, 2H).

[0397] Example 26

[0398] 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphth yridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l,l-difluoropropan-2-ol

[0399] The title compound was obtained as a white solid, 20 mg, 6.7%, from Intermediate 19 and 3-bromo-l,l-difluoropropan-2-ol, following a similar procedure to that described in Example 22 and 23, step 1. The crude product was further purified by prep-HPLC (Column:CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1; Flow rate: 20 inL / inin; Gradient (B%): isocratic 30. LCMS: m / z = 546 [M+H]+, 1H NMR (400 MHz, DMSO-d6) 69.68 (s, 1H), 9.57 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.92 (d, 1H), 7.83 (s, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 6.16 - 5.71 (m, 2H), 4.42 (tt, 1H), 4.29 (dd, 1H), 4.13 (dd, 1H), 4.09 - 3.95 (m, 1H), 2.19 (s, 3H), 1.33 (q, 2H), 1.22 (td, 2H).

[0400] Example 2790ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0401] (R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diol or (S)-3-(4-((8-((5- (2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethyny 1)- 1 H-pyrazol- l-yl)-2-methylpropane- 1,2-diolFF

[0402] 3-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yD-2-methylpropane-l,2-diol (Example 12, 120 mg, 222 pmol) was purified by Prep-Chiral-HPLC (Method 2, Gradient 50% B isocratic) to give Peak 1, 42.5 mg, as a solid and Peak 2, the title compound, as a light yellow solid, 41.2 mg. LCMS: m / z = 540 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.74 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.14 (d, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 4.86 -4.73 (m, 2H), 4.49 (tt, 1H), 4.19 - 4.06 (m, 2H), 3.27 - 3.16 (m, 2H), 2.26 (s, 3H), 1.44 - 1.31 (m, 2H), 1.33 - 1.21 (m, 2H), 0.96 (s, 3H).

[0403] Example 28

[0404] 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-metliylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-3-methyl-lH-pyrazol-l-yl)methoxy)ethan-l-ol

[0405] And Example 29

[0406] 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-5-methyl-lH-pyrazol-l-yl)methoxy)ethan-l-ol91ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0407] Step 1: Synthesis oj'2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-3-methyl-lH-pyrazol-l-yl)methoxy)ethyl acetate and 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-5-methyl-lH-pyrazol-l-yl)methoxy)ethyl acetate

[0408] A mixture of the title compounds was obtained as a yellow solid, 100 mg, 53.4%, from Intermediate 27 and (2-(acetyloxy)ethoxy)methyl acetate, following a similar method to that described in Example 10, step 1. LCMS m / z = 582 [M+H]+

[0409] Step 2: Synthesis of2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-3-methyl-lH-pyrazol-l-yl)methoxy)ethan- 1 -ol and 2-(( 4-( ( 8-( ( 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-inethylphenyl)atnino)-2, 7- naphthyridin-4-yl)ethynyl)-5-methyl-lH-pyrazol-l-yl)methoxy)ethan-l-ol

[0410] NH3H2O (0.5 mL) was added to a mixture of 2-((4-((8-((5-(2-cyclopropyl-2H- tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-3-methyl-lH- pyrazol-l-yl)methoxy)ethyl acetate and 2-((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro- 2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-5-methyl-lH-pyrazol-l- yl)methoxy)ethyl acetate (90 mg, 154 pmol) in MeOH (20 mL) and the reaction mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1. The product was purified by prep-HPLC Column (Method A, Gradient: 27% B to 57% B in 8 min), to afford a mixture of the title compounds. This mixtureME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTwas purified by prep-Chiral-HPLC (Method 1, Gradient: 40% B isocratic) to give Peak 1, Example 29, 7.5 mg as a white solid. LCMS: m / z = 540 [M+H]+; 1H NMR (400 MHz, DMSO- ds) 59.75 (s, 1H), 9.64 (s, 1H), 8.85 (s, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 7.99 (d, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 5.41 (s, 2H), 4.69 (s, 1H), 4.49 (tt, 1H), 3.49 - 3.47 (m, 4H), 2.36 (s, 3H), 2.26 (s, 3H), 1.40 (s, 2H), 1.40 - 1.21 (m, 2H).

[0411] Further elution provided Peak 2, Example 28, 5.2 mg as a light yellow solid. LCMS:m / z = 540 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.75 (s, 1H), 9.64 (s, 1H), 8.86 (d, 1H), 8.15 (d, 1H), 7.99 (d, 1H), 7.82 (d, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 5.51 (s, 2H), 4.68 (s, 1H), 4.49 (tt, 1H), 3.46 (s, 4H), 2.36 (s, 3H), 2.26 (s, 3H), 1.40 (p, 2H), 1.33 - 1.21 (m, 2H).

[0412] Example 30

[0413] (R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile or (S)-4-(4- ((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)- 1 H-pyrazol- 1 -y l)-3-hy droxy-3-methylbutanenitrile

[0414] A mixture of Intermediate 4A, (85.9 mg, 454 pmol), Intermediate 15 (200 mg, 454 pmol), Cui (8.62 mg, 45.4 pmol), TEA (91.7 mg, 908 pmol) and Pd(PPh3)4(52.3 mg, 45.4 pmol) in DMF (4 mL) was stirred for 4 h at 80 °C. The mixture was poured into H2O (40 mL), extracted with EtOAc (20 mL x 3), washed with brine (30 mL) and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH=10: 1) and the product was further purified by Prep-HPLC (Method A, Gradient: 39% B to 50% B in 7 min) to give the title compound, 100 mg, as a light yellow solid. LCMS: m / z = 549 [M+H]+; 1H NMR (400 MHz, DMSO-dg) 59.75 (s, 1H), 9.62 (s, 1H), 8.84 (s, 1H), 8.18 (s, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.89 (s, 1H), 7.42 (d, 1H), 7.35 - 7.28 (m, 1H), 5.60 (s, 1H), 4.54 - 4.44 (m, 1H), 4.19 (s, 2H), 2.76 - 2.60 (m, 2H), 2.26 (s, 3H), 1.45 - 1.33 (m, 2H), 1.36 - 1.24 (m, 2H), 1.19 (s, 3H).

[0415] Example 31

[0416] ((4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-3-methyl-l H-pyrazol- l-yl)methyl)dimethylphosphine oxideME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0417] The title compound was obtained, 7.7 mg, 7.7%, from chloro(dimethylphosphoryl)methane and Intermediate 27 following a similar procedure to that described in Example 5. The crude product was purified by Prep-Chiral-HPLC: Column:CHIRALPAK IG-34.6*50mm, 3.0um; Mobile Phase A: Hex (0.2% DEA): (EtOH: DCM=1: l)=30: 70; Flow rate: 1.0 mL / min; Gradient: isocratic. LCMS: m / z = 556 [M+H]+. 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.15 (d, 1H), 7.99 (d, 1H), 7.82 (s, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 4.67 (d, 2H), 4.51-4.46 (m, 1H), 2.50 (s, 3H), 2.26 (s, 3H), 1.49 (d, 6H), 1.42-1.37 (m, 2H), 1.32-1.26 (m, 2H).

[0418] Example 32

[0419] 1-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0420] The title compound was obtained as a yellow solid, 10.2 mg, 21.7%, from Intermediate 21 and 2,2-dimethyloxirane, following tire procedure described in Example 2. LCMS: m / z = 498 [M+H]+, 1H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.61 (s, 1H), 8.82 (d, 1H), 8.14 (t, 2H), 8.02 (d, 1H), 7.83 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 4.77 (d, 1H), 4.44 (d, 3H), 4.07 (s, 2H), 2.26 (s, 3H), 1.08 (d, 6H).

[0421] Example 33

[0422] (2R,4S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diol or (2S,4S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diol

[0423] And

[0424] Example 3494ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0425] (2S,4S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diol or (2R,4S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diolTBDPSCI m-CBPA OHstep 1 OTBDPS step 2 OTBDPSF

[0426] Step 1: Synthesis of(S)-tert-butyl(pent-4-en-2-yloxy)diphenylsilane

[0427] tert-Butyl(chloro)diphenylsilane (1.91 g, 6.95 mmol) was added to (2S)-pent-4-en-2- ol (500 mg, 5.80 mmol) and imidazole (592 mg, 8.70 mmol) in DCM (8 mL) at 0°C. The resulting mixture was stirred for 12h at rt under N2. Water (40 mL) was added and the resulting solution was extracted with EtOAc (3x30 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column (PE: EtOAc= 1: 1) to give the title compound (260 mg, 13.8%) as a white solid.

[0428] Step 2: Synthesis oftert-butyl(((2S)-l-(oxiran-2-yl)propan-2-yl)oxy)diphenylsilane

[0429] The title compound was obtained as a white solid, 210 mg, 83.6%, from (S)-tert- butyl(pent-4-en-2-yloxy)diphenylsilane and m-CBPA, following a similar procedure to that described in Example 24, step 2.Step 3: Synthesis of (2R,4S)-1-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diol and (2S,4S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)pentane-2,4-diol

[0430] l-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)pentane-2,4-diol was obtained as a white solid, from tert-butyl(((2S)-1-(oxiran-2-yl)propan-2-yl)oxy)diphenylsilane and Intermediate 19 following aME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTsimilar procedure to that described in Example 12. This was further purified by Prep-Chiral- HPLC: Column: CHIRALPAK SZ 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient 25% B isocratic, to give Peak 1, Example 34, 16.1 mg, 24.8%

[0431] LCMS: m / z = 554 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s,1H), 9.62 (s, 1H), 8.82 (s, 1H), 8.20 - 8.11 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.88 (d, 1H), 4.49 (t, 1H), 4.41 (d, 1H), 4.14 (q, 1H), 4.04 (t, 2H), 3.82 (s, 1H), 2.26 (s, 3H), 1.34 (s, 2H), 1.44 - 1.21 (m, 5H), 1.07 (d, 3H).

[0432] and Peak 2, Example 33, 11.2 mg, 17.3%, as a yellow solid. LCMS: m / z = 554[M+H]+; 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.66 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.99 (s, 1H), 4.49 (t, 1H), 4.17 (d, 1H), 4.06 (d, 1H), 3.97 (d, 1H), 3.82 (q, 1H), 2.26 (s, 3H), 1.50 (t, 1H), 1.44 - 1.21 (m, 6H), 1.06 (d, 3H).

[0433] Example 35

[0434] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l- ( (methylsulfinyl)methyl)- 1 H-pyrazol-4-yl)ethyny l)-2,7-naphthyridin- 1 -amine

[0435] The title compound was obtained as a white solid, 12 mg, 4.8%, from 4-ethynyl-l- ((methylsulfinyl)methyl)-lH-pyrazole (Example 18, step 2) and Intermediate 15, following a similar procedure to that described in Example 11, step 2. LCMS: m / z = 528 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.76 (s, 1H), 9.63 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 8.15 (d, 1H), 8.06 - 7.96 (m, 2H), 7.42 (d, 1H), 7.33 (d, 1H), 5.57 (d, 1H), 5.35 (d, 1H), 4.49 (tt, 1H), 2.57 (s, 3H), 2.26 (s, 3H), 1.45 - 1.32 (m, 2H), 1.35 - 1.21 (m, 2H).

[0436] Example 36

[0437] (R)-4-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile or (S)-4-(4-((8- ((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)-3-hydroxy-3-methylbutanenitrileME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0438] Step 1: Synthesis ofN-(5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-((l- ((2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-1-amine

[0439] A mixture of Intermediate 20 (200 mg, 455 jimol), 2-(chloromethyl)-2-methyloxirane (72.6 mg, 682 pmol) and Cs2CO3(296 mg, 910 pmol) in DMF (3 mL) was stirred at 50°C for 12 h under N2. Water (40 mL) was added and the resulting solution was extracted with EtOAc (3 x 30 mL). The organic layer was dried with anhydrous Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column with DCM: MeOH= 22: 1 to give the title compound (220 mg, 86.5%) as a white solid. LCMS m / z = 510 [M+H]+

[0440] Step 2: Synthesis of(R)-4-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-3-hydroxy-3- methylbutanenitrile or (S)-4-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-3- methylbutanenitrile

[0441] Trimethylsilyl cyanide (70.0 mg, 706 pmol) was added to N-(5-(2-ethyl-2H-tetrazol- 5-yl)-4-fluoro-2-methylphenyl)-5-((l-((2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)- 2,7-naphthyridin-l-amine (180 mg, 353 pmol), and TBAF (350 mg, 1.05 mmol) in THF (2 mL) at rt and the reaction mixture was stirred at 50°C for 12 h under N2. Water (30 mL) was added and the resulting solution was extracted with EtOAc (3 x 20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column (DCM: MeOH= 16: 1) and the product was purified by prep-HPLC (Method A, Gradient (B%): 28% B to 53% B in 8 min) to give 4-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-3-97ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTmethylbutanenitrile. This was further purified by chiral HPLC: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1; Flow rate: 20 mL / min; Gradient: 20% B in 18 min) to give Peak 1, the title compound, 21.8 mg, 43.6%, as an off-white solid. LCMS: m / z = 537 [M+H]+H NMR (400 MHz, DMSO-d₆) δ 9.75 (s,1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.21 - 8.12 (m, 2H), 8.02 (d, 1H), 7.89 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 5.60 (s, 1H), 4.78 (q, 2H), 4.19 (s, 2H), 2.72 (d, 1H), 2.64 (d, 1H), 2.26 (s, 3H), 1.57 (t, 3H), 1.23 (s, lH), 1.19 (s, 3H).

[0442] Example 37

[0443] (R)-3-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)etliynyl)-lH-pyrazol-l-yl)-2-metliy Ipropane- 1,2-diol or (S)-3-(4-((8-((5-(2- ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)etliynyl)-lH- pyrazol-1-yl)-2-methylpropane-1,2-diol

[0444] And Example 39

[0445] (S)-3-(4-((8-((5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diol or (R)-3-(4-((8-((5-(2- ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH- pyrazol-1-yl)-2-methylpropane-1,2-diol

[0446] 3-(4-((8-((5-(2-Ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-2-methy Ipropane- 1,2-diol was obtained from Intermediate 20 and (2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 36, step 1. This was further purified by Chiral-HPLC Column:CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1 Flow rate: 19 mL / min; Gradient: isocratic 40%B; to give Peak 1, Example 39, 31.6 mg, 31.6%98ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0447] LCMS: m / z = 528 [M+H]+;1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.63 (s,1H), 8.83 (s, 1H), 8.18 - 8.11 (m, 2H), 8.02 (d, 1H), 7.83 (s, 1H), 7.43 (d, 1H), 7.35 - 7.29 (m, 1H), 4.87 (t, 1H), 4.83 - 4.71 (m, 3H), 4.19 - 4.06 (m, 2H), 3.28 - 3.12 (m, 2H), 2.26 (s, 3H), 1.57 (t, 3H), 0.96 (s, 3H), 0.94 (t, 1H).

[0448] and Peak 2, Example 37, 31.5 mg, 31.5% as an off-white solid.

[0449] LCMS: m / z = 528 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.18 - 8.11 (m, 2H), 8.02 (d, 1H), 7.83 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 4.86 (t, 1H), 4.83 - 4.71 (m, 3H), 4.19 - 4.06 (m, 2H), 3.32 (s, 1H), 3.28 - 3.16 (m, 2H), 2.26 (s, 3H), 1.57 (t, 3H), 0.96 (s, 3H), 0.94 (t, 1H).

[0450] Example 38

[0451] (2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)ethyl)(imino)(methyl)-X6-sulfanone

[0452] The title compound was obtained as a white solid, from 4-ethynyl-lH-pyrazole, (2- chloroethyl)(methyl)sulfane and Intermediate 15, following a similar 5 step procedure to that described in Example 18. LCMS: m / z = 557 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.75 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.15 (d, 1H), 7.99 (d, 1H), 7.92 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 4.59 (t, 2H), 4.49 (tt, 1H), 3.93 (s, 1H), 3.65 (hept, 2H), 2.81 (s, 3H), 2.26 (s, 3H), 1.40 (q, 2H), 1.36 - 1.21 (m, 2H).

[0453] Example 41

[0454] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2-(methoxymethyl)propan-2-ol99ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0455] The title compound was obtained as a yellow solid, 2 mg, 3%, from Intermediate 19 and 2,2-bis(methoxymethyl)oxirane, following a similar procedure to that described in Example 12. LCMS: m / z = 584 [M+H]+; 1 H NMR (400 MHz, DMSO-de) 89.74 (d, 1 H), 9.63 (s, 1 H), 8.83 (s, 1H), 8.14 (d, 1H), 8.11 - 8.06 (m, 1H), 7.99 (d, 1H), 7.84 (d, 1H), 7.42 (d, 1H), 7.31 (dd, 1H), 5.11 (s, 1H), 4.49 (tt, 1H), 4.18 (s, 2H), 3.27 (s, 6H), 3.19 (s, 4H), 2.26 (s, 3H), 1.44 - 1.21 (m, 4H).

[0456] Example 42

[0457] l-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-olL00458J A mixture of Intermediate 16 (200 mg, 434 pmol), Intermediate 2 (106 mg, 651nmol), Cui (8.24 mg, 43.4 nmol), Pd(PPh3)2C12 (30.4 mg, 43.4 nmol) and TEA (483 pL, 6.51 mmol) in DMF (15 mL) was stirred at 80°C for 3 h under N2. The reaction mixture was cooled to rt and diluted with water (8 mL). The resulting solution was extracted with EtOAc (2 x 20 mL), the combined organic extracts were washed with brine (10 mL), dried over Na2SO4 andconcentrated in vacuo. The crude product was purified by prep-HPLC (Method A, Gradient:33% B to 60% B in 7 min) to give the title compound (134.2 mg, 56.7 %) as a pink solid. LCMS: m / z = 544 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.84 (s,lH), 9.74 (s, 1H), 8.85 (s, 1H),8.25 - 8.14 (m, 3H), 7.85 (d, 2H), 7.39 (d, 1H), 4.79 (s, 1H), 4.54-4.49 (m, 1H), 4.07 (s, 1H),1.44-1.39 (m, 2H), 1.32-1.26 (m, 2H), 1.09 (s, 6H).

[0459] Example 43

[0460] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol or (R)-l-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol100ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0461] Step 1: Synthesis of 1-(4-ethynyl-1H-pyrazol-1-yl)-2,3-dimethylbutane-2,3-diol

[0462] To a mixture of methyl 3-(4-ethynyl-1H-pyrazol-1-yl)-2-hydroxy-2- methylpropanoate (700 mg, 3.36 mmol) in THF (12 mL), was added MeMgBr (3.3 mL, 10.0 mmol, 3M) at 0°C and the reaction mixture was stirred at 25 °C for 16 h. The resulting mixture was filtered and concentrated in vacuo, and tire residue extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to afford the title compound (300 mg) as an off-white oil. LCMS m / z = 209 [M+H]+

[0463] Step 2: Synthesis of(S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3- diol or (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol

[0464] l-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol was obtained as a yellow solid, 60 mg, 22%, from l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol and Intermediate 15, following a similar procedure to that described in Example 11, step 2. The mixture was purified by prep Chiral HPLC: Column: CHIRALPAK IE-34.6*50mm, 3.0um; Mobile Phase A: Hex (0.2%DEA): (EtOH: DCM=1: l)=30: 70; Gradient: isocratic) to afford Peak 1, 14.3 mg as a yellow solid and Peak 2, the title compound, 14.5 mg as a yellow solid. LCMS: m / z = 568 [M+H]+, 1H NMR (400 MHz, DMSO-d6) 59.75 (s, 1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.22 - 8.09 (m, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 4.49 (td, 3H), 4.33 -4.20 (m, 2H), 2.26 (s, 3H), 1.40 (q, 2H), 1.35 - 1.25 (m, 2H), 1.17 (d, 6H), 0.83 (s, 3H).

[0465] Example 44ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0466] (S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)-3-methoxy-2-methylbutan-2-ol or (R)-4-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2-methylbutan-2-ol[00467J Step 1: Synthesis of methyl 3-(4-ethynyl-lH-pyrazol-l-yl)-2-hydroxypropanoate

[0468] The title compound was obtained as a yellow solid, 700 mg, 33%, from 4-ethynyl- IH-pyrazole and methyl oxirane- 2-carboxylate, following a similar procedure to that described in Example 36, step 1. LCMS: m / z = 195 [M+H]+.

[0469] Step 2: Synthesis of methyl 3-(4-ethynyl-lH-pyrazol-l-yl)-2-methoxypropanoate

[0470] NaH (172 mg, 7.20 mmol) was added to methyl 3-(4-ethynyl-lH-pyrazol-l-yl)-2- hydroxypropanoate (700 mg, 3.60 mmol) in THF (10 mL) at 0 °C. Mel (1.01 g, 7.20 mmol) was added and the reaction mixture was stirred at 40°C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel column with DCM: MeOH = 25: 1 to give the title compound (320 mg, 42.7%) as a yellow solid. LCMS m / z = 209 [M+H]+

[0471] Step 3: Synthesis of4-(4-ethynyl-lH-pyrazol-l-yl)-3-methoxy-2-methylbutan-2-ol102ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100472] The title compound was obtained as a yellow solid, 120 mg, 60.3%, from MeMgBr and methyl 3-(4-ethynyl-lH-pyrazol-l-yl)-2-methoxypropanoate, following a similar procedure to that described in Example 43, step 2. LCMS m / z = 209 [M+H]+

[0473] Step 4: Synthesis of(S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2- methylbutan-2-ol or (R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2- methylbutan-2-ol

[0474] 4-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-3-methoxy-2-methylbutan-2-ol was obtained from 4-(4-ethynyl-lH-pyrazol-l-yl)-3-methoxy-2-methylbutan-2-ol and Intermediate 15, following a similar procedure to that described in Example 42. This was further purified by Prep-Chiral- HPLC: Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: IPA: DCM=1: 1; Flow rate: 20 mL / min; Gradient 45% B isocratic to give Peak 1, the title compound, 20.8 mg, 23%, as a yellow solid. LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.76 (s, 2H), 8.86 (s, 1H), 8.26 (s, 1H), 8.11 (d, 1H), 8.02 (d, 1H), 7.90 (s, 1H), 7.45 (d, 1H), 7.33 (d, 1H), 4.49 (tt, 2H), 4.43 (dd, 1H), 4.06 (dd, 1H), 3.34 (dd, 1H), 2.99 (s, 3H), 2.27 (s, 3H), 1.42 - 1.36 (m, 2H), 1.35 - 1.22 (m, 2H), 1.17 (s, 3H), 1.10 (s, 3H).

[0475] Example 45

[0476] 2-methyl-l-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)propan-2-ol

[0477] The title compound was obtained as a yellow solid, 23.5 mg, 20%, from Intermediate 22 and 2,2-dimethyloxirane, following a similar procedure to that described in Example 2. LCMS: m / z = 480 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.76 (s, 1H), 9.60 (s, 1H), 8.83 (s, 1H), 8.16 (d, 2H), 8.08 (d, 1H), 7.89 - 7.81 (m, 2H), 7.49 (d, 1H), 7.33 (d, 1H), 4.78 (s, 1H), 4.42 (s, 3H), 4.07 (s, 2H), 2.27 (s, 3H), 1.09 (s, 6H).

[0478] Example 46103ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT[004791 (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2-methylbutan-2-ol or (S)-l-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2-methylbutan-2-ol

[0480] And

[0481] Example 47

[0482] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2-methylbutan-2-ol or (R)-l-(4-((8- ((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2-methylbutan-2-ol

[0483] Step 1: Synthesis of(((3-methylbut-3-en-l-yl)oxy)methanetriyl)tribenzene

[0484] A mixture of 3-methylbut-3-en-l-ol (2 g, 23.2 mmol), triphenylmethyl chloride (12.9 g, 46.4 mmol) and TEA (7.04 g, 69.6 mmol) in EtOAc (30 mL) was stirred at 25°C for 3 h under N2. The resulting solution was extracted with DCM (3x100 mL) and the combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography with PE: EtOAc= 4: 1 to afford the title compound (4 g) as an off-white solid.

[0485] Step 2: Synthesis of2-methyl-2-(2-(trityloxy)ethyl)oxiraneME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100486] The title compound was obtained as an off-white solid, from (((3-methylbut-3-en-l- yl)oxy)methanetriyl)tribenzene and m-CPBA following a similar procedure to that described in Example 24, step 2.

[0487] Step 3: Synthesis of l-(4-ethynyl-l H-pyrazol-1 -yl)-2-methyl-4-( trityloxy )butan-2-ol

[0488] The title compound was obtained as a yellow solid, 1.7 g, from 2-methyl-2-(2- (trityloxy)ethyl)oxirane and 4-ethynyl-lH-pyrazole, following a similar procedure to that described in Intermediate 2.

[0489] Step 4: Synthesis of3-( ( tert-butyldimethylsilyl)oxy)-4-(4-ethynyl-l H-pyrazol-1 -yl)-3- methylbutan-l-ol

[0490] TMSOTf (362 mg, 1.37 mmol) was added dropwise to 1 -(4-ethynyl-l H-pyrazol-1 - yl)-2-methyl-4-(trityloxy)butan-2-ol (600 mg, 1.37 mmol) and TEA (415 mg, 4.11 mmol) in DCM ( 15 mL) at 0°C under N2 and the reaction mixture was stirred at rt for 16 h. The resulting mixture was filtered and concentrated in vacuo and the residue extracted with EtOAc (3 x 80 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to afford the title compound (180 mg) as a yellow solid.

[0491] Step 5: Synthesis of l-(2-(( tert-butyldimethylsilyl)oxy)-4-methoxy-2-methylbutyl)-4- ethynyl-lH-pyrazole

[0492] The title compound was obtained as an off-white solid, 100 mg, from 3-((tert- butyldimethylsilyl)oxy)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-methylbutan-l-ol and Mel, following a similar procedure to that described in Example 44, step 2.

[0493] Step 6: Synthesis of5-((l-(2-((tert-butyldimethylsilyl)oxy)-4-inethoxy-2-methylbutyl)- lH-pyrazol-4-yl)ethynyl)-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-2,7- naphthyridin-1 -amine

[0494] A mixture of l-(2-((tert-butyldimethylsilyl)oxy)-4-methoxy-2-methylbutyl)-4- ethynyl-lH-pyrazole (100 mg, 310 pmol), Intermediate 15 (136 mg, 310 pmol), Xantphos (17.9 mg, 31.0 pmol), Pd2(dba)3(28.3 mg, 31.0 pmol) and Cs2CO3(303 mg, 930 pmol) in dioxane (8 mL) was stirred at 100°C for 16 h under N2. The resulting mixture was filtered and concentrated in vacuo. The residue was extracted with EtOAc (3x50 mL) and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to afford the title compound (100 mg) as a yellow solid.105ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0495] Step 7 Synthesis of (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2- methylbutan-2-ol and (S)-l-(4-(( 8-( ( 5-( 2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-4-methoxy-2- methylbutan-2-ol

[0496] A mixture of 5-((l-(2-((tert-butyldimethylsilyl)oxy)-4-methoxy-2-methylbutyl)-lH- pyrazol-4-yl)ethynyl)-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-2,7- naphthyridin-1 -amine (80 mg, 117 pmol) and TBAF (36.9 mg, 117 pmol) in THF (5 mL) was stirred at 25°C for 2 h. The resulting mixture was filtered and concentrated in vacuo. The residue was extracted with EtOAc (3x30 mL), the organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 25: 1) to afford l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-4-methoxy-2-methylbutan-2-ol (100 mg) as a yellow solid. This was further purified by chiral HPLC (Column: CHIRALPAK IE-34.6*50mm, 3.0um; Mobile Phase A: MtBE (0.2%DEA): (EtOH: DCM=1: l)=60: 40; Gradient: isocratic) to afford Peak 1, Example 46, 4.6 mg as a yellow solid. LCMS: m / z = 568 [M+H]+, 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.17 -8.11 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.32 (dd, 1H), 4.79 (s, 1H), 4.49 (tt, 1H), 4.09 (s, 2H), 3.47 (t, 2H), 3.23 (s, 3H), 2.26 (s, 3H), 1.61 (td, 2H), 1.44 - 1.33 (m, 2H), 1.33 - 1.27 (m, 1H), 1.30 - 1.21 (m, 1H), 1.04 (s, 3H).

[0497] And Peak 2, Example 47, 9.2 mg, as a yellow solid. LCMS: m / z = 568 [M+H]+, 1H NMR (400 MHz, DMSO-de) 59.66 (s, 1H), 9.56 (s, 1H), 8.75 (s, 1H), 8.05 (d, 2H), 7.91 (d, 1H), 7.76 (s, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 4.71 (s, 1H), 4.40 (tt, 1H), 4.01 (s, 2H), 3.39 (t, 2H), 3.14 (s, 3H), 2.18 (s, 3H), 1.53 (td, 2H), 1.32 (p, 2H), 1.20 (dt, 2H), 0.95 (s, 3H).

[0498] Example 48

[0499] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-one

[0500] A mixture of Intermediate 3 (20 mg, 0.12 mmol), Intermediate 15 (52.8 mg, 0.12 mmol), XantPhos (7 mg, 0.012 mmol), Pd₂(dba)₃ (11 mg, 0.012 mmol) and Cs₂CO₃ (78.7 mg, 0.24 mmol) in dioxane (3 mL) was stirred at 100°C in N2 for 12 h. The solids were filtered off106ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTand the resulting solution was extracted with EtOAc (3x10 mL) and the combined extracts concentrated in vacuo. The residue was purified by prep-HPLC (Method B, Gradient: 6% B to 25% B in 12 min) to give the title compound as an off-white solid, 2.2 mg. LCMS: m / z = 522 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.75 (s,1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.20 - 8.11 (m, 2H), 7.99 (d, 1H), 7.88 (d, 1H), 7.42 (d, 1H), 7.32 (dd, 1H),5.2O (s, 2H), 4.49 (tt, 1H), 3.26 (s, 2H),2.26 (s, 3H), 1.39 (q, 2H), 1.36 - 1.27 (m, 1H), 1.30 - 1.23 (m, 1H), 0.97 (t, 3H).

[0501] Example 49

[0502] 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylbutan-2-ol

[0503] K2CO3 (182 mg, 1.32 mmol), intermediate 19 (300 mg, 664 pmol) and 3- chlorobutan- 2-one (84.8 mg, 796 pmol) were combined in DMF (10 mL) and stirred at rt for 16h under N2.

[0504] The reaction mixture was diluted with EtOAc (120 mL), and washed with water (60 mL). The organic layer was dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (Column: Xbridge BEH Shield RP18, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 43% B to 68% B in 8 min) to furnish the title compound (18.9mg) as an off-white solid.

[0505] LCMS: m / z = 538 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.78 - 9.73 (m, 1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.40 (s, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.00 (d, J = 7.0 Hz, 2H), 7.42 (d, J = 11.4 Hz, 1H), 7.32 (dd, J = 5.8, 0.8 Hz, 1H), 5.27 (q, J = 7.2 Hz, 1H), 4.49 (tt, J = 7.5, 3.8 Hz, 1H), 2.26 (s, 3H), 2.02 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H), 1.47 - 1.31 (m, 2H), 1.33 - 1.21 (m, 2H).

[0506] Example 50

[0507] 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide107ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0508] The title compound was obtained as a yellow solid, from Intermediate 5 and Intermediate 15, following a similar procedure to that described in Example 47, step 6. LCMS: m / z = 567 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.75 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.09 -7.96 (m, 2H), 7.82 (d, 2H), 7.37 (dd, 2H), 5.81 (s, 1H), 4.49 (tt, 1H), 4.39 - 4.20 (m, 2H), 2.58 (d, 3H), 2.26 (s, 3H), 1.40 (q, 2H), 1.29 (h, 2H), 1.21 (s, 3H).

[0509] Example 51

[0510] (2R,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol, (2S,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol, (2R,3S)-3-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-2-methoxybutan-l-ol or (2S,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)- 4-fluoro-2-methylpheny l)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)-2- methoxybutan- 1 -ol

[0511] And Example 52

[0512] (2S,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l-methoxybutan-2-ol, (2R,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l-methoxybutan-2-ol, (2S,3S)-3-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1-yl)- l-methoxybutan-2-ol or (2R,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5- yl)-4-fluoro-2-methy Ipheny l)amino)-2,7 -naphthyridin-4-yl)etliynyl)- 1 H-pyrazol- 1 -yl)- 1 - methoxybutan-2-ol

[0513] And Example 53

[0514] (2S,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)-2-methoxybutan- 1 -ol, (2R,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol, (2R,3R)-3-(4-((8-((5-(2-108ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-2-methoxybutan-l-ol or (2S,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)- 4-fluoro-2-methylpheny l)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)-2- methoxybutan- 1 -ol[005151 Step 1: Synthesis of l-(but-3-en-2-yl)-4-ethynyl-lH-pyrazole109ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100516] The title compound was obtained as a yellow solid, 1.2 g, 74.9%, from 3-chlorobut-l- ene and 4-ethynyl-lH-pyrazole, following a similar procedure to that described in Example 5. LCMS m / z = 147 [M+H]+

[0517] Step 2: Synthesis of3-(4-ethynyl-lH-pyrazol-l-yl)butane-l,2-diol

[0518] A mixture of l-(but-3-en-2-yl)-4-ethynyl-lH-pyrazole (1.2g, 8.20 mmol), K₂OsO₄·H₂O) (480 mg, 1.64 mmol) and NalCL (5.21 g, 24.5 mmol) in THF (10 mL) and water (10 mL) was stirred at rt for 6 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by silica gel column with DCM: MeOH = 15: 1 to give the title compound (400 mg, 27.2%) as a yellow solid. LCMS m / z = 181 [M+H]+

[0519] Step 3: Synthesis of 3-(4-ethynyl-l H-pyrazol-1 -yl)-2-methoxybutan-l -ol and 3-(4- ethynyl-lH-pyrazol-1 -yl)-l -methoxybutan-2-ol

[0520] The title compounds were obtained as a yellow solid, 120 mg, 27.9%, from 3-(4- ethynyl-lH-pyrazol-l-yl)butane-l,2-diol and Mel, following a similar procedure to that described in Example 44, step 2.

[0521] Step 4: Synthesis of 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l-methoxybutan-2-ol and 3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin- 4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol

[0522] A mixture of the title compounds were obtained, from 3-(4-ethynyl-1H-pyrazol-1-yl)- 2-methoxybutan-l-ol and 3-(4-ethynyl-lH-pyrazol-l-yl)-l-methoxybutan-2-ol and 3-(4-ethynyl- lH-pyrazol-l-yl)-2-methoxybutan-l-ol, following a similar procedure to that described in Example 23, step 3.

[0523] The product was further purified by prep SFC (Column: YMC-Actus Triart Diol- HILIC 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeCN (1% 2mM NH₃-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 50% B; to give 3-(4-((8-((5-(2-cyclopropyl-2H- tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)- 1-methoxybutan-2-ol (30 mg, 10.5%) as a yellow solid and 3-(4-((8-((5-(2-cyclopropyl-2H- tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)- 2-methoxybutan-l-ol (40 mg, 14.0%) as a yellow solid.

[0524] Step 5: Synthesis of(2S,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino )-2,7-naphthyridin-4-yl)ethynyl)-l H-pyrazol-1 -yl)-l-methoxybutan-2-ol,110ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT(2R,3S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2.7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l-methoxybutan-2-ol, ( 2S,3S)-3-(4-((8-( ( 5-( 2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-l-methoxybutan-2-ol and (2R,3R)-3-(4-{(8-((5-(2-cyclopropyl-2H-tetrazol-5- yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l- methoxybutan-2-ol

[0525] 3-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-l-methoxybutan-2-ol (30 mg, 54.1 pmol) was purified by Chiral-HPLC (Method 2, Gradient 50% B isocratic) to give Peak 1, (2.5 mg, 8.36 %) as an off-white solid, Peak 2, (2.3 mg, 7.69 %) as a yellow solid and a mixture of Peak 3 and 4 (15 mg). The mixture was purified by Chiral-HPLC: (Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1; Flow rate: 20 mL / min; Gradient (B%): isocratic 30 to give Peak 3, 1.7 mg as an off-white solid, and Peak 4, Example 52, (2.2 mg). Example 52, LCMS: m / z = 554 [M+H]+; 1 H NMR (400 MHz, DMSO- d6) 59.74 (s, 1H), 9.66 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.82 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 5.18 (s, 1H), 4.54 - 4.38 (m, 2H), 3.82 (q, 1H), 3.25 (s, 3H), 3.22 (m, 2H), 2.26 (s, 3H), 1.44 (d, 3H), 1.39 (q, 2H), 1.32 - 1.17 (m, 2H).

[0526] Step 6: Synthesis of(2R,3R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol

[0527] 3-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methoxybutan-l-ol (40 mg, 72.2 iimol) was purified by Chiral-HPLC (Method 2, Gradient: isocratic 45%B), to give Peak 1, Example 51, (2.8 mg, 7.0 %) as an off-white solid, Peak 2 (3.3 mg, 8.3 %) as an off-white solid, and a mixture of Peak 3 and 4. This mixture was purified by Chiral-HPLC (Column: CHIRALPAK IK 2*25 cm, 5 tun; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1, Flow rate: 20 mL / min; Gradient (B%): isocratic 30; to give Peak 3, 1.7 mg, as an off-white solid and Peak 4, Example 53, (2.2 mg, 7.4 %) as a yellow solid.

[0528] Example 51: LCMS: m / z = 554 [M+H]+; 1H NMR (400 MHz, DMSO- d6) 59.74 (d, 1H), 9.63 (s, 1H), 8.82 (s, 1H), 8.26 (d, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.87 (d, 1H), 7.42 (d, 1H), 7.32 (dd, 1H), 4.78 (t, 1H), 4.62 -4.51 (m, 1H), 4.48 (dq, 1H), 3.47 (q, 1H), 3.41 (dd, 1H), 3.32 (s, 4H), 2.26 (s, 3H), 1.46 (d, 3H), 1.43 - 1.37 (m, 2H), 1.37 - 1.21 (m, 2H).

[0529] Example 53: LCMS: m / z = 554 [M+H]+; 1H NMR (400 MHz, DMSO- d6) 89.74 (s, 1H), 9.65 (s, 1H), 8.83 (s, 1H), 8.26 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.87 (s, 1H), 7.43 (d,111ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT1H), 7.33 (d, 1H), 4.62 - 4.44 (m, 3H), 3.52 - 3.40 (m, 1H), 3.26 (s, 5H), 2.26 (s, 3H), 1.46 (d, 3H), 1.39 (q, 2H), 1.37 - 1.26 (m, 2H).

[0530] Example 54

[0531] (S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-metlrylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y l)-3-(2-methoxyethoxy)propan-2-ol or (R)- 1-(4- ((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethyny 1)- 1 H-pyrazol- 1 -y 1) -3- (2-methoxy ethoxy )propan-2-ol

[0532] And

[0533] Example 55

[0534] (R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-tluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -y I )-3-(2- met hoxyethoxy )propan-2-ol or (S)-l-(4- ((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-metliylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)propan-2-ol

[0535] A mixture of Intermediate 19 (200 mg, 442 pmol), 2-((2- methoxyethoxy)methyl)oxirane (87.6 mg, 663 pmol) and K2CO3 (185 mg, 1.32 mmol) in DMF (10 mL) was heated at 80°C for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel column (DCM: MeOH; Gradient: 0% B to 10% B in 30 min). The product was purified by Prep-HPLC (Method A, Gradient: 35% B to 50% B in 7 min). The product was further purified by Prep-Chiral-HPLC (Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH), Mobile Phase B: EtOH: DCM=1:1; Flow rate: 20 mL / min; Gradient: isocratic 60; to give Peak 1, Example 55, (50.0 mg, 49.5%) as a yellow solid and Peak 2, Example 54, (49.8 mg, 49.6%) as a pink solid.

[0536] Example 55: LCMS: m / z = 548 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 69.74 (s,1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.85 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.22 (s, 1H), 4.55 - 4.41 (m, 1H), 4.32 - 4.15 (m, 1H), 4.13 - 4.03 (m, 1H),ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT3.97 (s, 1H), 3.59 - 3.50 (m, 2H), 3.49 - 3.45 (m, 2H), 3.37 (d, 2H), 3.27 (s, 3H), 2.26 (s, 3H), 1.45 - 1.35 (m, 2H), 1.35 - 1.21 (m, 2H).

[0537] Example 54: LCMS: m / z = 584 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.21 - 8.12 (m, 2H), 8.00 (d, 1H), 7.85 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.22 (s, 1H), 4.62 - 4.35 (m, 1H), 4.33 - 4.18 (m, 1H), 4.17 -4.07 (m, 1H), 3.97 (s, 1H), 3.60 - 3.50 (m, 2H), 3.41 - 3.38 (m, 2H), 3.37 (d, 2H), 3.27 (s, 3H), 2.26 (s, 3H), 1.44 - 1.32 (m, 2H), 1.31 - 1.23 (m, 2H).

[0538] Example 56

[0539] (3R,4R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile, (3S,4S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-inethylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile, (3S,4R)-4-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-hydroxypentanenitrile or (3R,4S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5- yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3- hydroxypentanenitrile

[0540] And Example 58

[0541] (3R,4S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile, (3S,4R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile, (3S,4S)-4-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-hydroxypentanenitrile and (3R,4R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol- 5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1 H-pyrazol-l-yl)-3- hy droxypentan en itrile113ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0542] Step 1: Synthesis of 3-(4-ethynyl-l H-pyrazol-l-yl)-2-hydroxybutyl 4- methylbenzenesulfonate

[0543] A mixture of 3-(4-ethynyl-lH-pyrazol-l-yl)butane-l,2-diol (Example 51, step 2, 600 mg, 3.32 mmol) and TsCl (630 mg, 3.32 mmol) in pyridine (10 mL) was stirred at rt for 16 h.The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The crude product was purified by silica gel column with DCM: MeOH = 10: 1 to give the title compound (150 mg, 13.5%) as a yellow solid. LCMS m / z = 335 [M+H]+

[0544] Step 2: Synthesis of4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxypentanenitrile

[0545] NaCN (21.9 mg, 448 pmol) was added to 3-(4-ethynyl-lH-pyrazol-l-yl)-2- hydroxybutyl 4-methylbenzenesulfonate (150 mg, 448 pmol) in DMF (5 mL) at 0 °C and the reaction was stirred at 50 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC with DCM:MeOH = 15: 1 to give the title compound (50 mg, 59.0%) as a yellow solid. LCMS m / z = 190 [M+H]+

[0546] Step 3: Synthesis of 4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile

[0547] The title compound was obtained as a yellow solid, 30 mg, 26%, from 4-(4-ethynyl- lH-pyrazol-l-yl)-3-hydroxypentanenitrile and Intermediate 15, following a similar procedure to that described in Example 23, step 3. LCMS m / z = 549 [M+H]+

[0548] Step 4: Synthesis of(3S,4S)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyraz.ol-l-yl)-3-hydroxypentanenitrile, 3R,4R)-4-(4-( ( 8-( ( 5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2, 7-114ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTnaphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile, ( 3S.4R)-4-( 4-( (8-( (5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol-l-yl)-3-hydroxypentanenitrile and ( 3R,4S)-4-(4-( ( 8-( ( 5-( 2-cyclopropyl-2H-tetrazol- 5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3- hydroxypentanenitrile

[0549] 4-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxypentanenitrile (30 mg) was purified by Prep-Chiral-HPLC (Method 2, Gradient 40% B isocratic) to give Peak 1, (4.5 mg, 15.0%) as a yellow solid. Further elution provided Peak 2 and Peak 3, as a mixture, and Peak 4, Example 58, (4.7 mg, 15.7%) as a yellow solid. The mixture of Peak 2 and peak 3 was purified by Chiral- HPLC (Method 1, Gradient 50% B isocratic), to give Peak 2, Example 56, (3.2 mg, 10.7%) as a yellow solid, and Peak 3 (2.7 mg, 12.7%) as a yellow solid.

[0550] Example 56: LCMS: m / z = 549 [M+H]+; 1H NMR (400 MHz, DMSO- d6) 59.75 (s, 1H), 9.68 (s, 1H), 8.83 (s, 1H), 8.31 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.89 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 6.01 (s, 1H), 4.49 (tt, 1H), 4.36 (p, 1H), 4.03 (s, 1H), 2.34 (dd, 2H), 2.26 (s, 3H), 1.49 (d, 3H), 1.39 (q, 2H), 1.38 - 1.21 (m, 2H).

[0551] Example 58: LCMS: m / z = 549 [M+H]+; 1H NMR (400 MHz, DMSO- d6) 59.75 (s, 1H), 9.66 (s, 1H), 8.83 (s, 1H), 8.26 (s, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.85 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 5.86 (d, 1H), 4.49 (tt, 1H), 4.40 (p, 1H), 4.04 (t, 1H), 2.69 (dd, 2H), 2.26 (s, 3H), 1.45 (d, 3H), 1.35 - 1.25 (m, 2H), 1.25 (m, 2H).

[0552] Example 57

[0553] l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-ol

[0554] Step 1: Synthesis of l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-one

[0555] The title compound was obtained as a white solid, 160 mg, 26%, from Intermediate 3 and Intermediate 15, following a similar procedure to that described in Example 47, step 6.LCMS m / z = 522 [M+H]+ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0556] Step 2: Synthesis of l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-ol

[0557] To a solution of l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butan-2-one (160 mg, 0.31 mmol) in MeOH (8 mL) was added NaBH4(12 mg, 0.31 mmol) at 0°C and the solution was stirred for 2h at rt. The mixture was diluted with EtOAc (15 mL) and water (15 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3x5 mL) and the combined organic phase was washed with brine. The organic layer was dried with anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by prep-HPLC (Method C, Gradient: 31% B to 45% B in 8 min) to give the title compound (6.3 mg, 4%) as an off-white solid. LCMS: m / z = 524 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 59.74 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.96 (s, 1H), 4.49 (tt, 1H), 4.13 (dd, 1H), 4.04 (dd, 1H), 3.76 (s, 1H), 2.26 (s, 3H), 1.50 - 1.32 (m, 2H), 1.34 - 1.21 (m, 4H), 0.95 -0.81 (m, 3H).

[0558] Example 59

[0559] (2S,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2- methylbutan-2-ol or (2R,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2- methylbutan-2-ol

[0560] Step 1: Synthesis of(Z)-4-ethynyl-l-(2-methylbut-2-en-l-yl)-lH-pyrazole116ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100561] The title compound was obtained as a white solid, 1.8 g, 85.5%, from (2Z)-2- methylbut-2-en-l-ol and 4-ethynyl-lH-pyrazole, following a similar procedure to that described in Example 9, step 1.

[0562] Step 2: Synthesis ofl-(( 2,3-dimethyloxiran-2-yl)methyl)-4-ethynyl-lH-pyrazole

[0563] The title compound was obtained as a white solid, 1.4 g, 70%, from (Z)-4-ethynyl-l- (2-methylbut-2-en-l-yl)-lH-pyrazole, following a similar procedure to that described in Example 24, step 2. LCMS m / z = 177 [M+H]+

[0564] Step 3: Synthesis of 1 -(4-ethynyl-l H-pyrazol-1 -yl)-3-methoxy-2-methylbutan-2-ol

[0565] A mixture of l-((2,3-dimethyloxiran-2-yl)methyl)-4-ethynyl-lH-pyrazole (1.4 g, 7.94 mmol) and NaOMe (2.14 g, 39.7 mmol) in MeOH (18 mL) was stirred for 12 h at 60°C under N2. Water (60 mL) was added and the resulting solution was extracted with EtOAc (3x50 mL). The organic layer was dried over Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column with DCM: MeOH= 18: 1 to give the title compound (1 g, 60.6%) as a white solid. LCMS m / z = 209 [M+H]+

[0566] Step 4: Synthesis ofl-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2- methylbutan-2-ol

[0567] A mixture of l-(4-ethynyl-lH-pyrazol-l-yl)-3-methoxy-2-methylbutan-2-ol (470 mg, 2.26 mmol), Intermediate 15 (500 mg, 1.13 mmol), Cui (64.3mg, 338 nmol), TEA (457 mg, 4.52 mmol) and Pd(PPli3)4 (130 mg, 113 pmol) in THF (8 mL) was stirred for 16 h at 80°C under N2. Water (60 mL) was added and the resulting solution was extracted with EtOAc (3x50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-TLC with DCM: MeOH= 12: 1. The crude product was purified by prep-HPLC (Method A, Gradient: 31% B to 65% B in 8 min) to give the title compound, (400 mg, 62.4%) as a yellow solid.

[0568] Step 5: Synthesis of (2S,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-l H-pyrazol-1 -yl)-3-methoxy-2- methylbutan-2-ol or (2R,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-l H-pyrazol-1 -yl)-3-melhoxy-2- methylbutan-2-ol

[0569] l-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-methoxy-2-methylbutan-2-ol (350 mg, 616 pmol) was purified by Prep-Chiral- HPLC (Method 2, Gradient: isocratic 40%B) to give Peak 1,117ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTenantiomer 1, (152.8 mg, 43.5%) and Peak 2, the title compound (146.0 mg, 41.8%) as a yellow solid. LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.66 (s, 1H), 8.84 (s, 1H), 8.14 (d, 2H), 8.00 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.73 (s, 1H), 4.49 (t, 1H), 4.16 (d, 2H), 3.09 (q, 1H), 2.26 (s, 3H), 1.44 - 1.31 (m, 2H), 1.33 - 1.21 (m, 2H), 1.12 (d, 3H), 0.91 (s, 3H).

[0570] Example 60

[0571] (S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-5-methyl-lH-pyrazol-l-yl)-2-methylpropaiie-l,2-diol

[0572] (R)-(2-methyloxiran-2-yl)methanol (37.7 mg, 429 pmol) was added dropwise to Intermediate 27 (200 mg, 429 pmol) and K2CO3 (88.8 mg, 643 pmol) in DMF (15 mL) at 25°C.The reaction mixture was stirred at 50°C for 3 h under N2. The cooled reaction mixture was diluted with water (8 mL), the mixture was extracted with EtOAc (2x20 mL) and the combined organic extracts were washed with saturated brine. The organic layer was dried with Na₂SO₄ and concentrated in vacuo. The crude product was purified by Prep-HPLC (Method C, Gradient:56% B to 68% B in 8 min). The product was purified by prep-SFC (Column: YMC-Pack Polyamine II 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeCN: MeOH=4:1(20mM NH3); Flow rate: 75 mL / min; Gradient: isocratic 45% B to give Peak 1, (S)-3-(4-((8-((5- (2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-3-methyl-lH-pyrazol-l-yl)-2-methylpropane-l,2-diol (21.1mg, 30.2 %) as a yellow solid and Peak 2, the title compound (24.5 mg, 35.1 %) as a yellow solid. LCMS: m / z = 554 [M+H]+. 1H NMR (400 MHz, DMSO-de) 59.73 (s, 1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.07-7.92 (m, 2H), 7.42 (d, 1H), 7.29 (d, 1H), 4.86-4.83 (m, 1H), 4.70 (s, 1H), 4.52-4.46(m, 1H), 4.11-3.97 (m, 2H), 3.42-3.38 (m, 1H), 2.34 (s, 3H), 2.26 (s, 3H), 1.42-1.38 (m, 2H), 1.31-1.26(m, 2H), 0.97 (s, 3H).

[0573] Example 61

[0574] 3-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diolME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0575] A mixture of Intermediate 25 (100 mg, 211 pmol), (2-methyloxiran-2-yl)methanol (37.1 mg, 422 pmol) and Cs₂CO₃ (137 mg, 422 pmol) in DMF (2 mL) was stirred for 16 h at 25 °C. The residue was purified by Prep-TLC (DCM: MeOH=10:l ) to give the crude product. The residue was purified by Prep-HPLC (Method A, Gradient: 26% B to 56% B in 7 min) to give the title compound (45.8 mg, 38.8%) as an off white solid. LCMS: m / z =560 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.84 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.20 (d, 2H), 8.14 (s, 1H), 7.89 - 7.82 (m, 2H), 7.39 (d, 1H), 4.90 - 4.83 (m, 1H), 4.73 (s, 1H), 4.57 - 4.46 (m, 1H), 4.19 - 4.06 (m, 2H), 3.25 - 3.16 (m, 2H), 1.45 - 1.38 (m, 2H), 1.38 - 1.21 (m, 3H), 0.96 (s, 3H).

[0576] Example 62

[0577] 2-methyl-l-(4-((8-((2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)propan-2-olN=N step 1

[0578] Step 1: Synthesis of2-(methyl-d3)-5-(4-methyl-3-nitrophenyl)-2H-tetrazole

[0579] The title compound was obtained as an off-white solid, 1.88g, 17%, from CD3I and Intermediate 7, following a similar procedure to that described in Intermediate 11, step 1. LCMS m / z = 223 [M+H]+

[0580] Step 2: Synthesis of2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)ani!ine

[0581] A mixture of Fe (2.36 g, 42.2 mmol), NH4CI (2.27 g, 42.2 mmol) and 2-(methyl-d3)- 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (1.88 g, 8.45 mmol) in EtOH / HiO (10 mL / 2 mL) was heated at 80°C for 3 h under N2. The reaction mixture was filtered through Celite® and119ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTconcentrated in vacuo. The reaction mixture was diluted with EtOAc (120 mL) and washed with water (60 mL) and the layers separated. The organic layer was evaporated under reduced pressure to give the title compound (911 mg) as an off-white solid. LCMS m / z = 193 [M+H]+

[0582] Step 3: Synthesis of5-bromo-N-(2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)- 2, 7-naphthyridin-l-amine

[0583] The title compound was obtained as an off-white solid, 593 mg, 47.6%, from 2- methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)aniline and 5-bromo-l-chloro-2,7-naphthyridine, following a similar procedure to that described in Intermediate 20, step 1. LCMS m / z = 399 [M+H]+

[0584] Step 4: Synthesis of2-methyl-l-(4-((8-((2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)propan-2-ol

[0585] The title compound was obtained as a yellow solid, 47 mg, 39%, from 5-bromo-N-(2- methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)-2, 7-naphthyridin-l-amine and Intermediate 2, following a similar procedure to that described in Example 7. LCMS: m / z = 483 [M+H]+, 1H NMR (400 MHz, DMSO-de) 59.76 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.16 (d, 2H), 8.08 (d, 1H), 7.89 - 7.82 (m, 2H), 7.49 (d, 1H), 7.33 (d, 1H), 4.78 (s, 1H), 4.07 (s, 2H), 2.27 (s, 3H), 1.09 (s, 6H).

[0586] Example 63

[0587] (R)-3-hydroxy-2,2-dimethyl-4-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphdryridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butanenitrile or (S)-3- hydroxy-2,2-dimediyl-4-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- l-yl)butanenitrile

[0588] 3-Hydroxy-2,2-dimethyl-4-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butanenitrile was obtained in a 2 step procedure. In step 1, a similar procedure to that described in Intermediate 2, except120ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTK2CO3 was used employing Intermediate 22 and 4-chloro-2,2-dimethyl-3-oxobutanenitrile, and the crude was purified by Prep-HPLC (Method B, Gradient: 18% B to 46% B in 7 min). The desired product was furnished in step 2 using a similar procedure to that described in example 57 (step 2) except the product was purified by Prep-Chiral-HPLC (Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH:DCM=1:1; Flow rate: 20 mL / min; Gradient: 30% B isocratic) to give Peak 1, (30.6 mg, 15%) as a yellow solid and Peak 2, the title compound (41.0 mg, 20.4%) as a yellow solid. LCMS m / z = 519 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.77 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.89 (s, 1H), 7.86 (m, 1H), 7.49 (d, 1H), 7.32 (d, 1H), 5.97 (d, 1H), 4.42 (s, 4H), 4.11 (m, 1H), 3.81 (m, 1H), 2.27 (s, 3H), 1.35 (d, 6H).

[0589] Example 64

[0590] (R)-4-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitile or (S)-4- (4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile

[0591] 4-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile was obtained, 300 mg, from Intermediate 19 and 4-chloro-2,2-dimethyl-3-oxobutanenitrile, following a similar procedure to that described in Example 63. This was purified by prep-chiral-SFC (Column:YMC-Actus Triart Diol-HILIC 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (20mM NH3); Flow rate: 75 mL / min; Gradient: isocratic 30% B to give Peak 1 (81.9 mg, 27.2%) as a yellow solid and Peak 2, the title compound (85.0 mg, 28.3%) as a yellow solid. LCMS: m / z = 563 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.74 (s, 1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 8.14 (d, 1H), 7.99 (d, 1H), 7.88 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.97 (d, 1H), 4.54 - 4.39 (m, 2H), 4.25 - 4.01 (m, 1H), 3.98 - 3.72 (m, 1H), 2.26 (s, 3H), 1.43 - 1.37 (m, 2H), 1.35 (d, 6H), 1.31 - 1.25 (m, 2H).121ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0592] Example 65

[0593] 4-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenihileF

[0594] Step 1: Synthesis of4-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,2-dimethyl-3- oxobutanenitrile

[0595] The title compound was obtained as a yellow solid, 180 mg, 49%, from Intermediate 25 and 4-chloro-2,2-dimethyl-3-oxobutanenitrile, following a similar procedure to that described in Intermediate 11, step 1. LCMS m / z = 581 [M+H]+

[0596] Step 2: Synthesis of4-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile

[0597] To a mixture of 4-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,2-dimethyl-3- oxobutanenitrile (150 mg, 258 pmol) in MeOH (3 mL) and THF (3 mL) was added NaBH4(9.76 mg, 258 pmol) and the reaction mixture was stirred at 0°C for 2 h. The mixture was quenched with H2O (1 mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (DCM: MeOH; Gradient: 0% B to 10% B) and the product further purified by Prep-HPLC (Method A, Gradient: 38% B to 61% B in 7 min) to give the title compound (16.6 mg, 11.0%) as a yellow solid. LCMS: m / z = 583 [M+H]+; 1H NMR (400 MHz, DMSO-de) 89.84 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.28 (s, 1H), 8.25 - 8.15 (m, 2H), 7.91 - 7.82 (m, 2H), 7.38 (d, 1H), 5.97 (d, 1H),122ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT4.60 - 4.50 (m, 1H), 4.46 - 4.39 (m, 1H), 4.25 -4.00 (m, 1H), 3.80 (t, 1H), 1.45 - 1.40 (m, 2H), 1.35 (d, 6H), 1.32 - 1.25 (m, 2H).

[0598] Example 66

[0599] 2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-1-yl)amino)-5-methylbenzonitrile

[0600] Step 1: Synthesis of4-((5-((lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-2- (2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0601] The title compound was obtained as a yellow solid, 153 mg, 74.9%, from Intermediate 18 and 4-ethynyl-1 H-pyrazole, following a similar procedure to that described in Example 30. LCMS: m / z = 459 [M+H]+.

[0602] Step 2: Synthesis of2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((1-(2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-1-yl)amino)-5-methylbenzonitrile

[0603] The title compound was obtained as a yellow solid, 26.5 mg, 18.6%, from 4-((5-((1H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-1-yl)amino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile and (2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 14. LCMS: m / z = 547 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ9.74 (d, 2H), 8.87 (s, 1H), 8.38 (s, 1H), 8.27 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.48 (d, 1H), 4.90-4.86(m, 1H),4.74 (s, 1H), 4.57-4.51 (m, 1H), 4.19 -4.08 (m, 2H), 3.25-3.18(m, 2H), 2.35 (s, 3H), 1.45 - 1.40 (m, 2H), 1.35 - 1.28 (m, 2H), 0.96 (s, 3H).

[0604] Example 67

[0605] (R)-2-methyl-3-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)propane-l,2-diol123ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0606] The title compound was obtained as a yellow solid, 13.8 mg, 22.6%, from Intermediate 22 and (2R)-2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 14, except the compound was purified by prep-HPLC (Method A, Gradient: 17% B to 47% B in 7 min). LCMS: m / z = 496 [M+H]+; 1H NMR (400 MHz, DMSO- d6) δ9.76 (s, 1H), 9.59 (s, 1H), 8.83 (s, 1H), 8.19 - 8.11 (m, 2H), 8.08 (d, 1H), 7.89 - 7.81 (m, 2H), 7.49 (d, 1H), 7.32 (d, 1H), 4.84 (t, 1H), 4.71 (s, 1H), 4.42 (s, 3H), 4.20 - 4.06 (m, 2H), 3.28 - 3.16 (m, 2H), 2.27 (s, 3H), 0.97 (s, 3H).[00607J Example 68

[0608] (2S,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol, (2S,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol, (2R,3R)-l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-ethoxybutan-2-ol or (2R,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- l-yl)-3-ethoxybutan- 2-ol

[0609] And Example 69

[0610] (2R,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-tluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxy-2-butan-2-ol, (2S,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol, (2S,3S)-l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- l-yl)-3-ethoxybutan-2-ol or (2R,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)- 4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3- ethoxybutan-2-ol

[0611] And Example 70

[0612] (2R,3R)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol, (2S,3R)- 1 -(4-( (8-( (5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol, (2S,3S)-l-(4-((8-((5-(2- cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-3-ethoxybutan-2-ol or (2R,3S)-l-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-124ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTfluoro-2-methy Ipheny l)amino )-2,7-naphthyridin-4-yl )ethynyl )- 1 H-pyrazol- 1 -y l)-3-ethoxybutan- 2-ol

[0613] l-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-ethoxybutan-2-ol (Example 24, 130 mg) in MeOH (10 mL) was purified by Prep-HPLC (Column: CHIRALPAK IE, 2*25 cm, 5 pm;Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: IPA: DCM=1:1; Flow rate: 18 mL / min; Gradient: isocratic 35%B) to afford Peak 1, 15.2 mg as a yellow solid, Peak 2, Example 68, 7.1 mg as a yellow solid, Peak 3, Example 70, 11.1 mg, as a yellow solid and Peak 4, Example 69, 3.1 mg as a yellow solid.

[0614] Example 68, LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ9.74 (d, 1H), 9.62 (s, 1H), 8.83 (d, 1H), 8.24 - 8.12 (m, 2H), 8.00 (dd, 1H), 7.85 (d, 1H), 7.42 (d, 1H), 7.31 (dd, 1H), 5.02 (dd, 1H), 4.49 (ddd, 1H), 4.32 - 3.97 (m, 2H), 3.85 (d, 1H), 3.62 - 3.49 (m, 1H), 3.44 - 3.34 (m, 2H), 2.26 (d, 3H), 1.50 - 1.35 (m, 2H), 1.33 - 1.23 (m, 2H), 1.13 (ddd, 6H).

[0615] Example 69, LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-de) δ9.71 (d, 2H), 8.83 (s, 1H), 8.30 - 8.06 (m, 2H), 8.00 (d, 1H), 7.85 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 5.04 (d, 1H), 4.49 (tt, 1H), 4.23 (dd, 1H), 4.09 (dd, 1H), 3.84 (dq, 1H), 3.55 (dt, 1H), 3.46 - 3.35 (m, 2H), 2.26 (s, 3H), 1.40 (t, 2H), 1.29 (dd, 2H), 1.17 - 1.04 (m, 6H).

[0616] Example 70, LCMS: m / z = 568 [M+H]+; 1H NMR (400 MHz, DMSO-de) δ9.74 (s, 1H), 9.63 (s, 1H), 8.82 (s, 1H), 8.21 - 8.08 (m, 2H), 7.99 (d, 1H), 7.84 (s, 1H), 7.41 - 7.20 (m, 2H), 5.15 (d, 1H), 4.49 (tt, 1H), 4.31 (dd, 1H), 4.05 (dd, 1H), 3.69 (s, 1H), 3.55 (dq, 1H), 3.48 - 3.39 (m, 1H), 3.26 (q, 1H), 2.26 (s, 3H), 1.40 (q, 2H), 1.29 (dt, 2H), 1.15 - 1.07 (m, 6H).

[0617] Example 71

[0618] (S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- IH-pyrazol- 1 -y l)-N-ethyl-2-hydroxy-2-methylpropanamide or (R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-metliylphenyl)amino)-2,7- naphthyridin-4-y l)ethynyl)- 1 H-pyrazol- l-yl)-N-ethyl-2-hydroxy-2-methylpropan amide125ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTstep 1 Step 2

[0619] Step 1: Synthesis ofN-ethyl-2-methyloxirane-2-carboxamide

[0620] The title compound was obtained as an off-white solid, 300 mg, 21.8%, from N- ethylmethacrylamide, following a similar procedure to that described in Example 24, step 2. LCMS m / z = 130 [M+H]+

[0621] Step 2: Synthesis of(S)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-N-ethyl-2-hydroxy-2- methylpropanamide or (R)-3-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-N-ethyl-2-hydroxy-2- methylpropanamide

[0622] 3-(4-((8-((5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-N-ethyl-2-hydroxy-2- methylpropanamide was obtained as a yellow oil, 150 mg, from N-ethyl-2-methyloxirane-2-carboxamide and Intermediate 19 following a similar procedure to that described in Intermediate 2. This was further purified by prep chiral HPLC ( Column: CHIRALPAK IE-34.6*50mm, 3.0um; Mobile Phase A: Hex (0.2%DEA): (MeOH: DCM=l:l)=55:45; Gradient: isocratic) to afford Peak 1, the title compound, 39.5 mg as a yellow solid and Peak 2, 26.0 mg as a yellow solid. LCMS: m / z = 581 [M+H]+1¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.14 (d, 1H), 8.05 (s, 1H), 7.99 (d, 1H), 7.81 (d, 2H), 7.42 (d, 1H), 7.30 (d, 1H), 5.81 (s, 1H), 4.49 (tt, 1H), 4.35 (d, 1H), 4.24 (d, 1H), 3.17 - 2.96 (m, 2H), 2.26 (s, 3H), 1.45 - 1.31 (m, 2H), 1.33 - 1.27 (m, 1H), 1.30 - 1.21 (m, 1H), 1.22 (s, 3H), 0.97 (t, 3H).

[0623] Example 72

[0624] l-methoxy-2-((4-((8-((2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- 1 -yl)methyl)butan-2-ol126ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0625] The title compound was obtained as a yellow solid, 7.4 mg, 5%, from Example 23, step 2 and Example 62, step 3, following a similar procedure to that described in Example 7. LCMS: m / z = 527 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ9.76 (s, 1H), 9.61 (s, 1H), 8.84 (s, 1H), 8.16 (d, 1H), 8.09 (dd, 2H), 7.89 - 7.82 (m, 2H), 7.49 (d, 1H), 7.32 (dd, 1H), 4.80 (s, 1H), 4.20 -4.08 (m, 2H), 3.29 (s, 3H), 3.15 (d, 1H), 3.05 (d, 1H), 2.27 (s, 3H), 1.40 (dt, 1H), 1.34 - 1.21 (m, 1H), 0.85 (t, 3H).

[0626] Example 73

[0627] (S)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide or (R)-3-(4- ((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)- 1 H-pyrazol- l-yl)-2-hydroxy-N,2-dimethylpropanamide

[0628] And Example 75

[0629] (R)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-l H-pyrazol- l-yl)-2-hydroxy-N,2-dimethylpropanamide or (S)-3-(4- ((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamideME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0630] 3-(4-((8-((4-Fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide was obtained as a yellow solid, 12.8 mg, 18.3%, from Intermediate 5 and Intermediate 21, step 1, following a similar procedure to that described in Example 23, step 3, except THF was used as the reaction solvent. The residue was purified by Chiral-HPLC: CHIRALPAK IF-3, 4.6*50mm, 3.0um; Mobile Phase A: Hex (0.2%DEA): (EtOH: DCM=1:1) = 40:60; Flow rate: 1.0 mL / min; Gradient (B%): isocratic; to give Peak 1, Example 75 (14.5 mg, 20.8%) as an off-white solid and Peak 2, Example 73, (12.8 mg, 18.3%) as a yellow solid.

[0631] Example 75: LCMS: m / z = 541 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.15 (d, 1H), 8.08 - 7.99 (m, 2H), 7.81 (d, 2H), 7.43 (d, 1H), 7.31 (d, 1H), 5.79 (s, 1H), 4.45 (s, 3H), 4.33 (d, 1H), 4.25 (d, 1H), 2.58 (d, 3H), 2.27 (s, 3H), 1.20 (s, 3H).

[0632] Example 73: LCMS: m / z = 541 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.15 (d, 1H), 8.08 - 7.99 (m, 2H), 7.81 (d, 2H), 7.43 (d, 1H), 7.31 (d, 1H), 5.79 (s, 1H), 4.45 (s, 3H), 4.33 (d, 1H), 4.25 (d, 1H), 2.58 (d, 3H), 2.26 (s, 3H), 1.20 (s, 3H).

[0633] Example 74

[0634] (R)-3-(4-((8-((4-cyano-5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide or (S)-3- (4-((8-((4-cyano-5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)- 1H-pyrazol-1-yl)-2-hydroxy-N,2-dimethylpropanamide

[0635] And Example 81

[0636] (S)-3-(4-((8-((4-cyano-5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide or (R)-3- (4-((8-((4-cyano-5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide128ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0637] 3-(4-((8-((4-Cyano-5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropanamide was obtained as a white solid, from Intermediate 5 and Intermediate 15, following a similar procedure to that described in Example 11. The product (70 mg, 122 pmol) was purified by Prep-Chiral-HPLC (Method 3, gradient isocratic 50%B) to give Peak 1, Example 74 (25.2 mg, 36.0%) as a white solid LCMS: m / z =574 [M+H]+1H NMR (400 MHz, DMSO-de) δ9.76 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.37 (s, 1H), 8.27 (d, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.86 - 7.76 (m, 2H), 7.41 (d, 1H), 5.80 (s, 1H), 4.59 - 4.49 (m, 1H), 4.38 - 4.22 (m, 2H), 2.58 (d, 3H), 2.35 (s, 3H), 1.47 - 1.39 (m, 2H), 1.39 - 1.27 (m, 2H), 1.21 (s, 3H).

[0638] and Peak 2, Example 81 (26.8 mg, 38.3%) as a white solid. LCMS: m / z =574[M+H]+; 1H NMR (400 MHz, DMSO-ds) δ9.73 (d, 2H), 8.87 (s, 1H), 8.37 (s, 1H), 8.27 (d, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.86 - 7.76 (m, 2H), 7.41 (d, 1H), 5.80 (s, 1H), 4.59 - 4.49 (m, 1H), 4.37 -4.21 (m, 2H), 2.58 (d, 3H), 2.34 (s, 3H), 1.47 - 1.39 (m, 2H), 1.39 - 1.26 (m, 2H), 1.21 (s, 3H).

[0639] Example 76

[0640] 3-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-hydroxy-N,2-dimethylpropan amide129ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0641] Step 1: Synthesis of N,2-dimethyloxirane-2-carboxamide

[0642] The title compound was obtained as a white solid, 4 g, 68.9%, from N,2- dimethylprop-2-enamide and m-CPBA, following a similar procedure to that described in Example 24, step 2.

[0643] Step 2: Synthesis of3-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4- fluorophenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-hydroxy-N,2-dimethylpropanamide

[0644] The title compound was obtained as an off-white solid from Intermediate 25 and N,2- dimethyloxirane-2-carboxamide, following a similar procedure to that described in Example 2. LCMS: m / z = 587 [M+H]+;1H NMR (400 MHz, DMSO-de) 89.83 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.20 (dd, 2H), 8.06 (s, 1H), 7.88 - 7.82 (m, 3H), 7.38 (d, 1H), 5.79 (s, 1H), 4.51 (tt, 1H), 4.33 (d, 2H), 2.58 (d, 3H), 1.41 (t, 2H), 1.41 - 1.22 (m, 2H), 1.20 (s, 3H).

[0645] Example 77

[0646] (S)-3-(4-((8-((2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)- 1 H-pyrazol- l-yl)-2-methylpropane-1,2-diol

[0647] And Example 78

[0648] (R)-3-(4-((8-((2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diolME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT[006491 Step 1: Synthesis of2-chloro-5-(2-methyl-2H-tetrazol-5-yl)aniline

[0650] The title compound was obtained as a light yellow solid, 330 mg, 62%, from 2- chloro-5-(2H-l,2,3,4-tetrazol-5-yl)aniline and CH3I, following a similar procedure to that described in Example 15. LCMS m / z = 210 [M+H]+

[0651] Step 2: Synthesis of 5-bromo-N-(2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-2,7- naphthyridin-1 -amine

[0652] The title compound was obtained as a solid, 400 mg, 67%, from 2-chloro-5-(2- methyl-2H-l,2,3,4-tetrazol-5-yl)aniline and 5-bromo-l-chloro-2,7-naphthyridine, following a similar procedure to that described in Intermediate 20, step 1. LCMS m / z = 416 [M+H]+

[0653] Step 3: Synthesis of5-((lH-pyrazol-4-yl)ethynyl)-N-(2-chloro-5-(2-methyl-2H- tetrazol-5-yl)phenyl)-2, 7-naphthyridin-l -amine

[0654] The title compound was obtained as a yellow solid, 60 mg, 98.1%, from 5-bromo-N- (2-chloro-5-(2-methy l-2H-tetrazol-5-y l)phenyl)-2,7-naphthyridin- 1 -amine and 4-ethynyl- 1 H- pyrazole, following a similar procedure to that described in Example 23, step 3, except DMF was tire reaction solvent. LCMS: m / z = 428 [M+H]+

[0655] Step 4: Synthesis of(R)-3-(4-((8-((2-chloro-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diol, Example 78.

[0656] The title compound was obtained as a light yellow solid, 10.3 mg, 28.5%, from 5- ((lH-pyrazol-4-yl)ethynyl)-N-(2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-2,7-naphthyridin- 1 -amine and ((2R)-2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 61. LCMS: m / z =516 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.81 (s, 1H), 9.76 (s, 1H), 8.86 (s, 1H), 8.31 (d, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 7.97 - 7.90 (m, 1H), 7.84 (s, 1H), 7.77 (d, 1H), 7.41 (d, 1H), 4.90 - 4.83 (m, 1H), 4.73 (s, 1H), 4.44 (s, 3H), 4.20 - 4.06 (m, 2H), 3.25 - 3.16 (m, 2H), 0.96 (s, 3H).

[0657] Step 5: Synthesis of(S)-3-(4-((8-((2-chloro-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropane-l,2-diol, Example 77.

[0658] The title compound was obtained as a solid, 5.3 mg, 11%, from 5-((lH-pyrazol-4- yl)ethynyl)-N-(2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-2,7-naphthyridin-l-amine and ((2S)-2-methyloxiran-2-yl)methanol, following the procedure described in Example 61. LCMS: m / z =516 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), δ 9.76 (s, 1H), 8.86 (s, 1H),131ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT8.31 (d, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 7.98 - 7.91 (m, 1H), 7.84 (s, 1 H), 7.77 (d, 1H), 7.41 (d, 1H), 4.90 - 4.83 (m, 1H), 4.73 (s, 1H), 4.44 (s, 3H), 4.20 - 4.06 (m, 2H), 3.25 - 3.16 (m, 2H), 0.96 (s, 3H).

[0659] Example 79

[0660] (R)-4-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile or (S)-4-(4- ((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile

[0661] And Example 80[00662J (S)-4-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile or (R)-4-(4- ((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile

[0663] Step 1: Synthesis of4-(4-ethynyl-lH-pyrazol-l-yl)-2,2-dimethyl-3-oxobutanenitrile132ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT100664] The title compound was obtained as a yellow oil, 150 mg, 34.4%, from 4-ethynyl-lH- pyrazole and 4-chloro-2,2-dimethyl-3-oxobutanenitrile, following a similar procedure to that described in Example 43, step 1. LCMS: m / z = 202 [M+H]+;

[0665] Step 2: Synthesis of(3R)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile and(3S)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile

[0666] To a mixture of 4-(4-ethynyl-lH-pyrazol-l-yl)-2,2-dimethyl-3-oxobutanenitrile (150 mg, 745 pmol) in MeOH (5 mL) and THF (5 mL) were added NaBH₄ (56.3 mg, 1.49 mmol) at - 10°C. The mixture was stirred at rt for 2 h. The mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH= 10: 1). The residue was purified by Prep-HPLC (Method A, Gradient (B%): 8% B to 38% B in 7 min). The product was purified by Prep-Chiral-HPLC (Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH: DCM=1:1; Flow rate: 20 mL / min; Gradient (B%): 10% B isocratic to give Peak 1, (3R)-4-(4-ethynyl-lH-pyrazol- l-yl)-3-hydroxy-2,2-dimethylbutanenitrile or (3S)-4-(4-ethynyl-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile (30 mg, 19.8%) as a white solid, and Peak 2, (3S)-4-(4-ethynyl-lH- pyrazol-l-yl)-3-hydroxy-2,2-dimethylbutanenitrile or (3R)-4-(4-ethynyl-lH-pyrazol- l-yl)-3- hydroxy-2,2-dimethylbutanenitrile (30 mg, 19.8%) as a white solid.

[0667] Step 3: Synthesis of(R)-4-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile or (S)-4-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-2,2- dimethylbutanenitrile, Example 79

[0668] The title compound was obtained as an off-white solid, 20.2 mg, 31%, from Intermediate 21, step 1 and Peak 1, from step 2, following a similar procedure to that described in Example 11. LCMS: m / z = 537 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.27 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.88 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 5.96 (d, 1H), 4.45 (s, 4H), 3.25 - 4.00 (m, 1H), 3.92 - 3.68 (m, 1H), 2.27 (s, 3H), 1.35 (d, 6H).

[0669] Step 4: Synthesis of(S)-4-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl )-l H-pyrazol-1 -yl)-3-hydroxy-2,2- dimethylbutanenitrile or (R)-4-( 4-(( 8-((4-fluoro-2-methyl-5-( 2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl )-l H-pyrazol-1 -yl)-3-hydroxy-2, 2- dimethylbutanenitrile, Example 80133ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0670] The title compound was obtained as an off-white solid, 19.5 mg, 30%, from Intermediate 21, step 1 and Peak 2, step 2, following a similar procedure to that described in Example 11. LCMS: m / z = 537 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.27 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.88 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 5.96 (d, 1H), 4.45 (s, 4H), 4.25 - 4.11 (m, 1H), 3.95 - 3.70 (m, 1H), 2.27 (s, 3H), 1.35 (d, 6H).

[0671] Example 82

[0672] (R)-2,3-dimethyl-l-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butane-2,3-diol or (S)-2,3-dimethyl-l-(4-((8-((2- methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol- l-yl)butane-2,3-diolstep 1Step 2

[0673] Step 1: Synthesis of (R)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol or (S)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol

[0674] MeMgBr (1.6 mL, 4.80 mmol, 3 N) was added dropwise to a mixture of Intermediate 6 (200 mg, 960 pmol) in THF (5 mL) at 0 °C and the reaction mixture stirred for 16 h at 25 °C. The reaction was quenched with NH4C1 (10 mL), extracted with EtOAc (20 mLx3), washed with brine (30 mL), concentrated and purified by Prep-TLC (EtOAc), to give the title compound (150 mg, 75.3 %) as a light yellow solid. LCMS m / z = 209 [M+H]+

[0675] Step 2: Synthesis of (R)-2,3-dimethyl-l-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)butane-2,3-diol or (S)-2,3- dimethyl-l-(4-((8-((2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-! H-pyrazol-l-yl)butane-2,3-diol134ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0676] The title compound was obtained as a light yellow solid, 4.3 mg, 6.5%, from Intermediate 22, step 1 and (R)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol or (S)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol, following a similar procedure to that described in Example 30. LCMS: m / z = 209 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.61 (s, lH), 8.84 (s, 1H), 8.19 - 8.13 (m, 2H), 8.08 (d, 1H), 7.89 - 7.81 (m, 2H), 7.49 (d, 1H), 7.32 (d, 1H), 4.50 (d, 2H), 4.42 (s, 3H), 4.29 - 4.23 (m, 2H), 2.27 (s, 3H), 1.17 (d, 6H), 0.83 (s, 3H).

[0677] Example 83

[0678] (R)-l-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol or (S)-l-(4-((8-((4- fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)- lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol[00679J The title compound was obtained as a light yellow solid, 12.5 mg, 9.6%, from Intermediate 21, step 1 and (R)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol or (S)-l-(4-ethynyl-lH-pyrazol-l-yl)-2,3-dimethylbutane-2,3-diol (Example 82, step 1), following a similar procedure to that described in Example 30. LCMS: m / z =542 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.15 (d, 2H), 8.03 (d, 1H), 7.83 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 4.50 (d, 2H), 4.45 (s, 3H), 4.28 - 4.23 (m, 2H), 2.27 (s, 3H), 1.17 (d, 6H), 0.83 (s, 3H).

[0680] Example 84

[0681] 2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-N-methylacetamide135ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0682] Step 1: Synthesis ofN-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-ethynyl-2,7-naphthyridin-l -amine

[0683] N; was bubbled into Intermediate 15 (3 g, 6.81 mmol) in MeCN (90 mL), then ethynyl(trimethyl)silane (1.34 g, 13.63 mmol), Pd(PPh3)4(787 mg, 0.681 mmol), Cui (259.5 mg, 1.36 mmol) and TEA (2.07 g, 20.44 mmol) were added sequentially. The reaction was degassed under vacuum, purged with N2, then heated to 80 °C under N2 for 16 h. The reaction mixture was filtered and the filter cake was washed with 2-MeTHF (50 mLx 4). The filtrate was washed with brine (200 mL), then dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by column chromatography (silica gel, EtOAc / DCM = 0 ~ 50%) to give the title compound (3.47 g, 93.6%) as yellow solid. LCMS: m / z = 458 [M+H]+.

[0684] Step 2: Synthesis of2-(4-((8-((5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2- methylphenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-N-methylacetamide

[0685] Cs₂CO₃ (97.8 mg, 0.30 mmol) and Pd(PtBu3)2 (5.11 mg, 0.01 mmol) were added to a solution of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fhioro-2-methylphenyl)-5-ethynyl-2,7- naphthyridin-l-amine (38.5 mg, 0.10 mmol) and 2-(4-bromo-lH-pyrazol-l-yl)-N- methylacetamide (32.55 mg, 0.15 mmol) in dioxane (2 mL) and the reaction mixture was shaken at 90°C for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (4.36 mg, 8.35%). LCMS m / z = 523 [M+H]+.

[0686] Example 85

[0687] (R)-l-(4-((8-((4-fhioro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)propan-2-ol or (S)-l-(4-((8- ((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)propan-2-ol

[0688] And Example 86

[0689] (S)-l-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)propan-2-ol or (R)-l-(4-((8- 136ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- y l)ethyny 1)- 1 H-pyrazol- l-yl)-3-(2-methoxyethoxy)propan-2-ol

[0690] l-(4-((8-((4-Fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(2-methoxyethoxy)propan-2-ol was obtainedfrom Intermediate 21 and 2-((2-methoxyethoxy)methyl)oxirane following a similar procedure to that described in Example 61. The product was further purified by Prep-Chiral-HPLC: Column:CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile PhaseB: MeOH: DCM=10: 1; Flow rate: 20 mL / min; Gradient: isocratic 50% to give Peak 1,Example 85 (21.4 mg, 42.8%) as a light yellow solid and Peak 2, Example 86 (21.1 mg, 42.2%) as a light yellow solid.

[0691] Example 85: LCMS: m / z =558 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.74 (s,1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.21 - 8.12 (m, 2H), 8.02 (d, 1H), 7.85 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 5.22 (d, 1H), 4.45 (s, 3H), 4.28 - 4.20 (m, 1H), 4.12 - 4.03 (m, 1H), 4.01 - 3.93 (m, 1H), 3.59 - 3.52 (m, 2H), 3.50 - 3.43 (m, 2H), 3.39 - 3.34 (m, 2H), 3.27 (s, 3H), 2.26 (s, 3H).

[0692] Example 86. LCMS: m / z =558 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.75 (s,1H), 9.63 (s, 1H), 8.83 (s, 1H), 8.21 - 8.12 (m, 2H), 8.03 (d, 1H), 7.85 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 5.22 (d, 1H), 4.45 (s, 3H), 4.26 - 4.20 (m, 1H), 4.12 - 4.03 (m, 1H), 4.01 - 3.93 (m, 1H), 3.58 - 3.51 (m, 2H), 3.50 - 3.43 (m, 2H), 3.42 - 3.33 (m, 2H), 3.27 (s, 3H), 2.27 (s, 3H).

[0693] Example 87

[0694] (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-methoxypropyl)-3- methyl- lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrileME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0695] A mixture of Intermediate 24 (100 mg, 211 pmol) (2S)-2-(methoxymethyl)oxirane (22.2 mg, 253 pmol) and Cs₂CO₃ (137 mg, 422 pmol ) in DMF (1 mL) was stirred for 16 h at 25 °C. The mixture was poured into H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (20 mL), concentrated and purified by Prep-TLC (DCM: MeOH=10:l). The residue was purified by Prep-HPLC (Column: XBridge Prep RP18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 30 mL / min; Gradient: 32% B to 53% B in 8 min). The product was further purified by Prep-Chiral-HPLC (Method 1, Gradient: isocratic 50%B) to give Peak 1, the title compound (16.7 mg, 41.8%) as a light yellow solid and Peak 2, (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((2-(l-hydroxy-3-methoxypropyl)-5- methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile (7.4 mg, 18.5%) as a light yellow solid. LCMS: m / z =561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 9.73 (d, 2H), 8.87 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.45 (d, 1H), 5.17 (s, 1H), 4.59 - 4.49 (m, 1H), 4.19 - 4.09 (m, 1H), 4.03 - 3.94 (m, 2H), 3.29 (s, 5H), 2.34 (s, 6H), 1.47 - 1.35 (m, 2H), 1.38 - 1.26 (m, 2H).

[0696] Example 88

[0697] l-(4-((8-((4-fhioro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methyl-3-((2,2,2-trifluoroethyl)amino)propan-2- ol

[0698] The title compound was obtained as an off-white solid, 9.3 mg, 16%, from Example 95, step 1 and 2,2,2-trifluoroethan-l-amine, following a similar procedure to that described in Example 25, step 2. LCMS: m / z = 595 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.59 (s, 1H), 8.82 (s, 1H), 8.17 - 8.09 (m, 2H), 8.02 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.82 (s, 1H), 4.44 (s, 3H), 4.14 (d, 2H), 3.36 - 3.31 (m, 1H), 2.54 (d, 3H), 2.38 - 2.32 (m, 1H), 2.27 (s, 3H), 1.03 (s, 3H).

[0699] Example 89

[0700] (R)-4-((5-((l-(3-cyano-2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)ethynyl)-2,7- naphthyridin-l-yl)amino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile or (S)-4-((5-138ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT((l-(3-cyano-2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l- yl)amino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0701] The title compound was obtained as a yellow solid, 63.5 mg, 51%, from Intermediate 18 and Intermediate 4A, following a similar procedure to that described in Example 30. LCMS: m / z = 556 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.70 (s, 1H), 8.87 (s, 1H), 8.37 (s, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48 (d, 1H), 5.59 (s, 1H), 4.54 (tt, 1H), 4.20 (s, 2H), 2.72 (d, 2H), 2.35 (s, 3H), 1.47 - 1.35 (m, 2H), 1.38 - 1.26 (m, 2H), 1.19 (s, 3H).

[0702] Example 90

[0703] (S)-4-((5-((l-(3-cyano-2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)ethynyl)-2,7- naphthyridin-l-yl)amino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile or (R)-4-((5- (( l-(3-cyano-2-hydroxy-2-methylpropyl)- 1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin- 1 - yl)ainino)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0704] The title compound was obtained as a yellow solid, 74.8 mg, 60%, from Intermediate 18 and Intermediate 4B, following a similar- procedure to that described in Example 30. LCMS: m / z = 556 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.37 (s, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48 (d, 1H), 5.59 (s, 1H), 4.54 (tt, 1H), 4.20 (s, 2H), 2.72 (d, 2H), 2.35 (s, 3H), 1.42 (dd, 2H), 1.38 - 1.26 (m, 2H), 1.20 (s, 3H).

[0705] Example 91

[0706] (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-lH- pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile139ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0707] A mixture of Example 66, step 1 (100 mg, 218 pmol), Cs₂CO₃ (142 mg, 436 pmol) and ((2R)-2-methyloxiran-2-yl)methanol (22.9 mg, 261 pmol) in DMF (10 mL) was stirred atrt for 16 h under N2. The reaction mixture was diluted with EtOAc (120 L) and washed with water (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC: Column: Xselect CSH C18 OBD Column 19*250mm 5|.un; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeOH; Flow rate: 30 mL / min; Gradient:60% B to 82% B in 7 min to give the title compound (32.1 mg) as a yellow solid. LCMS: m / z = 547 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.70 (s, 1H), 8.87 (s, 1H), 8.38 (s, 1H), 8.27 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.48 (d, 1H), 4.85 (t, 1H), 4.72 (s, 1H), 4.54 (tt, 1H), 4.20 - 4.07 (m, 2H), 3.21 (dt, 2H), 2.35 (s, 3H), 1.47 - 1.35 (m, 2H), 1.39 - 1.26 (m, 2H), 0.97 (s, 3H).

[0708] Example 92

[0709] (S)-4-(4-((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-hydroxy-3-methylbutanenitrile or (R)-4-(4- ((8-((2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)amino)-2,7-naphthyridin-4- y l)ethyny 1)- 1 H-pyrazol- l-yl)-3-hydroxy-3-methylbutanenitrile

[0710] The title compound was obtained as a yellow solid, 9.7 mg, 7.9%, from Intermediate 16 and Intermediate 4B, following a similar procedure to that described in Example 11. LCMS: m / z = 569 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.75 (s, 1H), 8.86 (s, 1H), 8.22 (d, 1H), 8.20 - 8.15 (m, 2H), 7.89 (s, 1H), 7.85 (d, 1H), 7.39 (d, 1H), 5.60 (s, 1H), 4.51 (tt, 1H), 4.19 (s, 2H), 2.72 (d, 1H), 2.64 (d, 1H), 1.46 - 1.37 (m, 2H), 1.30 (td, 2H), 1.19 (s, 3H).

[0711] Example 93140ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT[007121 (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-(2- methoxyethoxy)propyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile or (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-(2- methoxyethoxy)propyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile

[0713] 2-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-(2- methoxyethoxy)propyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile was obtained as a yellow solid, 30 mg, 23.4%, from Example 66, step 1 and 2-((2-methoxyethoxy)methyl)oxirane, following a similar procedure to that described in Example 91. This compound was purified by Prep-Chiral-HPLC: Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH:DCM=1: 1; Flow rate: 20 mL / min; Gradient: 50% B isocratic to give Peak 1, (10.1 mg, 33.7%) as an off-white solid and Peak 2, the title compound (10.8 mg, 36.1%) as an off white solid. LCMS: m / z =591 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.71 (s, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 8.26 (d, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.48 (d, 1H), 5.21 (d, 1H), 4.59 - 4.49 (m, 1H), 4.29 - 4.19 (m, 1H), 4.13 - 4.04 (m, 1H), 4.01 - 3.94 (m, 1H), 3.59 - 3.52 (m, 2H), 3.49 - 3.43 (m, 2H), 3.39 - 3.33 (m, 2H), 3.27 (s, 3H), 2.34 (s, 3H), 1.47 - 1.39 (m, 2H), 1.39 - 1.26 (m, 2H).

[0714] Example 95

[0715] (S)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-inethylpropan-2-ol or (R)- l-(dimetlrylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)- 2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-olME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0716] Step 1: Synthesis ofN-(4-fluoro-2-niethyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-5-((l- (2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine

[0717] The title compound was obtained as a yellow oil, 100 mg, 43%, from Intermediate 21 and 2-(chloromethyl)-2-methyloxirane, following a similar procedure to that described inExample 36, step 1. LCMS m / z = 496 [M+H]+

[0718] Step 2: Synthesis of(S)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl- 2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol or(R)-l-( dimethylamino)-3-(4-(( 8-( (4-fluoro-2-methyl-5-( 2-methyl-2H- tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2- ol

[0719] A mixture of N-(4-fhioro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-5-((l-((2- methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-amine (100 mg, 201 pmol), dimethylamine (10.8 mg, 241 pmol) and DIEA (25.9 mg, 201 pmol) in EtOH (10 mL) was heated at 60°C for 3 h. The mixture was filtered and purified by Prep-HPLC (Method A, Gradient: 28% B to 49% B in 7 min). The product was further purified by Prep-Chiral-HPLC (Method 2, Gradient: isocratic 50%B), to give Peak 1, the title compound, (15.5 mg, 14.1%) as an off-white solid and Peak 2, (15.4 mg, 14.0%) as a light yellow solid.

[0720] LCMS: m / z = 541 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.61 (s,1H), 8.83 (s, 1H), 8.15 (d, 2H), 8.02 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.71 (s,1H), 4.45 (s, 3H),4.15 (d, 2H), 2.33-2.27 (m, 11H), 1.00 (s, 3H).

[0721] Example 96

[0722] (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-methoxypropyl)-3- methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile142ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT? v°

[0723] A mixture of (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3- methoxypropyl)-3-methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile and (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3- methoxypropyl)-5 -methyl -1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile was obtained, from Intermediate 24 and (2R)-2-(methoxymethyl)oxirane, following a similar procedure to that described in Example 2. This mixture was purified by prep- Chiral-HPLC: (Method 1, Gradient: 50% B isocratic) to give Peak 1, the title compound, 33.3 mg, and Peak 2, (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-3-methoxypropyl)- 5-methyl- 1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin- l-yl)amino)-5-methylbenzonitrile (19.0 mg) as an orange solid. LCMS: m / z = 561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, 2H), 8.87 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.45 (d, 1H), 5.21 - 5.15 (m, 1H), 4.54 (tt, 1H), 4.13 (t, 1H), 4.03 - 3.93 (m, 2H), 3.29 (s, 5H), 2.34 (s, 6H), 1.42 (q, 2H), 1.39 - 1.26 (m, 2H).

[0724] Example 97

[0725] (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-3- methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile

[0726] And Example 98

[0727] (R)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-5- inethyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrileHO143ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0728] A mixture of the title compounds, Example 97 and 98, was obtained, 129.7 mg, 91%, as a solid, from Intermediate 24 and ((2S)-2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 2. The mixture was purified by prep-Chiral-HPLC (Method 2, Gradient: isocratic 45%B) to give Peak 1, Example 98, (31.8 mg) as a yellow solid and Peak 2, Example 97, (30.0 mg) as an orange solid.

[0729] Example 97, LCMS: m / z = 561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, 2H), 8.88 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.46 (d, 1H), 4.80 (t, 1H), 4.66 (s, 1H), 4.54 (tt, 1H), 4.14 -4.01 (m, 2H), 3.31 (s, lH), 3.16 (m, 1H), 2.47 (s, 3H), 2.34 (s, 3H), 2.08 (s, 1H), 1.42 (q, 2H), 1.39 - 1.26 (m, 2H), 1.05 (s, 3H).

[0730] Example 98, LCMS: m / z = 561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, 2H), 8.87 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 8.01 (d, 2H), 7.46 (d, 1H), 4.83 (t, 1H), 4.69 (s, 1H), 4.54 (tt, 1H), 4.11 - 3.98 (m, 2H), 3.21 (h, 2H), 2.34 (s, 6H), 1.42 (q, 2H), 1.39 - 1.26 (m, 2H), 0.97 (s, 3H).

[0731] Example 99

[0732] (S)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-3-methyl- 1 H-pyrazol-1-yl)-2-methylpropane-1,2-diol

[0733] And Example 100

[0734] (S)-3-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-5-inethyl- 1 H-pyrazol-1-yl)-2-methylpropane-1,2-diol

[0735] A mixture of the title compounds of Example 99 and 100 was obtained as a yellow oil, 200 mg, 37.9%, from Intermediate 24 and ((2R)-2-methyloxiran-2-yl)methanol, following a similar procedure to that described in Example 17, step 1. The mixture was purified by prep Chiral HPLC (Column: CHIRALPAK IG 3; Mobile Phase A: Hex (0.2% DEA): (EtOH:144ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTDCM=l:l)=50:50; Flow rate: 1 mL / min; Gradient: isocratic, to afford Peak 1, Example 100, as a yellow solid and Peak 2, Example 99 (59.9 mg) as a yellow solid.

[0736] Example 100: LCMS: m / z = 528 [M+H]+1H NMR (400 MHz, DMSO-d6) 59.74 (s,1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.02 (d, 2H), 7.43 (d, 1H), 7.29 (d, 1H), 4.83 (s,1H), 4.69 (s, 1H), 4.45 (s, 3H), 4.11 - 3.98 (m, 2H), 3.27 - 3.16 (m, 2H), 2.34 (s, 3H), 2.26 (s,3H), 0.97 (s, 3H).

[0737] Example 99: LCMS: m / z = 528 [M+H]+1H NMR (400 MHz, DMSO-d6) 89.74 (s,1H), 9.65 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.03 (d, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.30 (d,1H), 4.72 (d, 2H), 4.45 (s, 3H), 4.15 - 3.93 (m, 2H), 3.31 - 3.11 (m, 2H), 2.52 (s, OH), 2.51 (s, 3H), 2.27 (s, 3H), 1.05 (s, 3H).

[0738] Example 101

[0739] (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-3- methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile

[0740] And Example 102

[0741] (S)-2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2,3-dihydroxy-2-methylpropyl)-5- methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5-methylbenzonitrile

[0742] A mixture of the title compounds of Example 101 and 102 was obtained as an off- white solid, 131.1 mg, from Intermediate 24 and (R)-(2-methyloxiran-2-yl)methanol, following a similar procedure to drat described in Example 61. This was purified by Prep-Chiral-HPLC(Method 2, Gradient: isocratic 45%B); to give Peak 1, Example 101, 21.6 mg, as a yellow solid and Peak 2, Example 102, (24.7 mg) as a yellow solid.

[0743] Example 101, LCMS: m / z = 561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (d,2H), 8.88 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 8.01 (d, 1H), 7.99 (s, 1H), 7.46 (d, 1H), 4.84 (t, 1H), 4.70 (s, 1H), 4.54 (tt, 1H), 4.11 - 3.98 (m, 2H), 3.21 (t, 2H), 2.34 (s, 6H), 1.42 (s, 2H), 1.32 (dd, 2H), 1.23 (s, 1H), 1.17 (d 1H), 0.97 (s, 3H).

[0744] Example 102, LCMS: m / z = 561 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (d,2H), 8.88 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.46 (d, 1H), 4.80 (s, 1H),145ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT4.66 (s, 1H), 4.54 (tt, 1H), 4.14 - 4.01 (m, 2H), 3.27 (d, 1H), 3.20 (d, 1H), 2.53 (s, 3H), 2.34 (s, 3H), 1.42 (q, 2H), 1.31 (td, 2H), 1.23 (s, 1H), 1.17 (d, 1H), 1.05 (s, 3H).

[0745] Example 103

[0746] (R)-l-(4-((8-((4-fhioro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-5-inethyl- 1 H-pyrazol- 1 -yl)-3-methoxypropan-2-ol

[0747] And Example 104

[0748] (R)-l-(4-((8-((4-fluoro-2-metliyl-5-(2-metliyl-2H-tetazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-3-methyl- 1 H-pyrazol- 1 -yl)-3-inethoxypropan-2-ol— o

[0749] A mixture of the title compounds of Example 103 and 104 was obtained from Intermediate 26 and (R)-2-(methoxymethyl)oxirane following a similar procedure to that described in Example 14. The product was further purified by Prep-Chiral-HPLC: Column:CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH: DCM=1:1; Flow rate: 20 mL / min; Gradient:30% B in 29 min, to give Peak 1, Example 104 (10 mg, 10%) as a yellow solid and Peak 2, Example 103, (10.4 mg, 11%) as a yellow solid.

[0750] Example 104: LCMS: m / z = 528 [M+H]+;XH NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.65 (s, 1H), 8.83 (s, 1H), 8.15 (d, 1H), 8.05 (s, 1H), 8.02 (d, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 5.19 (s, 1H), 4.14 (q, 1H), 4.02 - 3.94 (m, 2H), 3.34 (s, 5H), 2.34 (s, 3H), 2.26 (s, 3H).

[0751] Example 103: LCMS: m / z = 528 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.68 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 5.19 (s, 1H), 4.45 (s, 3H), 4.14 (m, 1H), 4.01 (m, 2H), 3.36-3.31 (m, 5H), 2.47 (s, 3H), 2.27 (s, 3H).

[0752] Example 105

[0753] (S)-l-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-5-inethyl-lH-pyrazol-l-yl)-3-methoxypropan-2-ol

[0754] And Example 106146ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0755] (S)-l-(4-((8-((4-fluoro-2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphth yridin-4-yl)ethynyl)-3-methyl- 1 H-pyrazol- 1 -yl)-3-inethoxypropan-2-ol

[0756] To a stirred solution of Intermediate 26 (120 mg, 273 pmol) in DMF (2 mL) were added (S)-2-(methoxymethyl)oxirane (28.8 mg, 327 pmol) and Cs₂CO₃ (88.9 mg, 273 pmol) and the reaction was stirred for 2 h at 100°C. The resulting mixture was filtered and the filtrate was purified by prep-HPLC (Method B, Gradient: 20% B to 30% B in 10 min) and Prep-Chiral- HPLC (Method 3, Gradient: isocratic 40%B) to give Peak 1, Example 106 (27.7 mg, 19%) as a yellow solid and Peak 2, Example 105, (23.1 mg, 16%) as a yellow solid.

[0757] Example 106: LCMS: m / z = 528 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.75 (s,1H), 9.67 (s, 1H), 8.83 (s, 1H), 8.15 (d, 1H), 8.08 - 8.00 (m, 2H), 7.43 (d, 1H), 7.29 (d, 1H), 5.19 (s, 1H), 4.45 (s, 3H), 4.13 (t, 1H), 3.98 (d, 2H), 3.29 (s, 5H), 2.34 (s, 3H), 2.27 (s, 3H).

[0758] Example 105: LCMS: m / z = 528 [M+H]+; 1H NMR (400 MHz, DMSO-de) 59.75 (s,1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.29 (d,1H), 5.18 (d, 1H), 4.45 (s, 3H), 4.18 - 4.00 (m, 3H), 3.98 (m, 4H), 2.47 (s, 3H), 2.26 (s, 3H).

[0759] Example 107

[0760] (R)-l-(4-((8-((2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2-methylpropan-2-ol or (S)-l- (4-((8-((2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4- yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2-methylpropan-2-olME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT[007611 Step 1: Synthesis ofN-(2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-5-((l- ((2-methyloxiran-2-yl)methyl)-lH-pyraz.ol-4-yl)ethynyl)-2,7-naphthyridin-l-amine

[0762] The title compound was obtained as a yellow oil, 110 mg, 63.5%, from Intermediate 23 and 2-(chloromethyl)-2-methyloxirane, following a similar procedure to that described in Example 36, step 1. LCMS: m / z = 446 [M+H]+

[0763] Step 2: Synthesis of(R)-l-(4-((8-((2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2- methylpropan-2-ol or (S)-l-(4-((8-((2-chloro-4-fluoro-5-(2-methyl-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2- methylpropan-2-ol

[0764] A mixture of the title compounds was obtained from N-(2-chloro-4-fluoro-5-(2- methyl-2H-tetrazol-5-yl)phenyl)-5-((l-((2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)- 2,7-naphthyridin-l-amine and Me2NH in THF, following a similar procedure to that described in Example 25, step 2. The mixture was purified by Prep-Chiral-HPLC (Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.2% DEA), Mobile Phase B: EtOH: DCM=1:1; Flow rate: 20 mL / min; Gradient: isocratic 40, to give Peak 1, the title compound (15.7 mg, 14.3%) as a light yellow solid and Peak 2 (15.7 mg, 14.3%) as a light yellow solid. LCMS: m / z - 561 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.75 (s, 1H), 8.85 (s, 1H), 8.25 (d, 1H), 8.18 (t, 2H), 7.86 (d, 2H), 7.39 (d, 1H), 4.66 (d, 1H), 4.47 (s, 3H), 4.16 (s, 2H), 2.80 (d, 1H), 2.27 (s, 7H), 1.00 (s, 3H).

[0765] Example 108

[0766] 2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-2-methylpropyl)-3-methyl- 1 H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin- 1 -yl)amino)-5-methylbenzonitrile

[0767] A mixture of the title compound and 2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2- hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile was obtained, 60 mg, 34.7%, from Intermediate 24 and 2,2-dimethyloxirane, following a similar procedure to that described in Intermediate 2. This was purified by prep chiral HPLC (Method 1, Gradient: isocratic 50%B) to afford Peak 1, Example 108, 20.0 mg as a148ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTyellow solid and Peak 2, 2-(2-cyclopropyl-2H-tetrazol-5-yl)-4-((5-((l-(2-hydroxy-2- methylpropyl)-5-methyl-lH-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-l-yl)amino)-5- methylbenzonitrile, 7.5 mg as a yellow solid. LCMS: m / z = 545 [M+H]+1H NMR (400 MHz, DMSO-de) 59.73 (d, 2H), 8.87 (s, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.46 (d, 1 H), 4.74 (s, 1 H), 4.54 (tt, 1 H), 3.98 (s, 2H), 2.34 (s, 6H), 1.42 (d, 2H), 1.35 - 1.19 (m, 2H),1.09 (s, 6H).

[0768] Example 109

[0769] l-(4-((8-((4-fhioro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol

[0770] The title compound was obtained, 25.3 mg, 21%, from Intermediate 2 andIntermediate 17, following a similar procedure to that described in Example 30. LCMS: m / z =501 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.18 - 8.12 (m, 2H), 8.03 (d, 1H), 7.83 (s, 1H), 7.43 (d, 1H), 7.35 - 7.29 (m, 1H), 4.78 (s, 1H), 4.07 (s, 2H), 2.27 (s, 3H), 1.09 (s, 6H).

[0771] Example 110

[0772] l-(4-((8-((2-chloro-4-fluoro-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)amino)-2,7- naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2-methylpropan-2-ol149ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0773] Step 1: Synthesis of5-(4-chloro-2-fluoro-5-nitrophenyl)-2-(methyl-d3)-2H-tetrazole

[0774] Cs₂CO₃ (4.00 g, 12.3 mmol) was added to Intermediate 8 (2 g, 8.21 mmol) and iodo(2H3)methane (2.37 g, 16.4 mmol) in DMF (40 mL) and tire resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into H2O (200 mL), the precipitated solid filtered off and dried in vacuo to afford the title compound (1 g, 46.9 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.15 (d, 1H).

[0775] Steps 2 and 3: Synthesis of5-bromo-N-(2-chloro-4-fluoro-5-(2-(methyl-d3)-2H- tetrazol-5-yl)phenyl)-2, 7-naphthyridin-l -amine

[0776] The title compound was obtained as a yellow solid, from 5-(4-chloro-2-fluoro-5- nitrophenyl)-2-(methyl-d3)-2H-tetrazole and 5-bromo-l-chloro-2,7-naphthyridine, following a similar 2 step procedure to that described in Intermediate 17, steps 2 and 3. LCMS m / z = 437 [M+H]+

[0777] Step 4: Synthesis of5-( (lH-pyrazol-4-yl)ethynyl)-N-(2-chloro-4-fluoro-5-(2-(methyl- d3)-2H-tetrazol-5-yl)phenyl)-2, 7-naphthyridin-l -amine

[0778] A mixture of Cui (26.0 mg, 137 pmol), Pd(PPh3)4(79.1 mg, 68.5 pmol), TEA (137 mg, 1.36 mmol), 5-bromo-N-(2-chloro-4-fluoro-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)-2,7- naphthyri din- 1 -amine (300 mg, 685 pmol) and 4-ethynyl-lH-pyrazole (93.9 mg, 1.02 mmol) in MeCN (15 inL) was heated at 80°C for 16 h. The reaction mixture was poured into H2O (100 mL), the resulting solid filtered off and recrystallized from DCM, to afford the title compound (280 mg, 91.2 %) as a yellow solid. LCMS m / z = 449 [M+H]+

[0779] Step 5: Synthesis ofN-(2-chloro-4-fluoro-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)- 5-((l-((2-methyloxiran-2-yl)methyI)-lH-pyrazol-4-yl)ethynyl)-2, 7-naphthyridin-l -amine150ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0780] The title compound was obtained as a yellow solid, 128 mg, 39.6%, from 5-((lH- pyrazol-4-yl)ethynyl)-N-(2-chloro-4-fluoro-5-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)-2,7- naphthyridin-l-amine and 2-(chloromethyl)-2-methyloxirane, following a similar procedure to that described in Example 36, step 1. LCMS m / z = 519 [M+H]+

[0781] Step 6: Synthesis of 1-(4-((8-((2-chloro-4-fluoro-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-3-(dimethylamino)-2- methylpropan-2-ol

[0782] DIEA (37.1 mg, 288 pmol) was added to N-(2-chloro-4-fluoro-5-(2-(methyl-d3)-2H- tetrazol-5-yl)phenyl)-5-((l-((2-methyloxiran-2-yl)methyl)-lH-pyrazol-4-yl)ethynyl)-2,7- naphthyri din- 1 -amine (100 mg, 192 pmol) and dimethylamine (2 M in THF, 17.3 mg, 384 pmol) in EtOH (10 mL) at rt. The resulting mixture was heated at 80°C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The crude product was purified by prep-TLC with DCM: MeOH= 20: 1. The residue was purified by Prep-HPLC (Method A, Gradient: 32% B to 52% B in 7 min), to afford the title compound (37.8 mg, 35%) as a white solid. LCMS: m / z = 564 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.83 (s, 1H), 9.75 (s, 1H), 8.85 (s, 1H), 8.25 (d, 1H), 8.22 - 8.19 (m, 1H), 8.17 - 8.14 (m, 1H), 7.90 - 7.87 (m, 1H), 7.85- 7.40 (m, 1H), 7.39 (d, 1H), 4.69 (s, 1H), 4.15 (d, 2H), 2.27 (s, 6H), 2.22 (d, 2H), 0.99 (s, 3H).

[0783] Example 111

[0784] (S)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol or (R)- l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0785] And Example 112

[0786] (R)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol or (S)- l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl-d3)-2H-tetrazol-5- yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol151ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT

[0787] Step 1: Synthesis of4-ethynyl-l-((2-methyloxiran-2-yl)methyl)-lH-pyrazole

[0788] The title compound was obtained as a solid, 220 mg, 35.8%, from 4-ethynyl-1H- pyrazole and 2-(chloromethyl)-2-methyloxirane, following a similar procedure to that described in Intermediate 2. LCMS m / z = 163 [M+H]+

[0789] Step 2: Synthesis of 1 -( dimethylamino)-3-(4-ethynyl-lH-pyrazol-l -yl)-2- methylpropan-2-ol

[0790] A mixture of 4-ethynyl-1-((2-methyloxiran-2-yl)methyl)-1H-pyrazole (220 mg, 1.36 mmol), dimethylamine (62 mg, 1.36 mmol) and Cs₂CO₃ (656 mg, 2 mmol) in MeOH (10 mL) was stirred at 75 °C for 12 h. The mixture was filtered, the filtrate extracted with EtOAc (3x10 mL) and the combined organic extracts concentrated in vacuo. The residue was purified by silica gel column with DCM / MeOH (20 / 1) to give the title compound (160 mg, 56.9%) as an off-white solid. LCMS m / z = 208 [M+H]+

[0791] Step 3: Synthesis of(S)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl- d3)-2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol and (R)-l-(dimethylamino)-3-(4-((8-((4-fluoro-2-methyl-5-(2-(methyl-d3)- 2H-tetrazol-5-yl)phenyl)amino)-2,7-naphthyridin-4-yl)ethynyl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol

[0792] A mixture of l-(dimethylamino)-3-(4-ethynyl-lH-pyrazol-l-yl)-2-methylpropan-2-ol (160 mg, 0.77 mmol), Intermediate 17 (321 mg, 0.77 mmol), Pd(PPh₃)₄ (89 mg, 0.08 mmol), Cui (15 mg, 0.08 mmol) in TEA / DMF (1:4,10 mL) was stirred for 2 h at 100°C under N2. The mixture was diluted with EtOAc (15 mL) and water (15 mL). The water phase was extracted with EtOAc (3 x 5 mL) and the combined organic phase was washed with brine. The organic layer was dried with anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by Chiral-HPLC (Column: CHIRALPAK IE-3 4.6*50mm, 3.0um; Mobile Phase A: Hex (0.2% DEA): (MeOH: DCM=1: 1) = 50: 50; Flow rate: 1.0 mL / min; Gradient (B%): isocratic; to give152ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTPeak 1, Example 112, 28.8 mg (19.3%), as an off-white solid and Peak 2, Example 111, 26.9 mg (18.0%) as an light yellow solid.

[0793] Example 112: LCMS: m / z = 544 [M+H]+. 1H NMR (400 MHz, DMSO-de) 59.74 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.15 (d, 2H), 8.02 (d, 1H), 7.84 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 4.67 (s, 1H), 4.15 (d, 2H), 2.32-2.22 (m, 11H), 0.99 (s, 3H).

[0794] Example 111: LCMS: m / z = 544 [M+H]+. 1H NMR (400 MHz, DMSO-de) 59.75 (s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.18 - 8.12 (m, 2H), 8.02 (d, 1H), 7.85 (s, 1H), 7.43 (d, 1H), 7.31 (dd, 1H), 4.69 (s, 1H), 4.16 (d, 2H), 2.32-2.22 (m, 11H), 1.01 (s, 3H).

[0795] Example 113: Compounds of the Disclosure Inhibit Wild Type c-Kit in a cellular Phospho c-Kit Inhibition Assay

[0796] The ability of compounds of the disclosure (described herein as test compounds) to inhibit autophosphorylation of wild type c-kit was measures using a PathScan phospho c-kit (Tyr719) sandwich ELISA (CST#7298).

[0797] For the PathScan phospho c-kit (Tyr719) sandwich ELISA: M-07e cells were resuspended at 2 x 106cells / mL in phenol red free, serum-free, GM-CSF-free Iscove's Modified Dulbecco's Medium (IMDM) media with 1% Penicillin-Streptomycin. The cells were then dispensed into the wells of a U-bottom, 96-well plate at 50 uL per well using a multichannel pipet. The plate was allowed to incubate at 37°C in a humidified tissue culture incubator for 4 hours.

[0798] After 4 hours of incubation, each well was dosed with 6.25 uL of test compound at a final DMSO concentration of 0.25% for 60 min at 37°C to generate an 8-point dose concentration series of test compounds in duplicate. Cells were then incubated for 1 hour at 37°C in a humidified tissue culture incubator. Next, human SCF at 500 ng / mL was added to the appropriate wells at 6.25 uL / well and tire plate was shaken at 450 rpm at room temperature for 10 minutes. AlphaLISA 5X Lysis Buffer supplemented with IX protease and phosphatase inhibitor was then added at 16 uL / well. The plate was sealed with an adherent cover and shaken at 4°C at 600 rpm for 30 minutes. After this period of lysis, the plate was stored at -80°C.

[0799] When tire 96-well plate containing M07e lysates was ready to be processed, tire plate was brought to room temperature and 40 pl from each well was transferred to tire wells of a PathScan Phospho-c-Kit (Tyr719) Sandwich ELISA plate (CST, Catalog #7298). The ELISA plate was sealed with an adherent cover and incubated for 2 hours at 37°C. Next, the wells were washed 4 times with tire provided IX Wash Buffer, and 100 uL / well of reconstituted Detection Antibody was added to each well, the plate sealed with an adherent cover, and incubated at 37°C153ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTfor 1 hour. The wash procedure was repeated and 100 uL / well of reconstituted HRP-Linked secondary antibody was added. The plate was sealed with an adherent cover and incubated at 37°C for 1 hour. The wash procedure was repeated and 100 uL / well of TMB Substrate was added. The plate was incubated for 10 minutes at room temperature or until the positive reaction elicited a blue color in the appropriate wells. 100 uL / well of STOP solution was added and shaken gently for a few seconds a microplate reader or conventional spectrophotometer e.g., a Perkin Elmer Envision multimode plate reader, part #2105-0010.

[0800] The raw data was normalized using the values derived with 10 pM staurosporine as 100% inhibition of c-kit phosphorylation and DMSO as 0% inhibition of c-kit phosphorylation. An IC50 was calculated using a 4-parameter logistic nonlinear regression.

[0801] Table 2 shows the activity of the exemplified compounds in tire pKIT assay according to the ELISA assay described herein.

[0802] Some compounds of the disclosure are substrates of the human P-glycoprotein (P-gp).The potential for compounds prepared according to the examples to be substrates of P-gp was evaluated using in vitro on Multidrug Resistance Mutation 1-Mardin-Darby Canine Kidney (MDCK-MDR1)) (Mardin-Darby Canine Kidney) cell monolayers overexpressing P-gp grown on permeable supports. A higher efflux ratio of P-gp means drat the compound is pushed out of the brain tissue by the transporter.

[0803] Preparation for cell seeding: MDCK-MDR1 cell culture medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) with high glucose and L-glutamine supplemented with: 10% FBS, 0.1 mg / mL of streptomycin, 0.6 pg / mL of Kanamycin sulfate and 100 units of penicillin was prepared. 50 pL of culture medium was added to each well of the Transwell insert. The Transwell insert was removed from the reservoir and 25 mL of culture medium was added. After incubation at 37 °C, 5% CO2 for 1 hour, the plates were ready for cell seeding. The cells were cultivated in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity until they reached 80-90% confluence before detaching and splitting. The cultivated cells were rinsed in T-75 flasks with 5 mL PBS and aspirated off, and then 1.5 mL trypsin / EDTA was added and incubated at 37 °C for approximately 5 to 10 minutes or until the cells detach and float. The trypsin / EDTA was inactivated by adding excess serum containing medium. The cell suspension was transferred to a conical tube and the cells pelleted by centrifugation at 120 x g for 10 minutes. The cells were resuspended in seeding medium at a density of 1.56xl06cells / mL. This cell concentration was used to seed 5.45xl05cells / cm2.

[0804] Seeding and feeding of MDCK-MDR1 cells into transwell plates: 50 pL of the above cell suspension was added to each well of a previously prepared Transwell plate and the plate 154ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTwas incubated for 4-8 days, replacing the medium every other day beginning no sooner than 48 hours after initial plating. The medium must be replaced on the day before conducting the experiment, and the procedure for medium changes was carried out as follows. The plate was removed from the incubator and placed in a hood. The medium was aspirated from a reservoir and each Transwell was inserted. 100 pL of culture medium was added to each well of the Transwell inserts and 25 mL of culture medium to reservoir tray. The plate was returned to the incubator.[00805 J Assessment of cell monolayer integrity: When tire 4-day cultured MDCK-MDR1 cells reached confluence and were differentiated, the medium was removed from the reservoir and Transwell inserts. 100 pL of prewarmed culture medium was added to each transwell insert and 25 mL was added to the reservoir tray. The electrical resistance across the monolayer was measured using a Millicell Epithelial Volt-Ohm measuring system. The electrical resistance for each well was measured and then the plate was returned to the incubator. TEER values were calculated using this formula: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm cm2). Any monolayer with a TEER value < 42 ohms cm2, indicating poor monolayer formation, was discarded.

[0806] Performing the drug transport assay: The MDCK-MDR1 plate was removed from the incubator and the monolayer was washed, exchanging the volume two times using pre-warmed HBSS (Hank’s balanced salt solution) (10 mM HEPES, pH 7.4). The plate was then incubated at 37 °C for 30 minutes. A 1 pM compound working solution was prepared as follows: Added 2 pL of stock solution (10 mM in DMSO) of test compound and control compounds (Metoprolol, Prazosin and Imatinib) in one 96 well plate, then added 98 pL of DMSO into the same well to obtain 0.2 mM stock solutions (note a stock solution was further diluted 1: 10 for eventually making a 0.1 uM compound working solution). Transferred 3 pL of 0.2 mM solution into 597 pL of transport buffer in one 96 well plate to prepare the 1 pM compound working solution. The plate was shaken at 1000 rpm for 10 min. The final concentration of DMSO in the incubation system was 0.5%. The rate of drug transport in the apical to basolateral direction was carried out as follows: Added 125 pL of the 1 pM working solution to the Transwell insert (apical compartment), and transferred 50 pL of sample immediately from tire apical compartment to 250 pL of quenching solvents in a new 96-well plate as the initial donor sample (A-B). The plate was shaken at 1000 rpm for 5 minutes. The wells in tire receiver plate (basolateral compartment) were filled with 235 pL of transport buffer.

[0807] The rate of drug transport in the basolateral to apical direction was carried out as follows: Added 285 pL of the 1 pM working solution to the receiver plate wells (basolateral155ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTcompartment), and transferred 50 pL of sample immediately from the basolateral compartment to 250 pL quenching solvents in a new 96-well plate as the initial donor sample (B-A). Filled the Transwell insert (apical compartment) with 75 pL of transport buffer. The plate was shaken at 1000 rpm 5 minutes.

[0808] The multiwell insert plate was placed into the basolateral receiver plate and the plate was placed into the incubator, incubating at 37 °C for 2 hours. At the end of the transport period, 50 pL of samples was transferred from donor sides (apical compartment for Ap— > B1 flux, and basolateral compartment for Bl— > Ap flux) to 250 pL quenching solvents in a new 96-well plate.50 pL was removed directly from receiver sides (basolateral compartment for Ap— > B1 flux, and apical compartment for Bl— > Ap flux) and transferred to new 96-well plates with 250 pL quenching solvents. The samples were vortexed at 1000 rpm for 5 minutes and then centrifuged at 4,000 rpm for 20 minutes. An aliquot of 100 pL of the supernatant mixed with 100 pL of pure water was used for LC / MS / MS analysis. All incubations were performed in duplicates. To determine the Lucifer Yellow leakage after 2-hour transport period, stock solutions of Lucifer yellow in water were prepared and diluted with HBSS containing 25 mM HEPES, pH 7.4 to reach the final concentration of 100 pM. 100 pL of the Lucifer yellow solution was added to the Transwell insert (apical compartment) and the wells in the receiver plate (basolateral compartment) were filled with 300 pL of HBSS containing 25 mM HEPES, pH 7.4., incubating at 37 °C for 30 mins. 80 pL was removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to new 96 wells plates. Lucifer Yellow fluorescence was measured (to monitor monolayer integrity) in a fluorescence plate reader at 485 nM excitation and 530 nM emission.

[0809] Data calculations: All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The Lucifer yellow leakage of MDCK- MDR1 cell monolayers was calculated using the following equation: LY Leakage=({Iacceptorx0.3} / {Iacceptorx0.3+Idonorx0.1 })xl00%, where lacceptoris die fluorescence intensity in the acceptor well (0.3 mL), and Idonor is the fluorescence intensity in the donor well (0.1 mL) and expressed as % leakage. Any monolayer that produces a Lucifer yellow leakage > 1%, indicating poor monolayer formation, was excluded from the evaluation.

[0810] The apparent permeability (Papp), in units of centimeter per second, was calculated for MDCK-MDR1 drug transport assays using the following equation:Papp=[VA / (Area×time)]×{[drug]acceptor} / {[drug]initial, donor}, where VA is the volume (in mL) in the acceptor well (0.235 mL for Ap— > B1 flux and 0.075 mL for Bl— > Ap flux),156ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCTArea is the surface area of the membrane (0.143 cm2 for HTS Transwell-96 Well Permeable Supports), and time is the total transport time in seconds.

[0811] The efflux ratio was determined using the following equation: Efflux Ratio=Papp (B-A)! Papp (A-B), where Papp (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B) indicates tire apparent permeability coefficient in apical to basolateral direction.

[0812] The recovery rate was determined using tire following equation:Recovery%=({[drug]acceptor×VA+[drug]donor×VD} / {[drug]initial, donor×VD})×100, where VA is the volume (in mL) in the acceptor well (0.235 mL for Ap— > B1 flux, and 0.075 mL for Bl— > Ap), VD is the volume (in mL) in the donor well (0.075 mL for Ap— > B1 flux, and 0.235 mL for Bl— > Ap).

[0813] Table 2 shows pgp efflux ratio data at 1 uM concentration of compound.Table 2Compound No pKIT IC50 (nM) Pgp Efflux Ratio1 1.3 3.92 0.92 2.33 1.16 12.54 1.49 4.35 0.56 0.45 2.87 1.188 1.359 6.6410 1.2611 3.3312 1.0813 214 1.2 29.715 2.04 1.116 5 10.217 1.3318 1.36 60.619 0.94 3820 2.5521 0.9622 0.7523 0.59157ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT24 0.825 2.23 4526 1.727 0.71 66.628 1.3629 1.0630 1.01 1331 1.5532 3.7 3.833 1.5134 1.635 0.8936 1.3237 1.0738 0.4739 0.840 1.4241 342 0.97 2.643 1.2 4.244 2.245 1.06 1.946 1.2547 1.7848 1.849 3.5750 0.44 29.251 0.8352 1.353 1.15 3.654 2.1255 0.8356 0.9357 1.8658 0.6959 0.55 2.960 0.18 37.461 0.64 4.762 0.9563 1.5464 1.8465 7.5266 2.33158ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT67 2.2668 1.47 10.469 2.270 0.9471 0.8172 1.2573 2.5174 2.2675 4.776 0.64 3.277 1.7778 1.3879 2.2480 5.6181 1.8482 1.3783 4.2884 1.1 32.285 1.6486 1.6287 0.2588 11.12 489 2.26 124.690 6.62 33.391 1.8 104.392 1.6493 5.0995 3.3596 2.3297 2.0398 2.1799 1.57100 1.86101 2.02102 2.42103 2.3104 1.84105 2.45106 2.8107 3.64 3.3108 4.51109 1.2 3.4110 5.45159ME1\59352399.v1Atty. Dkt. No.: 134108-861202024-8061 PCT Ill 1.67112 3.29*When the examples above separate different stereoisomers based on elution times, the stereoisomers with elution peak labeled as the “title compound’’ were tested and their pKIT activity and pgp efflux ratio were reported in Table 2 above.160ME1\59352399.v1

Claims

1. Atty. Dkt. No.: 134108-861202.2024-8061 PCT3.CLAIMS4.What is claimed is:

1. A compound having the structure of Formula (I):

7. 9.or a pharmaceutically acceptable salt thereof, wherein:10.R1is selected from Ci-ealkyl, deuterated Ci-ealkyl, Cw, cycloalkyl, wherein said Ci-salkyl and deuterated Ci-ealkyl are optionally substituted with Cs-scycloalkyl;11.each R2is independently selected from Ci-salkyl, Cuhaloalkyl, halogen, CN, and Cs-4cycloalkyl;12.R3and R4are each independently selected from hydrogen and C1-4alkyl;13.R5is selected from Ci^alkyl, deuterated Ci-galkyl, Ci-ehaloalkyl, hydroxymethyl, C2. ehydroxyalkyl, Ci fhydroxyhaloalkyl, S(O)Ci-3alkyl, S(O)(NH)Ci-salkyl, and C(O)NH(Ci-jalkyl), wherein:14.Ci-galkyl and Ci-ghaloalkyl represented by R5are each optionally substituted with R5aselected from Ci-drydroxyalkoxy, S(O)Ci-3alkyl, S(O)(NH)Ci-3alkyl, C(O)NH(Ci.jalkyl), C(O)(Ci-3alkyl), P(O)(Ci-galkyl)2, N(Ci-3alkyl)(Ci-3hydroxyalkyl), N(Ci-3alkyl)2, and Ci- salkoxy;15.wherein Ci-salkoxy represented by R5ais optionally substituted with NH(Ci- salkyl) or N(Ci-3alkyl)2; and16.C2.6hydroxyalkyl and C2.6hydroxyhaloalkyl represented by R5are each optionally substituted with two Ci-salkoxy or Rsbselected from OH, CN, Ci-salkoxy, Ci-salkoxy. salkoxy, C(O)NH(Ci-3alkyl), C(O)O(Ci-3alkyl), NH(Ci-6alkyl), N(Ci-6alkyl)2, N(Ci- shaloalkyl)2, and NHlCi-ehaloalkyl); and17.n is 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is Ci^alkyl, deuterated Cwalkyl, or Cs-ecycloalkyl.19.16120.ME1\59352399.v1 Atty. Dkt. No.: 134108-8612021.2024-8061 PCT3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1is methyl, -CD3, ethyl, or cyclopropyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R2is independently Ci-3alkyl, halogen or CN.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each R2is independently methyl, fluoro, chloro or CN.

6. The compound of any one of claims 1-5, having the structure of Formula (II) or (III):

27. 29.or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently selected from hydrogen and methyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3and R4are both hydrogen or one of R3and R4is hydrogen and the other of R3and R4is methyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R5is Cualkyl, deuterated Cualkyl, Cwhaloalkyl, Ci-shydroxyhaloalkyl, or Cishy droxyalkyl, wherein:33.Ci-3alkyl and Ci-Jialoalkyl represented by R5are each optionally substituted with R5' selected from Ci-4hydroxyalkoxy, S(O)Ci-3alkyl, S(O)(NH)Ci-3alkyl, C(O)NH(Ci-3alkyl), C(O)(Ci-3alkyl), P(O)(Ci-3alkyl)2, N(Ci-3alkyl)(Ci-3hydroxyalkyl), N(Ci-3alkyl)2and Ci-salkoxy,34.wherein Ci-salkoxy represented by R5ais optionally substituted with NHtCualkyl) or N(Ci-3alkyl)2; and35.C2-shydroxyalkyl and C2-shydroxyhaloalkyl represented by R5are each optionally substituted with two Ci-salkoxy or R5bselected from OH, CN, Ci-salkoxy, Ci-salkoxy Ci-salkoxy, C(O)NH(Ci-salkyl), C(O)O(Ci.3alkyl), NH(Ci.3alkyl), N(Ci.3alkyl)2, N(Ci.3haloalkyl)2andNH(Ci.3haloalkyl).36.16237.ME1\59352399.v1 Atty. Dkt. No.: 134108-8612038.2024-8061 PCT 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R5is39.methyl, -CD3, -CH2CHF2, -CH2CH(OH)-CH3, -CH(CH3)CH(OH)(CH3),40.-CH2C(OH)(CH3)2, -CH2CH(OH)CH2CH3, - CH2CH(OH)CF3, -CH2CH(OH)CHF2, -CH2C(OH)(CH3)CH2OH,41.CH2CH(OH)CH(OH)CH3, -CH2CH(OH)C(OH)(CH3)2CH2CH(OH)CH2CH(OH)(CH3),, -CH2C(OH)(CH3)C(CH3)2OH, -CH2C(OH)(CH3)CH2CN,42.CH2C(OH)(CH3)CH2OCH2CH3, — / -CH2C(OH)(CH2CH3)CH2OCH3,43.CH(CH3)CH(OH)CH2OCH3, / , / 44.

45. ME1\59352399.v1 Atty. Dkt. No.: 134108-8612046.2024-8061 PCT47.CH2C(OH)(CH3)CH2OCH2CH2OCH3,48.CH2C(OH)(CH2-OCH3)2, -CH2CH(OH)CH2OCH2CH2OCH3,49.-CH2CH2OCH2CH2OH, -CH2OCH2CH2OH, -CH2CH2OCH2C(CH3)2OH, - CH2S(O)CH3, -CH2S(O)(NH)CH3, -CH2CH2S(O)(NH)CH3, -CH2C(O)NHCH3, -50.CH2C(OH)(CH3)C(O)NH(CH3), O, o51.CH2C(OH)(CH3)C(O)NH(CH2CH3), CH2C(OH)(CH3)C(O)OCH3, -CH2C(O)(CH2CH3), -CH(CH3)C(O)(CH3), -CH2P(O)(CH3)2, - CH2CH2OCH2CH2N(CH3)2, -CH2CH2N(CH3)CH2CH2(OH), -CH2CH(OH)CH2N(CH3)2, - I \ J I \ J C52.

53. H2C(OH)(CH3)CH2N(CH3)2, OH, OH;and - CH2C(OH)(CH3)CH2NHCH2CF3.

11. The compound of claim 1, having the structure of Formula (IV):55.16456.ME1\59352399.v1 Atty. Dkt. No.: 134108-8612057.2024-8061 PCT58.I60.

61. R5(IV), or a pharmaceutically acceptable salt thereof, wherein:62.R1is cyclopropyl;63.R2aand R2bare each independently methyl, fluoro or chloro; and64.R5is Ci-rhydroxyalky 1.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R2ais chloro or methyl and R2bis fluoro.

13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein R5is -CH2C(OH)(CH3)2.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a compound in Table 1.

15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

16. A method of treating a subject suffering from a disease or disorder mediated by wild type c-kit kinase, comprising administering to the subject an effective amount of a compound of any one of claims 1-14, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15.

17. The method of claim 16, wherein the disease or disorder is selected from urticaria, dermatosis, idiopathic anaphylaxis, asthma, hereditary alpha tryptasemia (HAT), neurofibromatosis, idiopathic pulmonary fibrosis, bullous pemphigoid, prurigo nodularis, age-related macular degeneration, allergic conjunctivitis, allergic rhinitis, alpha-1 antitrypsin deficiency, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), bronchiectasis, Celiac disease, chronic graft verse host disease, chronic rhinosinusitis with nasal polyps, colorectal cancer, dermatitis herpetiformis, irritable bowel syndrome (IBS), fibromyalgia, fibrosis, food allergies, insulin-dependent diabetes mellitus, mast cell activation syndrome (MCAS), mast cell leukemia, migraine, multiple sclerosis, Parkinson’s disease, psoriasis, rheumatoid arthritis, pulmonary arterial hypertension (PAH), inflammatory bowel71.16572.ME1\59352399.v1 Atty. Dkt. No.: 134108-8612073.2024-8061 PCT74.disease (IBD), scleroderma, dermatosis, dermatitis herpetiformis, melanoma, gastrointestinal stromal tumor, mast cell tumor, anaphylactic syndrome, idiopathic anaphylaxis, eosinophilic esophagitis and mastocytosis.

18. The method of claim 17, wherein the disease or disorder is chronic urticaria.

19. The method of claim 18, wherein the chronic urticaria is chronic spontaneous urticaria (CSU).

20. The method of claim 19, wherein the subject is resistant to antihistamine treatment (i.e., the subject remains symptomatic despite antihistamine treatment).78.ME1\59352399.v1

Images