Spirobicyclic Compounds

Abstract

The present invention provides spirobicic compounds, particularly compounds of formula I, and pharmaceutical combinations thereof. The present invention further provides a method of treating diseases associated with or regulated by FGFR2 using compounds of formula I, including cancers with aberrant activation of FGFR2. [Formula 1] JPEG2025511287000154.jpg29169

Description

Detailed Description of the Invention

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application Serial No. 64 / 425,721, filed April 41, 2022, and U.S. Application Serial No. 64 / 419,448, filed October 26, 2022, the contents and disclosures of which are hereby incorporated by reference in their entireties.

[0002] Technical Field The present invention provides spiro-bicyclic compounds, pharmaceutical combinations thereof, methods of use thereof and methods of making thereof.

[0003] Background technology The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases consists of four transmembrane receptors (FGFR1, FGFR2, FGFR4, and FGFR5). Fibroblast growth factors (FGFs) and heparin sulfate proteoglycans (HSPGs) synergize as high-affinity FGFR agonists. Binding of FGFs / HSPGs to FGFRs induces receptor dimerization and activation of the FGFR tyrosine kinase, followed by trans-autophosphorylation of tyrosine residues in the cytoplasmic kinase domain. This event triggers the activation of multiple downstream signaling cascades, including the RAS-MAPK-ERK, PI4K-AKT, PKC and JAK-STAT pathways, thereby promoting cell survival, anti-apoptosis, proliferation, migration, development, differentiation and angiogenesis (Gallo et al., Cytokine & Growth Factor Reviews 2015 26, 425; Ahmad et al., Biochimica et Biophysica Acta 2012, 1824, 850).

[0004] It has been demonstrated that an abnormally activated FGF / FGFR signaling (i.e., FGFR gene amplification, mutation, gene rearrangement or fusion) axis causes constitutive activation of downstream signal pathways, leading to uncontrolled cell growth and thereby malignant tumors (Nakamura, npj Precis. Onc. 2021, 5, 66; Gallo et al., Cytokine & Growth Factor Reviews 2015 26, 425; Ahmad et al., Biochimica et Biophysica Acta 2012, 1824,850). In particular, gene amplification of FGFR1 was identified in approximately 10% of breast cancer and 10-25% of squamous cell lung cancer cases, respectively. FGFR2 gene amplification occurred in 4%-10% of gastric cancer cases with poor prognosis. FGFR2 mutations or fusions were found in approximately 10% of endometrial cancer and 15% of intrahepatic cholangiocarcinoma, respectively. FGFR4 fusions are common in bladder cancer, lung cancer and glioblastoma (Nakamura, npj Precis. Onc. 2021, 5, 66; Goyal et al., Cancer Treatment Reviews 2021, 95,102170). Thus, aberrantly activated FGFRs are promising therapeutic targets in cancer as oncogenic drivers. Indeed, several pan-FGFR tyrosine kinase inhibitors (TKIs) have proven to be successful therapeutic strategies in many tumor types. However, acquired resistance to pan-FGFR-TKIs is becoming increasingly prominent due to target-specific mutations, such as gatekeeper, molecular breaker mutations, and other mutations induced by FGFR-TKIs (Yue et al., J Hematol Oncol 2021, 14, 24; Goyal et al., Cancer Discov. 2019 9, 1064). Also, on-target toxicity limits the clinical use of these inhibitors. One of the most common adverse events associated with pan-FGFR-TKIs is hyperphosphatemia, which is an off-target effect of FGFR1 inhibition.In view of the causes of pan-FGFR-TKI acquired resistance and hyperphosphatemia adverse events, there is a new need for the development of new generation FGFR selective inhibitors, such as FGFR2 selective inhibitors, which can overcome the resistance of cancers with abnormal activation of FGFR2 (i.e., endometrial cancer, gastric cancer, intrahepatic cholangiocarcinoma, etc.) to pan-FGFR-TKI and reduce the side effects.

[0005] International Publication No. WO2020 / 241990A1 describes several compounds as FGFR inhibitors. Chinese Application Publication No. CN115594682 also discloses several compounds as FGFR inhibitors. International Publication No. WO2022 / 109551A1 also describes several compounds as non-receptor tyrosine protein kinase Src inhibitors.

[0006] Summary of the Invention The present invention provides a novel compound that inhibits FGFR2. The present invention further provides a novel compound that selectively inhibits FGFR2 with respect to FGFR1, FGFR4 or FGFR4. Therefore, the compound of the present invention is used to treat diseases and / or conditions associated with or regulated by FGFR2, including but not limited to cancers with FGFR2 aberrant activation, such as endometrial cancer, gastric cancer, intrahepatic cholangiocarcinoma, breast cancer, urinary tract cancer, non-small cell lung cancer (NSCLC). The compound of the present invention is also used to treat diseases or conditions associated with or regulated by FGFR2, and can reduce or attenuate toxicity or adverse events associated with FGFR1, FGFR4 or FGFR4.

[0007] The present invention provides novel compounds that inhibit FGFR2 and therefore can be used to treat the conditions discussed herein. The novel compounds of the present invention provide an alternative approach to treating said conditions.

[0008] The present invention provides a compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0009] [ka]

[0010] wherein R1, R2 and R4 are each defined in the Examples, classes and subclasses herein. The present invention also provides compounds of formula I, pharmaceutical compositions thereof, methods of use thereof and methods of making thereof.

[0011] The present invention provides a compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0012] [ka]

[0013] Where: R1 is hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl; R2 is a substituted C7-C19 spirobicycloalkyl, a substituted C7-C19 spirobicycloalkenyl, a substituted C7-C19 spiroheterobicycloalkyl or a substituted C7-C19 spiroheterobicycloalkenyl; and R4 is C1-C6 alkyl, substituted C1-C6 alkyl, C4-C10 cycloalkyl, substituted C4-C10 cycloalkyl, 4-10 membered heterocycloalkyl, substituted 4-10 membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl.

[0014] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0015] [ka]

[0016] Where: R1 is hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl; R2 is

[0017] [ka]

[0018] and; (A) m CR a R b and; (A) n CR a R b and; (A) o CR a R b or O; (A) p CR a R b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl;

[0019] [ka]

[0020] is a single or double bond; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; The conditions are as follows: (A) o if is O, then o is 1; Xa is H or a halogen; W is COR5 or SO2R5; R5 is,

[0021] [ka]

[0022] and; R WA , RWB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; R WD is H or C1-C6 alkyl; and R4 is C1-C6 alkyl, substituted C1-C6 alkyl, substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl, or CN.

[0023] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0024] wherein each occurrence of m, n, o, and p is independently selected from 0, 1, or 2. Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof. Here, R5 is

[0025] [ka]

[0026] and R WA , R WB , R WC is independently selected at each occurrence from H and C1-C6 alkyl.

[0027] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0028] Here, R2 is

[0029] [ka]

[0030] It is.

[0031] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof. Here, R2 is

[0032] [ka]

[0033] and; (A) m CR a R b and; (A) n CR a R b and; (A) o CR a R b or O; (A) p is CRaR b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; The conditions are as follows: (A) o if is O, then o is 1; Xa is H or a halogen; W is COR5 or SO2R5; R5 is,

[0034] [ka]

[0035] and; R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN.

[0036] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0037] Wherein R1 is CH4; R2 is

[0038] [ka]

[0039] and; R4 is,

[0040] [ka]

[0041] R4 is,

[0042] [ka]

[0043] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0044] where R1 is CH4, CHF2, CH2CN, CH2CH2OH or CH2POMe2, preferably CH4 or CHF2; R2 is

[0045] [ka]

[0046] R4 is,

[0047] [ka]

[0048] R4 is,

[0049] [ka]

[0050] The present invention further provides a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein R2 is a bicyclic partially unsaturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, two of the ring carbon atoms are replaced by N and O, and N is replaced by COR5; R5 is,

[0051] [ka]

[0052] and R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN.

[0053] The present invention further provides a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein R2 is a bicyclic partially unsaturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, one of the ring carbon atoms is replaced by N, and N is replaced by COR5; R5 is,

[0054] [ka]

[0055] and R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN.

[0056] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof. where COR5 is independently

[0057] [ka]

[0058] is selected from.

[0059] Additionally, the present invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0060] where COR5 is independently

[0061] [ka]

[0062] is selected from.

[0063] The present invention further provides a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein R WA , R WB , R WC is independently selected at each occurrence from H and C1-C6 alkyl.

[0064] Additionally, the present invention provides compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein each occurrence of m, n, o, and p is independently selected from 0, 1, or 2.

[0065] The present invention further provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, which is selected from:

[0066] 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)prop-2-en-1-one; 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)-2-methylprop-2-en-1-one; 1-(6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptan-2-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-en-2-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undecan-4-yl)prop-2-en-1-one; N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide; 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; N-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide; 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)acrylamide; 1-(9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(6-(methylamino)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxy-5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-(cyclopentyloxy)pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(6-(4-methylcyclobutoxy)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclobutoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-((tetrahydrofuran-4-yl)oxy)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoro-6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-(difluoromethoxy)pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridazin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2,2-dimethyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(4-methylpyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 5-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-5-yl)picolinonitrile; 1-(9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2,2-dimethyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-en-9-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-methoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoropyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-cyclopropylpyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-(oxetan-4-yloxy)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6,7dihydrofurano[4,2-d]pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-fluoropyridin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 2-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile; 1-(9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-(2-hydroxyethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridazin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile; 1-(9-(4-amino-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrazin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; and 1-(9-(4-amino-5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0067] The present invention further provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, which is selected from:

[0068] 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; and 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0069] One or more embodiments of the invention are set forth in detail in the following description. Other features, objects, and advantages of the invention will become apparent from the description and claims that follow.

[0070] Detailed Description of the Invention The term "halogen" as used herein, unless otherwise specified in the context, refers to fluorine, chlorine, bromine or iodine. One specific example of a halogen is fluorine.

[0071] The term "C1-C6 alkyl" as used herein refers to a straight or branched monovalent saturated aliphatic chain having from 1 to 6 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0072] The term "C1-C4 deuterated alkyl" as used herein refers to a linear or branched monovalent saturated aliphatic chain having 1-4 carbon atoms substituted with one or more deuterium atoms (D). In some embodiments, the C1-C4 deuterated alkyl is substituted with one deuterium atom. In some embodiments, the C1-C4 deuterated alkyl is substituted with one, two, or four deuterium atoms. In some embodiments, the C1-C4 deuterated alkyl is substituted with one, two, four, four, five, or six deuterium atoms. The term C1-C4 deuterated alkyl includes CD4, CH2D, CHD2, CH2CD4, CD2CD4, CHDCD4, CH2CH2D, CH2CHD2, and the like. One specific example of a C1-C4 deuterated alkyl is CD4.

[0073] The term "substituted C1-C6 alkyl" as used herein refers to a linear or branched monovalent saturated aliphatic chain having 1-6 carbon atoms, in which one or more of the carbon atoms are substituted with 1-4, or preferably 1 or 2, groups independently selected from the following: C4-C10 heterocycloalkyl, halogen, C2-C4 alkenyl optionally substituted with 1-4 halogens, C2-C4 alkynyl optionally substituted with 1-4 halogens, hydroxy, OR9, cyano, phosphorus, CONR7R8, NR7R8, NR7COR8, NR7S. 02R8, NR7COOR8, COR7, COOR7, SR7 and SONR7R8; where R7, R8 and R9 at each occurrence are independently selected from hydrogen, C1-C6 alkyl optionally substituted with 1-4 halogens, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, C1-C4 deuterated alkyl, C2-C4 alkenyl optionally substituted with 1-4 halogens, and C2-C4 alkynyl optionally substituted with 1-4 halogens.

[0074] The term "C1-C4 alkyl" as used herein refers to a straight or branched monovalent saturated aliphatic chain having from 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like.

[0075] The term "C2-C6 alkenyl" as used herein refers to a straight or branched monounsaturated aliphatic chain having 2-6 carbon atoms and one or more carbon-carbon double bonds. Exemplary C2-C6 alkenyls include vinyl, 1-methylvinyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.

[0076] As used herein, the term "C2-C4 alkenyl" refers to a straight or branched monounsaturated aliphatic chain having 2-4 carbon atoms and one or more carbon-carbon double bonds. Exemplary C2-C4 alkenyls include vinyl, 1-methylvinyl, 1-methyl-1-propenyl, 1-butenyl, and the like.

[0077] The term "C2-C6 alkynyl" as used herein refers to a straight or branched alkynyl chain having from 2 to 6 carbon atoms and one or more carbon-carbon triple bonds, including ethynyl, 2-propynyl, 2-butynyl, 4-methylbutynyl, 1-pentynyl, and the like.

[0078] The term "C2-C4 alkynyl" as used herein refers to a straight or branched alkynyl chain having from 2 to 4 carbon atoms and one or more carbon-carbon triple bonds, including ethynyl, 2-propynyl, and the like.

[0079] The term "C4-C10 cycloalkyl" as used herein refers to a saturated hydrocarbon having one or more rings containing 4-10 carbon atoms. When multiple rings are used, the term should be understood to include fused, bridged, and spiro ring systems. Exemplary C4-C10 cycloalkyls include monocyclic, bicyclic, and spiro rings, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, cyclohexyl, cycloheptyl, cyclooctyl, and decahydronaphthalene.

[0080] The term "substituted C4-C10 cycloalkyl" as used herein refers to a saturated hydrocarbon having one or more rings containing 4-10 carbon atoms, where one or more of the ring atoms are substituted with 1-4, or preferably 1 or 2, groups independently selected from the following: halogen, cyclopropyl, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C4 alkenyl optionally substituted with 1-4 halogens, C2-C4 alkynyl optionally substituted with 1-4 halogens, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. , hydroxy, OR, cyano, CONR, R, NR, NR, COR, NR, SO, R, NR, COOR, COR, COOR, SR, and SONR; where R, R, and R are independently selected at each occurrence from hydrogen, C-C alkyl, substituted C-C alkyl, C-C deuterated alkyl, C-C alkenyl optionally substituted with 1-4 halogens, C-C alkynyl optionally substituted with 1-4 halogens, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. When multiple rings are used, the term should be understood to include fused, bridged, and spiro ring systems.

[0081] As used herein, the term "substituted C7-C19 spirobicycloalkyl" refers to a bicyclic saturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, where one or more of the ring atoms are substituted with 1-4 or preferably 1 or 2 NR6COR5 groups, where R6 is H or C1-C4 alkyl, and R5 is

[0082] [ka]

[0083] and; R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0084] In some embodiments, the substituted C7-C19 spirobicycloalkyl is

[0085] [ka]

[0086] Includes; Where: A is CR a R b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; W is COR5; R5 is,

[0087] [ka]

[0088] and; R WA , R WB , R WC is independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0089] In some embodiments, the substituted C7-C19 spirobicycloalkyl is

[0090] [ka]

[0091] etc.

[0092] As used herein, the term "substituted C7-C19 spirobicycloalkenyl" refers to a bicyclic partially unsaturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, where one or more of the ring atoms are substituted with 1-4 or preferably 1 or 2 NR6COR5 groups, where R6 is H or C1-C4 alkyl, and R5 is

[0093] [ka]

[0094] and; R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0095] In one embodiment, the term "substituted C7-C19 spirobicycloalkenyl" refers to a partially unsaturated hydrocarbon having two double bonds. In another embodiment, the term "substituted C7-C19 spirobicycloalkenyl" refers to a partially unsaturated hydrocarbon having one double bond.

[0096] In some embodiments, the term "substituted C7-C19 spirobicycloalkenyl" refers to a bicyclic partially unsaturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, one of the ring atoms being substituted with one or two NR6COR5 groups, where R6 is H or C1-C4 alkyl, and R5 is

[0097] [ka]

[0098] and; R WA , R WB , R WC is independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl. In some embodiments, the substituted C7-C19 spirobicycloalkenyl is

[0099] [ka]

[0100] Includes; Where: A is CR a R b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; W is COR5; R5 is,

[0101] [ka]

[0102] and; R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0103] In some embodiments, the substituted C7-C19 spirobicycloalkenyl is

[0104] [ka]

[0105] etc.

[0106] As used herein, the term "substituted C7-C19 spiroheterobicycloalkyl" refers to a bicyclic saturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, where at least one of the ring carbon atoms is replaced by N, where N is replaced by COR5 and R5 is:

[0107] [ka]

[0108] and; R WA , R WB , R WCis independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0109] For the term "substituted C7-C19 spiroheterobicycloalkyl," other ring carbon atoms may be replaced with one or more O, S, SO, or SO2.

[0110] In some embodiments, the term "substituted C7-C19 spiroheterobicycloalkyl" is

[0111] [ka]

[0112] Refers to; Where: A is CR a R b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; W is COR5; R5 is,

[0113] [ka]

[0114] and; R WA , R WB , R WC is independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0115] In some embodiments, the "substituted C7-C19 spiroheterobicycloalkyl" is

[0116] [ka]

[0117] etc.

[0118] As used herein, the term "substituted C7-C19 spiroheterobicycloalkenyl" refers to a bicyclic partially unsaturated hydrocarbon having 7-19 carbon atoms and sharing one carbon atom, in which at least one of the ring carbon atoms is replaced by N, where N is replaced by COR5 and R5 is

[0119] [ka]

[0120] and; R WA , R WB , R WC is independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and R WD is H or C1-C6 alkyl.

[0121] For the term "substituted C7-C19 spiroheterobicycloalkenyl," other ring carbon atoms may be replaced with one or more O, S, SO, or SO2.

[0122] In one embodiment, the term "substituted C7-C19 spiroheterobicycloalkenyl" refers to a partially unsaturated hydrocarbon having two double bonds. In another embodiment, the term "substituted C7-C19 spiroheterodicycloalkenyl" refers to a partially unsaturated hydrocarbon having one double bond.

[0123] In some embodiments, the term "substituted C7-C19 spiroheterobicycloalkenyl" is

[0124] [ka]

[0125] Refers to; Where: (A) m CR a R b and; (A) n CR a R b and; (A) o CR a R b or O; (A) p is CRaR b and; R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o, and p are independently selected from 0, 1, 2, or 4 at each occurrence; The conditions are as follows: (A) o if is O, then o is 1; Xa is H or a halogen; W is COR5; R5 is,

[0126] [ka]

[0127] and; R WA , R WB , R WC is independently selected at each occurrence from H, C-C alkyl, substituted C-C alkyl, halogen, and CN; and RWD is H or C1-C6 alkyl.

[0128] In some embodiments, the term "substituted C7-C19 spiroheterobicycloalkenyl" is

[0129] [ka]

[0130] etc.

[0131] The term "C4-C10 heterocycloalkyl" as used herein refers to a saturated hydrocarbon having one or more rings containing 4-10 carbon atoms, where one or more of the ring carbon atoms are replaced by N, O, or S. When multiple rings are used, the term should be understood to include fused, bridged, and spiro ring systems. Exemplary C4-C10 heterocycloalkyl include aziridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, tetrahydropyranyl, 2-azaspiro[4.4]heptanyl, 8-azabicyclo[4.2.1]octanyl, and the like.

[0132] The term "substituted C4-C10 heterocycloalkyl" as used herein refers to a saturated hydrocarbon having one or more rings containing 4-10 carbon atoms, wherein one or more of the ring carbon atoms are replaced with N, O, or S. For that term, one or more of the ring atoms are substituted with 1-4, or preferably 1 or 2, groups independently selected from the following: halogen, cyclopropyl, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C4 alkenyl optionally substituted with 1-4 halogens, C2-C4 alkynyl optionally substituted with 1-4 halogens, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, hydroxy, hydroxy, OR9, cyano, CONR7R8, NR7R8, NR7COR8, NR7SO2 R, NR, COOR, COR, COOR, SR, and SONR, R, where R, R, and R are independently selected at each occurrence from the following: hydrogen, C-C cycloalkyl, substituted C-C cycloalkyl, C-C alkyl, substituted C-C alkyl, C-C deuterated alkyl, C-C alkenyl optionally substituted with 1-4 halogens, C-C alkynyl optionally substituted with 1-4 halogens, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. When multiple rings are used, the term should be understood to include fused, bridged, and spiro ring systems.

[0133] The term "aryl" as used herein refers to a monovalent carbocyclic group containing one or more fused or unfused phenyl rings. When multiple rings are used, the term should be understood to include partially unsaturated ring systems. Exemplary aryls include phenyl, biphenyl, 1-naphthyl or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,4,4-tetrahydronaphthyl, indenyl, indanyl, and the like.

[0134] The term "substituted aryl" as used herein refers to a carbocyclic group containing one or more fused or unfused phenyl rings, in which one or more of the ring carbon atoms are substituted with 1-4, or preferably 1 or 2, groups independently selected from the following: halogen, C2-C4 alkenyl optionally substituted with 1-4 halogens, C2-C4 alkynyl optionally substituted with 1-4 halogens, C1-C6 alkyl, substituted C1-C6 alkyl, C4-C10 cycloalkyl, substituted C4-C10 cycloalkyl, hydroxy, O R9, cyano, CONR7R8, NR7R8, NR7COR8, NR7SO2R8, NR7COOR8, COR7, COOR7, SR7, and SONR7R8; where R7, R8, and R9 are independently selected at each occurrence from hydrogen, C4-C10 cycloalkyl, C1-C4 deuterated alkyl, C1-C6 alkyl or C4-C10 heterocycloalkyl optionally substituted with 1-4 halogens, C2-C4 alkenyl optionally substituted with 1-4 halogens, and alkynyl optionally substituted with 1-4 halogens. When multiple rings are used, the term should be understood to include partially unsaturated ring systems. In some embodiments, the substituted aryl is

[0135] [ka]

[0136] etc.

[0137] The term "heteroaryl" as used herein refers to an aromatic hydrocarbon having one or more rings, in which one or more of the ring carbon atoms are replaced by N, O or S. When multiple rings are used, the term should be understood to include partially unsaturated ring systems. Exemplary heteroaryls include pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, and the like.

[0138] The term "substituted heteroaryl" as used herein refers to an aromatic hydrocarbon having one or more rings, in which one or more of the ring carbon atoms are replaced with N, O, or S, and one or more of the ring atoms are substituted with 1-4, or preferably 1 or 2, groups independently selected from the following: halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C4-C10 cycloalkyl, substituted C4-C10 cycloalkyl, C2-C4 alkenyl optionally substituted with 1-4 halogens ... -C4 alkynyl, hydroxy, OR9, cyano, CONR7R8, NR7R8, NR7COR8, NR7SO2R8, NR7COOR8, COR7, COOR7, SR7 and SONR7R8; where R7, R8 and R9 are independently selected at each occurrence from hydrogen, C1-C6 alkyl optionally substituted with 1-4 halogens, C1-C4 deuterated alkyl, C2-C4 alkenyl optionally substituted with 1-4 halogens, C4-C10 heterocycloalkyl and C2-C4 alkynyl optionally substituted with 1-4 halogens. When multiple rings are used, it should be understood that the term includes partially unsaturated ring systems.

[0139] Exemplary unsubstituted and substituted heteroaryls include:

[0140] [ka]

[0141] etc.

[0142] The term "pharmaceutical acceptable salts" as used herein includes acid addition salts that are associated with the basic moiety of the compound of Formula I. Such pharmaceutical acceptable salts include those listed in Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition, PH Stahl and CG Wermuth (eds.), Wiley-VCH, New York, (2011).

[0143] In addition to pharma- ceutically acceptable salts, the invention contemplates other salts, which are used as intermediates in the purification of the compounds or in the preparation of other pharma- ceutical acceptable salts, or which are used to identify, characterize, or purify the compounds of the invention.

[0144] The compounds of the present invention should be understood to include single or double bonds. As used herein, for example, the solid and dashed lines in the formula below represent:

[0145] [ka]

[0146] Indicates that the structure may contain single or double bonds.

[0147] [ka]

[0148] It should be understood to include.

[0149] It should be understood that the compound of the present invention can exist in the form of stereoisomers.It should be understood that the compound of the present invention includes all forms of stereoisomers, including enantiomers, non-enantiomers, and mixtures thereof.Preferred stereoisomers are predominantly non-enantiomers.More preferred stereoisomers are predominantly enantiomers.

[0150] As used herein, an asterisk (*) in a chemical formula denotes the point of attachment of a group to the corresponding parent formula.

[0151] The present invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0152] The present invention also provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0153] The present invention also provides a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0154] The present invention also provides a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein said cancer has aberrant activation of FGFR2.

[0155] The present invention also provides a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof, wherein the cancer is selected from endometrial cancer, gastric cancer, intrahepatic cholangiocarcinoma, breast cancer, urinary tract cancer and non-small cell lung cancer (NSCLC).

[0156] The present invention also provides a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from endometrial cancer, gastric cancer and intrahepatic cholangiocarcinoma.

[0157] The present invention also provides a compound of formula I or a pharma- ceutically acceptable salt thereof for the treatment of cancer, said cancer having aberrant activation of FGFR2.

[0158] The present invention also provides a compound of formula I or a pharma- ceutically acceptable salt thereof for the treatment of cancer, wherein the cancer is selected from endometrial cancer, gastric cancer, intrahepatic cholangiocarcinoma, breast cancer, urinary tract cancer and non-small cell lung cancer (NSCLC).

[0159] The present invention also provides a compound of formula I or a pharma- ceutically acceptable salt thereof for the treatment of cancer, said cancer being selected from endometrial cancer, gastric cancer and intrahepatic cholangiocarcinoma.

[0160] The present invention also provides the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in a medicament for the treatment of cancer.

[0161] As used herein, the term "patient" refers to animals such as mammals, including humans. The preferred patient is a human.

[0162] Those skilled in the art should recognize that cancer can be treated by administering to a patient currently exhibiting symptoms an effective amount of a compound of Formula I. Thus, the term "treatment" refers to any process that can slow, interrupt, arrest, control, or stop the progression of an existing disease and / or its symptoms, but does not necessarily indicate the complete elimination of all symptoms.

[0163] Those skilled in the art should also recognize that cancer can be treated, and is intended to include prophylactic treatment, by administering an effective amount of a compound of Formula I to a patient at risk for a future condition.

[0164] As used herein, the term "effective amount" of a compound of formula I refers to an amount, i.e., dosage, effective for treating a condition, such as a disease described herein. As a skilled practitioner, the attending diagnostician can easily determine the effective amount by observing the results obtained in this analogous situation using known techniques. In determining the effective amount or dosage of a compound of formula I, many factors are taken into consideration, including, but not limited to, the compound of formula I administered; other co-administered drugs (if used); the species of mammal; its size, age, and general health; fatigue or severity of a condition, such as cancer; individual patient response; mode of administration; bioavailability characteristics of the formulation administered; the administration regime selected; use with other drug treatments; and other relevant circumstances.

[0165] Formula I compound can be administered alone or in the form of a pharmaceutical composition containing pharmaceutically acceptable carrier, diluent or excipient. Such pharmaceutical compositions and their preparation methods are known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, ed., 24th ed., Academic Press, 2020).

[0166] In the present invention, it should be understood that the combination, composition, kit, method, use, or compound used according to the present invention is intended to be administered simultaneously, in parallel, in sequence, sequentially, alternately, or alone. It should be recognized that the FGFR2 inhibitor compound (e.g., the compound of formula (I)) and at least one other pharmacologically active substance are administered dependently or independently, for example, the FGFR2 inhibitor compound (e.g., the compound of formula (I)) and at least one other pharmacologically active substance are administered as part of the same drug composition / dosage form, or preferably as a single drug composition / dosage form. In this context, the "combination" according to the present invention includes, but is not limited to, a product produced by mixing or combining one or more active ingredients, and includes fixed and non-fixed (e.g., free) combinations and applications, such as simultaneous, parallel, sequence, sequential, alternate, or alone use of the components or ingredients. The term "fixed combination" means that the active ingredients are administered to a patient at the same time in the form of a single entity or dose. The term "non-fixed combination" refers to the administration of active ingredients to a patient in the form of a single entity simultaneously, in parallel or sequentially, without any specific time limit, such administration providing therapeutically effective levels of the two compounds in the patient's body.

[0167] The administration of the FGFR2 inhibitor compound (e.g., a compound of formula (I)) and at least one other pharmacologically active substance can be carried out by co-administration of the active ingredients or components, for example, by administering them simultaneously or in parallel in one single formulation or dosage form, or in two or more single formulations or dosage forms. Alternatively, the administration of the FGFR2 inhibitor compound (e.g., a compound of formula (I)) and at least one other pharmacologically active substance can be carried out by administering the active ingredients or components in a sequence or alternation, for example, by administering them in two or more single formulations or dosage forms.

[0168] For example, simultaneous administration includes administration at substantially the same time. This form of administration is also referred to as "concomitant" administration. Concurrent administration includes administration of active agents within the same general time period (e.g., on the same day, but not necessarily at the same time). Alternating administration includes administration of one agent during one period (e.g., within the time of a few days or a week), followed by administration of another agent during a subsequent period (e.g., within the time of a few days or a week), and then repeating this pattern for one or more cycles. Sequential or sequential administration includes administration of one agent in one or more doses during a first period (e.g., within the time of a few days or a week), followed by administration of another agent in one or more doses during a second and / or other period (e.g., within the time of a few days or a week). Overlapping schedules can also be employed, including administration of active agents on different days within a treatment period, and need not follow a regular sequence. Variations of these general criteria can also be employed, depending, for example, on the agents used and the individual's condition.

[0169] The combination units of the present invention can be administered (depending or independent) by conventional methods known to those skilled in the art, for example, by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implant), nasal, vaginal, rectal or topical administration routes, and can be formulated, alone or together, as suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and / or carriers suitable for each administration route.

[0170] Thus, in one aspect, the present invention provides a method for the treatment and / or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of an FGFR2 inhibitor compound (e.g., a compound of Formula (I)) and a therapeutically effective amount of at least one other pharmacologically active substance, wherein the FGFR2 inhibitor compound (e.g., a compound of Formula (I)) and the at least one other pharmacologically active substance are administered simultaneously, concurrently, sequentially, sequentially or independently.

[0171] In another aspect, the present invention provides an FGFR2 inhibitor compound (e.g., a compound of formula (I)) for the treatment and / or prevention of cancer, wherein the FGFR2 inhibitor compound (e.g., a compound of formula (I)) and at least one other pharmacologically active substance are administered simultaneously, concurrently, sequentially, sequentially, alternatingly or independently.

[0172] In another aspect, the present invention provides a kit comprising a first pharmaceutical composition or dosage form and at least a second pharmaceutical composition or dosage form, wherein the first pharmaceutical composition or dosage form comprises an FGFR2 inhibitor compound (e.g., a compound of Formula (I)) and optionally one or more pharma- ceutically acceptable carriers, excipients and / or carriers, and the second pharmaceutical composition or dosage form comprises another pharmacologically active agent and optionally one or more pharma- ceutically acceptable carriers, excipients and / or carriers, the kit being used for the treatment and / or prevention of cancer, and wherein the first pharmaceutical composition and the second pharmaceutical composition or dosage form are administered simultaneously, concurrently, sequentially, sequentially, alternatingly or independently.

[0173] In another embodiment of the invention, the components (ie combination partners) of the compounds for the combinations, kits, uses, methods and uses used according to the present invention (including all embodiments) are administered simultaneously.

[0174] In another embodiment of the invention, the components (i.e. combination partners) of the compounds for the combinations, kits, uses, methods and uses used according to the present invention (including all embodiments) are administered in parallel.

[0175] In another embodiment of the invention, the components (i.e. combination partners) of the compounds for the combinations, kits, uses, methods and uses used according to the present invention (including all embodiments) are administered sequentially.

[0176] In another embodiment of the invention, the components (i.e. combination partners) of the compounds for the combinations, kits, uses, methods and uses to be used according to the present invention (including all embodiments) are administered sequentially.

[0177] In another embodiment of the invention, the components (ie combination partners) of the compounds for the combinations, kits, uses, methods and uses used according to the present invention (including all embodiments) are administered in alternation.

[0178] In another embodiment of the invention, the components (ie combination partners) of the compounds for the combinations, kits, uses, methods and uses used according to the present invention (including all embodiments) are administered alone.

[0179] A "therapeutically effective amount" of an active compound administered is the minimum amount necessary to prevent, ameliorate or treat a disease or condition. The combination of the present invention can be administered in single or divided daily doses that are therapeutically effective. The active ingredients of the combination can be administered in a therapeutically effective dose in monotherapy, or in a dose that is lower than the dose used in monotherapy but that produces the required (combined) therapeutically effective amount when combined.

[0180] In another embodiment, the present invention provides a method for selectively inhibiting FGFR2 against one or more of FGFR1, FGFR4 and FGFR4. In some embodiments, the compound of the present invention has FGFR2 selectivity over FGFR1, FGFR4 or FGFR4 more than 50-fold. In some embodiments, the compound of the present invention has FGFR2 selectivity over FGFR1, FGFR4 or FGFR4 more than 500-fold. In some embodiments, the compound of the present invention has FGFR2 selectivity over FGFR1, FGFR4 or FGFR4 more than 1000-fold. In some embodiments, the compound of the present invention has FGFR2 selectivity over FGFR1, FGFR4 or FGFR4 more than 2000-fold.

[0181] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0182] All publications cited in this text are incorporated herein by full citation. The following examples illustrate the preparation and efficacy evaluation of the compounds of the present invention.

[0183] biological measurements pERK potency assay The purpose of this measurement is to measure the ability of test compounds to suppress downstream signal cascades mediated by FGFR, i.e., ERK phosphorylation in cells with FGFR abnormalities. FGFR abnormalities are constitutively active, thereby inducing a cascade of cell signaling events, leading to increased phosphorylation of ERK at threonine 202 and tyrosine 204 (pERK). The In Cell ELISA procedure described below measures cellular pERK levels in response to FGFR-specific inhibitor compounds in FGFR abnormalities in AN4CA (FGFR2 / k410R, N549K), DMS114 (FGFR1 amplified), RT112 (FGFR4 overexpression / FGFR4-TACC4 fusion) and Hep4B (FGF19 amplified) cells. AN4CA, DMS114 and Hep4B cells are from ATCC. RT112 cells are from Sigma. DMS114 cells were grown and maintained using RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum. AN4CA, Hep4B and RT112 cells were grown and maintained using DMEM supplemented with 10% heat-inactivated fetal bovine serum. The day before adding the test compounds, cells were plated at 40,000 cells / well / 100 microliters in a poly-D-lysine coated 96-well cell culture plate (Corning® BioCoat® Cat#456640) and grown overnight at 47°C in a 5% CO2 culture chamber. Test compounds were prepared by 4-fold serial dilution in DMSO, in which the highest concentration was 10 μM. On the day of analysis, test compounds diluted in 50 μL of medium were added to each well of the cell culture plate, with the final compound concentration spanned from 0.000048 μM to 10 μM. After adding the compounds, the cells were incubated at 47°C, 5% CO2 for 4 hours, after which the medium was removed. The cells were fixed with 4% formaldehyde in phosphate buffered saline (PBS) and incubated at room temperature (RT) for 20 min. The plates were then washed 4 times with PBST (PBS containing 0.05% tween-20) and then incubated at -20°C for 20 min with 100 μL pre-chilled methanol. After incubation, the methanol was removed and the plates were washed once with PBST.Cells were permeabilized with 100 microliters / well of 0.1% TritonX-100 in PBS for 20 min at room temperature, then quenched with quenching buffer (PBST containing 1% H2O2 and 0.1% sodium azide) for 20 min under gentle rocking at room temperature. After one wash with PBST, blocking buffer (250 microliters / well, Pierce™ Protein-Free-PBS Blocking Buffer, Cat# 47572) was added to the cells and incubated at room temperature for 1 h, followed by overnight incubation with anti-pERK antibody (cell signaling, 1:1000 dilution in PBST containing 5% BSA) at 4°C, and secondary antibody-HRP (Jackson immunoresearch, 1:4000 dilution in PBST containing 5% BSA) at room temperature for 1 h. PBST washes were performed four times after each step. Before adding the substrate (Advansta ELISABright), the culture plate was washed twice with PBS to remove detergent residues. The cellular pERK levels were measured using a microplate reader (Biotek Synergy H1) to detect the chemiluminescence signal. The IC was calculated by fitting a four-parameter S-shaped concentration-response model. 50 Under the same analytical procedure described above, FGFR wild-type cells (H1975, PC-9 and AGS) were used as negative controls (FGFR selectivity).

[0184] The results of pERK efficacy of FGFR1, FGFR2 and FGFR4, and selectivity of FGFR2 over FGFR1 and FGFR4 are shown in Table A.

[0185] In Table A, IC of 1 nM or less 50 Compounds with an IC value of greater than 1 nM but less than or equal to 10 nM are designated as "A". 50 Compounds with an IC of greater than 10 nM but less than or equal to 40 nM are designated as "B". 50 Compounds with an IC of greater than 40 nM but less than or equal to 100 nM are designated as "C" 50 Compounds with IC > 100 nM are designated as "D". 50Compounds with the formula "E" are designated "E" and "ND" indicates not determined.

[0186] In addition, in Table A, compounds with a selectivity ratio greater than 50 but less than 150 are represented as "F", compounds with a selectivity ratio greater than 150 but less than 500 are represented as "G", compounds with a selectivity ratio greater than 500 but less than 1000 are represented as "H", compounds with a selectivity ratio greater than 1000 but less than 2000 are represented as "I", compounds with a selectivity ratio greater than 2000 are represented as "J", and "ND" indicates not determined.

[0187] These data demonstrate that the example compounds of the present invention (the results of which are given in Table A) are potent and selective inhibitors of FGFR2 versus FGFR1 or FGFR4.

[0188] [Table 1] JPEG2025511287000044.jpg138169

[0189] 2D cell proliferation assay The cell proliferation assay was used to test the efficacy of the compounds in inhibiting in vitro cell proliferation of cancer cell lines carrying FGFR aberrations or FGFR wild type. This demonstrated the molecular mode of action of the compounds. Low IC 50 The values ​​indicate high potency of FGFR inhibitor compounds under this measurement situation. It was observed that FGFR inhibitor compounds exhibit strong inhibitory effects on the proliferation of human cancer cell lines carrying FGFR abnormalities. Cell proliferation assays were performed under two-dimensional (2D) anchorage-dependent conditions in 96-well plates (Corning® Black / Clear flat Bottom, Cat# 4604) using the following cell lines: Ba / F4 FGFR2-BICC1 (human FGFR2 / V546F): The mouse Ba / F4 cell line stably expresses an exogenous human FGFR2-BICC1 fusion gene and carries the V546F mutation in FGFR2Ba / F4; FGFR2-BICC1 (human FGFR2 / N546K): The mouse Ba / F4 cell line stably expresses an exogenous human FGFR2-BICC1 fusion gene and carries the N549K mutation in FGFR2; Snu-16: human gastric cancer cells with FGFR2 amplification; KATO III: human gastric cancer cells with FGFR2 amplification; AN4CA: human endometrial carcinoma with FGFR2 mutations (k410R, N549K); MFM-224: human breast cancer with FGFR1 / 2 amplification; MFE-296: human endometrial carcinoma with FGFR2 mutation (N549K); MFE-280: human endometrial carcinoma with FGFR2 mutation (B252W); NCI-H1581: human non-small cell lung cancer with FGFR1 amplification; KG-1a: acute myeloid leukemia with FGFR1OP2-FGFR1 rearrangement; DMS114: human small cell lung cancer with FGFR1 amplification; RT112: human bladder cancer with FGFR4 overexpression / FGFR4-TACC4 fusion; SW780: human bladder cancer with FGFR4 overexpression / FGFR4-BALAP2L1 fusion; Hep4B: liver cancer with FGF19 amplification (FGFR4 ligand); AGS: human gastric cancer with Kras G12D mutation and FGFR wild type; PC-9: human non-small cell lung cancer (NSCLC) with wild-type FGFR and EGFR del19 mutation; or H1975: Human non-small cell lung cancer (NSCLC) with wild-type FGFR and EGFR L858R / T790M mutations.

[0190] Cell lines were purchased from the American Type Culture Collection (ATCC) or Sigma. All cell lines were maintained in RPMI-1640 or DMEM, both supplemented with 10% heat-inactivated fetal bovine serum.

[0191] 2D cell proliferation measurement conditions Cells grown in log phase were isolated using Gibco™ TrypLE™ Express enzyme and seeded at 4000-5000 cells / well in 100 μL medium in 96-well plates. After overnight incubation in a 47°C, 5% CO2 culture chamber, cells were treated with compounds (50 microliters / well) at final concentrations (4-fold serial dilutions, 10 points in total) spanning 0.000048 μM to 10 μM. Cells were incubated for 96 h in a culture chamber at 47°C, 5% CO2, and 95% humidity. At the end of incubation, 2D CTG reagent from Promega was added to each well according to the supplier's recommendations and mixed for 10 min in the dark. Biotek TM Luminescence signals were measured using a plate reader. Data were fitted using a S-curve analysis program with variable hill slope (GraphPad Prism®) to obtain IC 50 was measured.

[0192] In Table B, IC of 1 nM or less 50 Compounds with an IC value of greater than 1 nM but less than or equal to 10 nM are designated as "A". 50 Compounds with an IC of greater than 10 nM but less than or equal to 40 nM are designated as "B". 50 Compounds with an IC of greater than 40 nM but less than or equal to 100 nM are designated as "C" 50 Compounds with IC > 100 nM are designated as "D". 50 Compounds with the formula "E" are designated "E" and "ND" indicates not determined. These data indicate that the tested compounds have potent inhibitory effects on the proliferation of cancer cell lines harboring FGFR2 abnormalities, including FGFR2 amplification (KATO III, SNU-16) or FGFR2 mutations (AN4CA, Ba / F4 FGFR2-N549K, Ba / F4 FGFR2-V564F), respectively.

[0193] [Table 2]

[0194] The abbreviations used herein are those commonly used in the art, some of which have the corresponding definitions below.

[0195] [Table 3]

[0196] General synthetic procedure The compounds of formula I can be prepared by methods known in the chemical arts or by novel methods described herein. The methods for preparing the compounds of formula I and novel intermediate compounds used in the preparation of the compounds of formula I provide further features of the invention and are described in the following procedures.

[0197] In general, the compound of formula I can be synthesized by the method shown in Scheme 1. More specifically, the compound of formula IVa (wherein X is iodine, bromine, chlorine (preferably iodine)) is reacted with the compound of formula Va (wherein Pg is a suitable amine protecting group, for example BOC), in the presence of a Pd coupling catalyst and a base, for example potassium carbonate, in a solvent, for example dioxane and water, to obtain the compound of formula IIIa. The compound of formula IIIa is reacted with a suitable deprotecting agent, for example trifluoroacetic acid, in a solvent, for example dichloromethane, to obtain the compound of formula IIa. The compound of formula IIa is reacted with acryloyl chloride under acylation conditions to obtain the compound of formula Ia.

[0198] [ka]

[0199] In general, the compound of formula IVa can be synthesized by the method shown in scheme 2. More specifically, the compound of formula IIXa (wherein Y is bromine) is reacted with an R4 halide, such as iodine methane, and a base, such as cesium carbonate, in a solvent, such as DMF, to obtain the compound of formula VIIa, where Y is bromine and R1 is methyl. The compound of formula VIIa is reacted with a boronic acid derivative of R4 in the presence of a Pd coupling catalyst and a base, such as potassium carbonate, in a solvent, such as dioxane and water, to obtain the compound of formula VIa. The compound of formula VIa is reacted with N-iodosuccinimide and trifluoroacetic acid in a solvent, such as dichloromethane, to obtain the compound of formula IVa, where X is iodine. Alternatively, NBS (wherein X is Br) or NCS (wherein X is Cl) can be used instead of N-iodosuccinimide.

[0200] [ka]

[0201] In general, the compound of formula I can be further synthesized by the method shown in Scheme 4. More specifically, the compound of formula IXb (wherein Y is bromine (alternatively, iodine or chlorine)) is reacted with a boronic acid derivative of R4 in the presence of a Pd coupling catalyst and a base such as potassium carbonate in a solvent such as dioxane and water to obtain the compound of formula IIIb. The compound of formula IIIb is reacted with a suitable deprotecting agent such as trifluoroacetic acid in a solvent such as dichloromethane to obtain the compound of formula IIb. The compound of formula IIb is reacted with acryloyl chloride under acylation conditions to obtain the compound of formula Ib.

[0202] [ka]

[0203] In general, the compound of formula IXb can be synthesized using the method shown in Scheme 4. More specifically, the compound of formula IXb (where Y is bromine (alternatively, iodine or chlorine)) is reacted with N-iodosuccinimide and trifluoroacetic acid in a solvent such as dichloromethane to obtain the compound of formula Xb, where X is iodine. NBS (where X is Br) or NCS (where X is Cl) can be used instead of N-iodosuccinimide. The compound of formula Xb is reacted with the compound of formula Vb (where Pg is a suitable amine protecting group, for example BOC) in the presence of a Pd coupling catalyst and a base such as potassium carbonate in a solvent such as dioxane and water to obtain the compound of formula IXb. The compound of formula IXb can be synthesized by methods known in the chemical arts or by the methods described in the Preparations and Examples.

[0204] [ka]

[0205] In the description of synthetic methods herein, the term "drying and concentrating" generally refers to drying a solution in an organic solvent with sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature appropriate for the stability of the material being produced). Column chromatography is performed using conventional gravity or high-pressure chromatography, or by pre-packing a silica gel column and using a medium-pressure chromatography device (e.g., Biotage Isolera One®) and eluting with the indicated solvent or solvent mixture. In some cases, the final product is purified by preparative thin layer chromatography using 20 cm x 20 cm x 0.5 mm or 20 cm x 20 cm x 1 mm silica gel plates developed in the appropriate solvent system. Preparative high performance liquid chromatography (HPLC) is performed in the following manner: An inverted column of a size appropriate for the amount of material to be separated (e.g., Waters® Sunfire®) is used. TM C18, Waters® Xbridge TM C18) is used; typically eluted with an increasing gradient of methanol or acetonitrile in water, which further contains 0.05% or 0.1% formic acid (or trifluoroacetic acid) or 10 mM ammonium acetate; at an elution rate appropriate to the column size and the separation to be achieved. Chemical names are generated using ChemDraw® Professional version 19.1. The selection and use of appropriate protecting groups is known in the chemical arts. See, for example, Greene's Protective Groups in Organic Synthesis 4th Edition P. Wuts and T. Greene, John Wiley & Sons, 2006. The mass weighting ratios of intermediates and products are reported based on the most abundant isotope. The mass weighting ratios of other isotopes may or may not be recorded.

[0206] Working Example Manufacturing 1 Synthesis of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]non-6-en-7-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine

[0207] [ka]

[0208] Method A, Step 1. Synthesis of t-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.5]non-6-ene-2-carboxylate.

[0209] To a stirred solution of t-butyl 7-oxo-2-azaspiro[4.5]nonane-2-carboxylate (1 g, 4.18 mmol, 1 eq) in anhydrous THF (20 mL) at -78 °C under N2, LiHMDS solution (5 mL, 5.02 mmol, 1.2 eq, 1 M in THF) was added dropwise, and the mixture was stirred at -78 °C for 1 h, after which PhNTf2 (1.65 g, 4.59 mmol, 1.1 eq) was added, and the mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (5:1) to give the title compound (890 mg, 57% yield) as a colorless oil.

[0210] Method A, Step 2. Synthesis of t-butyl 7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-2-azaspiro[4.5]non-6-ene-2-carboxylate.

[0211] To a stirred solution of compound t-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.5]non-6-ene-2-carboxylate (0.89 g, 2.4 mmol, 1 eq) in DMF (15 mL), B2Pin2 (0.67 g, 2.6 mmol, 1.1 eq), KOAc (0.71 g, 7.2 mmol, 4 eq) and Pd(dppf)Cl2 (196 mg, 0.24 mmol, 0.1 eq) were added and stirred at 70 °C for 4 h under N2. The reaction mixture was concentrated under vacuum, diluted with EtOAc (20 mL), filtered through a Celite® filter pad and concentrated under vacuum. The residue was used in the next step.

[0212] Method A, Step 4. Synthesis of t-butyl 7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-ene-2-carboxylate.

[0213] A mixture of 6-iodo-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (544 mg, 1.2 mmol, 1 eq), tert-butyl 7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-2-azaspiro[4.5]non-6-ene-2-carboxylate (848 mg, 2.4 mmol, 2 eq), Pd(dppf)Cl2 (98 mg, 0.12 mmol, 0.1 eq) and K2CO4 (497 mg, 4.6 mmol, 4 eq) in dioxane (15 mL) and HO (1.5 mL) was stirred at 100 °C under N2 for 6 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the title compound (440 mg, 51% yield) as a yellow solid.

[0214] LCMS: m / z 540.15 [M+1] +.

[0215] Method A, Step 4. Synthesis of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]non-6-en-7-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0216] [ka]

[0217] To a stirred solution of t-butyl 7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)-phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-ene-2-carboxylate (440 mg, 0.61 mmol, 1 eq) in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated. The crude 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]non-6-en-7-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine was treated with aqueous NH4OH and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-TLC (DCM / MeOH = 10 / 1) to give the title compound (160 mg, 60% yield) as a yellow solid.

[0218] LCMS: m / z 440.20 [M+1] + .

[0219] Example 1 Synthesis of 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)prop-2-en-1-one.

[0220] [ka]

[0221] To a solution of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro-[4.5]non-6-en-7-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (62 mg, 0.141 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (44 mg, 0.424 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (15.4 mg, 0.169 mmol, 1.2 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (40.7 mg, 44% yield) as a white solid.

[0222] LCMS: m / z 494.35 [M+1] + .

[0223] 1 H NMR(400 MHz, CD3OD) δ 8.63(d, J = 4.0 Hz, 2H), 8.30(s, 1H), 7.49(d, J = 8.0 Hz, 2H), 7.33(d, J = 8.0 Hz, 2H), 7.26(t, J = 4.0 Hz, 1H), 6.35 - 6.18(m, 2H), 5.94(brs, 1H), 5.71(d, J = 12.0 Hz, 1H), 4.01 - 3.92(m, 2H), 3.80(s, 3H), 3.78 - 3.70(m, 2H), 2.49 - 2.46(m, 2H), 2.23 - 2.16(m, 2H), 1.90(t, J = 4.0 Hz, 2H).

[0224] Example 2 Synthesis of 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)-2-methylprop-2-en-1-one.

[0225] [ka]

[0226] To a solution of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]non-6-en-7-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (65 mg, 0.15 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (44 mg, 0.424 mmol, 4 eq). At 0 °C, a solution of methacryloyl chloride (18.6 mg, 0.178 mmol, 1.2 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (24.9 mg, 42% yield) as a white solid.

[0227] LCMS: m / z 508.45 [M+1] + .

[0228] 1H NMR(400 MHz, CD3OD) δ 8.63(d, J = 4.0 Hz, 2H), 8.30(s, 1H), 7.48(d, J = 8.0 Hz, 2H), 7.30(d, J = 8.0 Hz, 2H), 7.26(t, J = 4.0 Hz, 1H), 5.93(brs, 1H), 5.43(s, 1H), 5.33(s, 1H), 3.97 - 3.89(m, 2H), 3.79(s, 3H), 3.76 - 3.68(m, 2H), 2.47 - 2.42(m, 2H), 2.22 - 2.12(m, 2H), 1.90 - 1.85(m, 5H).

[0229] Manufacturing 2 Synthesis of 6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptane.

[0230] [ka]

[0231] Method B, Step 1. Synthesis of t-butyl 6-(tosyloxy)-2-azaspiro[4.4]heptane-2-carboxylate.

[0232] To a stirred solution of t-butyl 6-hydroxy-2-azaspiro[4.4]heptane-2-carboxylate (4.5 g, 21.1 mmol, 1 eq) in anhydrous DCM (50 mL) at 0° C., TEA (4.4 g, 42.2 mmol, 2 eq) was added followed by TsCl (6.1 g, 41.6 mmol, 1.5 eq) and the mixture was stirred at room temperature under N2 for 16 h. The reaction mixture was quenched with water and extracted with DCM (4×40 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (6:1) to give the title compound (6.1 g, 78% yield) as a white solid.

[0233] Method B, Step 2. Synthesis of t-butyl 6-iodo-2-azaspiro[4.4]heptane-2-carboxylate.

[0234] To a stirred solution of t-butyl 6-(tosyloxy)-2-azaspiro[4.4]heptane-2-carboxylate (9.5 g, 25.9 mmol, 1 eq) in methyl ethyl ketone (80 mL) was added NaI (15.6 g, 104.6 mmol, 4 eq). The reaction was stirred at 100 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, filtered through a filter pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1) to give the compound (8.2 g, 98% yield) as a white solid.

[0235] Method B, Step 4. Synthesis of t-butyl 6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptane-2-carboxylate.

[0236] A mixture of 6-iodo-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]-pyrimidin-4-amine (1 g, 2.25 mmol, 1 eq), t-butyl 6-iodo-2-azaspiro[4.4]heptane-2-carboxylate (2.18 g, 6.75 mmol, 4 eq), NiBr-DME (79 mg, 0.225 mmol, 0.1 eq), picoline imitamide hydrochloride (46 mg, 0.225 mmol, 0.1 eq), manganese (619 mg, 11.25 mmol, 5 eq) and KI (112 mg, 6.75 mmol, 4 eq) in anhydrous DMAc (20 mL) was stirred at 80 °C under N for 16 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (4 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (40:1) to give the title compound (250 mg, 22% yield) as a yellow solid.

[0237] LCMS: m / z 514.45 [M+1] + .

[0238] Method B, Step 4. Synthesis of 6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptane.

[0239] [ka]

[0240] To a stirred solution of t-butyl 6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptane-2-carboxylate (250 mg, 0.487 mmol, 1 eq) in DCM (5 mL) under N2, TFA (5 mL) was added and the mixture was stirred at room temperature for 2 h. The solution was concentrated. The crude material was treated with aqueous NH4OH and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-TLC (CH2Cl2 / MeOH = 10 / 1) to give the title compound (120 mg, 60% yield) as a yellow solid.

[0241] LCMS: m / z 414.40 [M+1] + .

[0242] Example 4 Synthesis of 1-(6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptan-2-yl)prop-2-en-1-one.

[0243] [ka]

[0244] To a solution of 6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptane (60 mg, 0.145 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (44 mg, 0.425 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (16 mg, 0.174 mmol, 1.2 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (9.4 mg, 14.7% yield) as a white solid.

[0245] LCMS: m / z 468.45 [M+1] + .

[0246] 1 H NMR(400 MHz, CD3OD) δ 8.64(d, J = 4.0 Hz, 2H), 8.26(s, 1H), 7.51(d, J = 8.0 Hz, 2H), 7.33(d, J = 8.0 Hz, 2H), 7.29 - 7.26(m, 1H), 6.33 - 6.12(m, 2H), 5.74 - 5.63(m, 1H), 4.37(s, 1H), 4.13(s, 1H), 3.99(s, 1H), 3.86 - 3.79(m, 4H), 3.76(s, 1H), 2.59 - 2.49(m, 2H), 2.26 - 2.18(m, 2H).

[0247] Example 4 Synthesis of 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0248] [ka]

[0249] Method C, Step 1. Synthesis of t-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0250] To a stirred solution of t-butyl 9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (0.8 g, 4 mmol, 1 eq) in anhydrous THF (20 mL) at -78 °C under N2, LiHMDS solution (4.6 mL, 4.6 mmol, 1.2 eq, 1 M in THF) was added dropwise and the mixture was stirred at -78 °C for 1 h. Then PhNTf2 (1.18 g, 4.4 mmol, 1.1 eq) was added and the mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (5:1) to give the title compound (247 mg, 21% yield) as a colorless oil.

[0251] Method C, Step 2. Synthesis of t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0252] To a stirred solution of t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (247 mg, 0.64 mmol, 1 eq) in DMF (5 mL) was added B2Pin2 (179 mg, 0.7 mmol, 1.1 eq), KOAc (188 mg, 1.92 mmol, 4 eq) and Pd(dppf)Cl2 (52 mg, 0.064 mmol, 0.1 eq). The reaction mixture was stirred at 70 °C under N2 for 4 h, then concentrated in vacuo, diluted with EtOAc (20 mL) and filtered through a filter pad. The filtrate was concentrated in vacuo. The resulting residue was used in the next step.

[0253] Method C, Step 4. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0254] A mixture of the compound 6-iodo-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (177.6 mg, 0.4 mmol, 1 eq) (prepared essentially according to the method described in WO2020241990), tert-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (241 mg, 0.64 mmol, 1.6 eq), Pd(dppf)Cl2 (42 mg, 0.04 mmol, 0.1 eq) and K2CO4 (165 mg, 1.2 mmol, 4 eq) in dioxane (5 mL) and HO (0.5 mL) was stirred at 100 °C under N2 for 6 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the title compound (148 mg, 60% yield) as a yellow solid.

[0255] LCMS: m / z 568.25 [M+1] + .

[0256] Method C, Step 4. Synthesis of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0257] To a stirred solution of t-butyl 9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (148 mg, 0.24 mmol, 1 eq) in DCM (5 mL) under N2, TFA (5 mL) was added and the mixture was stirred at room temperature for 2 h. The solution was concentrated. The crude residue was treated with aqueous NH4OH and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound (114.6 mg, 80% yield) as a yellow solid.

[0258] LCMS: m / z 468.24 [M+1] + .

[0259] Method C, Step 5. Synthesis of 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0260] [ka]

[0261] To a stirred solution of the compound 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (114.6 mg, 0.24 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (96.9 mg, 0.96 mmol, 4 eq). At 0° C., a solution of acryloyl chloride (21 mg, 0.24 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0° C. under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (22 mg, 20% yield) as a white solid.

[0262] LCMS: m / z 522.20 [M+1] + .

[0263] 1 H NMR(400 MHz, CD3OD) δ 8.63(d, J = 4.0 Hz, 2H), 8.12(s, 1H), 7.45(d, J = 8.0 Hz, 2H), 7.26 - 7.24(m, 3H), 6.73(dd, J = 16.0, 8.0 Hz, 1H), 6.15(d, J = 16.0 Hz, 1H), 5.87(brs, 1H), 5.70(d, J = 8.0 Hz, 1H), 3.69(s, 3H), 3.68 - 3.46(m, 4H), 2.18 - 2.02(m, 4H), 1.62 - 1.58(m, 2H), 1.47 - 1.39(m, 4H).

[0264] Example 5 Synthesis of 1-(8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-en-2-yl)prop-2-en-1-one.

[0265] [ka]

[0266] Method D, Step 1. Synthesis of t-butyl 8-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.5]dec-7-ene-2-carboxylate.

[0267] To a stirred solution of compound t-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (1 g, 4.91 mmol, 1 eq) in anhydrous THF (20 mL) at -78 °C, LiHMDS solution (4.7 mL, 4.69 mmol, 1.2 eq, 1 M in THF) was added dropwise and the mixture was stirred at -78 °C under N2 for 1 h. Then PhNTf2 (1.5 g, 4.41 mmol, 1.1 eq) was added and the resulting mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (5:1) to give the title compound (1.4 g, 94% yield) as a colorless oil.

[0268] Method D, Step 2. Synthesis of t-butyl 8-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-2-azaspiro[4.5]dec-7-ene-2-carboxylate.

[0269] To a stirred solution of compound t-butyl 8-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.5]dec-7-ene-2-carboxylate (1.4 g, 4.7 mmol, 1 eq) in DMF (15 mL) was added B2Pin2 (0.99 g, 4.9 mmol, 1.1 eq), KOAc (1.15 g, 11.7 mmol, 4 eq) and Pd(dppf)Cl2 (422 mg, 0.47 mmol, 0.1 eq). The reaction mixture was stirred at 70 °C under N2 for 4 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (20 mL), filtered through a filter pad and concentrated in vacuo. The obtained residue was used in the next step.

[0270] Method D, Step 4. Synthesis of t-butyl 8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-ene-2-carboxylate.

[0271] A mixture of the compounds 6-iodo-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (821 mg, 1.85 mmol, 1 eq), t-butyl 8-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-2-azaspiro[4.5]dec-7-ene-2-carboxylate (4.7 mmol, 2 eq), Pd(dppf)Cl2 (150 mg, 0.18 mmol, 0.1 eq) and K2CO4 (765 mg, 5.5 mmol, 4 eq) in dioxane (15 mL) / HO (1.5 mL) was stirred at 100 °C under nitrogen atmosphere for 6 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (40:1) to give the title compound (720 mg, 72% yield) as a yellow solid.

[0272] LCMS: m / z 554.28 [M+1] + .

[0273] Method D, Step 4. Synthesis of 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of the compound t-butyl 8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-ene-2-carboxylate (450 mg, 0.81 mmol, 1 eq) in CHCl (5 mL) at room temperature under N was added TFA (5 mL) and stirred for 2 h. The solution was concentrated. The crude residue was treated with aqueous NHOH and diluted with CHCl. 2( The mixture was extracted with 100 mL of ethyl acetate (4×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the title compound (440 mg, 92% yield) as a yellow solid.

[0274] LCMS: m / z 454.24 [M+1] + .

[0275] Method D, Step 5. Synthesis of 1-(8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-en-2-yl)prop-2-en-1-one.

[0276] [ka]

[0277] To a stirred solution of the compound 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(2-azaspiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (140 mg, 0.28 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (144.4 mg, 1.42 mmol, 4 eq). At 0° C., a solution of acryloyl chloride (25.9 mg, 0.286 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and stirred at 0° C. under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The resulting residue was purified by prep-HPLC (ACN / H2O containing 0.1% TFA) to give the HCl salt of the title compound (44.2 mg, 26% yield) as a white solid.

[0278] LCMS: m / z 508.50 [M+1] + .

[0279] 1 H NMR(400 MHz, CD3OD) δ 8.63(d, J = 4.0 Hz, 2H), 8.30(s, 1H), 7.49(d, J = 8.0 Hz, 2H), 7.33(d, J = 8.0 Hz, 2H), 7.26(t, J = 4.0 Hz, 1H), 6.63 - 6.40(m, 1H), 6.25 - 6.20(m, 1H), 6.00 - 5.95(m, 1H), 5.78 - 5.70(m, 1H), 3.80(s, 3H), 3.75 - 3.70(m, 1H), 3.60 - 3.50(m, 1H), 3.42 - 3.37(m, 1H), 3.29 - 3.24(m, 1H), 2.20 - 2.16(m, 4H), 1.88 - 1.83(m, 1H), 1.77 - 1.65(m, 3H).

[0280] Example 6 Synthesis of 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undecan-4-yl)prop-2-en-1-one.

[0281] [ka]

[0282] To a stirred solution of the compound 7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(4-azaspiro[5.5]undecan-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (42 mg, 0.089 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (27 mg, 0.269 mmol, 4 eq). At 0° C., a solution of acryloyl chloride (7.6 mg, 0.106 mmol, 1.2 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0° C. under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (1.5 mg, 4.5% yield) as a white solid.

[0283] LCMS: m / z 524.40 [M+1] + .

[0284] 1H NMR(400 MHz, CD3OD) δ 8.62(d, J = 4.0 Hz, 2H), 7.57(d, J = 8.0 Hz, 2H), 7.42(s, 1H), 7.32(d, J = 8.0 Hz, 2H), 7.26(t, J = 4.0 Hz, 1H), 6.77(dd, J = 16.0 Hz, 12.0 Hz, 1H), 6.18(d, J = 16.0 Hz, 1H), 5.73(d, J = 12.0 Hz, 1H), 3.91(s, 3H), 3.69 - 3.62(m, 4H), 2.89 - 2.81(m, 1H), 2.03 - 1.92(m, 6H), 1.70 - 1.65(m, 2H), 1.51 - 1.36(m, 4H).

[0285] Example 7 Synthesis of N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide.

[0286] [ka]

[0287] Method E, Step 1. Synthesis of 2-((t-butoxycarbonyl)amino)spiro[4.5]non-6-en-7-yl trifluoromethanesulfonate.

[0288] To a stirred solution of compound t-butyl (7-oxospiro[4.5]nonan-2-yl)carbamate (254 mg, 1 mmol, 1 eq) in anhydrous THF (5 mL) at -78 °C, LiHMDS solution (2.2 mL, 2.2 mmol, 2.2 eq, 1 M in THF) was added dropwise, and the resulting mixture was stirred at -78 °C under N2 for 1 h. Then, PhNTf2 (492 mg, 1.1 mmol, 1.1 eq) was added, and then the mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (4 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with hexane / EtOAc (5:1) to give the title compound (241 mg, 60% yield) as a colorless oil.

[0289] Method E, Step 2. Synthesis of t-butyl (7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)spiro[4.5]non-6-en-2-yl)carbamate.

[0290] To a stirred solution of compound 2-((t-butoxycarbonyl)amino)spiro[4.5]non-6-en-7-yl trifluoromethanesulfonate (241 mg, 0.6 mmol, 1 eq) in DMF (5 mL) was added B2Pin2 (167 mg, 0.66 mmol, 1.1 eq), KOAc (194 mg, 1.98 mmol, 4 eq) and Pd(dppf)Cl2 (5.2 mg, 0.06 mmol, 0.1 eq). The resulting mixture was degassed with N2 four times and then stirred at 70 °C under N2 for 4 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (10 mL), filtered through a filter pad and concentrated in vacuo. The resulting residue was used in the next step.

[0291] Method E, Step 4. Synthesis of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate.

[0292] A mixture of 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (77 mg, 0.2 mmol, 1 eq), tert-butyl (7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)spiro[4.5]non-6-en-2-yl)carbamate (94 mg, 0.26 mmol, 1.4 eq), Pd(dppf)Cl2 (16.5 mg, 0.02 mmol, 0.1 eq) and K2CO4 (82.8 mg, 0.6 mmol, 4 eq) in dioxane (10 mL) and HO (1 mL) was degassed four times with N2 and then stirred at 100 °C under N2 for 6 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the title compound (75 mg, 75% yield) as a yellow solid.

[0293] LCMS: m / z 490.40 [M+1] + .

[0294] Method E, Step 4. Synthesis of 6-(2-aminospiro[4.5]non-6-en-7-yl)-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0295] To a stirred solution of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate (75 mg, 0.15 mmol, 1 eq) in DCM (2 mL) under N2, TFA (2 mL) was added and the resulting mixture was stirred at room temperature for 2 h. The solution was concentrated. The crude residue was treated with aqueous NH4OH and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give the title compound (40 mg, 60% yield) as a yellow solid.

[0296] LCMS: m / z 490.44 [M+1] + .

[0297] Method E, Step 5. Synthesis of N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide.

[0298] [ka]

[0299] To a stirred solution of 6-(2-aminospiro[4.5]non-6-en-7-yl)-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (40 mg, 0.07 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (28 mg, 0.28 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (6.9 mg, 0.07 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The resulting residue was purified by prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (14.4 mg, 46% yield) as a white solid.

[0300] LCMS: m / z 444.35 [M+1] + .

[0301] 1 H NMR(400 MHz, CD3OD) δ 8.29(s, 1H), 7.32(d, J = 8.0, 2H), 7.04(d, J = 8.0, 2H), 6.23 - 6.17(m, 2H), 5.88 - 5.82(m, 1H), 5.68 - 5.60(m, 1H), 4.46 - 4.24(m, 1H), 3.84(s, 3H), 3.77(d, J = 4.0 Hz, 3H), 2.36 - 2.30(m, 1H), 2.28 - 2.17(m, 3H), 2.14 - 1.99(m, 2H), 1.80 - 1.69(m, 3H), 1.65(t, J = 6.0 Hz, 1H).

[0302] Example 8 Synthesis of 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0303] [ka]

[0304] Method F, Step 1. Synthesis of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0305] To a stirred solution of compound 5-bromo-7H-pyrrolo[2,4-d]pyrimidin-4-amine (10 g, 46.9 mmol, 1 eq), Cs2CO4 (40.48 g, 94.8 mmol, 2 eq) in DMF (100 mL) at 0 °C under N2, MeI (7.98 g, 56.2 mmol, 1.2 eq) was added and the resulting mixture was stirred at room temperature for 4 h. The solution was concentrated. The crude compound was partitioned between water (150 mL) and EtOAc (4x100 mL). The combined organic layers were washed with brine (4x100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound (4.2 g, 40%) as a white solid.

[0306] Method F, Step 2. Synthesis of 5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0307] A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (2.47 g, 10.8 mmol, 1 eq), compound 4-methoxyphenylboronic acid (4.28 g, 21.6 mmol, 2 eq), KCO (4.47 g, 42.4 mmol, 4 eq) and Pd(dppf)Cl (840 mg, 1.08 mmol, 0.1 eq) in dioxane (25 mL) and H0 (2.5 mL) was degassed four times with N and then stirred at 90 °C under N for 16 h. The resulting mixture was diluted with H0 (200 mL) and extracted with EtOAc (4 x 40 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (14:1) to give the title compound (1.7 g, 62%) as a white solid.

[0308] LCMS: m / z 255.10 [M+1] + .

[0309] Method F, Step 4. Synthesis of 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0310] To a solution of 5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1.7 g, 6.69 mmol, 1 eq) in DCM (20 mL) was added NIS (1.8 g, 8 mmol, 1.2 eq) and CF4COOH (1.52 g, 14.48 mmol, 2 eq) under N2 at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with aqueous NaHCO4 (10 mL), 10% Na2SO4 solution (10 mL) and H2O (20 mL) under stirring. The resulting precipitate was collected by filtration, washed with water and purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (1.5 g, 59%) as a white solid.

[0311] LCMS: m / z 481.20 [M+1] + .

[0312] Method F, Step 4. Synthesis of t-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0313] To a stirred solution of t-butyl 9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (400 mg, 1.5 mmol, 1 eq) in THF (5 mL) at −78 °C under N2, LiHMDS solution (1.8 mL, 1.8 mmol, 1.2 eq, 1 M in THF) was added dropwise and the resulting mixture was stirred at −78 °C under N2 for 1 h. A solution of PhNTf2 (586 mg, 1.65 mmol, 1.1 eq) in anhydrous THF (1 mL) was added dropwise at −78 °C and the mixture was stirred at room temperature under N2 for 16 h. The solution was concentrated. The crude residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound (0.6 g, 100%) as a light brown oil.

[0314] Method F, Step 5. Synthesis of t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0315] t-Butyl 9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (600 mg, 1.5 mmol, 1 eq), B2Pin 2( A mixture of Pd(dppf)Cl2 (124 mg, 0.15 mmol, 1 eq) and KOAc (441 mg, 4.5 mmol, 0.1 eq) in DMF (10 mL) was degassed with N2 four times and then stirred at 80 °C under N2 for 4 h. The solution was concentrated. The crude compound was filtered through a filter pad. The filtrate was concentrated under reduced pressure to give the title compound (566 mg, 99%) as an oil, which was used directly in the next step.

[0316] Method F, Step 6. Synthesis of t-butyl 9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0317] A mixture of 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (480 mg, 1 mmol, 1 eq), tert-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (566 mg, 1.5 mmol, 1.5 eq), KCO (414 mg, 4 mmol, 4 eq) and Pd(dppf)Cl (82.4 mg, 0.1 mmol, 0.1 eq) in dioxane (10 mL) and HO (1 mL) was degassed 4 times with N and then stirred at 100 °C under N for 6 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (440 mg, 75%) as a white solid.

[0318] LCMS: m / z 504.4 [M+1] + .

[0319] Method F, Step 7. Synthesis of 5-(4-methoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0320] A mixture of t-butyl 9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (140 mg, 0.258 mmol, 1 eq) in TFA (1 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (104 mg, 99%) as a yellow oil, which was used directly in the next step without further purification.

[0321] Method F, Step 8. Synthesis of 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0322] [ka]

[0323] To a mixture of the compound 5-(4-methoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (104 mg, 0.25 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (104 mg, 1.042 mmol, 4 eq). At 0° C., a solution of acryloyl chloride (20 mg, 0.258 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise, and the mixture was stirred at 0° C. under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O containing 0.1% TFA) to give the title compound (24.4 mg, 20% yield) as a white solid.

[0324] LCMS: m / z 458.2 [M+1] + .

[0325] 1H NMR(400 MHz,CD3OD) δ 8.30(s, 1H), 7.33(d, J = 8.0 Hz, 2H), 7.05(d, J = 8.0 Hz, 2H), 6.74(dd, J = 16.0, 12.0 Hz, 1H), 6.16(d, J = 16.0 Hz, 1H), 5.92(brs, 1H), 5.72(d, J = 12.0 Hz, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.70 - 3.62(m, 2H), 3.60 - 3.50(m, 2H), 2.16 - 2.13(m, 2H), 2.05 - 2.01(m, 2H), 1.61 - 1.57(m, 2H), 1.45 - 1.39(m, 4H).

[0326] Example 9 Synthesis of N-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamin.

[0327] [ka]

[0328] Method G, Step 1. Synthesis of t-butyl (7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate.

[0329] A mixture of 6-iodo-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (209 mg, 0.47 mmol, 1 eq), tert-butyl (7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)spiro[4.5]non-6-en-2-yl)carbamate (441 mg, 0.94 mmol, 2 eq), Pd(dppf)Cl2 (48 mg, 0.047 mmol, 0.1 eq) and K2CO4 (194 mg, 1.41 mmol, 4 eq) in dioxane (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 100 °C under N2 for 6 h. The resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (4 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the title compound (182 mg, 70% yield) as a yellow solid.

[0330] LCMS: m / z 445.56 [M+1] + .

[0331] Method G, Step 2. Synthesis of 6-(2-aminospiro[4.5]non-6-en-7-yl)-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0332] To a stirred solution of t-butyl (7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate (182 mg, 0.44 mmol, 1 eq) in DCM (5 mL) under N2, TFA (5 mL) was added and the resulting mixture was stirred at room temperature for 2 h. The solution was concentrated. The crude residue was treated with aqueous NH4OH and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give the title compound (90 mg, 60% yield) as a yellow solid.

[0333] LCMS: m / z 454.44 [M+1] + .

[0334] Method G, Step 4. Synthesis of N-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamin.

[0335] [ka]

[0336] To a stirred solution of 6-(2-aminospiro[4.5]non-6-en-7-yl)-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (90 mg, 0.198 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (76 mg, 0.76 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (17 mg, 0.198 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise. The resulting mixture was stirred at 0 °C under N2 for 0.5 h and then quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% HCOOH) to give the title compound (44.4 mg, 41% yield) as a white solid.

[0337] LCMS: m / z 508.40 [M+1] + .

[0338] 1 H NMR(400 MHz, CD3OD) δ 8.59(d, J = 5.0 Hz, 2H), 8.11(s, 1H), 7.43(d, J = 8.0 Hz, 2H), 7.24 - 7.20(m, 3H), 6.18(d, J = 8.0 Hz, 2H), 5.86 - 5.76(m, 1H), 5.62(t, J = 4.0 Hz, 1H), 4.45 - 4.26(m, 1H), 3.66(s, 3H), 2.33 - 2.04(m, 6H), 1.78-1.62(m , 4H).

[0339] Example 10 Synthesis of 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0340] [ka]

[0341] Method H, Step 1. Synthesis of 4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine.

[0342] To a solution of 4-chloro-7H-pyrrolo[2,4-d]pyrimidine (50 g, 426 mmol, 1 eq) in DMF (400 mL) at 0 °C under N2, Cs2CO4 (160 g, 489 mmol, 1.5 eq) was added followed by MeI (92 g, 652 mmol, 2 eq) and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water (4000 mL). The precipitated solid was collected by filtration, washed with water and dried under vacuum to give the title compound (41 g, 75%) as a white solid.

[0343] LCMS: m / z 168.44 [M+1] + .

[0344] Method H, Step 2. Synthesis of 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine. To a solution of the compound 4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine (41 g, 245 mmol, 1 eq) in DMF (450 mL) at 0 °C under N2, NBS (52.4 g, 294 mmol, 1.2 eq) was added in one portion followed by NBS (52.4 g, 294 mmol, 1.2 eq) and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give the title compound (54 g, 88%) as a white solid.

[0345] LCMS: m / z 247.80 [M+1] + .

[0346] Method H, Step 4. Synthesis of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0347] A mixture of 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine (15 g, 60.9 mmol, 1 eq) in NH4-H2O (150 mL) was stirred at 100 °C in a sealed tube for 72 h. The mixture was cooled to room temperature and diluted with water. The solid was filtered, washed with water, and dried under vacuum to give the title compound (12 g, 87%) as a white solid.

[0348] LCMS: m / z 227.04 [M+1] + . Method H, Step 4. Synthesis of 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0349] To a solution of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (6 g, 26.4 mmol, 1 eq) in DCM (60 mL) at 0 °C under N2, TFA (15 g, 142 mmol, 5 eq) and NIS (5.6 g, 41.7 mmol, 1.2 eq) were added in one portion. The mixture was stirred at room temperature for 2 h. The mixture was poured into a saturated aqueous solution of Na2SO4. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give the title compound (8.2 g, 88%) as a grey solid.

[0350] LCMS: m / z 452.96 [M+1] + .

[0351] Method H, Step 5. Synthesis of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0352] A mixture of 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (4 g, 8.5 mmol, 1 eq), tert-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (6.4 g, 17 mmol, 2 eq), Pd(PPh4)4 (981 mg, 0.85 mmol, 0.1 eq) and K4PO4 (4.52 g, 25.5 mmol, 4 eq) in DMF (24 mL) and HO (4 mL) was degassed four times with N2 and then stirred at 50 °C under N2 for 16 h. The resulting mixture was diluted with HO (50 mL) and extracted with EtOAc (4 × 40 mL). The combined organic layers were washed with brine (4×40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (70:1) to give the title compound (892 mg, 22% yield) as a yellow solid.

[0353] LCMS: m / z 476.20 [M+1] + .

[0354] Method H, Step 6. Synthesis of t-butyl 9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0355] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.442 mmol, 1 eq), 4-fluoro-phenylboronic acid (92 mg, 17 mmol, 1.5 eq), Pd(DtBPF)Cl2 (28 mg, 0.044 mmol, 0.1 eq) and K4PO4 (182 mg, 1.4 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 90 °C under N2 for 2 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (40 mg, 18% yield) as a yellow solid.

[0356] LCMS: m / z 491.25 [M+1] + . Method H, Step 7. Synthesis of 5-(4-fluorophenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0357] To a stirred solution of t-butyl 9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (40 mg, 0.08 mmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (41 mg, 99% yield) as a yellow solid.

[0358] LCMS: m / z 492.40 [M+1] + .

[0359] Method H, Step 8. Synthesis of 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0360] [ka]

[0361] To a stirred solution of 5-(4-fluorophenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (41 mg, 0.081 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (42 mg, 0.42 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (7.2 mg, 0.18 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (20.4 mg, 57% yield) as a white solid.

[0362] LCMS: m / z 446.30 [M+1] + .

[0363] 1HNMR(400 MHz, CD3OD) δ 8.34(s, 1H), 7.54 - 7.48(m, 1H), 7.25 - 7.14(m, 3H), 6.76(dd, J = 16.0, 12.0 Hz, 1H), 6.16(d, J = 16.0 Hz, 1H), 5.95(brs, 1H), 5.72(d, J = 12.0 Hz, 1H), 3.81(s, 3H), 3.75 - 3.61(m, 2H), 3.58 - 3.46(m, 2H), 2.17 - 2.14(m, 2H), 2.06 - 2.01(m, 2H), 1.60(t, J = 5.9 Hz, 2H), 1.48 - 1.38(m, 4H).

[0364] Example 11 Synthesis of 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0365] [ka]

[0366] Method I, Step 1. Synthesis of t-butyl 9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0367] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 1 eq), 4-fluoro-phenylboronic acid (44 mg, 0.41 mmol, 1.5 eq), Pd(DtBPF)Cl2 (14 mg, 0.02 mmol, 0.1 eq) and K4PO4 (87 mg, 0.64 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 90 °C for 2 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (91 mg, 88% yield) as a yellow solid.

[0368] LCMS: m / z 492.60 [M+1] + .

[0369] Method I, Step 2. Synthesis of 5-(4-fluorophenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0370] To a stirred solution of t-butyl 9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (90 mg, 0.18 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (56 mg, 78% yield) as a yellow solid.

[0371] LCMS: m / z 492.60 [M+1] + .

[0372] Method I, Step 4. Synthesis of 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0373] [ka]

[0374] To a stirred solution of 5-(4-fluorophenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (56 mg, 0.14 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (72 mg, 0.71 mmol, 5 eq). At 0 °C, a solution of acryloyl chloride (14 mg, 0.14 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (21.2 mg, 44% yield) as a white solid.

[0375] LCMS: m / z 446.30 [M+1] + .

[0376] 1H NMR(400 MHz, CD3OD) δ 8.30(s, 1H), 7.44 - 7.40(m, 2H), 7.24 - 7.20(m, 2H), 6.75(dd, J = 16.0, 10.6 Hz, 1H), 6.15(d, J = 16.0 Hz, 1H), 5.91(brs, 1H), 5.70(d, J = 10.6 Hz, 1H), 3.79(s, 3H), 3.75 - 3.59(m, 2H), 3.57 - 3.45(m, 2H), 2.15 - 2.11(m, 2H), 2.04 - 1.98(m, 2H), 1.61 - 1.55(m, 2H), 1.46 - 1.34(m, 4H).

[0377] Example 12 Synthesis of 1-(9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0378] [ka]

[0379] Method J, Step 1. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0380] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.42 mmol, 1 eq), pyridin-4-ylboronic acid (104 mg, 0.84 mmol, 2 eq), Pd(DtBPF)Cl (26 mg, 0.04 mmol, 0.1 eq) and KPO (174 mg, 1.26 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N and then stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (15:1) to give the title compound (160 mg, 80% yield) as a yellow solid.

[0381] LCMS: m / z 475.40 [M+1] + .

[0382] Method J, Step 2. Synthesis of 7-methyl-5-(pyridin-4-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0383] To a stirred solution of t-butyl 9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (160 mg, 0.44 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (100 mg, 80% yield) as a yellow solid.

[0384] LCMS: m / z 475.40 [M+1] + .

[0385] Method J, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0386] [ka]

[0387] To a stirred solution of 7-methyl-5-(pyridin-4-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (100 mg, 0.266 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (80 mg, 0.79 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (24 mg, 0.246 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (22 mg, 19% yield) as a white solid.

[0388] LCMS: m / z 429.35 [M+1] + .

[0389] 1H NMR(400 MHz, CD3OD) δ 9.00(s, 1H), 8.92(d, J = 4.0 Hz, 1H), 8.67(d, J = 8.0 Hz, 1H), 8.42(s, 1H), 8.21(t, J = 6.0 Hz, 1H), 6.77(dd, J =18.0, 10.0 Hz, 1H), 6.17(d, J = 18.0 Hz, 1H), 6.00(brs, 1H), 5.73(d, J =10.0 Hz, 1H), 3.84(s, 3H), 3.74 - 3.64(m, 2H), 3.59 - 3.51(m, 2H), 2.16(brs, 4H), 1.66(brs, 2H), 1.46 - 1.39(m, 4H).

[0390] Example 14 Synthesis of 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0391] [ka]

[0392] Method K, Step 1. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0393] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.42 mmol, 1 eq), (1-methyl-1H-pyrazol-5-yl)boronic acid (159 mg, 1.26 mmol, 4 eq), Pd(DtBPF)Cl2 (27 mg, 0.04 mmol, 0.1 eq) and K4PO4 (267 mg, 1.26 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 90 °C under N2 for 2 h. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (70 mg, 45% yield) as a yellow solid.

[0394] LCMS: m / z 478.40 [M+1] + .

[0395] Method K, Step 2. Synthesis of 7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (70 mg, 0.15 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (55 mg, 99% yield) as a yellow solid.

[0396] LCMS: m / z 477.0 [M+1] + .

[0397] Method K, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0398] [ka]

[0399] To a stirred solution of 7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-6-(4-azaspiro[5.5]-undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (55 mg, 0.14 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (59 mg, 0.58 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (14 mg, 0.146 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (46.5 mg, 57% yield) as a white solid.

[0400] LCMS: m / z 432.35[M+1] + .

[0401] 1 H NMR(400 MHz, CD3OD) δ 8.40(s, 1H), 8.16(s, 1H), 6.81 - 6.74(m , 2H), 6.17(d, J = 16.0, 1H), 5.99(brs, 1H), 5.75(d, J = 12.0 Hz, 1H), 3.88(s, 3H), 3.85(s, 3H), 3.61 - 3.58(m, 2H), 3.55 - 3.50(m, 2H), 2.19 - 2.16(m, 2H), 2.13 - 2.05(m, 2H), 1.71 - 1.61(m, 2H), 1.51 - 1.36(m, 4H).

[0402] Example 14 Synthesis of 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0403] [ka]

[0404] Method L, Step 1. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0405] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.42 mmol, 1 eq), (1-methyl-1H-pyrazol-4-yl)boronic acid (159 mg, 1.26 mmol, 4 eq), Pd(DtBPF)Cl (27 mg, 0.042 mmol, 0.1 eq) and KPO (267 mg, 1.26 mmol, 4 eq) in DMF (5 mL) and HO (0.5 mL) was stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (100 mg, 50% yield) as a yellow solid.

[0406] LCMS: m / z 478.6 [M+1] + .

[0407] Method L, Step 2. Synthesis of 7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (70 mg, 88% yield) as a yellow solid.

[0408] LCMS: m / z 478.7 [M+1] + .

[0409] Method L, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0410] [ka]

[0411] To a stirred solution of 7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(4-azaspiro[5.5]-undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (70 mg, 0.18 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (75 mg, 0.74 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (17 mg, 0.18 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (7.9 mg, 10% yield) as a white solid.

[0412] LCMS: m / z 432.4 [M+1] + .

[0413] 1 H NMR(400 MHz, CD3OD) δ 8.31(s, 1H), 7.95(s, 1H), 7.80(s, 1H), 6.77(dd, J = 16.0, 10.7 Hz, 1H), 6.17(d, J = 16.0 Hz, 1H), 5.95(brs, 1H), 5.73(d, J = 12.0 Hz, 1H), 4.04(s, 3H), 3.78(s, 3H), 3.73 - 3.59(m, 4H), 2.22 - 2.19(m, 2H), 2.14 - 2.11(m, 2H), 1.68 - 1.64(m, 2H), 1.51 - 1.41(m, 4H).

[0414] Example 15 Synthesis of 1-(9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0415] [ka]

[0416] Method M, Step 1. Synthesis of 7-methyl-5-(prop-1-en-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0417] A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1.8 g, 7.9 mmol, 1 eq), potassium trifluoro(prop-1-en-2-yl)boronate (1.76 g, 11.9 mmol, 1.5 eq), Pd(dppf)Cl2-DCM (650 mg, 0.79 mmol, 0.1 eq) and K2CO4 (2.74 g, 19.9 mmol, 4 eq) in dioxane (24 mL) and HO (4 mL) was degassed four times with N2 and then stirred at 100 °C under N2 for 16 h. The resulting mixture was diluted with HO (50 mL) and extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (70:1) to give the title compound (610 mg, 41% yield) as a yellow solid.

[0418] LCMS: m / z 189.24 [M+1] + .

[0419] Method M, Step 2. Synthesis of 5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0420] A suspension of 7-methyl-5-(prop-1-en-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (240 mg, 1.27 mmol, 1 eq) and Pd / C (50 mg) in MeOH (6 mL) was degassed with H2 four times and then stirred at room temperature under H2 for 2 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (220 mg, 91% yield) as a yellow solid, which was used directly in the next step without further purification.

[0421] LCMS: m / z 191.48 [M+1] + .

[0422] Method M, Step 4. Synthesis of 6-iodo-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a solution of compound 5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (440 mg, 1.74 mmol, 1 eq) in DCM (6 mL) at 0° C. under N2, TFA (990 mg, 8.7 mmol, 5 eq) and NIS (508 mg, 2.26 mmol, 1.4 eq) were added in one portion and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured into a saturated aqueous solution of Na2SO4. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (450 mg, 64%) as a grey solid.

[0423] LCMS: m / z 417.58 [M+1] + .

[0424] Method M, Step 4. Synthesis of t-butyl 9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0425] A mixture of 6-iodo-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (110 mg, 0.45 mmol, 1 eq), tert-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (196 mg, 0.52 mmol, 1.5 eq), Pd(dppf)Cl-DCM (29 mg, 0.045 mmol, 0.1 eq) and KCO (120 mg, 120 mmol, 2.5 eq) in dioxane (6 mL) and HO (0.6 mL) was degassed 4 times with N and then stirred at 100 °C under N for 16 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (110 mg, 72% yield) as a yellow solid.

[0426] LCMS: m / z 440.41 [M+1] + .

[0427] Method M, Step 5. Synthesis of 5-isopropyl-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0428] To a stirred solution of t-butyl 9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (110 mg, 0.25 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (60 mg, 70% yield) as a yellow solid.

[0429] LCMS: m / z 440.29 [M+1] + .

[0430] Method M, Step 6. Synthesis of 1-(9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0431] [ka]

[0432] To a stirred solution of 5-isopropyl-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (58 mg, 0.54 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (18.4 mg, 0.2 mmol, 1.2 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (29.8 mg, 49.5% yield) as a white solid.

[0433] LCMS: m / z 394.30 [M+1] + .

[0434] 1 H NMR(400 MHz, CD3OD) δ 8.24(s, 1H), 6.80(dd, J = 16.0, 10.0 Hz, 1H), 6.18(d, J = 16.0 Hz, 1H), 5.90(brs, 1H), 5.73(d, J = 10.0 Hz, 1H), 3.82 - 3.72(m, 2H), 3.66(s, 3H), 3.61 - 3.57(m, 2H), 3.37 - 3.32(m, 1H), 2.28 - 2.24(m, 4H), 1.79 - 1.75(m, 2H), 1.63 - 1.55(m, 4H), 1.34(d, J = 8.0Hz, 6H).

[0435] Example 16 Synthesis of 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0436] [ka]

[0437] Method N, Step 1. Synthesis of t-butyl 9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate. A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 1 eq), 4-methoxyphenylboronic acid (64 mg, 0.42 mmol, 2 eq), Pd(DtBPF)Cl2 (14 mg, 0.02 mmol, 0.1 eq) and K4PO4 (87 mg, 0.64 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed four times with N2 and then stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (74 mg, 70% yield) as a yellow solid. LCMS: m / z 504.6 [M+1] + . Method N, Step 2. Synthesis of 5-(4-methoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (74 mg, 0.15 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (48 mg, 81% yield) as a yellow solid. LCMS: m / z 404.50 [M+1] + . Method N, Step 4. Synthesis of 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0438] [ka]

[0439] To a stirred solution of 5-(4-methoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (48 mg, 0.12 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (61 mg, 0.6 mmol, 5 eq). At 0 °C, a solution of acryloyl chloride (11 mg, 0.12 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (28.9 mg, 54% yield) as a white solid.

[0440] LCMS: m / z 458.40 [M+1] + .

[0441] 1H NMR(400 MHz, CD3OD) δ 8.32(s, 1H), 7.43 - 7.39(m, 1H), 7.03 - 6.96(m , 3H), 6.75(dd, J = 16.0, 12.0 Hz, 1H), 6.16(dd, J = 16.0 Hz, 1H), 5.94(brs, 1H), 5.73 - 5.70(d, J = 12.0 Hz, 1H), 3.83(s, 3H), 3.80(s, 3H), 3.75 - 3.60(m, 2H), 3.57 - 3.45(m, 2H), 2.18 - 2.14(m, 2H), 2.06 - 2.02(m, 2H), 1.63 - 1.55(m, 2H), 1.48-1.37(m, 4H).

[0442] Example 17 Synthesis of 1-(9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0443] [ka]

[0444] Method O, Step 1. Synthesis of t-butyl 9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0445] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 1 eq), 4-difluoro-methoxyphenylboronic acid (79 mg, 0.42 mmol, 2 eq), Pd(DtBPF)Cl2 (14 mg, 0.02 mmol, 0.1 eq) and K4PO4 (87 mg, 0.64 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (98 mg, 86% yield) as a yellow solid.

[0446] LCMS: m / z 540.27 [M+1] + .

[0447] Method O, Step 2. Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (98 mg, 0.18 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (65 mg, 81% yield) as a yellow solid.

[0448] LCMS: m / z 404.50 [M+1] + .

[0449] Method O, Step 4. Synthesis of 1-(9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0450] [ka]

[0451] To a stirred solution of 5-(4-(difluoromethoxy)phenyl)-7-methyl-6-(4-azaspiro[5.5]-undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (65 mg, 0.15 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (76 mg, 0.75 mmol, 5 eq). At 0 °C, a solution of acryloyl chloride (14 mg, 0.15 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (25.9 mg, 45% yield) as a white solid. LCMS: m / z 494.35 [M+1] + . 1H NMR(400 MHz, CD3OD) δ 8.32(s, 1H), 7.45(d, J = 8.0 Hz, 2H), 7.27(d, J = 8.0 Hz, 2H), 7.92(t, J = 76.0 Hz, 1H), 6.74(dd, J = 16.0, 12.0 Hz, 1H), 6.16(d, J = 16.0 Hz, 1H), 5.93(brs, 1H), 5.72(dd, J = 12.0 Hz, 1H), 3.80(s, 3H), 3.74 - 3.59(m, 2H), 3.57 - 3.46(m, 2H), 2.16 - 2.13(m, 2H), 2.06 - 2.02(m, 2H), 1.61 - 1.58(m, 2H), 1.45 - 1.37(m, 4H). Example 18 Synthesis of 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0452] [ka]

[0453] Method P, Step 1. Synthesis of t-butyl 9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0454] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 1 eq), 4-cyclopropoxy-phenylboronic acid (75 mg, 0.42 mmol, 2 eq), Pd(DtBPF)Cl2 (14 mg, 0.02 mmol, 0.1 eq) and K4PO4 (87 mg, 0.64 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was degassed 4 times with N2 and stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (4×15 mL), dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (80 mg, 72% yield) as a yellow solid.

[0455] LCMS: m / z 540.70 [M+1] + .

[0456] Method P, Step 2. Synthesis of 5-(4-cyclopropoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (80 mg, 0.15 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (41 mg, 61% yield) as a yellow solid.

[0457] LCMS: m / z 440.60 [M+1] + .

[0458] Method P, Step 4. Synthesis of 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0459] [ka]

[0460] To a stirred solution of 5-(4-cyclopropoxyphenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (41 mg, 0.09 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (48 mg, 0.48 mmol, 5 eq). At 0 °C, a solution of acryloyl chloride (9 mg, 0.09 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (15.5 mg, 44% yield) as a white solid.

[0461] LCMS: m / z 484.40 [M+1] + .

[0462] 1H NMR(400 MHz, CD3OD) δ 8.29(s, 1H), 7.32(d, J = 8.0 Hz, 2H), 7.16(d, J = 8.0 Hz, 2H), 6.74(dd, J = 16.0, 12.0 Hz, 1H), 6.15(d, J = 16.0 Hz, 1H), 5.91(brs, 1H), 5.71(dd, J = 12.0 Hz, 1H), 3.86 - 3.80(m, 1H), 3.79(s, 3H), 3.73 - 3.59(m, 2H), 3.57 - 3.44(m, 2H), 2.16 - 2.12(m, 2H), 2.05 - 2.00(m, 2H), 1.62 - 1.52(m, 2H), 1.47 - 1.31(m, 4H), 0.87 - 0.78(m, 2H), 0.77 - 0.66(m, 2H).

[0463] Example 19 Synthesis of N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)acrylamide.

[0464] [ka]

[0465] Method Q, Step 1. Synthesis of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate.

[0466] A mixture of 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (600 mg, 1.57 mmol, 1 eq), tert-butyl (7-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)spiro[4.5]non-6-en-2-yl)carbamate (1.08 g, 4.14 mmol, 2 eq), Pd(dppf)Cl2 (129 mg, 0.157 mmol, 0.1 eq) and K2CO4 (648 mg, 4.71 mmol, 4 eq) in dioxane (15 mL) and HO (1.5 mL) was degassed four times with N2 and then stirred at 100 °C under microwave irradiation for 40 min. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (40:1) to give the crude product (490 mg, 50% purity). The crude product was purified by Prep-C18 eluting with H2O / ACN (4:2) to give the title compound (110 mg, 24% yield) as a yellow solid.

[0467] LCMS: m / z 490.40 [M+1] + .

[0468] Method Q, Step 2. Synthesis of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)carbamate. To a stirred solution of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)carbamate (110 mg, 0.22 mmol, 1 eq) in MeOH (40 mL) was added Pd / C (100 mg). The resulting mixture was degassed with H2 four times and stirred at room temperature under H2 for 48 h, then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give the title compound (24 mg, 12% yield) as a yellow solid.

[0469] LCMS: m / z 492.44 [M+1] + .

[0470] Method Q, Step 4. Synthesis of 6-(2-aminospiro[4.5]phenyl-7-yl)-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0471] To a stirred solution of t-butyl (7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)carbamate (24 mg, 0.046 mmol, 1 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (16.7 mg, 92% yield) as a yellow solid.

[0472] LCMS: m / z 492.44 [M+1] + .

[0473] Method Q, Step 4. Synthesis of N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)acrylamide.

[0474] [ka]

[0475] To a stirred solution of 6-(2-aminospiro[4.5]-amino-7-yl)-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (16.7 mg, 0.042 mmol, 1 eq) in anhydrous CHCl4 (5 mL) was added TEA (12.7 mg, 0.126 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (4.8 mg, 0.042 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (2.7 mg, 14% yield) as a white solid.

[0476] LCMS: m / z 446.40 [M+1] + .

[0477] 1 H NMR(400 MHz, CD3OD) δ 8.25(s, 1H), 7.33 - 7.30(m, 2H), 7.08 - 7.05(m, 2H), 6.18(d, J = 8.0 Hz, 2H), 5.62(t, J = 6.0 Hz, 1H), 4.27 - 4.18(m, 1H), 3.90(s, 3H), 3.86(s, 3H), 2.89 - 2.82(m, 1H), 2.11 - 2.05(m, 2H), 1.82 - 1.79(m, 1H), 1.71 - 1.66(m, 2H), 1.62 - 1.56(m, 3H), 1.49 - 1.40(m, 4H).

[0478] Example 20 Synthesis of 1-(9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0479] [ka]

[0480] Method R, Step 1. Synthesis of 1-(2-(4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)phenoxy)ethyl)pyrrolidine.

[0481] To a mixture of 4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)phenol (2 g, 9.1 mmol, 1 eq), 2-(pyrrolidin-1-yl)ethan-1-ol (1.25 g, 10.9 mmol, 1.2 eq) and PPh4 (4 g, 10.9 mmol, 1.2 eq) in anhydrous THF (20 mL) was added dropwise DIAD (2.2 g, 10.9 mmol, 1.2 eq) at 0 °C under N2, and the resulting mixture was stirred at room temperature under N2 for 16 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the title compound (1.8 g, 62% yield) as a white solid.

[0482] LCMS: m / z 418.5 [M+1] + .

[0483] Method R, Step 2. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0484] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.42 mmol, 1 eq), 1-(2-(4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)phenoxy)ethyl)pyrrolidine (418 mg, 0.84 mmol, 2 eq), Pd(DtBPF)Cl2 (26 mg, 0.042 mmol, 0.1 eq) and K4PO4 (267 mg, 1.26 mmol, 4 eq) in DMF (5 mL) and HO (0.5 mL) was bubbled with N2 for 2 min and then stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (4 x 15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (115 mg, 47% yield) as a yellow solid.

[0485] LCMS: m / z 487.8 [M+1] + .

[0486] Method R, Step 4. Synthesis of 7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)-phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (115 mg, 0.19 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give the title compound (85 mg, 89% yield) as a yellow solid.

[0487] LCMS: m / z 487.7 [M+1] + .

[0488] Method R, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0489] [ka]

[0490] To a stirred solution of 7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (85 mg, 0.17 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (71 mg, 0.70 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (15 mg, 0.17 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O containing 0.1% TFA) to give the title compound (26.2 mg, 28% yield) as a white solid.

[0491] LCMS: m / z 541.5 [M+1]+.

[0492] 1H NMR(400 MHz, CD3OD) δ 8.32(s, 1H), 7.39(d, J = 8.0 Hz, 2H), 7.17(d, J = 8.0 Hz, 2H), 6.78(dd, J = 16.0, 10.7 Hz, 1H), 6.17(d, J = 16.0 Hz, 1H), 5.93(brs, 1H), 5.73(d, J = 10.7 Hz, 1H), 4.43 - 4.41(m, 2H), 3.80(s, 3H), 3.76 - 3.63(m, 6H), 3.59 - 3.43(m, 2H), 3.28 - 3.22(m, 2H), 2.23 - 2.00(m, 8H), 1.61 - 1.54(m, 2H), 1.52 - 1.41(m, 2H), 1.38 - 1.31(m, 2H).

[0493] Example 21 Synthesis of 1-(9-(4-amino-7-methyl-5-(6-(methylamino)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0494] [ka]

[0495] Method S, Step 1. Synthesis of t-butyl 9-(4-amino-5-(6-((t-butoxycarbonyl)(methyl)amino)pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0496] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (260 mg, 0.54 mmol, 1 eq), t-butyl methyl-(5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)pyridin-2-yl)carbamate (468 mg, 1.1 mmol, 2 eq), Pd(DtBPF)Cl2 (46 mg, 0.05 mmol, 0.1 eq) and K4PO4 (226 mg, 1.64 mmol, 4 eq) in DMF (10 mL) and HO (1 mL) was bubbled with N2 for 2 min and then stirred at 120 °C under microwave irradiation for 40 min. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (4 x 15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (170 mg, 52% yield) as a red solid.

[0497] LCMS: m / z 604.70 [M+1] + .

[0498] Method S, Step 2. Synthesis of 7-methyl-5-(6-(methylamino)pyridin-4-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-(4-amino-5-(6-((t-butoxycarbonyl)(methyl)amino)-pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (120 mg, 0.2 mmol, 1 eq) in DCM (4 mL) was added TFA (4 mL) and the mixture was stirred at room temperature for 4 h. The solution was concentrated to give the crude title compound (64 mg, 78% yield) as a yellow solid.

[0499] LCMS: m / z 404.55 [M+1] + .

[0500] Method S, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(6-(methylamino)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0501] [ka]

[0502] To a stirred solution of 7-methyl-5-(6-(methylamino)pyridin-4-yl)-6-(4-azaspiro[5.5]-undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (64 mg, 0.15 mmol, 1 eq) in anhydrous CHCl4 (4 mL) was added TEA (79 mg, 0.78 mmol, 5 eq). At 0 °C, a solution of acryloyl chloride (14 mg, 0.15 mmol, 1 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O with 0.1% TFA) to give the title compound (28 mg, 49% yield) as a white solid.

[0503] LCMS: m / z 458.40 [M+1] + .

[0504] 1H NMR(400 MHz, CD3OD) δ 8.34(s, 1H), 7.89 - 7.85(m, 2H), 7.14(d, J = 8.0 Hz, 1H), 6.77(dd, J = 16.0, 12.0 Hz, 1H), 6.17(d, J = 16.0 Hz, 1H), 5.97(brs, 1H), 5.72(d, J = 12.0 Hz, 1H), 3.80(s, 3H), 3.72 - 3.55(m, 2H), 3.63 - 3.48(m, 2H), 3.10(s, 3H), 2.22 - 2.11(m, 4H), 1.71 - 1.62(m, 2H), 1.49 - 1.37(m, 4H).

[0505] Example 22 Synthesis of 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0506] [ka]

[0507] Method T, Step 1. Synthesis of 5-bromo-2-cyclopropoxypyridine.

[0508] To a solution of 5-bromo-2-fluoropyridine (7.5 g, 42.6 mmol) and cyclopropanol (2.97 g, 51.1 mmol) in THF (10 mL) was added t-BuOK (11.95 g, 106.5 mmol) batchwise. The mixture was stirred at 80 °C for 4 h, then poured into water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / PE = 0%-10%) to give 5-bromo-2-(cyclopropoxy)-pyridine (4.8 g, 22.424 mmol, 52.64%) as a yellow oil.

[0509] LC-MS m / e: 214.1(MH + ).

[0510] Method T, Step 2. Synthesis of 2-cyclopropoxy-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)pyridine.

[0511] To a mixture of 5-bromo-2-(cyclopropoxy)pyridine (4.4 g, 20.088 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,4,2-dioxaboran-2-yl)-1,4,2-dioxaborolane (6.246 mL, 24.1 mmol) in dioxane (50 mL) was added Pd(dppf)Cl2 (0.74 g, 1 mmol) and KOAc (5.91 g, 60.4 mmol) under nitrogen gas. The mixture was stirred at 100 °C for 4 h, then cooled to room temperature, poured into water (400 mL), extracted with EtOAc (200 mL x 2), and the combined organic layers were washed with brine (100 mL x 2) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 10% to 40% EtOAc:PE) to give 2-(cyclopropoxy)-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)pyridine (4.6 g, 17.6 mmol, 87.6%) as a yellow oil.

[0512] Method T, Step 4. Synthesis of t-butyl 9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate. To a mixture of 2-methylpropan-2-yl 9-(4-amino-5-bromo-7-methylpyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (600 mg, 1.26 mmol) and 2-(cyclopropoxy)-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)pyridine (494.4 mg, 1.889 mmol) in dioxane (40 mL) was added a solution of Pd(DtBPF)Cl2 (81.4 mg, 0.126 mmol) and K4PO4 (802 mg, 4.78 mmol) in HO (5 mL). The mixture was stirred at 90 °C for 2 h, then poured into water and extracted with EA (100 mL × 4). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with (EtOAc / PE=80%-100%, then DCM:MeOH=10:1) to give crude t-butyl 9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (1 g, 1.884 mmol, 149.64%) as a brown solid. LC-MS m / e: 541.1(MH + ). Method T, Step 4. Synthesis of 5-(6-cyclopropoxypyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a solution of t-butyl 9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (400 mg, 0.754 mmol) in DCM (4 mL) was added TFA (1 mL, 14.464 mmol) at 0° C., and the mixture was stirred for 1 h at 25° C. The mixture was concentrated in vacuo to give crude 5-(6-cyclopropoxypyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (420 mg, 0.744 mmol, 98.60%) as a brown solid. LC-MS m / e: 441.1(MH + ). Method T, Step 5. Synthesis of 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0513] [ka]

[0514] At 0° C., a solution of prop-2-enoyl chloride (0.06 mL, 0.744 mmol) in DCM (2 mL) was added to a mixture of 5-(6-cyclopropoxypyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (420 mg, 0.744 mmol) and TEA (0.207 mL, 1.49 mmol) in DCM (5 mL), and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by the addition of MeOH and then concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH / DCM=5%-10%) to give the crude product. The crude product was purified by prep-HPLC (ACN / HO containing 0.1% FA) to give 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]-undec-8-en-4-yl)prop-2-en-1-one (74.7 mg, 0.152 mmol, 20.46%) as a yellow solid.

[0515] 1H NMR(400 MHz, DMSO-d6) δ 8.15 - 8.11(m, 2H), 7.65(dd, J = 8.5, 2.4 Hz, 1H), 6.91(d, J = 8.4 Hz, 1H), 6.78(dd, J = 16.7, 10.5 Hz, 1H), 6.06(dd, J = 16.7, 2.4 Hz, 1H), 5.88(s, 2H), 5.78(s, 1H), 5.64(dd, J = 10.5, 2.4 Hz, 1H), 4.22(dt, J = 9.2, 3.1 Hz, 1H), 3.61(s, 3H), 3.58 - 3.40(m, 4H), 2.08 - 1.92(m, 4H), 1.50(t, J = 6.2 Hz, 2H), 1.37 - 1.11(m, 4H), 0.82 - 0.74(m, 2H), 0.74 - 0.64(m, 2H). LC-MS m / e: 485.3(MH + ).

[0516] Using the same or similar procedures described above, the compounds in Table 1 were prepared.

[0517] [Table 4] JPEG2025511287000096.jpg84169

[0518] Example 27 Synthesis of 1-(9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0519] [ka]

[0520] Method U, Step 1. Synthesis of t-butyl 9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0521] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.42 mmol), (5-fluoropyridin-4-yl)boronic acid (88.74 mg, 0.64 mmol), Pd(DtBPF)Cl2 (27.47 mg, 0.042 mmol) and K4PO4 (267.46 mg, 1.26 mmol) in dioxane (10 mL) and H2O (1 mL) was degassed four times with N2 and then stirred at 90 °C under N2 for 2 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with DCM / MeOH (20:1) to obtain the compound t-butyl 9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.204 mmol, 48.46%) as a yellow solid.

[0522] LC-MS m / e: 494.6(MH + ).

[0523] Method U, Step 2. Synthesis of 5-(5-fluoropyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a stirred solution of t-butyl 9-[4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl]-4-azaspiro[5.5]undec-8-ene-4-carboxylate (45 mg, 0.091 mmol) in DCM (10 mL), TFA (0.068 mL, 0.914 mmol) was added and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give crude 5-(5-fluoropyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (40 mg, 0.076 mmol, 84.67%) as a yellow solid.

[0524] LC-MS m / e: 494.4(MH + ).

[0525] Method U, Step 4. Synthesis of 1-(9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0526] [ka]

[0527] To a stirred solution of 5-(5-fluoropyridin-4-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (40 mg, 0.076 mmol) in DCM (10 mL) was added TEA (0.011 mL, 0.076 mmol). Then, at 0 °C, a solution of prop-2-enoyl chloride (0.007 mL, 0.084 mmol) in anhydrous DCM (1 mL) was added. After addition, the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched by the addition of MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / HO containing 0.1% FA) to obtain the compound 1-(9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (4.1 mg, 0.009 mmol, 12%) as a white solid.

[0528] LC-MS m / e: 447.3(MH + ).

[0529] 1 H NMR(400 MHz, DMSO-d6) δ 8.51(s, 1H), 8.38(s, 1H), 8.16(s, 1H), 7.60(d, J = 9.4 Hz, 1H), 6.79(dd, J = 16.0, 10.3 Hz, 1H), 6.15 - 6.00(m, 3H), 5.81(s, 1H), 5.64(d, J = 10.3 Hz, 1H), 3.65 - 3.37(m, 7H), 2.10 -1.96(m, 4H), 1.55 -1.47(m, 2H), 1.37 - 1.26(m, 4H).

[0530] Using the same or similar procedures as above, the examples in Table 2 were prepared.

[0531] [Table 5] JPEG2025511287000100.jpg69169

[0532] Example 44 Synthesis of 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0533] [ka]

[0534] Method V, Step 1. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0535] To a solution of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (400 mg, 0.64 mmol) in DMAc (10 mL) was added cuprous iodide (12 mg, 0.064 mmol), CsF (191 mg, 1.26 mmol), Pd(PPh4)4 (74 mg, 0.064 mmol) and 2-(tributylstannyl)pyrimidine (450 mg, 0.95 mmol). The suspension was degassed in vacuum and purged with N2 several times. The resulting mixture was stirred at 90 °C under N2 for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give t-butyl 9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol, 44%) as a brown solid.

[0536] LC-MS m / e: 476(MH + ).

[0537] Method V, Step 2. Synthesis of 7-methyl-5-(pyrimidin-2-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0538] To a solution of t-butyl 9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (100 mg, 0.21 mmol) in MeOH (2 mL) was added 4 M HCl in dioxane (4 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give a solid 7-methyl-5-(pyrimidin-2-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (78 mg, 0.21 mmol, quantitative), which was used directly in the next step without further purification.

[0539] LC-MS m / e: 476(MH + ).

[0540] Method V, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0541] [ka]

[0542] To a suspension of 7-methyl-5-(pyrimidin-2-yl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (78 mg, 0.21 mmol) and triethylamine (0.22 mL, 1.6 mmol) in DCM (10 mL) was added a solution of prop-2-enoyl chloride (22 mg, 0.25 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred for 40 min at 0° C. and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (20 mg, 46 μmol, 22%) as a white solid.

[0543] LC-MS m / e: 430.2(MH + ).

[0544] 1 H NMR(400 MHz, DMSO-d6) δ 8.77(d, J = 5.0 Hz, 2H), 8.10(s, 1H), 7.24(t, J = 5.0 Hz, 1H), 6.89 - 6.82(m, 3H), 6.11(dd, J = 16.8, 2.4 Hz, 1H), 5.69 - 5.64(m, 2H), 3.69 - 3.66(m, 2H), 3.59(s, 3H), 3.55 - 3.52(m, 2H), 2.35 - 2.25(m, 2H), 2.15 -2.05(m, 2H), 1.71 - 1.68(m, 2H), 1.59 - 1.55(m, 4H).

[0545] Using the same or similar procedures as above, the examples in Table 4 were prepared.

[0546] [Table 6] JPEG2025511287000104.jpg32169

[0547] manufacturing 4 Synthesis of t-butyl 9-(4-amino-5-bromo-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0548] [ka]

[0549] Method W, Step 1. Synthesis of 5-bromo-4-chloro-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidine.

[0550] To a stirred mixture of 5-bromo-4-chloro-7H-pyrrolo[2,4-d]pyrimidine (1.8 g, 7.74 mmol, 1 eq) and t-BuOK (1.7 g, 15.48 mmol, 2 eq) in ACN (40 mL) was added (bromodifluoromethyl)trimethylsilane (1.7 g, 8.51 mmol, 1.1 eq) at 0° C. under N2. The resulting mixture was stirred overnight at 45° C. and then poured into water (100 mL). The precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.1 g, 45.4%) as a yellow solid. LC-MS m / e: 282(MH + ).

[0551] Method W, Step 2. Synthesis of 5-bromo-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0552] A mixture of 5-bromo-4-chloro-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidine (1.1 g, 4.89 mmol, 1 eq) in NH4-H2O (20 mL) was stirred at 100 °C in a sealed tube for 24 h. The mixture was cooled to room temperature and diluted with water. The solid was filtered, washed with water, and dried under vacuum to give the title compound (1 g, 98%) as a white solid.

[0553] LC-MS m / e: 264(MH+ ).

[0554] Method W, Step 4. Synthesis of 5-bromo-7-(difluoromethyl)-6-iodo-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0555] To a solution of 5-bromo-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1 g, 4.8 mmol, 1 eq) in DMF (10 mL) was added NIS (1.28 g, 5.7 mmol, 1.5 eq) and CF4COOH (0.5 mL) at 0° C. under N2, and the resulting mixture was stirred at room temperature for 2 h. A saturated solution of Na2SO4 (10 mL) was added, and the mixture was poured into water (40 mL). The precipitated solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.9 g, 60.8%) as a yellow solid.

[0556] LC-MS m / e: 489(MH + ).

[0557] Method W, Step 4. Synthesis of t-butyl 9-(4-amino-5-bromo-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0558] A mixture of 5-bromo-7-(difluoromethyl)-6-iodo-7H-pyrrolo[2,4-d]pyrimidin-4-amine (0.4 g, 1 mmol, 1 eq), tert-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (0.5 g, 1.44 mmol, 1.4 eq), Pd(PPh4)4 (115.6 mg, 0.1 mmol, 0.1 eq) and K4PO4 (658.2 mg, 4.09 mmol, 4 eq) in DMF (10 mL) and HO (2 mL) was degassed four times with N2 and then stirred at 55 °C under N2 for 24 h. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine (4 x 40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (97:4) to give the title compound (400 mg, 75.9% yield) as a yellow solid. LC-MS m / e: 512(MH + ).

[0559] Example 46 Synthesis of 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0560] [ka]

[0561] Method X, Step 1. Synthesis of t-butyl 9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0562] A mixture of tert-butyl 9-(4-amino-5-bromo-7-(difluoromethyl)-7H-pyrrolo[2,4-d]-pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (400 mg, 0.78 mmol, 1 eq), 2-(4-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,4,2-dioxaborolane (404.6 mg, 1.17 mmol, 1.5 eq), Pd(DtBPF)Cl2 (50.4 mg, 0.078 mmol, 0.1 eq) and K4PO4 (498.4 mg, 2.44 mmol, 4 eq) in dioxane (10 mL) and HO (1 mL) was degassed 4 times with N2 and then stirred at 90 °C under N2 for 4 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (4 x 15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (97:4) to give the title compound (400 mg, 67.9% yield) as a yellow solid.

[0563] LC-MS m / e: 566(MH + ).

[0564] Method X, Step 2. Synthesis of 5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0565] To a stirred solution of t-butyl 9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (400 mg, 0.54 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 1 h. The solution was concentrated to give the title compound (150 mg, 60.8% yield) as a yellow solid.

[0566] LC-MS m / e: 466(MH + ).

[0567] Method X, Step 4. Synthesis of 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (Example 46) To a stirred solution of 5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-6-(4-azaspiro-[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (150 mg, 0.289 mmol) in DCM (20 mL) was added TEA (0.5 mL). Then, at 0 °C, a solution of acryloyl chloride (26.1 mg, 0.289 mmol) in anhydrous DCM (10 mL) was added dropwise. After addition, the resulting mixture was stirred at 0 °C under N2 for 0.5 h. The reaction mixture was quenched by addition of NH4Cl and extracted with DCM (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O containing 0.1% FA) to give the title compound (20 mg, 11.9% yield) as a white solid.

[0568] 5 1H NMR(400 MHz, DMSO-d6) δ 8.21(s, 1H), 7.92(t, J = 58.3 Hz, 1H), 7.31(d, J = 8.6 Hz, 2H), 7.14(d, J = 8.6 Hz, 2H), 6.77(dd, J = 16.7, 10.5 Hz, 1H), 6.06(dd, J = 16.7, 2.4 Hz, 1H), 5.85(s, 1H), 5.63(dd, J = 10.5, 2.4 Hz, 1H), 3.89(dt, J = 9.0, 3.0 Hz, 1H), 3.62 - 3.49(m, 2H), 3.45 - 3.32(m, 2H), 2.04 - 1.90(m, J = 18.4 Hz, 4H), 1.45(t, J = 6.0 Hz, 2H), 1.33 - 1.10(m, 4H), 0.88 - 0.78(m, 2H), 0.72 - 0.64(m, 2H).

[0569] LC-MS m / e: 520.3(MH + ).

[0570] Using the same or similar procedures as above, the examples in Table 4 were prepared.

[0571] [Table 7]

[0572] Example 48 Synthesis of 1-(9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0573] [ka]

[0574] Method Y, Step 1. Synthesis of t-butyl 9-((trimethylsilyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0575] t-Butyl 9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (2 g, 7.48 mmol) was dissolved in DMF (40 mL) and placed under inert atmosphere. Then, chlorotrimethylsilane (1.91 mL, 15 mmol) was added dropwise and TEA (4.12 mL, 22.4 mmol) was added. The resulting solution was heated to 80 °C and stirred overnight, after which the reaction mixture was cooled to room temperature and diluted with DCM and saturated NaHCO4 solution. The aqueous layer was extracted with DCM (20 mL x 4). The combined organic extracts were washed with H2O and filtered through a phase separator. The solvent was removed. The crude residue was purified by column chromatography (1% to 10% EtOAc / Hexanes) to give the title compound t-butyl 9-[(trimethylsilyl)oxy]-4-azaspiro[5.5]undec-8-ene-4-carboxylate (2.5 g, 7.464 mmol, 98.44%).

[0576] Method Y, Step 2. Synthesis of t-butyl 8-fluoro-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate.

[0577] t-Butyl 9-[(trimethylsilyl)oxy]-4-azaspiro[5.5]undec-8-ene-4-carboxylate (2.5 g, 7.4 mmol) was dissolved in CH4CN (40 mL) and cooled to 0°C. Then, l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Select-F, 4.91 g, 11 mmol, 1.5 eq.) was added. The resulting solution was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with EtOAc and brine, and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered through MgSO4. The solvent was removed to give the title compound t-butyl 8-fluoro-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (850 mg, 2.98 mmol, 40.5%) as a colorless oil.

[0578] Method Y, Step 4. Synthesis of t-butyl 8-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0579] To a stirred solution of t-butyl 8-fluoro-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (700 mg, 2.45 mmol) in anhydrous THF (15 mL) at -78 °C under N2, LiHMDS solution (2.94 mL, 2.94 mmol) was added dropwise and the mixture was stirred at -78 °C for 1 h. Then, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethane-sulfonamide (1414 mg, 4.68 mmol) in anhydrous THF (15 mL) was added dropwise and the mixture was allowed to warm slowly to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1-8:1) to give t-butyl 8-fluoro-9-(trifluoro-methanesulfonyloxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (595 mg, 1.425 mmol, 58.11%) as a colorless oil.

[0580] Method Y, Step 4. Synthesis of t-butyl 8-fluoro-9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0581] To a stirred solution of t-butyl 8-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (595 mg, 1.425 mmol) in DMF (10 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-1,4,2-dioxaboran-2-yl)-1,4,2-dioxaborolane (0.749 mL, 2.85 mmol), potassium acetate (419.7 mg, 4.28 mmol) and Pd(dppf)Cl2 (41.4 mg, 0.044 mmol). The reaction was stirred at 100 °C under N2 for 4 h, diluted with EtOAc (200 mL) and HO (200 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine (5×100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1-8:1) to give t-butyl 8-fluoro-9-(tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro-[5.5]undec-8-ene-4-carboxylate (400 mg, 1 mmol, 71%) as a colorless oil.

[0582] Method Y, Step 5. Synthesis of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0583] A mixture of the compounds 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (600 mg, 1.7 mmol), t-butyl 8-fluoro-9-(tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (1008 mg, 2.55 mmol), Pd(PPh4)4 (196.44 mg, 0.17 mmol) and K4PO4 (1082.52 mg, 5.1 mmol) in DMF (16 mL) and HO (2 mL) was degassed four times with N2 and then stirred at 50 °C under N2 for 16 h. The resulting mixture was diluted with HO (50 mL) and extracted with EtOAc (4 × 40 mL). The combined organic layers were washed with brine (4×40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM / MeOH (70:1) to give t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate (600 mg, 1.214 mmol, 71.49%) as a yellow solid.

[0584] LC-MS m / e: 496.4 (M+1) + .

[0585] Method Y, Step 6. Synthesis of t-butyl 9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0586] A mixture of t-butyl 9-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate (800 mg, 1.679 mmol), 2-(4-(methoxy-d4)-phenyl)-4,4,5,5-tetramethyl-1,4,2-dioxaborolane (95.92 mg, 0.405 mmol), 1,1'-bis(di-t-butyl-phosphino)ferrocene palladium dichloride (41.04 mg, 0.064 mmol) and K4PO4 (128.8 mg, 0.607 mmol) in DMF (5 mL) and HO (0.5 mL) was degassed four times with N2 and then stirred at 90 °C under N2 for 4 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (4 x 15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:EA 0% to 100% to give t-butyl 9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate (246 mg, 0.466 mmol, 27.7%) as a yellow solid.

[0587] LC-MS m / e: 525.6 (M+1) + .

[0588] Method Y, Step 7. Synthesis of 6-(8-fluoro-4-azaspiro[5.5]undec-8-en-9-yl)-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0589] To a stirred solution of t-butyl 9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-ene-4-carboxylate (80 mg, 0.152 mmol) in DCM (10 mL), TFA (0.044 mL, 0.456 mmol) was added and the mixture was stirred at room temperature for 2 h. The solution was concentrated to give crude 6-(8-fluoro-4-azaspiro[5.5]undec-8-en-9-yl)-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (50 mg, 0.118 mmol, 77.24%) as a yellow solid.

[0590] LC-MS m / e: 425.6 (M+1) + .

[0591] Method Y, Step 8. Synthesis of 1-(9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0592] [ka]

[0593] To a stirred solution of 6-(8-fluoro-4-azaspiro[5.5]undec-8-en-9-yl)-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (60 mg, 0.141 mmol) in DCM (10 mL) was added TEA (0.059 mL, 0.424 mmol). At 0° C., a solution of prop-2-enoyl chloride (0.014 mL, 0.17 mmol) in anhydrous DCM (1 mL) was added. The resulting mixture was stirred at 0° C. under N2 for 0.5 h and then quenched with MeOH. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O containing 0.1% TFA) to obtain the compound 1-(9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (40 mg, 0.084 mmol, 59.14%) as a white solid.

[0594] LC-MS m / e: 479.8(MH + ).

[0595] 1 H NMR(400 MHz, DMSO-d6) δ 8.20(s, 1H), 7.25(d, J = 8.5 Hz, 2H), 7.03(d, J = 8.5 Hz, 2H), 6.79(dd, J = 16.7, 10.5 Hz, 1H), 6.23(s, 2H), 6.07(dd, J = 16.7, 2.3 Hz, 1H), 5.65(dd, J = 10.5, 2.3 Hz, 1H), 3.68 - 3.42(m, 7H), 2.29(s, 2H), 2.15 - 1.70(m, 2H), 1.54 - 1.22(m, 6H).

[0596] Method Y, Step 9. Synthesis of 1-bromo-4-(methoxy-d4)benzene.

[0597] A solution of 4-bromophenol (2 g, 11.6 mmol) in THF (40 mL) was cooled to 0° C. and 60% sodium hydride dispersion in mineral oil (0.924 g, 24.1 mmol) was added batchwise. After the addition, the mixture was stirred at room temperature for 40 min, after which CD4I (1.08 mL, 17.4 mmol) was added. The mixture was stirred at room temperature for 2 h. Sodium sulfite solution was added to quench the reaction mixture, which was then extracted with EtOAc (4×20 mL). The combined organic layers were dried, filtered, and concentrated in vacuo to give 1-bromo-4-(methoxy-d4)benzene (2 g, 10.5 mmol, 91%) as a colorless oil.

[0598] Method Y, Step 10. Synthesis of 2-(4-(methoxy-d4)phenyl)-4,4,5,5-tetramethyl-1,4,2-dioxaborolane.

[0599] A mixture of 1-bromo-4-(methoxy-d4)benzene (2.21 g, 11.6 mmol), bis(pinacolato)diboron (4.54 g, 14 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.47 g, 0.58 mmol) and potassium acetate (2.85 g, 29 mmol) in anhydrous dioxane (50 mL) was purged four times with argon gas and placed under vacuum four times.

[0600] The mixture was stirred at 90° C. for 21 h, the reaction mixture was cooled to room temperature and then filtered through a filter pad. The organic solvent was removed under reduced pressure to give a black residue, 2-(4-(methoxy-d4)phenyl)-4,4,5,5-tetramethyl-1,4,2-dioxaborolane (2 g, 8.445 mmol, 72.46%), which was used directly in the next step without purification.

[0601] Example 49 Synthesis of 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0602] [ka]

[0603] Method Z, Step 1. Synthesis of t-butyl (Z)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate.

[0604] To a stirred solution of chloro(methoxymethyl)triphenyl-λ5-phosphane (12 g, 45 mmol) in anhydrous THF (150 mL) was added t-BuOK (4.94 g, 45.17 mmol) batchwise at 4° C. under N2 atmosphere. A bright orange color was observed and the reaction was continued for 1 h. At a temperature below 10° C., 2-methylpropan-2-yl 2-methyl-4-oxohexahydropyridine-1-carboxylate (5 g, 24.4 mmol) was added slowly. The resulting mixture was then allowed to warm to room temperature and stirred overnight. It was quenched with water and extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give t-butyl (Z)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate (5 g, 20.7 mmol, 88.4%) as a colorless oil.

[0605] LC-MS m / e: 242.1(MH + ).

[0606] Method Z, Step 2. Synthesis of t-butyl 4-formyl-2-methylpiperidine-1-carboxylate.

[0607] To a solution of t-butyl (Z)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate (5.4 g, 22.48 mmol) in MeCN (550 mL) was added 1 M HCl (22.4 mL) at 0° C. The reaction was then stirred at room temperature for 2 h. The mixture was quenched with NaHCO4 and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography to give t-butyl 4-formyl-2-methylpiperidine-1-carboxylate (4 g, 19.4 mmol, 86.5%) as a colorless oil.

[0608] LC-MS m / e: 228.1(MH + ).

[0609] Method Z, Step 4. Synthesis of t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undec-7-ene-4-carboxylate.

[0610] To a solution of t-butyl 4-formyl-2-methylpiperidine-1-carboxylate (6.4 g, 28 mmol) in EtOH (100 mL) was added but-4-en-2-one (4.5 mL, 55.4 mmol) followed by batchwise addition of t-BuOK (9.4 g, 84 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, acidified to pH=7 with 1N HCl and extracted with EA. The combined organic layers were dried, concentrated and purified by chromatography to give t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undec-7-ene-4-carboxylate (4 g, 10.7 mmol, 48.7%) as a yellow oil.

[0611] LC-MS m / e: 224 [M+H-56] + .

[0612] Method Z, Step 4. Synthesis of t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate.

[0613] To a solution of t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undec-7-ene-4-carboxylate (4 g, 14.42 mmol) in EtOH (50 mL) was added Pd / C 10% (4 g). The mixture was stirred under 50 psi H2 for 1 h. The mixture was filtered through a filter pad. The filtrate was concentrated to give t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (4.5 g, 12.4 mmol, 86.9%) as a colorless oil.

[0614] LC-MS m / e: 226.1 [M-55] + .

[0615] Method Z, Step 5. Synthesis of t-butyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0616] LiHMDS (21.4 mL) was added dropwise to a solution of t-butyl 2-methyl-9-oxo-4-azaspiro[5.5]undecane-4-carboxylate (4 g, 10.7 mmol) in THF (50 mL) at -60°C under N2 atmosphere and stirred for 1 h. A solution of N-[dioxo(trifluoromethyl)-λ6-sulfanyl]-1,1,1-trifluoro-N-phenylmethanesulfonamide (7.62 g, 21.4 mmol) in THF was added dropwise at -60°C, and the mixture was then allowed to warm slowly to room temperature and stirred overnight. The mixture was quenched with NH4Cl solution and extracted with EtOAc. The combined organic layers were dried, concentrated and purified by chromatography to give t-butyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (1.8 g, 4.45 mmol, 40.84%) as a colorless oil.

[0617] Method Z, Step 6. Synthesis of 2-methylpropan-2-yl 2-methyl-9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0618] To a solution of t-butyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro-[5.5]undec-8-ene-4-carboxylate (1 g, 2.42 mmol) in DMSO (10 mL) was added potassium acetate (0.47 g, 4.84 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-1,4,2-dioxaborolane (0.92 g, 4.64 mmol), followed by Pd(dppf)Cl2 (0.18 g, 0.242 mmol). The mixture was purged with N2 four times and stirred at 90 °C for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried, concentrated and purified by chromatography to give 2-methylpropan-2-yl 2-methyl-9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (600 mg, 1.54 mmol, 64.4%) as a colorless oil.

[0619] LC-MS m / e: 446.1 [M-55] + .

[0620] Method Z, Step 7. Synthesis of 2-methylpropan-2-yl 9-(4-amino-5-bromo-7-methylpyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0621] To a solution of 5-bromo-6-iodo-7-methylpyrrolo[2,4-d]pyrimidin-4-amine (400 mg, 1.14 mmol) in DMF (20 mL) was added 2-methylpropan-2-yl 2-methyl-9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (720 mg, 1.47 mmol), potassium phosphate tripotassium (481 mg, 2.27 mmol) in water (2 mL), followed by Pd(PPh4)4 (141 mg, 0.114 mmol). The mixture was purged with N2 four times and stirred at 50 °C for 16 h. It was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried, concentrated and purified by chromatography to give 2-methylpropan-2-yl 9-(4-amino-5-bromo-7-methylpyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate (450 mg, 0.714 mmol, 62.5%) as a colorless oil.

[0622] LCMS: m / z 490, 492(MH + ).

[0623] Method Z, Step 8. Synthesis of t-butyl 9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0624] To a solution of 2-methylpropan-2-yl 9-(4-amino-5-bromo-7-methylpyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate (450 mg, 0.714 mmol) in DMF (20 mL) was added (6-methoxypyridin-4-yl)boranediol (218 mg, 1.44 mmol), K4PO4 (404 mg, 1.44 mmol), followed by Pd(dtpf)Cl2 (46 mg, 0.07 mmol). The mixture was purged with N2 four times and stirred at 90 °C for 2 h. The mixture was cooled, diluted with water, and extracted with EtOAc. The combined organic layers were dried, concentrated and purified by chromatography to give t-butyl 9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate (240 mg, 0.444 mmol, 62.2%) as a brown solid.

[0625] LC-MS m / e: 519(MH + ).

[0626] Method Z, Step 9. Synthesis of 5-(6-methoxypyridin-4-yl)-7-methyl-6-(2-methyl-4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a solution of t-butyl 9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate (200 mg, 0.486 mmol) in MeOH (1 mL) was added HCl / dioxane (5 mL). The mixture was stirred at room temperature for 1 h and then concentrated to give 5-(6-methoxypyridin-4-yl)-7-methyl-6-(2-methyl-4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (180 mg, 0.44 mmol) as a brown solid.

[0627] LC-MS m / e: 419(MH + ).

[0628] Method Z, Step 10. Synthesis of 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0629] [ka]

[0630] To a suspension of t-butyl 9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-ene-4-carboxylate (160 mg, 0.41 mmol) in DCM (10 mL) at 0 °C was added EtN (0.2 mL, 1.54 mmol) followed by a solution of prop-2-enoyl chloride (46 mg, 0.4 mmol) in DCM (2 mL). After stirring at 0 °C for 40 min, the mixture was quenched with MeOH, concentrated, and purified by Prep-HPLC to give 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (40 mg, 0.064 mmol, 20.8%) as a white solid.

[0631] LC-MS m / e: 473.5(MH + ).

[0632] 1H NMR(400 MHz, DMSO-d6) δ 8.16(s, 1H), 8.08(d, J = 2.2 Hz, 1H), 7.64 - 7.61(m, 1H), 6.88(d, J = 8.5 Hz, 1H), 6.69 - 6.65(m, 1H), 6.07(s, 2H), 6.03(m, 1H), 5.74(d, J = 4.0 Hz, 1H), 5.66 - 5.62(m, 1H), 4.36 -4.07(m, 3H), 3.87(s, 3H), 3.61(s, 3H), 2.09 - 2.03(m, 1H), 1.98 -1.84(m, 3H), 1.56 - 1.54(m, 1H), 1.43 - 1.16(m, 5H), 1.14 - 1.07(m, 3H).

[0633] Example 49 can be further separated to obtain the following peaks (enantiomers): Instrument: Waters Thar 80 TM Preparative SFC, column: ChiralPak TM AD, 250×21.2 mm ID, 5 μm, mobile phase: A, CO2 and B, NH4 in 0.1% 7 mol / L MeOH, gradient: B 40%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 45° C., wavelength: 220 nm, circulation time: 40 min, elution time: 4H, peak 1 (retention time: 2.474 min), peak 2 (retention time: 2.911 min) and peak 4 (retention time: 4.477 min).

[0634] Using the same or similar procedures as above, the examples in Table 5 were prepared.

[0635] [Table 8]

[0636] Example 41 Synthesis of 1-(4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-en-9-yl)prop-2-en-1-one.

[0637] [ka]

[0638] Method AA, Step 1. Synthesis of t-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate.

[0639] To a stirred solution of compound t-butyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (400 mg, 1.11 mmol, 1 eq) in anhydrous THF (8 mL) at -78 °C under N2, LiHMDS solution (1.4 mL, 1.44 mmol, 1.2 eq, 1 M in THF) was added dropwise and the resulting mixture was stirred at -78 °C for 1 h. Then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesulfonamide (446 mg, 4.4 mmol, 1.1 eq) was added and the mixture was allowed to warm slowly to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (4 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1) to give the title compound (480 mg, 85% yield) as a colorless oil.

[0640] Method AA, Step 2. Synthesis of t-butyl 4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate.

[0641] To a stirred solution of compound t-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate (480 mg, 0.95 mmol, 1 eq) in DMF (5 mL) was added B2Pin2 (265 mg, 1.05 mmol, 1.1 eq), KOAc (280 mg, 2.85 mmol, 4 eq) and Pd(dppf)Cl2 (77.5 mg, 0.095 mmol, 0.1 eq). The reaction was stirred at 100 °C under N2 for 4 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (10 mL) and filtered through a filter pad. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (10:1) to give the title compound (280 mg, 77% yield) as a colorless oil.

[0642] Method AA, Step 4. Synthesis of 5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0643] A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (10 g, 44 mmol, 1 eq), (4-fluorophenyl)boronic acid (9.2 g, 66 mmol, 1.5 eq), K2CO4 (18.2 g, 142 mmol, 4 eq) and Pd(DtBPF)Cl2 (1.44 g, 2.2 mmol, 0.05 eq) in dioxane (150 mL) and H2O (15 mL) was stirred at 90 °C under N2 for 16 h. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (70:1) to give the title compound (9.5 g, 89%) as a brown solid.

[0644] LCMS: m / z 244.15 [M+1] + .

[0645] Method AA, Step 4. Synthesis of 5-(4-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0646] To a solution of 5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (9.5 g, 49.2 mmol, 1 eq) in DCM (120 mL) was added TFA (17.9 g, 157 mmol, 4 eq) and NIS (10.6 g, 47.1 mmol, 1.2 eq) in one portion under N2 at 0 °C and stirred at room temperature for 2 h. The mixture was poured into aqueous NaHCO4 (40 mL) and 10% aqueous Na2SO4 (20 mL). The resulting mixture was extracted with DCM (4 × 40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (70:1 to 50:1) to give the title compound (11.2 g, 78%) as a white solid.

[0647] LCMS: m / z 469.40 [M+1] + .

[0648] Method AA, Step 5. Synthesis of t-butyl 4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate.

[0649] A mixture of 5-(4-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (141 mg, 0.48 mmol, 1.1 eq), compound t-butyl 4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate (280 mg, 0.45 mmol, 1 eq), Pd(DtBPF)Cl2 (26 mg, 0.04 mmol, 0.1 eq) and K2CO4 (145 mg, 1.05 mmol, 4 eq) in dioxane (5 mL) / H2O (0.5 mL) was stirred at 90 °C under nitrogen atmosphere for 16 h. The resulting mixture was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (60:1) to give the title compound (90 mg, 48% yield) as a yellow solid.

[0650] LCMS: m / z 494.15 [M+1] + .

[0651] Method AA, Step 6. Synthesis of 5-(4-fluorophenyl)-7-methyl-6-(1-oxa-9-azaspiro[5.5]undec-4-en-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0652] To a mixture of t-butyl 4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-ene-9-carboxylate (90 mg, 0.18 mmol, 1 eq) in CHCl (4 mL) was added TFA (2 mL) under N. The reaction mixture was stirred at 0 °C for 1 h and then concentrated. The resulting residue was purified by TLC with DCM / MeOH (10:1) to give the title compound (46 mg, 51% yield) as a yellow solid.

[0653] LCMS: m / z 494.20 [M+1] + .

[0654] Method AA, Step 7. Synthesis of 1-(4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-en-9-yl)prop-2-en-1-one.

[0655] [ka]

[0656] To a mixture of 5-(4-fluorophenyl)-7-methyl-6-(1-oxa-9-azaspiro[5.5]undec-4-en-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (46 mg, 0.091 mmol, 1 eq) in anhydrous CHCl4 (10 mL) was added TEA (27.6 mg, 0.274 mmol, 4 eq). At 0 °C, a solution of acryloyl chloride (8.5 mg, 0.094 mmol, 1 eq) in anhydrous CHCl4 (1 mL) was added dropwise and stirred under N2 for 1 h. The reaction mixture was quenched with H2O, extracted with DCM (4 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified with DCM / MeOH (12:1) by TLC to give the title compound (18 mg, 44.4% yield).

[0657] LCMS: m / z 448.25 [M+1] + .

[0658] 1H NMR(400 MHz, CD3OD) δ 8.12(s, 1H), 7.46 - 7.38(m, 2H), 7.20(t, J = 8.0 Hz, 2H), 6.74(dd, J = 16.0, 10.0 Hz, 1H), 6.15(dd, J = 16.0, 2.0 Hz, 1H), 6.04(s, 1H), 5.70(dd, J = 10.0, 2.0 Hz, 1H), 4.19(d, J = 12.0 Hz, 1H), 3.97 - 3.88(m, 2H), 3.79(d, J = 12.0 Hz, 1H), 3.71(s, 3H), 3.35(t, J = 12.0 Hz, 1H), 2.99(t, J = 12.0 Hz, 1H), 2.18 - 2.11(m, 2H), 1.77(d, J = 12.0 Hz, 2H), 1.55 - 1.38(m, 2H).

[0659] Example 42 Synthesis of 1-(9-(4-amino-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0660] [ka]

[0661] Method AB, Step 1. Synthesis of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine.

[0662] A solution of 4-chloro-5-iodo-7H-pyrrolo[2,4-d]pyrimidine (20 g, 71.6 mmol) and CHI (6.68 mL, 107 mmol) in DMF (500 mL) was added to the reaction mixture, and the resulting solution was cooled to 5° C. 4(To the reaction mixture was added 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine (20.5 g, 69.84 mmol, 97% yield), which was not subjected to further purification.

[0663] 1 H NMR (400MHz, DMSO-d6): 8.65(s, 1H), 7.98(s, 1H), 3.83(s, 3H). Method AB, Step 2. 4-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7H-pyrrolo[2,4-d]pyrimidine At -10°C, a solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine (1.16 g, 4.96 mmol) in anhydrous THF (50 mL) was slowly added with a solution of i-PrMgCl in THF (2N, 2.4 mL, 4.8 mmol). After 40 min, 1-isopropoxy-4,4,4,4-tetramethyl-borolane (1.2 mL, 5.94 mmol) was added and stirred for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and evaporated. The crude material was triturated with petroleum ether to give 4-chloro-7-methyl-5-(4,4,5,5-tetramethyl-[1,4,2]dioxaboran-2-yl)-7H-pyrrolo[2,4-d]pyrimidine (850 mg, 2.89 mol, 74% yield) as a white solid.

[0664] 1 H NMR (400 MHz, DMSO-d6): 8.65(s, 1H), 8.04(s, 1H), 3.84(s, 3H), 1.30(s, 12H).

[0665] Method AB, Step 4. Synthesis of 4-chloro-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidine.

[0666] To a solution of 4-chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7H-pyrrolo[2,4-d]pyrimidine (500 mg, 1.71 mmol) in MeCN (6 mL) and HO (2 mL) was added Pd(PPh4)2Cl2 (240 mg, 0.442 mmol), K4PO4 (1.1 g, 5.18 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (410 mg, 1.7 mmol) at 25 °C. The mixture was stirred at 80 °C under N2 for 16 h. The reaction mixture was cooled to room temperature and partitioned between water (10 mL) and EtOAc (15 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, PE:EtOAc=5:1) to give the title compound (450 mg, 1.44 mmol, 84.4% yield) as a yellow solid.

[0667] LCMS m / e: 414(MH + ).

[0668] Method AB, Step 4. Synthesis of 7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0669] A solution of 4-chloro-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidine (450 mg, 1.44 mmol) in NHOH (40 mL, 28% in HO) was stirred at 100° C. overnight, cooled to room temperature, diluted with water (40 mL), and extracted with DCM (40 mL×2). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (200 mg, 0.68 mmol, 47.4% yield) as a pale solid.

[0670] LCMS m / e: 295(MH + ).

[0671] Method AB, Step 5. Synthesis of 6-bromo-7-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]pyrrolo[2,4-d]pyrimidin-4-amine.

[0672] To a solution of 7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (100 mg, 0.44 mmol) in MeCN (0.5 mL) and AcOH (0.5 mL) was added NBS (72 mg, 0.408 mmol). The resulting mixture was stirred at 40 °C for 18 h, diluted with saturated NaHCO4 (5 mL) at room temperature, and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, PE:EtOAc = 1:1) to give the title compound (60 mg, 0.161 mmol, 47.4%) as a yellow solid.

[0673] LCMS m / e: 474 / 475(MH + ).

[0674] Method AB, Step 6. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(5-(trifluoromethyl)-pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0675] To a solution of 6-bromo-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (60 mg, 0.161 mmol) and t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (79 mg, 0.209 mmol) in dioxane (2 mL) and water (0.2 mL) was added Na2CO4 (51 mg, 0.482 mmol) and Pd(dppf)Cl2 (12 mg, 0.016 mmol). The resulting mixture was stirred at 100 °C under N2 for 18 h. It was then cooled and purified by high performance silica gel chromatography (gradient, DCM:EtOAc=1:1) to give the title compound (60 mg, 0.11 mmol, 68.6%) as a pale solid.

[0676] LCMS m / e: 544(MH + ).

[0677] Method AB, Step 7. Synthesis of 7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0678] To a solution of t-butyl 9-(4-amino-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (60 mg, 0.11 mmol) in DCM (10 mL) at room temperature, TFA (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h and concentrated to give the title compound (60 mg, 0.108 mmol, 97.5%) as a yellow solid.

[0679] LCMS m / e: 444(MH + ).

[0680] Method AB, Step 8. Synthesis of 1-(9-(4-amino-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0681] [ka]

[0682] To a solution of 7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-5-(5-(trifluoromethyl)-pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (50 mg, 0.114 mmol) and TEA (45 mg, 0.45 mmol) in DCM (1 mL) was added acryloyl chloride (10 mg, 0.114 mmol) dropwise at 0° C. The mixture was stirred for 0.5 h, diluted with water (4 mL) and extracted with DCM (10 mL×2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase chromatography (SilaSep™ C18 high performance silica gel column, 0%-40% MeCN / H2O with 0.1% formic acid) to give the title compound (8.2 mg, 0.016 mmol, 14.6%) as a white solid.

[0683] 1 H NMR(400 MHz, DMSO) δ 9.16(s, 2H), 9.04(s, 1H), 8.13(s, 1H), 7.32(s, 1H), 6.86(dd, J = 16.7, 10.5 Hz, 1H), 6.11(d, J = 18.6 Hz, 1H), 5.68(d, J = 7.7 Hz, 2H), 3.76 - 3.64(m, 2H), 3.62(s, 3H), 3.57 - 3.48(m, 2H), 2.31 - 2.22(m, 2H), 2.12(s, 2H), 1.73(t, J = 4.9 Hz, 2H), 1.62 - 1.46(m, 4H). LCMS m / e: 498(MH + ). Using the same or similar procedures as above, the examples in Table 6 were prepared.

[0684] [Table 9] JPEG2025511287000118.jpg232169JPEG2025511287000119.jpg27169

[0685] Example 50 Synthesis of 1-(9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0686] [ka]

[0687] Method AC, Step 1. Synthesis of 2-bromo-5-cyclopropoxypyrimidine.

[0688] To a solution of cyclopropanol (5.91 g, 102 mmol) in THF (200 mL) was added NaH (4.88 g, 204 mmol, 60% suspension in mineral oil) batchwise under N2 at 0 °C. After stirring at 0 °C for 0.5 h, 2-bromo-5-fluoropyrimidine (12 g, 67.8 mmol) was added at 0 °C and stirred at 25 °C for 2 h. The resulting solution was poured into water (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, PE-PE:DCM = 1:4) to give the title compound (420 mg, 1.49 mmol, 2.19% yield) as a pale yellow solid.

[0689] LC-MS m / e: 215.1, 217.1(MH+ ).

[0690] Method AC, Step 2. Synthesis of 4-chloro-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidine.

[0691] To a solution of 2-bromo-5-(cyclopropoxy)pyrimidine (420 mg, 1.49 mmol) and 4-chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)pyrrolo[2,4-d]pyrimidine (447 mg, 1.49 mmol) in MeCN (20 mL) and water (10 mL) was added Pd(PPh4)2Cl2 (105 mg, 0.149 mmol) and K4PO4 (948 mg, 4.47 mmol). The resulting mixture was stirred at 80 °C under N2 for 2 h, cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (20 mL x 4). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by alumina column (gradient, PE to PE:EtOAc=2:1) ​​to give the title compound (250 mg, 0.829 mmol, 55.7% yield) as a pale yellow solid.

[0692] LC-MS m / e: 402(MH + ).

[0693] Method AC, Step 4. Synthesis of 5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine. A solution of 4-chloro-5-[5-(cyclopropoxy)pyrimidin-2-yl]-7-methylpyrrolo[2,4-d]pyrimidine (250 mg, 0.829 mmol) in NH4 (5 mL, 7 M MeOH solution) was stirred at 60 °C overnight, cooled to room temperature, concentrated in vacuo, and purified by high-performance silica gel chromatography (gradient, DCM to DCM:EtOAc = 1:1) to give the title compound (140 mg, 0.496 mmol, 59.9% yield) as a pale yellow solid.

[0694] LC-MS m / e: 245(MH + ).

[0695] Method AC, Step 4. Synthesis of 6-chloro-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0696] To a solution of 5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]-pyrimidin-4-amine (140 mg, 0.46 mmol) in MeCN (15 mL) was added NCS (92 mg, 0.691 mmol) and stirred at 40 °C for 2 h. The resulting solution was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (110 mg, 0.447 mmol, 75.5% yield) as a pale yellow solid.

[0697] LC-MS m / e: 417.1, 419.1(MH + ).

[0698] Method AC, Step 5. Synthesis of t-butyl 9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0699] To a solution of 6-chloro-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (90 mg, 0.284 mmol) and t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (214 mg, 0.568 mmol) in dioxane / water (40 mL, 4 / 1 v / v) was added K4PO4 (181 mg, 0.852 mmol) and Pd(dppf)Cl2 (21 mg, 0.29 mmol). The mixture was stirred at 80 °C under N2 for 2 h, cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography (gradient, DCM to DCM:MeOH=20:1) to give the title compound (140 mg, 0.147 mmol, 51.6% yield) as a pale yellow solid.

[0700] LC-MS m / e: 542(MH + ).

[0701] Method AC, Step 6. Synthesis of 5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. At 0°C, t-butyl 9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (140 mg, 0.147 mmol) in DCM (10 mL) was added with TFA (2 mL) and stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure and purified by alumina column (gradient, DCM to DCM:MeOH=44:1) to give the title compound (60 mg, 0.149 mmol, 94.8% yield) as a yellow solid.

[0702] LC-MS m / e: 442(MH + ). Method AC, Step 7. Synthesis of 1-(9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0703] [ka]

[0704] Acryloyl chloride (0.011 mL, 0.149 mmol) was added dropwise to a solution of 5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (60 mg, 0.149 mmol) and TEA (0.058 mL, 0.417 mmol) in DCM (10 mL) at 0° C. and stirred for 5 min at 0° C. The resulting solution was poured into water (10 mL) and extracted with EtOAc (40 mL×2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by prep-HPLC to give the title compound (14.6 mg, 0.04 mmol, 21.6% yield) as a white solid.

[0705] 1 H NMR(400 MHz, DMSO-d6) δ 9.06(peak, .6H), 8.62(s, 2H), 8.08(br s, .84H), 7.12(peak s, 0.7H), 6.86(t, J = 15.4 Hz, 1H), 6.11(d, J = 16.0 Hz, 1H), 5.73 - 5.48(m, 2H), 4.11(br s, 1H), 3.76 - 3.63(m, 2H), 3.58(s, 3H), 3.53 - 3.44(m, 2H), 2.28(m, 2H), 2.10(m, 2H), 1.74 - 1.64(m, 2H), 1.56(d, J = 19.6 Hz, 4H), 0.82(d, J = 30.2 Hz, 4H). LC-MS m / e: 486(MH + ).

[0706] Example 51 Synthesis of 2-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile.

[0707] [ka]

[0708] Method AD, Step 1. Synthesis of 5-(5-bromopyrimidin-2-yl)-4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine.

[0709] To a solution of 4-chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-pyrrolo[2,4-d]pyrimidine (2.5 g, 8.51 mmol) and 5-bromo-2-iodopyrimidine (2.91 g, 10.2 mmol) in MeCN (40 mL) and water (5 mL) was added Pd(PPh4)2Cl2 (0.99 g, 1.28 mmol) and K4PO4 (5.42 g, 25.5 mmol). The reaction mixture was stirred at 80 °C under N2 for 4 h, then cooled to room temperature, poured into water (200 mL), and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=20:1) to give the title compound (1.4 g, 4 mmol, 47% yield) as a yellow solid.

[0710] LC-MS m / e: 424.6, 426.6(MH + ).

[0711] Method AD, Step 2. Synthesis of 5-(5-bromopyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0712] A solution of 5-(5-bromopyrimidin-2-yl)-4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidine (1.4 g, 4 mmol) in NH4-H2O (20 mL) was stirred in a sealed tube at 80 °C for 12 h, cooled to room temperature, and poured into water (100 mL). The resulting suspension was filtered. The filter cake was washed with water (100 mL) and dried under vacuum to give the title compound (1.1 g, 4.6 mmol, 89.8% yield) as a grey solid.

[0713] LC-MS m / e: 405.4, 407.4(MH + ).

[0714] Method AD, Step 4. Synthesis of 2-(4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile.

[0715] To a solution of 5-(5-bromopyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (500 mg, 1.65 mmol) in DMA (10 mL) was added Zn(CN)2 (962 mg, 0.428 mmol), X-Phos (41 mg, 0.65 mmol) and Pd2(dba)4 (400 mg, 0.425 mmol). The reaction mixture was stirred at 120 °C under N2 for 12 h. The reaction mixture was cooled to room temperature and partitioned between water (50 mL) and EtOAc (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (400 mg, 1.59 mmol, 96.4% yield) as a white solid.

[0716] LC-MS m / e: 252.2(MH + ) Method AD, Step 4. Synthesis of 2-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile.

[0717] To a solution of 2-(4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile (400 mg, 1.19 mmol) in MeCN (10 mL) and AcOH (10 mL) was added NBS (255 mg, 1.46 mmol) and stirred at 20 °C for 12 h. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (gradient, PE to PE:EtOAc = 1:1) to give the title compound (400 mg, 0.909 mmol, 76.4% yield) as a yellow solid.

[0718] LC-MS m / e: 442.1, 442.1(MH + ).

[0719] Method AD, Step 5. Synthesis of t-butyl 9-(4-amino-5-(5-cyanopyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0720] To a mixture of 2-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile (400 mg, 0.909 mmol) and t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (456 mg, 0.909 mmol) in dioxane (4 mL) and water (1 mL) was added K2CO4 (476 mg, 2.74 mmol) and Pd(dppf)Cl2 (144 mg, 0.182 mmol). The reaction mixture was stirred at 100 °C under N2 for 12 h, then cooled to room temperature, diluted with HO (20 mL), and extracted with EtOAc (50 mL x 4). The organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (gradient, DCM to DCM:EtOAc = 20:1) to give the title compound (170 mg, 0.44 mmol, 47.4% yield) as a yellow solid.

[0721] LC-MS m / e: 501.4(MH + ).

[0722] Method AD, Step 6. Synthesis of 2-(4-amino-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile. To a solution of t-butyl 9-(4-amino-5-(5-cyanopyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (170 mg, 0.44 mmol) in DCM (4 mL) was added TFA (1 mL) at 0° C. and stirred at room temperature for 1 h. The reaction solution was concentrated in vacuo to give the title compound (140 mg, 0.425 mmol, 95.6% yield, crude material) as a yellow solid.

[0723] LC-MS m / e: 401(MH + ).

[0724] Method AD, Step 7. Synthesis of 2-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile.

[0725] [ka]

[0726] To a solution of 2-(4-amino-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile (140 mg, 0.425 mmol) and TEA (0.145 mL, 0.974 mmol) in DCM (5 mL) was added acryloyl chloride (0.029 mL, 0.457 mmol) at 0° C. and stirred under N2 for 0.5 h at 0° C. The resulting solution was poured into water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=15:1) followed by prep-HPLC to give the title compound (5 mg, 0.011 mmol, 4.49% yield) as a pale yellow solid.

[0727] 1H NMR(400 MHz, DMSO-d6) δ 9.19(s, 2 H), 9.03(s, 1 H), 8.13(peak, 0.7 H), 7.32(peak, 1 H), 6.87(dd, J = 16.9, 11.3 Hz, 1 H), 6.12(d, J = 17.0 Hz, 1 H), 5.68(d, J = 5.0 Hz, 2 H), 3.76 - 3.65(m, 2 H), 3.61(s, 3 H), 3.58 - 3.49(m, 1 H), 2.33 - 2.19(m, 2 H), 2.11(br s, 2 H), 2.02-1.95(m, 1H), 1.74 - 1.64(m, 2H), 1.56(d, J = 23.4Hz, 4H). LC-MS m / e: 455.3(MH + ).

[0728] Example 52 Synthesis of 1-(9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0729] [ka]

[0730] Method AE, Step 1. Synthesis of 5-(5-(2,5-dihydrofuran-4-yl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0731] To a solution of 5-(5-bromopyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (170 mg, 0.454 mmol) and 2-(2,5-dihydrofuran-4-yl)-4,4,5,5-tetramethyl-1,4,2-dioxaborolane (178 mg, 0.454 mmol) in dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl2 (66.4 mg, 0.091 mmol) and K2CO4 (188 mg, 1.46 mmol) and stirred at 100 °C under N2 for 12 h. The resulting solution was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=20:1) to give the title compound (140 mg, 0.442 mmol, 98.2% yield) as a yellow solid.

[0732] LC-MS m / e: 295.2(MH + ) Method AE, Step 2. Synthesis of 7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0733] To a solution of 5-(5-(2,5-dihydrofuran-4-yl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (150 mg, 0.51 mmol) in EtOAc (6 mL) and i-PrOH (2 mL) was added 10% Pd / C (150 mg, 55% water). The reaction mixture was stirred at 20° C. under H2 for 12 h. The resulting suspension was filtered through a Celite® pad and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the title compound (150 mg, 0.5 mmol, 99.1% yield) as a yellow solid.

[0734] LC-MS m / e: 297.2(MH + ) Method AE, Step 4. Synthesis of 6-bromo-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0735] To a solution of 7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (150 mg, 0.506 mmol) in AcOH (2 mL) and MeCN (2 mL) was added NBS (108 mg, 0.607 mmol) and stirred at 20 °C for 12 h. The reaction mixture was diluted with EtOAc (20 mL) and basified with saturated NaHCO4 solution (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 40:1) to give the title compound (170 mg, 0.454 mmol, 89.5% yield) as a yellow solid.

[0736] LC-MS m / e: 475.2 / 477.2(MH + ).

[0737] Method AE, Step 4. Synthesis of t-butyl 9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)-pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0738] To a solution of 6-bromo-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (170 mg, 0.454 mmol) and t-butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (178 mg, 0.454 mmol) in dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl2 (66 mg, 0.091 mmol) and K2CO4 (187 mg, 1.46 mmol) and stirred at 100 °C under N2 for 12 h. The resulting solution was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=40:1) to give the title compound (140 mg, 0.248 mmol, 52.6% yield) as a yellow solid.

[0739] LC-MS m / e: 546.8(MH + ) Method AE, Step 5. Synthesis of 7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0740] To a solution of t-butyl 9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (140 mg, 0.248 mmol) in DCM (4 mL) was added TFA (1 mL) at 0° C. and stirred at room temperature for 1 h. The reaction solution was concentrated in vacuo to give the title compound (80 mg, 0.18 mmol, 75.6% yield) as a brown solid.

[0741] LC-MS m / e: 446.4(MH + ).

[0742] Method AE, Step 6. Synthesis of 1-(9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0743] [ka]

[0744] To a solution of 7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (80 mg, 0.180 mmol) and TEA (0.1 mL, 0.718 mmol) in DCM (5 mL) was added acryloyl chloride (90.5 mg, 0.197 mmol) at 0° C. and stirred under N for 0.5 h. The resulting solution was poured into water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (gradient, DCM:MeOH=15:1) followed by prep-HPLC to give the title compound (22 mg, 0.044 mmol, 24.5% yield) as a pale yellow solid.

[0745] 1H NMR(400 MHz, DMSO-d6) δ 9.30(br s, .75H), 8.69(s, 2 H), 8.09(s, 1 H), 7.27(br, 2 H), 6.86(dd, J = 15.9, 10.8 Hz, 1H), 6.67(br, 1 H), 6.11(d, J = 16.9 Hz, 1 H), 5.68(d, J = 10.4 Hz, 1 H), 5.63(br. s, 1 H), 4.04(t, J = 7.7 Hz, 1 H), 3.98(m, 1 H), 3.86 - 3.79(m, 1 H), 3.69(m, 1H), 3.67 - 3.62(m, 2 H), 3.59(s, 3 H), 2.39 - 2.26(m, 3 H), 2.03(m, 1 H), 1.75(s, 4 H), 1.70(m, 2 H), 1.56(m, 4 H). LC-MS m / e: 500.5(MH + ).

[0746] Example 54 Synthesis of 1-(9-(4-amino-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0747] [ka]

[0748] Method AF, Step 1. Synthesis of 4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carboxamide.

[0749] Lithium hydroxide (22.8 mg, 0.952 mmol) and H2O2 (270 mg, 2.48 mmol, 40%) were added to a solution of 4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile (120 mg, 0.476 mmol) in DMSO (8 mL) at 0° C. and stirred at 25° C. for 6 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×4). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (110 mg, 0.407 mmol, 85.6% yield) as a colorless oil. LC-MS m / e: 270(MH + ).

[0750] Method AF, Step 2. Synthesis of 6-bromo-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. A mixture of 4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carboxamide (110 mg, 0.407 mmol) and 2-bromo-1,1-dimethoxyethane (4.8 mL, 40.7 mmol) was irradiated in a microwave at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (70 mL×4). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep-TLC to give the title compound (15 mg, 0.051 mmol, 12.5% ​​yield) as a yellow solid.

[0751] LC-MS m / e: 294(MH + ) / 296.

[0752] Method AF, Step 4. Synthesis of 1-(9-(4-amino-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0753] [ka]

[0754] To a solution of 6-bromo-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (15 mg, 0.051 mmol) in dioxane (6 mL) and water (1.5 mL) was added Pd(PPh4)2Cl2 (7 mg, 0.01 mmol), K4PO4 (44 mg, 0.154 mmol) and 1-(9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (25 mg, 0.077 mmol). The mixture was stirred at 80 °C under N2 for 4 h. The resulting mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-TLC to give the title compound (2.4 mg, 0.005 mmol, 10.8% yield) as a white solid.

[0755] 1 H NMR(400 MHz, DMSO-d6) δ 10.05(s, 1H), 9.23(s, 1H), 8.08(d, J = 1.1 Hz, 1H), 7.58(d, J = 1.1 Hz, 1H), 7.13(s, 1H), 6.84(dd, J = 16.7, 10.3 Hz, 1H), 6.09(dd, J = 16.7, 2.5 Hz, 1H), 5.68(m, 1H), 5.64(d, J=4.0. 1H), 3.74(s, 3H), 3.67 - 3.49(m, 4H), 2.33(br. s, 2H), 2.14(s, 2H), 1.67(t, J = 6.1 Hz, 2H), 1.61 - 1.48(m, 4H).

[0756] LC-MS m / e: 419(MH + ).

[0757] Example 54 Synthesis of 1-(9-(4-amino-7-(2-hydroxyethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0758] [ka]

[0759] Method AF, Step 1. Synthesis of 1-(9-(4-amino-7-(2-((t-butyldimethylsilyl)oxy)ethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0760] A mixture of 1-(9-(4-amino-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (46 mg, 0.11 mmol), Cs2CO4 (46.1 mg, 0.11 mmol) and Cs2CO4 (46.1 mg, 0.11 mmol) and 1-bromo-4,4,5,5-tetramethyl-4-oxa-4-silahexane (42 mg, 0.14 mmol) in DMF (10 mL) was stirred at 80 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to give the crude title compound (40 mg, 0.07 mmol, 62.7% yield) as a yellow solid.

[0761] LC-MS m / e: 574(MH + ).

[0762] Method AF, Step 2. Synthesis of 1-(9-(4-amino-7-(2-hydroxyethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0763] [ka]

[0764] A mixture of 1-(9-(4-amino-7-(2-((t-butyldimethylsilyl)oxy)ethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (40 mg, 0.07 mmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 0 °C for 1 h. The mixture was treated with saturated NaHCO4 solution (40 mL) and extracted with DCM (40 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC to give the title compound (15 mg, 0.04 mmol, 46.8% yield) as a yellow solid.

[0765] 1 H NMR(400 MHz, DMSO-d6) δ 9.34(peak, 0.70H), 8.78(d, J = 4.8 Hz, 2H), 8.09(s, 1H), 7.27 - 7.06(m, 2H), 6.90 - 6.80(m, 1H), 6.11(dd, J = 16.4, 2.0 Hz, 1H), 5.71 - 5.59(m, 2H), 4.95(t, J = 5.4 Hz, 1H), 4.19 - 4.06 m, 2H), 3.71-3.66(m, 4H), 3.58-3.51(m, 2H), 2.34-2.29(m, 2H), 2.11(br.s, 2H), 1.69-1.67(m, 2H), 1.63 - 1.49(m, 4H).

[0766] LC-MS m / e: 460(MH + ).

[0767] Example 55 Synthesis of 1-(9-(4-amino-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0768] [ka]

[0769] Method AG, Step 1. Synthesis of 4-(4-chloro-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)oxetan-4-ol.

[0770] To a solution of 4-chloro-5-iodo-7-methylpyrrolo[2,4-d]pyrimidine (2 g, 6.8 mmol) in THF (40 mL) was added n-BuLi (4.4 mL, 6.8 mmol, 2 M in THF) at -15 °C. The mixture was stirred at -15 °C for 40 min, and then oxetan-4-one (740 mg, 10.2 mmol) was added to the mixture at -15 °C. The reaction was stirred at -5 °C for 40 min, quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (150 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (1.2 g, 5.04 mmol, 74.5% yield) as a yellow solid.

[0771] LC-MS m / e: 240(MH + ) Method AG, Step 2. Synthesis of 4-chloro-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidine.

[0772] 0 oC. To a solution of 4-(4-chloro-7-methylpyrrolo[2,4-d]pyrimidin-5-yl)oxetan-4-ol (1.2 g, 5 mmol) in THF (40 mL), NaH (1.42 g, 45.5 mmol, 60% suspended in mineral oil) was added and stirred at room temperature for 2 h. Carbon disulfide (2.4 mL, 40 mmol) was then added to the mixture and stirring was continued for 40 min, followed by MeI (4.1 mL, 50 mmol). The resulting mixture was stirred at room temperature for 1 h, quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was dissolved in toluene (20 mL), AIBN (0.16 g, 1 mmol) and Bu4SnH (5.84 g, 20 mmol) were added to the solution, and the mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 50:1) to give the title compound (600 mg, 2.68 mmol, 54.6% yield) as a yellow solid.

[0773] LC-MS m / e: 224(MH + ).

[0774] Method AG, Step 4. Synthesis of 7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0775] A solution of 4-chloro-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidine (500 mg, 2.246 mmol) in NH4 (10 mL, 25% aqueous solution) was stirred at 100 °C in a sealed tube for 16 h. The reaction was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (460 mg, 1.76 mmol, 78.9% yield) as a yellow solid.

[0776] LC-MS m / e: 205(MH + ).

[0777] Method AG, Step 4. Synthesis of 6-bromo-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. A solution of 7-methyl-5-(oxetan-4-yl)pyrrolo[2,4-d]pyrimidin-4-amine (400 mg, 1.47 mmol) and NBS (492 mg, 2.2 mmol) in MeCN (10 mL) was stirred at room temperature for 4 h. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (100 mg, 0.45 mmol, 24% yield) as a yellow solid.

[0778] LC-MS m / e: 284, 285(MH + ).

[0779] Method AG, Step 5. Synthesis of 1-(9-(4-amino-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0780] [ka]

[0781] 6-Bromo-7-methyl-5-(oxetan-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (80 mg, 0.28 mmol), 1-[9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]-undec-8-en-4-yl]prop-2-en-1-one (112 mg, 0.448 mmol), Pd(dppf)Cl 2(A solution of KPO (21 mg, 0.0289 mmol) and KPO (180 mg, 0.848 mmol) in dioxane (8 mL) and water (20 mL) was stirred at 100 °C under N for 2 h. Then the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by prep-HPLC to give the title compound (8 mg, 0.02 mmol, 6.95% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6) Including HCOOH, δ 8.14(s, 1H, HCOOH), 8.09(s, 1H), 7.09(s, 2H), 6.82(dd, J = 16.6, 10.6 Hz, 1H), 6.09(dd, J = 16.8, 2.6 Hz, 1H), 5.70 - 5.62(m, 2H), 5.21 - 5.12(m, 2H), 4.48(t, J = 6.0 Hz, 2H), 4.29 - 4.16(m, 1H), 3.69 - 3.59(m, 2H), 3.59 - 3.48(m, 5H), 2.17- 2.04(m, 4H), 1.65(t, J = 6.0 Hz, 2H), 1.52 - 1.38(m, 4H). LC-MS m / e: 408(MH + ).

[0782] Example 56 Synthesis of 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0783] [ka]

[0784] Method AH, Step 1. Synthesis of 7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a solution of 5-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1 g, 4.65 mmol) in dioxane (25 mL) was added 4,4,5,5-tetramethyl-1,4,2-dioxaborolane (2.8 g, 21.9 mmol), Pd2(dba)4 (2.95 g, 4.65 mmol), X-Phos (1.74 g, 4.65 mmol) and Et4N (0.507 mL, 4.65 mmol) at 25 °C under N2. The mixture was stirred for 4 h at 75 °C under N2. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (40 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=9:1) to give the title compound (270 mg, 0.985 mmol, 27% yield) as a yellow solid.

[0785] LC-MS m / e: 275(MH + ).

[0786] Method AH, Step 2. Synthesis of 5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0787] To a mixture of 7-methyl-5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (400 mg, 1.09 mmol) and 2-chloro-5-(difluoromethyl)-pyrimidine (120 mg, 0.729 mmol) in DMSO (12 mL) and HO (2 mL) was added Pd(PPh4)2Cl2 (102 mg, 0.146 mmol) and K4PO4 (464 mg, 2.19 mmol). The reaction mixture was stirred at 75 °C under N2 for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with HO (20 mL) and extracted with EtOAc (20 mL x 4). The organic phase was washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=9:1) to give the title compound (190 mg, 0.688 mmol, 94.4% yield) as a white solid.

[0788] LC-MS m / e: 275(MH + ).

[0789] Method AH, Step 4. Synthesis of 6-bromo-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine. To a solution of 5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (200 mg, 0.724 mmol) in CH4CN (1.5 mL) was added NBS (194 mg, 1.09 mmol) at 25° C. and stirred at 25° C. for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined extracts were dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=9:1) to give the title compound (50 mg, 0.141 mmol, 19.45%) as a yellow solid.

[0790] LC-MS m / e: 455, 457(MH + ).

[0791] Method AH, Step 4. Synthesis of 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0792] [ka]

[0793] To a mixture of 6-bromo-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (40 mg, 0.114 mmol) and 1-(9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (56 mg, 0.169 mmol) in dioxane (5 mL) and HO (1 mL) was added Pd(PPh4)2Cl2 (79 mg, 0.114 mmol) and K4PO4 (24 mg, 0.114 mmol). The reaction mixture was stirred at 100 °C under N2 for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC to give the title compound (40 mg, 0.084 mmol, 74.1% yield) as a white solid.

[0794] 1H NMR(400 MHz, DMSO-d6) δ 9.14(peak, 0.65H), 8.98(s, 2H), 8.12(s, 1H), 7.37 - 7.00(m, 2H), 6.86(dd, J =16, 12 Hz, 1H), 6.12(dd, J =16, 1Hz, 1H), 5.71 - 5.64(m, 2H), 3.75 - 3.64(m, 2H), 3.61(s, 3H), 3.58 - 3.49(m, 2H), 2.34 - 2.24(m, 2H), 2.12(s, 2H), 1.72(t, J = 5.8 Hz, 2H), 1.63 - 1.50(m, 4H). LC-MS m / e: 480(MH + ).

[0795] Example 57 Synthesis of 6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile.

[0796] [ka]

[0797] Method AI, Step 1. Synthesis of 4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile.

[0798] To a solution of 5-bromo-7-methylpyrrolo[2,4-d]pyrimidin-4-amine (2 g, 8.8 mmol) and Zn(CN)2 (4.94 g, 42 mmol) in DMF (25 mL) was added Pd(PPh4)4 (1.94 g, 1.68 mmol) and stirred at 100 °C under N2 for 4 h. The resulting mixture was cooled to room temperature and filtered. It was quenched with saturated NaHCO4 solution (50 mL) and the filtrate was extracted with EtOAc (50 mL x 4). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by alumina high performance chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (640 mg, 4.64 mmol, 44.4% yield) as a yellow solid.

[0799] LC-MS m / e: 174(MH + ).

[0800] Method AI, Step 2. Synthesis of 4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile.

[0801] To a solution of 4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile (250 mg, 1.44 mmol) in MeCN (6 mL) was added NBS (511 mg, 2.87 mmol) at 0 °C and stirred under N2 for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by high-performance silica gel chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (247 mg, 0.94 mmol, 65.1% yield) as a yellow solid.

[0802] LC-MS m / e: 252, 254(MH + ).

[0803] Method AI, Step 4. Synthesis of 6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile.

[0804] [ka]

[0805] To a solution of 4-amino-6-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidine-5-carbonitrile (50 mg, 0.2 mmol), 1-(9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (100 mg, 0.4 mmol) and KPO (126 mg, 0.594 mmol) in dioxane (2 mL) and H0 (0.4 mL) was added Pd(PPh)Cl. The mixture was stirred at 90 °C under N for 12 h. The mixture was cooled to room temperature and concentrated to dryness. The residue was partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and purified by prep-HPLC to give the title compound (15 mg, 0.04 mmol, 20% yield) as a yellow solid.

[0806] 1 H NMR(400 MHz, DMSO-d6) δ 8.22(s, 1H), 6.8.3(dd, K=16, 8 Hz, 1H), 6.72(peak, 2H), 6.15 - 6.04(m, 2H), 5.66(dd, J = 10.4, 2.4 Hz, 1H), 3.64(s, 3H), 3.61 - 3.43(m, 4H), 2.40 - 2.33(m, 2H), 2.27 - 2.15(m, 2H), 1.69(t, J = 6.0 Hz, 2H), 1.53 - 1.37(m, 4H).

[0807] LC-MS m / e: 377(MH+ ).

[0808] Example 58 Synthesis of 1-(9-(4-amino-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0809] [ka]

[0810] Method AJ, Step 1. Synthesis of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidine. To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,4-d]pyrimidine (2 g, 7.156 mmol) in DMF (40 mL) was added K2CO4 (2.97 g, 21.4 mmol) at room temperature. After stirring for 20 min, SEMCl (1.9 mL, 10.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, then poured into water and extracted with EtOAc (50 mL x 4). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, PE~PE:EtOAc=5:1) to give the title compound (2.8 g, 6.84 mmol, 95.5% yield) as a brown solid.

[0811] LC-MS m / e: 410.2(MH + ).

[0812] Method AJ, Step 2. Synthesis of 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0813] A solution of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidine (2.8 g, 6.84 mmol) and NH4OH (40 mL, 25% in water) in dioxane (10 mL) was stirred at 120 °C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with PE (50 mL). The filter cake was dried in vacuum to give the title compound (2.4 g, 6.15 mmol, 90% yield) as a white solid.

[0814] LC-MS m / e: 491.1(MH + ).

[0815] Method AJ, Step 4. Synthesis of 5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0816] To a solution of 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (2.4 g, 5.89 mmol) in dioxane (50 mL) at 25 °C under N2 was added Pd2(dba)4 (1.08 g, 1.18 mmol), X-phos (1.12 g, 2.46 mmol), 4,4,5,5-tetramethyl-1,4,2-dioxaborolane (4.52 g, 45.4 mmol) and Et4N (4.9 mL, 45.4 mmol). The mixture was stirred at 80 °C under N2 for 4 h. The reaction mixture was cooled to room temperature and partitioned between water (50 mL) and EtOAc (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (1 g, 2.56 mmol, 44.4% yield) as a white solid.

[0817] LC-MS m / e: 491.4(MH + ).

[0818] Method AJ, Step 4. Synthesis of 5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0819] To a solution of 2-iodopyrimidine (450 mg, 1.7 mmol) and 5-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (700 mg, 1.79 mmol) in DMSO (10 mL) and water (2 mL) was added Pd(PPh4)4 (410 mg, 0.269 mmol) and K4PO4 (1.14 g, 5.48 mmol) at 20 °C under N2. The mixture was stirred at 70 °C under N2 for 4 h. The reaction mixture was cooled to room temperature and partitioned between water (20 mL) and EtOAc (80 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (420 mg, 1.24 mmol, 68.4% yield) as a white solid.

[0820] LC-MS m / e: 444.4(MH + ).

[0821] Method AJ, Step 5. Synthesis of 6-bromo-5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0822] To a solution of 5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (420 mg, 0.944 mmol) in MeCN (5 mL) was added NBS (262 mg, 1.47 mmol) at 15° C. and stirred for 2 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (40 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (250 mg, 0.594 mmol, 64.5% yield) as a white solid.

[0823] LC-MS m / e: 421.2, 424.2(MH + ).

[0824] Method AJ, Step 6. Synthesis of 1-(9-(4-amino-5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0825] To a solution of 6-bromo-5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (250 mg, 0.594 mmol) and 1-(9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (294 mg, 0.89 mmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl (87 mg, 0.119 mmol) and KPO (478 mg, 1.78 mmol) at 25 °C under N. The reaction mixture was stirred for 4 h at 80 °C under N. It was then cooled to room temperature and partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by high performance silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (420 mg, 0.528 mmol, 88.9% yield) as a yellow oil.

[0826] LC-MS m / e: 546.5(MH + ).

[0827] Method AJ, Step 7. Synthesis of 1-(9-(4-amino-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0828] [ka]

[0829] A solution of 1-(9-(4-amino-5-(pyrimidin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one (250 mg, 0.458 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 1 h. The mixture was concentrated and dissolved in MeOH (5 mL). Then, K2CO4 (415 mg, 2.29 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h. It was then partitioned between water (10 mL) and DCM (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase chromatography (SilaSep™ C18 high performance silica gel column, 0%-40% MeCN / H2O with 0.1% formic acid) to give the title compound (60 mg, 0.144 mmol, 41.5% yield) as a yellow solid.

[0830] 1 H NMR(400 MHz, DMSO-d6) Including HCOOH, δ 11.96(s, 1 H), 8.77(d, J = 4.8 Hz, 2 H), 8.14(s, 1H), 8.03(s, 1 H), 7.25(t, J = 4.8 Hz, 1 H), 6.86(dd, J = 16.8, 10.8 Hz, 1 H), 6.10(dd, J = 16.8, 2.4 Hz, 1 H), 5.75 - 5.60(m, 2 H), 3.75 - 3.62(m, 2 H), 3.34-3.56(m, 6.2 Hz, 2 H), 2.32 - 2.22(m, 2H), 2.12 - 2.02(m, 2H), 1.67 - 1.44(m, 6H).

[0831] LC-MS m / e: 416.4(MH + ).

[0832] In a similar manner was prepared Example 64: 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0833] [ka]

[0834] LC-MS m / e: 466.4(MH + ).

[0835] 1 H NMR(399 MHz, CD3OD) δ 8.90(s, 2H), 8.18(s, 1H), 6.92(t, J = 55.1 Hz, 1H), 6.74(dd, J = 16.8, 10.7 Hz, 1H), 6.11(dd, J = 16.8, 1.8 Hz, 1H), 5.79(s, 1H), 5.66(dd, J = 10.7, 1.9 Hz, 1H), 3.80-3.63(m, 2H), 3.62-3.49(m, 2H), 2.39-2.31(m, 2H), 2.16-2.09(m, 2H), 1.68(t, J = 6.3 Hz, 2H), 1.64-1.53(m, 4H).

[0836] manufacturing 4 Synthesis of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0837] [ka]

[0838] Method AK, Step 1. Synthesis of 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine.

[0839] A mixture of 4-bromo-2-fluorophenol (25 g, 141 mmol, 1 eq.), 2-chloro-4-methyl-pyrimidine (17.67 g, 147 mmol, 1.05 eq.) and Cs2CO4 (85.4 g, 262 mmol, 2 eq.) in NMP (400 mL) was stirred at 100 °C for 16 h. The reaction mixture was partitioned between water (400 mL) and EtOAc (4 x 200 mL). The combined organic layers were washed with brine (4 x 200 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give the title compound (27.4 g, 74%) as a white solid.

[0840] LCMS: m / z 284.15 [M+1] + .

[0841] Method AK, Step 2. Synthesis of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)phenoxy)-4-methylpyrimidine.

[0842] A mixture of 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (4 g, 10.6 mmol, 1 eq.), B2Pin2 (2.97 g, 11.7 mmol, 1.1 eq.), Pd(dppf)Cl2 (865 mg, 1.06 mmol, 0.1 eq.) and KOAc (4.12 g, 41.8 mmol, 4 eq.) in dioxane (40 mL) was degassed with N2 four times and then stirred at 90 °C under N2 for 16 h. The solution was filtered through a filter pad. The filtrate was concentrated under reduced pressure to give the title compound (4.4 g, 99%) as a brown oil which was used directly in the next step.

[0843] Method AK, Step 4. Synthesis of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0844] A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1.14 g, 5 mmol, 1 eq.), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)phenoxy)-4-methylpyrimidine (4.4 g, 10 mmol, 2 eq.), KCO (2.07 g, 15 mmol, 4 eq.) and Pd(DtBPF)Cl (164 mg, 0.25 mmol, 0.05 eq.) in dioxane (25 mL) and HO (2.5 mL) was degassed four times with N and then stirred at 90 °C under N for 16 h. The resulting mixture was diluted with HO (100 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (1.25 g, 71%) as a yellow solid.

[0845] LCMS: m / z 451.40 [M+1] + .

[0846] Method AK, Step 4. Synthesis of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0847] To a solution of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1.25 g, 4.57 mmol, 1 eq.) in DCM (20 mL) at 0 °C under N2, NIS (1.2 g, 5.46 mmol, 1.5 eq.) and CF4COOH (2.04 g, 17.9 mmol, 5 eq.) were added. The resulting mixture was stirred at room temperature for 2 h and diluted with aqueous NaHCO4 (20 mL), 10% Na2SO4 solution (15 mL) and H2O (20 mL). The resulting precipitate was collected by filtration, washed with water and purified by silica gel column chromatography eluting with DCM / MeOH (60:1) to give the title compound (1.44 g, 79%) as a white solid.

[0848] LCMS: m / z 477.25 [M+1] + .

[0849] Method AK, Step 5. Synthesis of t-butyl 9-(4-amino-5-(4-fluoro-4-((4-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate.

[0850] 5-(4-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-4-amine (1.44 g, 2.82 mmol, 1 eq.), t-Butyl 9-(4,4,5,5-tetramethyl-1,4,2-dioxaboran-2-yl)-4-azaspiro[5.5]undec-8 A mixture of 1.59 g, 4.22 mmol, 1.5 eq.), K2CO4 (1.17 g, 8.46 mmol, 4 eq.) and Pd(DtBPF)Cl2 (92 mg, 0.14 mmol, 0.05 eq.) in dioxane (20 mL) and H2O (2 mL) was degassed with N2 four times and then stirred at 90 °C under N2 for 16 h. The resulting mixture was diluted with H2O (40 mL) and extracted with EtOAc (4 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (60:1) to give the title compound (1.04 g, 61%) as a brown solid.

[0851] LCMS: m / z 599.45 [M+1] + .

[0852] Method AK, Step 6. Synthesis of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine.

[0853] [ka]

[0854] A mixture of t-butyl 9-(4-amino-5-(4-fluoro-4-((4-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-ene-4-carboxylate (1.04 g, 1.72 mmol, 1 eq.) in TFA (5 mL) and DCM (10 mL) was stirred at room temperature for 2 h. The resulting mixture was filtered. The residue was dissolved in DCM (10 mL) and the pH was adjusted to 9 with NH4OH. The precipitate was collected by filtration, washed with water and DCM, and dried under reduced pressure to give the title compound (515 mg, 60%) as a white solid.

[0855] LCMS: m / z 499.15 [M+1] + .

[0856] Example 62 Synthesis of 1-(9-(4-amino-5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one.

[0857] [ka]

[0858] To a stirred solution of 5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-azaspiro[5.5]undec-8-en-9-yl)-7H-pyrrolo[2,4-d]pyrimidin-4-amine (50 mg, 0.1 mmol, 1 eq.) in anhydrous CHCl4 (5 mL) was added DIEA (48.7 mg, 0.4 mmol, 4 eq.). At 0° C., a solution of acryloyl chloride (9.5 mg, 0.105 mmol, 1.05 eq) in anhydrous CHCl4 (0.5 mL) was added dropwise and the mixture was stirred at 0° C. under N2 for 0.5 h. The reaction mixture was quenched with water. The resulting mixture was extracted with DCM (4×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH =20 / 1) to give the title compound (25 mg, 45% yield) as a white solid.

[0859] LCMS: m / z 554.35 [M+1] + .

[0860] 1 H NMR(400 MHz, CD3OD) δ 8.42(d, J = 5.1 Hz, 1H), 8.13(s, 1H), 7.35(t, J = 8.4 Hz, 1H), 7.25(t, J = 9.0 Hz, 2H), 7.15(d, J = 5.0 Hz, 1H), 6.72(dd, J = 16.8, 10.7 Hz, 1H), 6.14(dd, J = 16.8, 1.9 Hz, 1H), 5.88(s, 1H), 5.69(dd, J = 10.7, 1.7 Hz, 1H), 3.74-3.62(m, 5H), 3.52-3.44(m, 2H), 2.48(s, 3H), 2.15(s, 2H), 2.15-2.06(m, 2H), 1.61(t, J = 6.3 Hz, 2H), 1.48-1.40(m, 4H).

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Where: R 1 is C1-C6 alkyl or substituted C1-C6 alkyl; R 2 is a substituted C7-C19 spirobicycloalkyl, a substituted C7-C19 spirobicycloalkenyl, a substituted C7-C19 spiroheterobicycloalkyl or a substituted C7-C19 spiroheterobicycloalkenyl; and R 4 is C1-C6 alkyl, substituted C1-C6 alkyl, C4-C10 cycloalkyl, substituted aryl, heteroaryl or substituted heteroaryl; A compound of formula I or a pharma- ceutically acceptable salt thereof.

2. R 1 is C1-C6 alkyl or substituted C1-C6 alkyl; R 2 teeth, 【Chemistry 2】 and (A) m CR a R b and (A) n CR a R b and (A) o CR a R b or O; (A) p is CRaR b and R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o and p are independently selected from 0, 1, 2 or 4 at each occurrence; The conditions are as follows: (A) o When is O, o is 1; Xa is H or a halogen; W is for COR 5 and R 5 teeth, 【Chemistry 3】 and R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; R WD is H or C1-C6 alkyl; and R 4 is C1-C6 alkyl, substituted C1-C6 alkyl, substituted aryl, heteroaryl or substituted heteroaryl 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. m, n, o and p are independently selected from 0, 1 or 2 at each occurrence.

3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

4. R 5 teeth, 【Chemistry 4】 and R WA , R WB , R WC is independently selected at each occurrence from H and C1-C6 alkyl; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

5. R 2 teeth, 【Chemistry 5】 is 5. The compound according to claim 2 or 4, or a pharma- ceutically acceptable salt thereof.

6. R 2 teeth, 【Chemistry 6】 and (A) m CR a R b and (A) n CR a R b and (A) o CR a R b or O; (A) p is CRaR b and R a is independently selected at each occurrence from H and C1-C4 alkyl; R b is independently selected at each occurrence from H and C1-C4 alkyl; m, n, o and p are independently selected from 0, 1, 2 or 4 at each occurrence; The conditions are as follows: (A) o When is O, o is 1; Xa is H or a halogen; W is for COR 5 and R 5 teeth, 【Chemistry 7】 and R WA , R WB , R WC is independently selected at each occurrence from H, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, and CN; 5. The compound according to claim 2 or 4, or a pharma- ceutically acceptable salt thereof.

7. R 1 is CH 4 and R 2 teeth, 【Chemistry 8】 and R 4 teeth, 【Chemistry 9】 【change】 is 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

8. R 1 is CH 4 or CHF 2 and R 2 teeth, 【Chemistry 10】 R 4 teeth, 【Chemistry 11】 is 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

9. 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)prop-2-en-1-one; 1-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]non-6-en-2-yl)-2-methylprop-2-en-1-one; 1-(6-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.4]heptan-2-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(8-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-azaspiro[4.5]dec-7-en-2-yl)prop-2-en-1-one; N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide; 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; N-(7-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]non-6-en-2-yl)acrylamide; 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-isopropyl-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-(difluoromethoxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; N-(7-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)spiro[4.5]nonan-2-yl)acrylamide; 1-(9-(4-amino-7-methyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(6-(methylamino)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxy-5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-(cyclopentyloxy)pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(6-(4-methylcyclobutoxy)pyridin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclobutoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoropyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoro-6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-(difluoromethoxy)pyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridazin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-5-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2,2-dimethyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(4-methylpyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-cyclopropoxyphenyl)-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 5-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-(difluoromethyl)-7H-pyrrolo[2,4-d]pyrimidin-5-yl)picolinonitrile; 1-(9-(4-amino-5-(4-(methoxy-d4)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-8-fluoro-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2-methyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-2,2-dimethyl-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(4-(4-amino-5-(4-fluorophenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-1-oxa-9-azaspiro[5.5]undec-4-en-9-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-methoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-fluoropyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-cyclopropylpyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-(oxetan-4-yloxy)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(5-((tetrahydrofuran-4-yl)oxy)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6,7 dihydrofurano[4,2-d]pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(4-fluoropyridin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 2-(6-(4-acryloyl-4-azaspiro[5.5]undec-8-en-9-yl)-4-amino-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-5-yl)pyrimidine-5-carbonitrile; 1-(9-(4-amino-7-methyl-5-(5-(tetrahydrofuran-4-yl)pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(oxazol-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-(2-hydroxyethyl)-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyridazin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrazin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(5-cyclopropoxypyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-4-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; and 1-(9-(4-amino-5-(4-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one A compound or a pharma- ceutically acceptable salt thereof.

10. 1-(9-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-cyclopropoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-5-(6-methoxypyridin-4-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; 1-(9-(4-amino-7-methyl-5-(pyrimidin-2-yl)-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one; and 1-(9-(4-amino-5-(5-(difluoromethyl)pyrimidin-2-yl)-7-methyl-7H-pyrrolo[2,4-d]pyrimidin-6-yl)-4-azaspiro[5.5]undec-8-en-4-yl)prop-2-en-1-one 10. The compound of claim 9 or a pharma- ceutically acceptable salt thereof.

11. Administering to a patient in need thereof an effective amount of a compound according to claim 1. Methods of cancer treatment.

12. The cancer is selected from endometrial cancer, gastric cancer, and intrahepatic cholangiocarcinoma. The method of claim 11.

13. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent or excipient. Drug compositions.

14. Used in therapy 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

15. Used in cancer treatment 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

16. Used in the manufacture of drugs for the treatment of cancer 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

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