N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives

Abstract

To provide compounds in the treatment of conditions, diseases and disorders mediated by Bruton's Tyrosine Kinase.SOLUTION: The invention relates to compounds of the formula (I) or pharmaceutically acceptable salts thereof, intermediates in the preparation of the compounds, pharmaceutical compositions comprising the compounds, and use of the compounds in the treatment of disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound comprising N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl ) Benzamide derivatives, their preparation, pharmaceutical compositions containing them and Bruton's tyrosine kinase The present invention relates to their use in the treatment of conditions, diseases and disorders mediated by enzymes. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a ubiquitous kinase involved in B cell receptor (BCR) signaling. It is a critical node in cancer and an important target in cancer. Many cancers and lymphomas are caused by BT. They express BTK and depend on BTK function. They also regulate BCR signaling in tumor-infiltrating B cells. ng has been implicated in the tumor-promoting microenvironment of solid cancers (J.A. Burger and A. Wiestner, Nat Rev Cancer 2018,18,148). We used an inhibitor that irreversibly binds to BTK via cysteine-481, specifically cysteine-481. Pharmacological inhibition of BTK is an established strategy, and BTK is the primary inhibitor of the molecule ibrutinib. (J.A. Burger and J.Buggy, Leukemia and Lymphoma 2013,54,2385). This is a treatment for some cancers. It has been shown that the placement of m.Practice 2016,22,92-104.V.Kaur&A.Swami ,Ann.Hematol.2017,96,1175) and at least one previous Acalabrutinib is indicated for the treatment of patients with mantle cell lymphoma who have received prior treatment It has also been shown (Wang M et al, Lancet 2018, 391 ,Issue 10121,659-667).

[0003] BTK also plays an essential role in autoimmune diseases. in rheumatoid arthritis (L. Jansson and R. Holmdahl, Clin ical and experimental immunology 1993,94 ,459;LENyhoff et al,Arthritis Rheumatoid arthritis l.2016,68,1856), systemic lupus erythematosus (Steinberg,BJ .et al., J.Clin.Invest.1982,70,587-597) Allergic diseases and anaphylaxis (Hata, D. et al., J. Exp. Med. 1998, 187, 1235-1247) Because BTK protects against immune deficiencies, pharmacological inhibition of BTK may be useful in treating immune deficiencies.

[0004] In view of the above, modulators of BTK may be useful in treating proliferative disorders such as cancer and immune (e.g., autoimmune) disorders. These compounds may be useful in the treatment of infectious diseases.

[0005] BTK-dependent diseases, especially those that are resistant to or do not respond adequately to currently available drugs New drugs to treat this condition are needed.

[0006] Reducing or eliminating BTK protein by inducing its degradation Molecules designed to inhibit BTK (hereafter referred to as "BTK degraders") have been shown to inhibit a wide range of B It may be effective in treating TK-mediated diseases, such as proliferative disorders (such as cancer) and immune disorders. Furthermore, BTK degraders are irreversible BTK inhibitors (which bind covalently to BTK). Resistance can be effective in situations where there is resistance to, for example, a substitution of cysteine-481 with serine. It may arise from mutation (or other amino acid substitution).

[0007] Potential indicators of BTK degraders include, but are not limited to, those of hematopoietic origin. Cancer, e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, hairy cell Leukemias, histiocytic neoplasms, dendritic neoplasms, B-cell neoplasms, such as chronic lymphocytic leukemia (C LL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom lymphoma Strohm's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma, Burkitt lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter's syndrome, precursor B-lymphoblastic lymphoma, primary multiple myeloma and secondary multiple myeloma Myeloma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, Plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma , mediastinal (thymus) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion These include exacerbated lymphoma, lymphoma granulomatosis, and acute lymphoblastic leukemia.

[0008] Potential indicators of BTK degraders include, but are not limited to, the following: Immune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, allergic diseases, These include inflammatory and inflammatory symptoms. As such, chronic graft-versus-host disease (cGvHD) and immunoglobulin light chain amyloidosis (A L) are mentioned.

[0009] The principle of induced degradation of protein targets as a potential therapeutic approach has been demonstrated, e.g., in C .M.Crews,2018,J.Med.Chem.,61(2),403-404 and and the references therein. Recruitment of target proteins to the E3 ubiquitin ligase IAP for incorporation and degradation The BTK degrader molecule incorporating an E3 ligase IAP-binding moiety for this purpose is described in International Publication No. 2002. 016 / 169989, page 12. Two additional BTK degrader molecules incorporating different moieties as BTK-binding components Huang et al., 2018, Cell Chemical Biolog The molecules described in that publication are ubiquitinated. and B to an E3 ligase complex containing cereblon (CRBN) for its subsequent degradation. Incorporating an immunomodulatory imide drug (IMiD) moiety (pomalidomide) for TK recruitment Also, Huang et al. described a method for identifying multiple targets, including BTK. and also binds the zinc finger DNA-binding protein IKZF1 (Ikaros). Promiscuous kinase binders have been reported to degrade certain non-kinase targets, including It is a molecule (TL12-186) based on IKZF1 and related protein IKZF3 ( Aiolos) is known to be degraded by pomalidomide and lenalidomide. (Kroenke, J. et al. 2014, Science 343, 301-3 05;Petzold et al.,Nature 2016,532,127-13 0;Bjorklund et al.,2015,Blood Cancer Jou rnal,5,e354;Lu et al.,2014,Science,343,3 05-309;Gandhi et al.,2014,Br.J.Haematol. 164,811-821). Summary of the Invention [Means for solving the problem]

[0010] The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, as defined herein below. The compounds of formula (I) are BTK degraders and therefore are capable of inhibiting BTK. These compounds are potentially useful in the treatment of conditions, diseases and disorders mediated by

[0011] In one embodiment of the present invention, a compound of formula (I) [ka] (In the formula, R 1 , R 1a , R 2 and R 2a is independently selected at each occurrence from H and F; R 6 is H or F; R 7 is selected from H, F, Cl, —CH3, —OCH3 and —OCH2CH3; X 1 is represented by formula (A) or (B): [ka] is a group of the formula * X 1a teeth, * -(CH2) 1~3 -and * -CH2C(CH3)2-, where: * represents X in formula (I).1a indicates the point of attachment of the group to the phenyl ring; * X 1b teeth, * -O-, * -OCH2- and * -CH2O-, wherein * represents X in formula (I). 1b indicates the point of attachment of the group to the phenyl ring; X 2a are represented by formulas (C), (D), (E), (F) and (G): [ka] is selected from: ** is X 1a indicates the point of attachment to; X 2b are represented by the formula (E1) and the formula (F1): [ka] is selected from: ** is X 1b indicates the point of attachment to; X 5 is CH or N; X 6 is CH or N; R 3 is H or -CH3; R 4 is H or —CHOH; R 5 is H or —CHOH; Z is absent or * -(CH2) 2~3 NH-, where * is the formula (C) Indicates the attachment point of Z to the N atom; Z 1 teeth, * -O-, * -C(O)-, * -(CH2) 1~3 -, * -(CH2)2O- and * -CHCH(CHOH)O-, wherein * is the formula (E) and the formula ( Z in E1) 1 X 5 indicates the point of attachment to; Z 2a is absent or NH(CH2)4- ** and; Z 2b is -(CH2) 3~4 NH(CH2)2- ** and; Z 3 is absent or ** -(CH2)4NH-, and Z 2a and Z 3 are both at the same time Not absent from; where Z 2a , Z 2b and Z 3 In each of ** is the formula (F) and the formula (F1) indicates the attachment points to each N atom in q is 0 or 1; and n and p are independently 0 or 1; (i) Z in formula (E) or formula (E1) 1 but * -O-, X 5 and X 6 teeth, is not N, and (ii) Z in formula (E) or formula (E1) 1 but * -(CH2)2-O -or * -CH2CH(CH2OH)O-, X 6 is not N) or a pharmaceutically acceptable salt thereof.

[0012] The present invention provides novel N-(3-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)- The present invention relates to a compound (phenyl)benzamide, which inhibits the activity of Bruton's tyrosine kinase ( The compound induces the degradation of BTK (BTK mutants, especially BTK It confers resistance to inhibitors, especially irreversible BTK inhibitors such as ibrutinib. By recruiting E3 ligases (including BTK) to induce degradation of BTK, protease activity is enhanced. It is designed to promote BTK ubiquitination and its subsequent degradation by the teasome. The compounds of the present invention are novel ligases that bind to the E3-ligase cereblon (CRBN). It contains a novel BTK binding domain portion linked to a ligand.

[0013] Thus, the compounds of the present invention are useful in treating proliferative autoimmune diseases, particularly those mediated by BTK. Disorders and diseases (e.g., mutation of cysteine-481 to serine (or other amino acid substitution) These compounds are potentially useful in treating a wide range of diseases and disorders, including those for which resistance has developed. The compounds of the present invention can be used in combination with IMiDs such as thalidomide, lenalidomide and poliostatin. Degraded by malidomid and also by the proteolytic molecule TL12-186 mentioned above. Other proteins, particularly other tyrosine kinase proteins and / or or proteins such as IKZF1 and / or IKZF3 (non-tyrosine kinase) IK The compounds of the present invention may further exhibit selectivity for BTK degradation over the ZF family. enzyme selectivity and / or other off-target proteins, e.g., ion channels and GTPases It may further exhibit selectivity for protein-coupled receptors (GPCRs).

[0014] Thus, the compounds of formula (I) (including pharmaceutically acceptable salts thereof) are capable of being catalyzed by BTK. conditions, diseases and disorders mediated by steroids, especially proliferative conditions, diseases and disorders, such as cancer, especially Hematopoietic cancers (B-cell neoplasms, e.g., chronic lymphocytic leukemia (CLL), mantle cell lymphoma) Small lymphocytic lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia Blood plasma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma Lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter's syndrome, precursor B lymphoma Lymphoblastic lymphoma, primary and secondary multiple myeloma, B-cell prolymphocytic Leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma , extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large cell B-cell Follicular lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, granulomatous lymphoma are considered suitable for use in the treatment of leukemia, including leukemia, bronchial asthma, and acute lymphoblastic leukemia. .

[0015] In another aspect, the present invention provides a method for treating, preventing, or treating a BTK-mediated condition, disease, or disorder. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for improving do.

[0016] In another aspect, the present invention provides a compound of formula (I) or Compositions comprising pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers are provided. Provide.

[0017] In another aspect, the present invention provides a compound of formula (I) or Combinations are provided that include pharmaceutically acceptable salts thereof and one or more therapeutically active agents. DETAILED DESCRIPTION OF THE INVENTION

[0018] Various embodiments of the present invention are described herein. The specified features of each embodiment are: It is recognized that the features may be combined with other specified features to provide further embodiments of the present invention. Also, various (enumerated) embodiments of the invention are described herein. .

[0019] Substituent definitions, where applicable, are provided in formulae (I), (I'), (I''), (I''') and This applies to compounds (Ia).

[0020] The substituent definitions apply to the final product and the corresponding intermediates.

[0021] Thus, the present invention provides a compound of formula (I) [ka] (In the formula, R 1 , R 1a , R 2 and R 2a is independently selected at each occurrence from H and F; R 6 is H or F; R 7 is selected from H, F, Cl, —CH3, —OCH3 and —OCH2CH3; X 1 is represented by formula (A) or (B): [ka] is a group of the formula * X 1a teeth, * -(CH2) 1~3 -and * -CH2C(CH3)2-, where: * represents X in formula (I). 1a indicates the point of attachment of the group to the phenyl ring; * X 1b teeth, * -O-, * -OCH2- and * -CH2O-, wherein * represents X in formula (I). 1b indicates the point of attachment of the group to the phenyl ring; X 2a are represented by formulas (C), (D), (E), (F) and (G): [ka] is selected from: ** is X 1a indicates the point of attachment to; X 2b are represented by the formula (E1) and the formula (F1): [ka] is selected from: ** is X 1b indicates the point of attachment to; X 5 is CH or N; X 6 is CH or N; R 3 is H or -CH3; R 4 is H or —CHOH; R 5 is H or —CHOH; Z is absent or * -(CH2) 2~3 NH-, where * is the formula (C) Indicates the attachment point of Z to the N atom; Z 1 teeth, * -O-, * -C(O)-, * -(CH2) 1~3 -, * -(CH2)2O- and * -CHCH(CHOH)O-, wherein* is the formula (E) and the formula ( Z in E1) 1 X 5 indicates the point of attachment to; Z 2a is absent or NH(CH2)4- ** and; Z 2b is -(CH2) 3~4 NH(CH2)2- ** and; Z 3 is absent or ** -(CH2)4NH-, and Z 2a and Z 3 are both at the same time Not absent from; where Z 2a , Z 2b and Z 3 In each of ** is the formula (F) and the formula (F1) indicates the attachment points to each N atom in q is 0 or 1; and n and p are independently 0 or 1; (i) Z in formula (E) or formula (E1) 1 but * -O-, X 5 and X 6 teeth, is not N, and (ii) Z in formula (E) or formula (E1) 1 but * -(CH2)2-O -or * -CH2CH(CH2OH)O-, X 6 is not N) or a pharmaceutically acceptable salt thereof.

[0022] Unless otherwise specified, the terms "compounds of the invention" or "a compound of the invention" , compounds of formula (I), its subformulas, and exemplary compounds, as well as salts thereof, and all related compounds. isomers (including diastereoisomers and enantiomers), rotamers, tautomers, and refers to isotopically labeled compounds (including deuterium substitutions) as well as naturally formed moieties .

[0023] Unless otherwise specified, the expressions used in this specification have the following meanings: Terminology used - (CH2) 1~3 - consists exclusively of carbon and hydrogen atoms and is unsaturated Contains no carbon atoms, has 1 to 3 carbon atoms, and is attached to other molecules at each end by a single bond This refers to (especially) linear hydrocarbon chain biradicals. The end that attaches to another molecule of * or ** It can be specified by -(CH2)2O-, -(CH2) 2~3 NH-, -(CH2) 3~4 Groups incorporating NH(CH2)2- and -(CH2)4NH- are to be construed accordingly It should be.

[0024] Enumerated embodiments: Embodiment 1. A compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.

[0025] Embodiment 2.R 1 is H, Acceptable salts.

[0026] Embodiment 3.R 1a is F, Pharmaceutically acceptable salts.

[0027] Embodiment 4.R 2 is H. or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 5.R 2a is F. or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 6.R 6 is H. or a pharmaceutically acceptable salt thereof.

[0030] Embodiment 7.R 7 is selected from F, —CH3, and —OCH3. A compound of formula (I) according to any one of the following or a pharmaceutically acceptable salt thereof:

[0031] Embodiment 8.R 7 is F. or a pharmaceutically acceptable salt thereof.

[0032] Embodiment 9.R 7 is —CH3, or a pharmaceutically acceptable salt thereof.

[0033] Embodiment 10.R 7 is —OCH3, I) or a pharmaceutically acceptable salt thereof.

[0034] Embodiment 11.X 1 is the formula (A): [ka] The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 10, Acceptable salts.

[0035] Embodiment 12. * X 1a teeth, * -(CH2)1~3 -, according to embodiment 11, I) or a pharmaceutically acceptable salt thereof.

[0036] Embodiment 13. * X 1a teeth, * -CH2- and * -(CH2)2- A compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 12.

[0037] Embodiment 14.X 2a are represented by formulas (C), (E) and (F): [ka] A compound of formula (I) or a drug thereof according to any one of embodiments 11 to 13, selected from A physiologically acceptable salt.

[0038] Embodiment 15.X 2a are represented by formulas (C) and (E): [ka] or a pharmaceutically acceptable salt thereof.

[0039] Embodiment 16.R 4 is H. The compound or a pharmaceutically acceptable salt thereof.

[0040] Embodiment 17.R 5 is H. The compound or a pharmaceutically acceptable salt thereof.

[0041] Embodiment 18.q is a compound of formula (I) according to any one of embodiments 1 to 17, wherein 1 is or a pharmaceutically acceptable salt thereof.

[0042] Embodiment 19. The method according to any one of embodiments 1 to 18, wherein n and p are both 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0043] Embodiment 20. A compound of formula (I) according to any one of embodiments 1 to 19, wherein Z is absent. The compound or a pharmaceutically acceptable salt thereof.

[0044] Embodiment 21.X 5 and X 6 and are both CH. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 22.X 5 and X 6 and are both N. or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 23.Z 1 teeth, * -O- according to any one of embodiments 1 to 21. I) or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 24.Z 1 teeth, * The compound of formula (I) according to embodiment 22, wherein -(CH2)2- or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 25.Z 2a is -NH(CH2)4- ** Any of embodiments 1 to 24, A compound of formula (I) according to any one of the following or a pharmaceutically acceptable salt thereof:

[0049] Embodiment 26.Z 2a is -NH(CH2)4- **Formula ( I) or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 27.Z 3 is absent, or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 28.Z 3 is absent, A commercially acceptable salt.

[0052] Embodiment 29. Formula (Ia) [ka] (In the formula, R 6 is H or F; R 7 is selected from H, F, Cl, —CH3, —OCH3 and —OCH2CH3; X 1 is represented by formula (A) or (B): [ka] is a group of the formula * X 1a teeth, * -(CH2) 1~3 -and * -CH2C(CH3)2-, where: * represents X in formula (Ia). 1a indicates the point of attachment of the group to the phenyl ring; * X 1b teeth, * -O-, * -OCH2- and * -CH2O-, wherein * represents X in formula (Ia). 1bindicates the point of attachment of the group to the phenyl ring; X 2a are represented by formulas (C), (D), (E), (F) and (G): [ka] is selected from: ** is X 1a indicates the point of attachment to; X 2b are represented by the formula (E1) and the formula (F1): [ka] is selected from: ** is X 1b indicates the point of attachment to; X 5 is CH or N; X 6 is CH or N; R 3 is H or -CH3; R 4 is H or —CHOH; R 5 is H or —CHOH; Z is absent or * -(CH2) 2~3 NH-, where * is the formula (C) Indicates the attachment point of Z to the N atom; Z 1 teeth, * -O-, * -C(O)-, * -(CH2) 1~3 -, * -(CH2)2O- and * -CHCH(CHOH)O-, wherein * is the formula (E) and the formula ( Z in E1) 1 X 5 indicates the point of attachment to; Z 2a is absent or NH(CH2)4- ** and; Z 2b is -(CH2) 3~4 NH(CH2)2- ** and; Z 3 is absent or ** -(CH2)4NH-, and Z 2a and Z 3 are both at the same time Not absent from; where Z 2a , Z 2b and Z 3 In each of ** is the formula (F) and the formula (F1) indicates the attachment points to each N atom in q is 0 or 1; and n and p are independently 0 or 1; (i) Z in formula (E) or formula (E1) 1 but * -O-, X 5 and X 6 teeth, is not N, and (ii) Z in formula (E) or formula (E1) 1 but * -(CH2)2-O -or * -CH2CH(CH2OH)O-, X 6 is not N) or a pharmaceutically acceptable salt thereof.

[0053] Embodiment 30.X 1 teeth, [ka] (In the formula, * indicates the point of attachment to the phenyl ring in formula (I) Formula (I) according to any one of embodiments 1 to 10 or formula (I) according to embodiment 29, selected from A compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0054] Embodiment 31.R 4is H, The compound or a pharmaceutically acceptable salt thereof.

[0055] Embodiment 32.R 5 is H. ) or a pharmaceutically acceptable salt thereof.

[0056] Embodiment 33.q is a compound of formula (Ia) according to any one of embodiments 29 to 32, wherein q is 1 or a pharmaceutically acceptable salt thereof.

[0057] Embodiment 34. Formula (Ia) according to any one of embodiments 29 to 33, wherein n is 1. or a pharmaceutically acceptable salt thereof.

[0058] Embodiment 35. p is a compound of formula (Ia) according to any one of embodiments 29 to 34, wherein p is 1 or a pharmaceutically acceptable salt thereof.

[0059] Embodiment 36. A compound of formula (Ia) according to embodiments 29 to 35, or and pharmaceutically acceptable salts thereof.

[0060] Embodiment 37.X 5 and X 6 and are both CH. A compound of formula (Ia) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

[0061] Embodiment 38.X 5 and X 6 and are both N. A compound of formula (Ia) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[0062] Embodiment 39.Z 1 teeth, * -O- and *-(CH2) 1~3 - selected from the implementation form 39. A compound of formula (Ia) according to any one of embodiments 29 to 38, or a pharmaceutically acceptable salt thereof.

[0063] Embodiment 40.Z 1 teeth, * -O- and * -(CH2)2-, 9. A compound of formula (Ia) according to claim 9 or a pharmaceutically acceptable salt thereof.

[0064] Embodiment 41.X 1 teeth, [ka] (In the formula, * indicates the atom attached to the phenyl ring in formula (I) or formula (Ia) Formula (I) according to any one of embodiments 1 to 10 or formula (I) according to embodiment 29, selected from A compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0065] Embodiment 42.X 1 teeth, [ka] (In the formula, * indicates the atom attached to the phenyl ring in formula (I) or formula (Ia) The compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof according to embodiment 41, selected from Acceptable salts.

[0066] Embodiment 43.Z 1 is -O- and X 5 and X 6 are both CH, 41. A compound of formula (I) or formula (Ia) according to form 41 or 42, or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 44.Z 1 is -(CH2)2- and X 5 and X 6 are both N , a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof according to embodiment 41 or 42. Salt that can be used.

[0068] Embodiment 45.R 4 and R 5 and are both H. A compound of formula (I) or formula (Ia) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[0069] Embodiment 46. Any one of embodiments 41 to 45, wherein n, p, and q are each 1. A compound of formula (I) or formula (Ia) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[0070] Embodiment 47. The compound of formula (I) according to any one of embodiments 41 to 46, wherein Z is absent. or a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0071] Embodiment 48.X 1 teeth, [ka] [ka] [ka] [ka] (In the formula, * indicates the atom attached to the phenyl ring in formula (I) or formula (Ia) Formula (I) or is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0072] Embodiment 49.X 1 teeth, [ka] (In the formula, * indicates the atom attached to the phenyl ring in formula (I) or formula (Ia) The compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof according to embodiment 48 is selected from Acceptable salts.

[0073] Embodiment 50. rac-N-(3-(6-(4-((9-(3-(2,4-dioxote tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-( ... (xymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl (yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methyl phenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) 1(2H)-imidin-4-yl-7-(hydroxymethyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyridyl (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) 1(2H)-imidin-4-yl-7-(hydroxymethyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyridyl (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]urethane (3-indecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy propan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydrochloride (4-fluorobenzoyl)piperidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl) Ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine (2H)-imidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl )Piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine 4-methoxybenzoyl)piperidin-1(2H)-yl)piperidin-4-yl)oxy )piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxide (ii)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (2H)-benzoyl)-3,9-diazaspiro[5.5]undecane-3 -yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5 -fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2 -yl)benzamide, N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydrochloride (4-methoxybenzoyl)piperidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) Ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-fluorobenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) 4-(4-hydroxypiperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyri 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-dioxote tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine-4 -yl)oxy)-3-hydroxypropyl)piperidin-4-yl)oxy)phenyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methyl (phenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyridine (2H)-imidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl )piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetrahydrochloride (4-Methoxybenzoyl)piperazin-1-yl) Ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidinyl) (2H)-inyl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazine Perazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy propan-2-yl)benzamide, rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine 4-Methoxybenzoyl)-1-(hydroxymethyl)-(4-methoxybenzoyl)-1(2H)-imidin-1(2H)-yl 3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyridyl (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) 4-Methoxybenzoyl)-1-(hydroxymethyl)-(4-methoxybenzoyl)-1(2H)-imidin-1(2H)-yl 3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyridyl (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) 4-Methoxybenzoyl)-1-(hydroxymethyl)-(4-methoxybenzoyl)-1(2H)-imidin-1(2H)-yl 3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyridyl (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidinyl) Benzyl-1(2H)-yl)-4-methoxybenzamido)butyl)piperazin-1-yl )methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro (2-hydroxypropan-2-yl)-2-fluoro-4-(2-hydroxy-2-methylphenyl)- ) benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecane (3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl)- (pan-2-yl)benzamide, 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Cypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3 -d]pyrimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenz amides, 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Cypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3 -d]pyrimidin-6-yl)benzyl)amino)pentyl)-4-methylbenzamide , 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-( (4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane-2 -yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin (6-phenyl)benzyl)amino)pentyl)-N,4-dimethylbenzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-2,7-diazaspiro[3.5]nona (phenyl-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-phenyl)benzamide, N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydropyridine (2H)-diphenyl-4-methoxybenzoyl)piperidine-4-carbonyl Perazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)o 7H-pyrrolo[2,3-d]pyrimidin-1-yl)ethyl)phenyl)- (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(2-(3-(2,4-dioxotetrahydropyrimidin Diazin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,8-diazaspirate (4.5)decane-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrrol 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(4-((2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (ethyl)amino)butoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl)- (pan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-chloro-3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)benzamido)ethyl)-1-oxa-4,9- Diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro bro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) ethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(3-(2,4-dioxotetrahydropyrimidin Diazin-1(2H)-yl)-4-methoxybenzamido)ethyl)-1-oxa-4,9 -diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro oro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyridine (2H)-(4-methoxybenzoyl)piperazin-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, N-(3-(6-(4-((((1s,4s)-4-((1-(3-(2,4-dioxo (isotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro bro-4-(2-hydroxypropan-2-yl)benzamide, 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3- d] pyrimidin-6-yl)benzyl)amino)pentyl)-N-methylbenzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) ethyl)piperidin-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyridine 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(2-(3-(2,4-dioxotetrahydropyrimidin Diazin-1(2H)-yl)-4-methoxybenzamido)ethyl)-3,9-diazaspirate (5.5)undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((3-((2-(4-(3-(2,4-dioxotetrahydrochloride (4-Methoxybenzoyl)piperazin-1-yl) Ethyl)amino)propoxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1r,4r)-4-((1-(3-(2,4-dioxo Tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (4-fluorobenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-((4-(3-(4-chloro-3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)benzamido)propyl)-1-oxa-4,9 -diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro oro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-2,8-diazaspiro[4.5]deca (phenyl-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-phenyl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine (2H)-imidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxy Piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) ethyl)piperidin-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyridine 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrimidin Diazin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,7-diazaspirillum (3,5)nonan-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyr 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrimidin Diazin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,8-diazaspirate (4,5)decane-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrrol 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1s,4s)-4-((1-(3-(2,4-dioxo Tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-2,8-diazaspiro[4.5]deca (phenyl-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-phenyl)benzamide, N-(3-(6-(4-((((1r,4r)-4-((1-(3-(2,4-dioxo (isotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro bro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(4-chloro-3-(2,4-dioxotetramethyl) Hydropyrimidin-1(2H)-yl)benzamido)propyl)-3,9-diazaspirate (5.5)undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, or N-(3-(6-(4-((1-(2-((1-(3-(2,4-dioxotetrahydrochloride (4-methoxybenzoyl)piperidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) Oxy)ethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 51. N-(3-(6-(4-((4-((1-(3-(2,4-dioxote tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine-4 -yl)oxy)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxide (ii)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)o 7H-pyrrolo[2,3-d]pyrimidin-1-yl)ethyl)phenyl)- (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyridine (2H)-(4-methoxybenzoyl)piperazin-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (4-fluorobenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide or a pharmaceutically acceptable salt thereof.

[0075] Embodiment 52. Compound N-(3-(6-(4-((4-((1-(3-(2,4-dihydro- 1(2H)-1-(4-methoxybenzoyl)-1(2H)-pyrimidin-1(2H)-yl phenyl-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro 4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof Salt.

[0076] Embodiment 53. The compound N-(3-(6-(4-((9-(3-(2,4-dioxoteto) (1(2H)-yl)-4-methoxybenzoyl)-3,9-diaza spiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 54. Compound N-(3-(6-(4-(2-(4-((1-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin 7H-pyrrolo[(4-yl)oxy)piperidin-1-yl)ethyl)phenyl] 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro oro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof Salt that can be used.

[0078] Embodiment 55. Compound N-(3-(6-(4-((4-(2-(4-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine (piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof Salt to be used.

[0079] Embodiment 56. Compound N-(3-(6-(4-(2-(9-(3-(2,4-dioxo Tetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-di azaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof salt.

[0080] Embodiment 57. Compound N-(3-(6-(4-(2-(4-((1-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine Lysin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof Salt to be used.

[0081] Embodiment 58. Compound N-(3-(6-(4-(((4-(4-(3-(2,4-dihydro- 1(2H)-1-(4-methoxybenzoyl)-1(2H)-tetrahydropyrimidin-1(2H)-yl (1-phenyl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyridine 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

[0082] Embodiment 59. Compound N-(3-(6-(4-(2-(9-(3-(2,4-dioxo Tetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)-3,9-di azaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof salt.

[0083] Depending on the choice of starting materials and procedures, the compound may exist in one of the possible stereoisomers. or mixtures of stereoisomers, e.g. pure optical isomers or mixtures of stereoisomers, e.g. It may exist as a racemic or diastereomeric mixture (depending on the number of asymmetric carbon atoms). The present invention provides racemic mixtures, diastereomeric mixtures and optically pure forms. It is intended to include all possible stereoisomers, including the optically active -(R) stereoisomer. The isomers and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents. or can be resolved using conventional techniques. If the compound contains a double bond, the substituents It may be in the E, E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl may be in the E, E or Z configuration. Alkyl substituents may have cis or trans configurations. Isomeric forms are intended to be included.

[0084] Compounds of formula (I) or formula (Ia) may exist in different tautomeric forms. All tautomeric forms of compounds of formula (Ia) are encompassed by the present invention. For example, The compound of (I) is a compound of formula (I') and formula (I'') [ka] (In the formula, R 1 , R 1a , R 2 , R 2a , X 1 , R 6 and R 7 is represented by formula (I) or formula (Ia) (as defined in accordance with The tautomeric forms according to the formula:

[0085] As used herein, the term "salt" or "salts" refers to an acid salt of a compound of the present invention. "Salt" refers to a salt or a base addition salt. "Salt" specifically includes "pharmaceutically acceptable salts." .

[0086] The term "pharmaceutically acceptable salts" refers to compounds that retain the biological effectiveness and properties of the compounds of the present invention. and typically refers to salts that are undesirable, biologically or otherwise. The presence of amino and / or carboxyl groups or groups similar thereto makes the acid salt and / or base salts may be formed.

[0087] The pharmaceutically acceptable salts of the present invention can be prepared by conventional chemical methods from a basic or acidic moiety. Typically, such salts can be prepared by converting the free acid form of the compound into a suitable base. or by reacting the free base form of the compound with a stoichiometric amount of a suitable acid. It can be prepared by reacting it with a stoichiometric amount of methyl methyl ether. Such a reaction is typically The process is carried out in water, an organic solvent, or a mixture of the two. ether, ethyl acetate, ethanol, isopropanol, acetonitrile or tetrahydrofuran The use of a non-aqueous medium such as orchid is preferred. A list of further suitable salts can be found, for example, in "R emington's Pharmaceutical Sciences”,20th ed., Mack Publishing Company, Easton, Pa., (1985) and “Handbook of Pharmaceutical Salts s:Properties,Selection,and Use”(Stahl an d Wermuth)(Wiley-VCH,Weinheim,Germany,20 02) can be found in

[0088] Also, when both basic and acid groups are present in the same molecule, the compounds of the present invention have an internal Salts, such as zwitterionic molecules, may be formed.

[0089] The compounds of the present invention are characterized in that the compounds contain at least one basic group, e.g., an amino group. It is particularly suitable for forming acid addition salts with

[0090] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0091] Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. can be.

[0092] Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, oxalic acid, Leic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, Examples include methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. can be done.

[0093] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. .

[0094] Examples of inorganic bases from which salts can be derived include ammonium salts and salts of the metals of groups I to XII of the periodic table. In certain embodiments, the salts include sodium, potassium, ammonium Particularly suitable salts are those derived from calcium, magnesium, iron, silver, zinc and copper. Included are the ammonium, potassium, sodium, calcium and magnesium salts.

[0095] Examples of organic bases from which salts can be derived include primary, secondary and tertiary amines, naturally occurring Examples of suitable amines include substituted amines, including substituted amines containing cyclic amines, as well as basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, cholinate, and diethanolamine. amines, diethylamine, lysine, meglumine, piperazine and tromethamine. do.

[0096] In another aspect, the present invention provides a compound of the present invention as a salt of acetate, ascorbate, adipine, or the like. Acid salts, aspartates, benzoates, besylates, bromides / hydrobromides, bicarbonates / Carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, Chlortheophyllonate, citrate, ethanedisulfonate, fumarate, Glucept acid salts, glucuronate, gluconate, glutamate, glutarate, glycolate , hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, Lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methyl sulfate, mucoate, naphthoate, napsylate, nicotinate, nitrate, octadecate Citric acid salts, oleate salts, oxalate salts, palmitate salts, pamoate salts, phosphate salts / phosphate water salts Dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearyl phosphate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenyl It is provided in the form of a difluoroacetate, trifluoroacetate or xinafoate salt.

[0097] Any formula given herein represents unlabeled and isotopically labeled forms of the compounds. isotopically labeled compounds are compounds in which one or more atoms are selected from the group consisting of: The atomic mass or mass number given herein is the same as that given in the present specification, except that it is replaced by an atom having the specified atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the present invention include: Examples include isotopes of hydrogen.

[0098] In another embodiment of the present invention, a compound of formula (I''') [ka] (In the formula, R 1 , R 1a , R 2 , R 2a , R 6 is defined for formula (I) or formula (Ia) As stated above, R 7 is -C(R 10 )3, -OC(R 10 )3 or -OC(R 10 ) 2C(R 10 )3 and X 1 teeth, [ka] is selected from Each R 8 , R 9 and R 10 is independently selected at each occurrence from H or deuterium; The symbol # is independently substituted by H which may be replaced by H or deuterium at each occurrence. (Indicates the position where it is indicated that The compound of formula (I) is provided.

[0099] Certain isotopes, especially deuterium (i.e. 2 Incorporation of H or D) results in greater metabolic stability for example, by increasing in vivo half-life, reducing dosing requirements, or improving therapeutic index or tolerability. Deuterium, in this context, is a compound of formula (I) and formula (II). It is understood that the concentration of deuterium is considered to be a substituent of the compound of formula (Ia). The term "isotopic enrichment factor" as used herein refers to the amount of an isotope The term "abundance" refers to the ratio between the abundance and the natural abundance of the specified isotope in the compounds of the present invention. When a substituent of is represented as deuterium, the compound isotopically divided into two groups for each specified deuterium atom. A total concentration factor of at least 3500 (52.5% deuterium at each designated deuterium atom) incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67. (5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 55 00 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), a little At least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation) hydrogen incorporation), at least 6600 (99% deuterium incorporation) or at least 6633. 3 (99.5% deuterium incorporation). The term "isotopic enrichment factor" is used to describe deuterium. It should be understood that the same applies to any isotope as listed. be.

[0100] Other examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, Isotopes of oxygen, fluorine and chlorine, e.g. 3 H, 11 C. 13 C. 14 C. 15 N , 18 F, 35 S, 36 Cl and 125 Therefore, the present invention includes, for example, , radioisotopes, e.g. 3 H and 14 Incorporating one or more of the above isotopes, including C compounds or non-radioactive isotopes, e.g. 2 H and 13 It is understood that C includes Such isotopically labeled compounds should be used in metabolic studies ( 14 C), anti Response research (e.g., 2 H or 3 H), detection or imaging techniques, e.g., positron emission PET or SPECT (drug or substrate tissue) In particular, 18 F-labeled compounds are This may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) typically involves substituting appropriate isotopically labeled reagents for previously used unlabeled reagents. , by conventional techniques known to those skilled in the art or similar to the processes described in the accompanying examples. It can be prepared by the process of

[0101] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition containing at least one pharmaceutically acceptable carrier. A compound of the invention or its derivatives in a form suitable for oral or parenteral administration together with a carrier. refers to a pharmaceutically acceptable salt of

[0102] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is suitable for use in the preparation of a pharmaceutical composition or refers to materials useful for use, such as suitable diluents, solvents, dispersants known to those skilled in the art. Vehicle, surfactant, antioxidant, preservative, isotonic agent, buffer, emulsifier, absorption retardant, salt, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and and combinations thereof (e.g., Remington's Pharmacy ical Sciences,18th Ed.Mack Printing Comp (See any, 1990, pp. 1289-1329).

[0103] The term "therapeutically effective amount" of a compound of the present invention refers to a therapeutically effective amount that elicits a biological or medical response in a subject. to inhibit, for example, enzyme or protein activity or to ameliorate disease symptoms or alleviating symptoms, slowing or delaying the course of the disease, or preventing the disease. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention, such as When administered to a subject, (1) a compound that (i) is mediated by BTK or (ii) exhibits BTK activity or (iii) characterized by BTK activity (normal or abnormal). at least partially alleviate, prevent, and / or ameliorate the symptoms, disorders, or diseases (2) decrease or inhibit the activity of BTK; or (3) decrease the expression of BTK. These effects refer to the amount of a compound of the present invention that is effective to reduce or inhibit This effect can be achieved by lowering the amount of BTK, for example by degrading it. In another embodiment, the term "therapeutically effective amount" refers to a therapeutically effective amount of a cell, tissue, or non-cellular When administered to biomaterials or culture media, it at least partially reduces or at least partially reduces the activity of BTK. or inhibiting the expression of BTK; or at least inhibiting the expression of BTK, e.g., by degrading BTK. The term "inhibitory effect" refers to an amount of a compound of the present invention effective to partially reduce or inhibit the progression of inflammatory bowel disease.

[0104] As used herein, the term "subject" refers to a primate (e.g., a human, male or female), an iguanosine monophosphate (II), a phosphodiesterase (P2 ... In certain embodiments, the term "animal" refers to a mammal, such as a rabbit, a guinea pig, a pig, a rat, or a mouse. Elephants are primates. In one embodiment, the subject is a human.

[0105] As used herein, the term "inhibition" or "inhibiting" refers to the inhibition of a given condition, symptom, disorder, or or reduction or suppression of disease or baseline biological activity or biological process Refers to a large decrease in activity.

[0106] As used herein, the term "degrade" or "degradation" refers to the reduction of the biological activity (e.g., loss of activity) of BTK. by the cell's proteasome system to the extent that it reduces or eliminates the activity of the proteasomes (especially abnormal activity) This refers to the partial or complete degradation of a target protein, such as BTK. Degradation can involve E3 ligases, This can be achieved in particular through the mediation of an E3 ligase complex that includes the protein cereblon. As used herein, the term "modulating BTK activity" or "modulating BTK activity" refers to the This means altering, especially reducing, inhibiting, or eliminating, the activity of BTK. The amount of degraded BTK can be measured before treatment with the compounds of the present invention. The initial amount or level of BTK present and the increase in BTK after treatment with the compounds of the invention were measured. In one embodiment, the initial level can be measured by comparing the residual amount. In one embodiment, at least about 30% of the BTK is degraded compared to the initial level. In one embodiment, at least about 40% of the BTK is degraded compared to the initial level. In one embodiment, at least about 50% of the BTK is degraded compared to the initial level. In one embodiment, at least about 60% of the BTK is degraded compared to the initial level. In one embodiment, at least about 70% of the BTK is degraded compared to the initial level. In one embodiment, at least about 80% of the BTK is degraded compared to the initial level. In one embodiment, at least about 90% of the BTK is degraded compared to the initial level. In one embodiment, at least about 95% of the BTK is degraded compared to the initial level. In one embodiment, greater than 95% of the BTK is degraded compared to the initial level. At least about 99% of the BTK is degraded.

[0107] In one embodiment, BTK is expressed in an amount that is about 30% to about 99% of the initial level. In one embodiment, BTK is reduced by about 40% to about 99% compared to initial levels. In one embodiment, BTK is degraded by about 50% to about 90% compared to the initial level. In one embodiment, BTK is degraded by about 60% compared to initial levels. In one embodiment, BTK is degraded by about 99% compared to the initial level. Between 70% and about 99% of the BTK is degraded. In one embodiment, the BTK is degraded to a level comparable to the initial level. In one embodiment, BTK is degraded at about 80% to about 99% of its initial level. In one embodiment, BTK is degraded by about 90% to about 99% compared to the initial amount. In one embodiment, BTK is degraded by about 95% to about 99% compared to the level. Approximately 90% to 95% of the initial level is decomposed.

[0108] As used herein, the term "BTK selectivity" refers to, for example, the ability of a compound of the present invention to selectively bind to BTK. It is intended to degrade a protein in preference to or to a greater extent than another protein. Taste.

[0109] As used herein, the term "treating" any disease or disorder or any "Treatment" of a disease or disorder means alleviating or ameliorating the disease or disorder (i.e., slowing or inhibiting the progression of the disease or at least one of its clinical symptoms. or associated with a disease or disorder (including those that may not be discernible to the patient) Alleviating or improving at least one associated physical parameter or biomarker. This refers to the following:

[0110] As used herein, the term "preventing" any disease or disorder or any "Prevention" of a disease or disorder means prophylactic treatment of the disease or disorder; or It refers to delaying the onset or progression of the disease.

[0111] As used herein, a subject is defined as a person who is biologically, medically, or otherwise affected by a treatment such as Treatment is "necessary" if one would benefit in quality of life from it.

[0112] As used herein, in connection with the present invention (especially in connection with the claims), The terms "a," "an," "the," and similar terms are used herein. Unless otherwise specified in the specification or clearly contradicted by context, the singular and plural It should be interpreted as including both.

[0113] All methods described herein are intended to be illustrative unless otherwise indicated herein or by context. The steps may be performed in any suitable order unless clearly contradicted by the principles set forth herein. Use of any and all examples or exemplary language (e.g., "etc." or "for example") provided The use is intended merely to better clarify the invention and, unless claimed, No limitation to the scope of the invention is posed.

[0114] Any asymmetric atoms (e.g., carbon) of the compounds of the present invention may be present in racemic or enantiomeric forms. It may be present in an asymmetrically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration. In this embodiment, each asymmetric atom is in enantiomeric excess of either the (R)- or (S)-configuration. at least 50%, enantiomeric excess of at least 60%, enantiomeric excess of at least 70% , enantiomeric excess of at least 80%, enantiomeric excess of at least 90%, enantiomeric excess of At least 95% or an enantiomeric excess of at least 99%. Substituents at atoms may be present in cis (Z)-form or trans (E)-form where possible. -It can exist in the form

[0115] Thus, as used herein, the compounds of the present invention are intended to encompass all possible stereoisomers, rotamers, and the like. In one form of isomer, atropisomer, tautomer or mixture thereof, e.g. substantially Pure geometric (cis or trans) stereoisomers, diastereoisomers, optical isomers (enantiomers) , racemic or as a mixture thereof.

[0116] Any resulting mixture of stereoisomers may be classified based on the physicochemical differences of the constituents, e.g. By chromatography and / or fractional crystallization, pure or substantially pure geometric isomers or It can be separated into optical isomers, diastereoisomers and racemates.

[0117] Any resulting racemates of the compounds or intermediates of the present invention can be prepared by known methods, e.g. For example, by separation of their diastereomeric salts obtained with optically active acids or optically active bases, and By liberating an optically active acidic compound or an optically active basic compound, the compound can be separated into enantiomers. Therefore, the basic moiety can be, in particular, an optically active acid, such as tartaric acid. , dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mannitol by fractional crystallization of salts formed with methyl, malic or camphor-10-sulfonic acid The racemization method of the present invention can be used to resolve the compounds of the present invention into their enantiomers. The compound or racemic intermediate can be purified by chiral chromatography, e.g., high pressure liquid chromatography using a chiral adsorbent. The compounds can be separated by chromatography (HPLC).

[0118] The compounds of the present application can be prepared by the methods of organic synthesis using commercially available starting materials, compounds known in the literature. The compounds can be prepared in a number of ways known to those skilled in the art or from readily prepared intermediates. Standard syntheses are known or will be apparent to those skilled in the art in view of the teachings herein. All examples can be prepared by using the methods and procedures. Alternative orthogonal protecting group strategies are discussed, e.g., Protective Groups in Org anic Synthesis,3 rdedition, John Wiley & Soc. ns: New York, 1999 or Protecting Groups, 3 rd Standards as described in the edition, Thieme, Stuttgart, 2004 Those skilled in the art will be able to use the techniques disclosed herein in accordance with standard textbook knowledge. You will recognize if a stereocenter exists in the compound.

[0119] The compounds of the present invention can be synthesized according to the following scheme: The final molecule is constructed using a set of reaction procedures in a modular fashion that allows for a variety of reaction sequences. Several reactive types are particularly useful for preparing the compounds. All of the compounds of the present invention can be prepared by the addition of a coupling reagent in a solvent such as DMF or DMA. (e.g., HATU or HBTU) and a base (e.g., DIPEA or NMM) , an amide function typically formed by an amide coupling reaction between an amine and a carboxylic acid Alternatively, the carboxylic acid may be first reacted with the pentafluorophenol ester. This can be converted to an amine in the presence of a base such as TEA in a solvent such as DMF. The present invention also includes a carbon-nitrogen bond-containing compound, which can be easily reacted with the compound to form an amide. These compounds are often synthesized by reductive amination starting from an amine and an aldehyde or ketone. The reaction can be prepared using N This occurs using conditions such as aBH3CN, ZnCl2, and TEA. , usually in the presence of a base (such as TEA) in a solvent such as THF, with an alkyl halide or alkyl group. Nucleophilic substitution reactions of amines with suitable reaction partners containing leaving groups such as alkyl mesylates Ether-containing compounds can also be formed by nucleophilic substitution reactions. In this case, the alcohol is reacted with the haloamine in the presence of a base (such as TEA) in a solvent such as THF. by reaction with a suitable partner containing a leaving group such as benzyl fluoride Another generally useful method for preparing ether-containing compounds of the invention is The Mitsunobu reaction is a reaction in which phenol and another alcohol are reacted in a solvent such as THF. Phosphines (triphenylphosphine, etc.) and azodicarboxylic acid esters (diethyl in the presence of diisopropyl azodicarboxylate or diisopropyl azodicarboxylate, etc. Another reaction that is highly useful for the synthesis of the compounds of the present invention is the reaction of two aromatic Palladium (Pd)-catalyzed cross-coupling reactions are particularly useful for linking aromatic groups together. The catalyst (e.g., PdCl2(dppf)) and Aromatic halides and aromatic compounds using a base (e.g., Na2CO3 or Cs2CO3) The Suzuki coupling reaction is between aromatic boronic acids or esters.

[0120] Specifically, compounds of formula (I) include R 1 , R 1a , R 2 , R 2a , X 1 , R 6 , R 7 , X 1a and X 2a prepared as shown in Scheme 1, where M may be defined as H or as a protecting group such as -SO2Ph or -SEM. , and LG is defined as a leaving group such as mesylate (OM).

[0121] Therefore, compounds of formula (I) can be prepared by reacting them with a coupling reagent (e.g., dimethylformamide) in a solvent such as DMF or DMA. amines and carboxylic acids using a base (e.g., HATU) and a base (e.g., DIPEA or NMM) Amide coupling between the carboxylic acids to give the compound of formula (II) and the compound of formula (III) Alternatively, compounds of formula (I) can be treated with TEA in a solvent such as DMF. by treating the amine of formula (II) with the acid (IIIa) Compounds of formula (II) can be prepared by amide coupling between aryl esters of formula (I). Compounds of formula (IV) where M is a protecting group such as -SO2Ph can be prepared from compounds of formula (IV). For example, deprotection can be achieved by the addition of a base (e.g., DMSO, THF, and water) in a solvent mixture (e.g., DMSO, THF, and water). , NaOH); when M is a -SEM protecting group, in a solvent such as DCM Deprotection using an acid such as TFA can be utilized and can be combined with a subsequent amine deprotection step. t-Butoxycarbonyl esters can be prepared by the addition of t-butoxycarbonyl esters ... to t-butoxycarbonyl esters using an acid (e.g., TFA) in a solvent such as DCM. Further deprotection of the aryl (Boc) group provides compounds of formula (II). [ka]

[0122] Compounds of formula (IV) can be prepared by reacting a base (e.g., KCO) to form a compound of formula (VI) with a compound of formula (V) Alternatively, the compound of formula (IV) can be provided by the reaction of a compound of the formula (IV) with THF and M For example, under conditions using NaBH3CN, ZnCl2, and TEA in a solvent mixture such as eOH For example, in a reductive amination reaction, a compound of formula (VII) may be reacted with a compound of formula (VII). Thus, it can be provided.

[0123] The compound of formula (V) is R 1 , R 1a , R 2 , R 2a , X 1 , M and LG are previously defined The group -B(OR x )2 is a boronic acid or Boronic ester functional groups (including cyclic boronates, e.g., boron pinacol esters) Therefore, Pd-catalyzed couplings, for example, in solvent mixtures (e.g., dioxane / A catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2CO3) are added to the reaction mixture in water. The second step is followed by a Suzuki reaction between the compound of formula (VIII) and the compound of formula (IX) In the process, for example, mesylation with MsO and TEA in a solvent such as THF to give X 1a Conversion of the alcohol functionality linked to ##STR00002## to a leaving group LG provides compounds of formula (V). Compounds of formula (VIII) can be prepared by Pd-catalyzed coupling, for example, in a solvent mixture (e.g., di oxane / water) with a catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2 by Suzuki reaction between a compound of formula (X) and a compound of formula (XI) using CO It can be done. [ka]

[0124] By analogy, compounds of formula (VII) may be prepared by reacting R 1 , R 1a , R 2 , R 2a , M, LG and - B(OR x ) 2 can be prepared according to Scheme 3, where 2 is as previously defined.

[0125] Therefore, Pd-catalyzed couplings, e.g., in solvent mixtures (e.g., dioxane / water), Using a catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2CO3), The Suzuki reaction between a compound of formula (XII) and a compound of formula (IX) gives a compound of formula (VII) The compound of formula (XII) can also be prepared by Pd-catalyzed coupling, for example, by the use of a solvent mixture ( For example, a catalyst (e.g., PdCl2(dppf)) and a base (e.g., dioxane / water) are For example, the Suzuki reaction between compounds of formula (X) and (XIII) using Cs2CO3 It can be produced by reaction. [ka]

[0126] Compounds of formula (II) can also be prepared according to Scheme 4. When is H, NaBH3CN, ZnCl2 and followed by reductive amination between compounds of formula (XIV) and formula (XV) using conditions such as methyltrimethylammonium bromide and TEA. In addition, deprotection of the amine with an acid (e.g., TFA) in a solvent such as DCM can give the compound of formula (II). The compound of formula (XIV) can be obtained by a similar sequence starting from the compound of formula (VII). The compound of formula (VII) can be prepared by the process of N-(t-butoxycarbonyl) followed by reductive amination with methyl)piperazine in a solvent such as DCM with an acid (e.g., TF Deprotection of the amine with A) can be performed to provide (XIV). [ka]

[0127] Compounds of formula (IV) can be prepared from compounds of formula (XVI) by Pd-catalyzed coupling according to Scheme 5. Pulling, e.g., a catalyst (e.g., PdCl2) in a solvent mixture (e.g., dioxane / water) (dppf)) and a base (e.g., CsCO) to give the compound of formula (IX The compound of formula (XVI) can also be prepared by reacting it with a compound of formula (XVI). Thus, compounds of formula (XVII) can be prepared by Pd-catalyzed coupling, for example in a solvent mixture (e.g. For example, a catalyst (e.g., PdCl(dppf)) and a base (e.g., dioxane / water) , Cs2CO3) with a compound of formula (X). [ka]

[0128] Compounds of formula (XVII) can be prepared by reaction of borane with borane in a solvent such as dioxane, as shown in Scheme 6. Boronate dimers (e.g., bis(pinacolato)diboron), PdCl2(dp pf) and a base such as KOAc, The compounds (where Hal is a halogen) can be prepared by halogen-boron exchange reaction. XVIII) is, for example, when Hal and LG in formula (XIX) are both bromine, Nucleophilic substitution using a base such as K2CO3 in a solvent such as acetonitrile is used to obtain the compound ( XIX) and compound (VI).

[0129] Certain compounds of formula (XVII) can also be prepared by a two-step process (first by reacting a hydroxyl group with Conversion of the group to a leaving group, e.g., mesylate, followed by nucleophilic substitution with a compound of formula (VI) Compound type (XI) can be accessed from compounds of formula (XI) via the reaction Compounds of type (XIXa) can be derived using a boron exchange reaction.

[0130] A particular subset of compounds (XVIII) described by formula (XVIIIa) is From the halophenylacetic acid derivative (XX) and the compound of formula (VI), a two-step procedure (DM A coupling reagent (e.g., HATU) and a base (e.g., D) in a solvent such as F or DMA Amide coupling reaction using IPEA or NMM) followed by a catalyst in a solvent such as THF This involves the addition of a Grignard reagent such as MeMgBr in the presence of (e.g., ZrCl4). Compound (XVIIIa) can be synthesized using the method described for compound (XVIII). This is converted to compound (XVII) by halogen-boron exchange in a manner similar to the conversion obtain. [ka]

[0131] Compounds of formula (I) can be prepared according to Scheme 7 by reacting compounds of formula (XXI) and formula (VIIa) Compounds (particular embodiments of compound type (VII) when M=H) can be prepared by, for example, THF and Reductive amines using NaBH3CN, ZnCl2, and TEA in a solvent mixture such as MeOH Alternatively, compounds of formula (I) can be prepared using hydroxyl coupling. In a nucleophilic substitution reaction using a base (e.g., K2CO3) in DMF and ACN, In the compound of formula (Va) (particular embodiment of compound type (V) when M=H), XI) with a compound of formula (II). [ka]

[0132] The compound of formula (XXI) can be prepared from the compound of formula (VI) and the compound of formula (III) by the reaction of DMF. or a coupling reagent (e.g., HATU) and a base (e.g., DI) in a solvent such as DMA. Amide coupling reaction using PEA or NMM followed by acid (e.g., For example, by deprotection of the t-butoxycarbonyl (Boc) group of the amine using TFA It is synthesized.

[0133] Compounds of formula (I) where Z is absent can be prepared by, for example, N In a reductive amination coupling using aBH3CN, ZnCl2, and TEA, can be prepared by reacting a compound of formula (XXII) with a compound of formula (XXIII) (Z, R 1 , R 1a , R 2 , R 2a , X 1a , R 4 , R 5 , R 6 , R 7 , n, p and q are as previously defined). By analogy, compound (XXIV) and compound (XX III) can be reacted under similar conditions to provide compounds of formula (I) according to Scheme 8 do. [ka]

[0134] Compounds of formula (XVI) can be prepared according to Scheme 9 by Pd-catalyzed coupling, e.g., solvent mixing. A catalyst (e.g., PdCl(dppf)) and a base (e.g., dioxane / water) are added to the catalyst (e.g., PdCl(dppf)) and a base (e.g., dioxane / water). For example, a Suzuki reaction using Cs2CO3 can be used to prepare a compound of formula (X) and a compound of formula (XXV) It can be synthesized from a compound. [ka]

[0135] Compounds of formula (XXV) can be prepared using various procedures under reaction conditions previously described. For example, in Scheme 10, the common boronic acid / ester starting material (XXVII Starting from (I), Mitsunobu reaction with a compound of structure (XXIX) followed by deprotection gives a compound of formula (X XVI), which in turn undergoes a nucleophilic substitution reaction with a compound of formula (XXVII): Upon reaction, a compound of formula (XXV) can be obtained. In some cases, the compound of formula (XXVIII) A Mitsunobu reaction with a compound of formula (XXX) can directly provide (XXV). [ka]

[0136] Compounds of formula (XXV) can also be prepared from the common starting material 4-bromobenzyl bromide (XXX I) can be synthesized from 1,2-dichloro-2,3-dichloro-2,4 ... Nucleophilic substitution reaction with compound (XXX) using a base such as potassium t-butoxide in a solvent Subsequent halogen-boron exchange using previously described conditions can directly lead to (XXV). In other cases, nucleophilic substitution with compound (XXXII) followed by halogen-boron exchange and and Boc deprotection gives new intermediates (XXXIII), which are of the type (XXVII) The compound reacts in a further nucleophilic substitution reaction with the compound to form a compound similar to those previously described. Under certain conditions, this can lead to (XXV). [ka]

[0137] As is well known to those skilled in the art, reaction sequences often vary but are similar. Scheme 12 shows the synthesis of compounds of formula (I) using procedures similar to those previously described. V) to construct compounds of formula V. Therefore, Pd-catalyzed coupling, e.g. A catalyst (e.g., PdCl2(dppf)) in a solvent mixture (e.g., dioxane / water) and and a base (e.g., Cs2CO3) using compound (X) and compound (XXVIII). The reaction gives intermediate (XXXIV), which can be reacted with a compound of formula (XXXII) Compound (XXXV) can then be further reacted to provide intermediate (XXXV). undergoes Suzuki coupling to give a compound of formula (IX) and a subsequent deprotection sequence The compound of formula (XXXVI) can be obtained by the reaction of the compound of formula (XX XVII) to give a compound of formula (IV). [ka]

[0138] The compound of formula (XXXVI) can also be prepared by the reductive amide reaction with the compound of formula (XXXVIII). can be converted to give compounds of formula (IV), as shown in Scheme 13. Alternatively, two products can be produced: Q is H or Q is CH2OH. Alternatively, compound (IV) where Q is H may be prepared by reacting a masked alkyl group with compound (XXXVIII) instead of compound (XXXVIII). It can be prepared using aldehyde (XXXIX). [ka]

[0139] Scheme 14 shows a further approach to provide compounds of formula (IV). The intermediate of formula (XL) can be, for example, the reaction between compound (XXVIII) and compound (XXIX) Alternatively, (XL) can be prepared by the Mitsunobu reaction. II) is generated in two steps from nucleophilic substitution between compounds followed by halogen-boron exchange reaction. The reaction of intermediate (XL) in the Pd-catalyzed coupling reaction with the compound of formula (X) can be carried out. The reaction gives a compound of formula (XLI), which can be further reacted with a compound of formula (IX) using a Pd catalyst. The coupling reaction followed by deprotection can give a compound of formula (XLII). XLII) undergoes reductive amination with a compound of formula (XXXVII) to give (IV ) may be provided. [ka]

[0140] Compounds of formula (I) can be prepared from intermediates of formula (XLIV) as shown in Scheme 15. This can be prepared by direct analogy with compound (XL) in Scheme 14. Therefore, intermediate (XLIV) can be prepared by combining (XLIII) with (XLIII). Compound (XLIV) is then prepared by the reaction of a Pd catalyst with the following formula: Compound (XLV) is obtained by two steps of coupling and deprotection. XLV) reacts with a compound of formula (XLVI) in a reductive amination reaction to give (I) Compound (XLVI) can be prepared by the reaction of N-(2-hydroxyethyl)piperazine with Mido-coupling reactions followed by oxidation reactions such as Swern oxidation (e.g., oxalyl chloride and DMSO followed by the addition of TEA in a solvent such as DCM) to form a compound of formula (III) It is produced from compounds. [ka]

[0141] The dihydrouracil molecule of formula (III) reacts with urea in acetic acid heated to approximately 120°C. Compound (XLVII) can be prepared by cyclization of a molecule of formula (XLVII) using Therefore, heating in acrylic acid at a temperature of typically about 100 °C (Scheme 16) from the corresponding aniline derivative (XLVIII). The compound of formula (I) can be prepared by the reaction of pentafluorophenyl ether with a base such as DIPEA in a solvent such as DMF. from the compound of formula (III) by reaction with 2,2,2-trifluoro-2,2,2-phenyl-2,2,2-trifluoroacetate It can be synthesized. [ka]

[0142] Compounds of formula (IX) can be prepared by the reaction between compounds of formulae (XLIX) and (L) according to Scheme 17. Amide coupling reaction, coupling reagent (e.g., HATU) and DMF or DMA The reaction is carried out using a base (e.g., DIPEA or NMM) in a solvent such as ethanol. [ka]

[0143] Specific preparations of intermediates and examples using the general methods described above are given in the experimental section. Please describe in detail.

[0144] In a further embodiment, the compound of formula (III) [ka] (In the formula, R 6 is selected from H and F; R 7are H, F, Cl, -CH3, -OCH3 and -OCH2CH3) or a salt thereof.

[0145] In another embodiment, the compound of formula (IIIa) [ka] (In the formula, R 6 is selected from H and F; R 7 are H, F, Cl, -CH3, -OCH3 and -OCH2CH3) or a salt thereof.

[0146] In another embodiment, the compound of formula (XXIa) [ka] (In the formula, R 6 is selected from H and F; R 7 are H, F, Cl, -CH3, -OCH3 and -OCH2CH3) or a salt thereof.

[0147] In a further embodiment, there is provided a compound selected from the group consisting of: do. 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Benzoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylammonium Zozoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluoro Benzoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethoxy Benzoic acid: [ka] tert-Butyl 9-(4-bromophenethyl)-3,9-diazaspiro[5.5]urea Indecane-3-carboxylate: [ka] 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro -4-Methylbenzoic acid: [ka] 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)ammonium salt Zozoic acid: [ka] Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidine-1(2H) -yl)-4-methoxybenzoate: [ka] and 1-(2-methoxy-5-(3,9-diazaspiro[5.5]undecane-3-yl) (1H,3H)-dihydropyrimidine-2,4(1H,3H)-dione: [ka]

[0148] The compounds of these embodiments are useful in the preparation of compounds of the invention.

[0149] The present invention further includes any variation of this process, wherein any stage thereof an intermediate available in is used as a starting material and the remaining steps are carried out, or Alternatively, the starting materials may be formed in situ under the reaction conditions, or the reaction components may be formed in situ. The compounds and intermediates of the present invention are used in the form of a salt or an optically pure material. can be prepared according to methods commonly known to those skilled in the art, for example by reduction of the resulting compound, By oxidation and / or other functionalization and / or any protecting groups optionally present or by cleavage of the linker moiety and recovery of the compound so available. can be converted into

[0150] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutical The present invention provides a pharmaceutical composition comprising a physiologically acceptable carrier.

[0151] In another aspect, the present invention provides a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier.

[0152] In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers: Pharmaceutical compositions may be administered by a particular route, e.g., oral, including those described herein. administration, parenteral administration (e.g., by injection, infusion, transdermal administration, or topical administration) and rectal administration The topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions may be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be manufactured by methods known in the art. Thus, it may be film coated or enteric coated.

[0153] Typically, the pharmaceutical composition is a tablet or gel containing the active ingredient together with one or more of the following: It is a latin capsule. a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, Thor, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium Calcium salts and / or polyethylene glycol; and for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin cellulose, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and and / or polyvinylpyrrolidone; optionally d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or boiling water. Sexual mixture; and e) Absorbents, colorants, flavorings and sweeteners.

[0154] The compounds of formula (I) or formula (Ia) or pharmaceutically acceptable salts thereof are valuable pharmacological agents. and / or other properties, such as modulation of BTK activity by acting as a BTK degrader. This can be achieved, for example, by using BTK or the BTK C481S mutant fusion protein described herein. By using engineered cell lines overexpressing the fusion protein as a fluorescent readout, This can be determined in vitro in cells and in cell lines that express endogenous BTK. The pharmacological usefulness of the compounds of the present invention can be demonstrated in patients with tumors such as TMD8 tumors. Compounds of the present invention are administered to animals, such as mice, to determine whether or not there is any significant difference in tumor tissue as a result of administration of the compound. This can be determined in vivo by measuring the reduction of BTK and the reduction in tumor volume in the Therefore, the compounds of formula (I) or formula (Ia) can be used to treat diseases mediated by BTK. These compounds may be useful in treating diseases such as

[0155] The compounds of formula (I) or formula (Ia) are useful for the study of diseases mediated by BTK. For example, they may be useful as tool compounds.

[0156] The compounds of the present invention, in free form or in the form of a pharmaceutically acceptable salt, are useful in treating cancer, e.g. The present invention may be useful for the prevention or treatment of cancers selected from tumor cancers and hematopoietic cancers.

[0157] Examples of solid tumor cancers include central nervous system cancer, brain cancer, breast cancer, head and neck cancer, lung cancer; esophageal cancer and Gastric junction cancer, stomach cancer, colorectal cancer, rectal cancer, anal cancer, hepatobiliary cancer, pancreatic cancer, non-melanoma skin cancer, melanoma Chromosomes, kidney cancer, prostate cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, bone cancer, neuroendocrine system cancer, These include mesothelioma cancer, testicular cancer, thymoma and thymic carcinoma, and thyroid cancer.

[0158] Examples of hematopoietic cancers include B-cell neoplasms (including rare B-cell malignancies) and Hodgkin's lymphoma. , non-Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, hairy cell leukemia, histiocytic neoplasms and Dendritic neoplasms include:

[0159] Examples of B-cell neoplasms include chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and CL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter's syndrome, precursor B lymphoblasts lymphoma, primary and secondary multiple myeloma, B-cell prolymphocytic leukemia, Lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal Marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphoma granulomatosis, and Acute lymphoblastic leukemia is one of the most common types of leukemia.

[0160] In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL), diffuse large cell type B DLBCL, mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL) and Waldenstrom's macroglobulinemia.

[0161] In a further embodiment, the cancer is chronic lymphocytic leukemia (CLL).

[0162] In another embodiment, the cancer is diffuse large B-cell lymphoma (DLBCL). do.

[0163] The compounds of the present invention are useful in treating cancers (e.g., CLL, DLBCL, MCL, SLL, and Waldenstrom syndrome). for the treatment of subjects with acquired resistance to ibrutinib (Ibrutinib macroglobulinemia) In the present invention, for example, a mutation of cysteine-481 to serine (i.e., mutation C It may be of particular use in cancers where resistance has been induced by 481S). For example, patients may have already been treated or continue to be treated with ibrutinib, Subjects had a reduced or no longer responded to treatment with ibrutinib. Therefore, the compounds of the present invention are effective in treating cancers that are resistant to ibrutinib, especially cancers that are resistant to ibrutinib. Niacin-resistant CLL, DLBCL, MCL, SLL, and Waldenstrom's macroglobulinemia It may be beneficially used in the treatment of CLL, particularly ibrutinib-resistant CLL.

[0164] In another embodiment, the compounds of the present invention are In the field of autoimmune disorders, inflammatory disorders, allergic diseases, anaphylaxis, allergies, For example, the compounds of the present invention may be useful in the prevention or treatment of chronic asthma and airway diseases, as well as in transplantation. The compound, in free form or in the form of a pharmaceutically acceptable salt, is effective in treating asthma; chronic obstructive pulmonary disease (COPD); COPD); transplant rejection; abnormalities in antibody production, antigen presentation, cytokine production, or lymphoid organogenesis Common or unwanted diseases; rheumatoid arthritis; systemic onset juvenile idiopathic arthritis (S OJIA); Gout; Pemphigus; Idiopathic thrombocytopenic purpura; Systemic lupus erythematosus; Multiple sclerosis myasthenia gravis; Sjogren's syndrome; autoimmune hemolytic anemia; antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis; cryoglobulinemia; thrombotic thrombocytopenic purpura; chronic autoimmune disease Urticaria; Allergies (atopic dermatitis, contact dermatitis, allergic rhinitis); Athero Atherosclerosis; Type 1 diabetes; Type 2 diabetes; Inflammatory bowel disease; Ulcerative colitis; Crohn's disease ;Pancreatitis;Glomerulonephritis;Goodpasture's syndrome;Hashimoto's disease;Graves' disease;Antibody-mediated transplant rejection Anti-Malignant Graft-versus-Host Disease (AMR); Graft-versus-Host Disease (GvHD); Chronic Graft-versus-Host Disease (cGvHD); B-cell Cell-mediated hyperacute; acute-chronic transplant rejection; thromboembolic disorders; myocardial infarction; angina; stroke; ischemic pulmonary embolism; polycythemia vera; essential thrombocythemia; and myelofibrosis due to myeloid metaplasia It may be useful for prevention or treatment.

[0165] In another embodiment, the compounds of the present invention are In this context, it may be useful for the prevention or treatment of immunoglobulin light chain amyloidosis (AL).

[0166] In a further aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition thereof for use in the treatment of and (iii) providing a physiologically acceptable salt thereof for use in the prevention or treatment of a disease mediated by BTK. In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is hematopoietic. In a further embodiment, the hematopoietic cancer is chronic lymphocytic leukemia (CLL), Diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small Lymphocytic lymphoma (SLL) and Waldenström's macroglobulinemia, especially CLL or DLBCL.

[0167] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt acceptable for

[0168] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-diaminobenzoates). Oxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof It is a salt that is used.

[0169] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl (I)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl -2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or pharmaceuticals thereof It is a commercially acceptable salt.

[0170] In one embodiment, the compound is N-(3-(6-(4-((4-(2-(4-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0171] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0172] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0173] In one embodiment, the compound is N-(3-(6-(4-(((4-(4-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperazin-1-yl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro- 4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof is.

[0174] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0175] In a further aspect, the present invention provides a compound of the invention or a pharmaceutical formulation thereof for use in therapy. In one embodiment, the present invention provides a method for treating BTK-mediated leukemia. The present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease. In one embodiment, the present invention provides a compound of the present invention for use in the prevention or treatment of cancer. In a further embodiment, the cancer is a hematopoietic In a further embodiment, the hematopoietic cancer is chronic lymphocytic leukemia (CLL), diffuse large bowel disease (LVHD), or leukemia. malignant large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphoma (SMLL) Lymphoid lymphoma (SLL) and Waldenström's macroglobulinemia, especially C LL or DLBCL.

[0176] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt acceptable for

[0177] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-diaminobenzoates). Oxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof It is a salt that is used.

[0178] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl (I)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl -2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or pharmaceuticals thereof It is a commercially acceptable salt.

[0179] In one embodiment, the compound is N-(3-(6-(4-((4-(2-(4-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0180] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0181] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0182] In one embodiment, the compound is N-(3-(6-(4-(((4-(4-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperazin-1-yl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro- 4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof is.

[0183] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0184] In a further aspect, the present invention is a method for treating a disease mediated by BTK. and administering a therapeutically acceptable amount of this compound to a patient in need of treatment for a BTK-mediated disease. The present invention provides a method for treating a rheumatoid arthritis, comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof. In an embodiment, the present invention provides a method of treating cancer, comprising administering to a patient in need of cancer treatment The method includes administering a therapeutically acceptable amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is a hematopoietic cancer. In this study, hematopoietic cancers included chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and leukemia-associated lymphoma (LEM). DLBCL, mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and and Waldenström's macroglobulinemia, especially CLL or DLBCL.

[0185] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt acceptable for

[0186] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-diaminobenzoates). Oxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof It is a salt that is used.

[0187] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl (I)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl -2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or pharmaceuticals thereof It is a commercially acceptable salt.

[0188] In one embodiment, the compound is N-(3-(6-(4-((4-(2-(4-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0189] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0190] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0191] In one embodiment, the compound is N-(3-(6-(4-(((4-(4-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperazin-1-yl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro- 4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof is.

[0192] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0193] In a further aspect, the present invention provides a pharmaceutical composition of the compounds of the present invention or pharmaceutically acceptable salts thereof. In one embodiment, the present invention provides a compound of the present invention or a compound of the present invention for use in the manufacture of a medicament. and a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease mediated by BTK. In one embodiment, the present invention provides a compound of the present invention or a compound of the present invention for use in the manufacture of a medicament. and the use of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer. In a further embodiment, the cancer is a hematopoietic cancer. Organ cancers include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBC), L), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL) and Waldenstrom's lymphoma and Ström's macroglobulinemia, especially CLL or DLBCL.

[0194] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt acceptable for

[0195] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-diaminobenzoates). Oxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fu Fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof It is a salt that is used.

[0196] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl (I)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl -2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or pharmaceuticals thereof It is a commercially acceptable salt.

[0197] In one embodiment, the compound is N-(3-(6-(4-((4-(2-(4-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0198] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0199] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzo yl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or its drug It is a physiologically acceptable salt.

[0200] In one embodiment, the compound is N-(3-(6-(4-(((4-(4-(3-(2 ,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl )piperazin-1-yl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro- 4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof is.

[0201] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl- 3,9-Diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyridin (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2 -fluoro-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutical It is an acceptable salt.

[0202] The pharmaceutical composition or combination of the present invention is administered in an amount of about 1 to 1,000 ml for a subject weighing about 50 to 70 kg. g of active ingredient or about 1 to 500 mg, about 1 to 250 mg, about 1 to 150 mg, about 0.5 to The unit dosage may be 100 mg or about 1 to 50 mg of the active ingredient. The therapeutically effective dosage of the composition or combination thereof depends on the species, weight, age and individual condition of the subject, It depends on the disorder or disease to be treated and its severity. If you are a physician, clinician, or veterinarian, you may be required to: The effective amount of each of the active ingredients can be readily determined.

[0203] The dosage characteristics cited above are for mammals, e.g., mice, rats, dogs, monkeys, or isolated animals. Demonstrated in vitro and in vivo tests using the selected organs, tissues and preparations thereof. The compounds of the present invention can be used in vitro and in the form of solutions, for example aqueous solutions. For example, it may be administered in vivo enterally, parenterally, preferably intravenously, as a suspension or in aqueous solution. The in vitro dosage is about 10 -6 Molar ~ 10-10 The concentration can range from molar to molar. The therapeutically effective in vivo amount is about 0.1 to 500 mg / kg or about 1 mg / kg, depending on the route of administration. It can range up to 100 mg / kg.

[0204] The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately by the same or different routes of administration, or may be administered in combination with other The therapeutic agents may be administered together in the same pharmaceutical composition, for example, in combination with the compounds of the present invention. Compounds that are therapeutically active or enhance therapeutic activity when administered in combination to a patient The antibody may be a substance, a peptide, an antibody, an antibody fragment, or a nucleic acid.

[0205] In one embodiment, the present invention provides a method for administering a compound of the present invention and at least one other therapeutic agent to a patient in need thereof, comprising administering to the patient: The present invention provides a product containing the compounds as a combined preparation for simultaneous, separate or sequential therapeutic use. In one embodiment, the therapy is treatment of a disease or condition mediated by BTK. In another embodiment, the therapy is the treatment of a cancer described herein. The compounds of the present invention and other therapeutic agents may be combined in the same pharmaceutical composition as a product provided as a combined preparation. The compounds of the present invention and other compounds may be used in a composition together in a product or in separate forms, such as in the form of a kit. Therapeutic agents include:

[0206] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In another embodiment, the present invention provides a therapeutically effective amount of a compound of the present invention and another Pharmaceutical compositions containing the therapeutic agents are provided.

[0207] Optionally, the pharmaceutical composition includes a pharmaceutically acceptable carrier, as described above. obtain.

[0208] In one embodiment, the present invention provides two or more pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises separate pharmaceutical compositions of Means for keeping things separate, such as containers, separate bottles or separate foil packets Examples of such kits include a package of tablets, capsules, etc. There are blister packs used for packaging.

[0209] The kit of the present invention may be used to administer separate compositions at different dosage intervals or to administer separate compositions. For administering various dosage forms, e.g., oral and parenteral, to titrate one against another. To aid compliance, the kits of the invention typically include instructions for administration. Includes instructions.

[0210] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be from the same manufacturer or from different manufacturers. Additionally, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by manufacturers of the same. The drug may be (i) administered prior to the release of the combination product to a physician (e.g., a compound of the present invention and (ii) by the physician (or a physician) immediately prior to administration; (iii) e.g., during sequential administration of a compound of the invention and another therapeutic agent; It may be combined with combination therapy in the patient himself.

[0211] Thus, the present invention provides another method for treating a disease or condition mediated by BTK. The use of therapeutic agents is also provided, where other therapeutic agents are administered in conjunction with the compounds of the invention.

[0212] The present invention also provides a method for treating a BTK-mediated disease or condition. The present invention provides a compound of the present invention for use in treating atopic dermatitis, wherein the compound of the present invention is administered in combination with another therapeutic agent.

[0213] The present invention also provides a method for treating a BTK-mediated disease or condition. The present invention provides another therapeutic agent for the treatment of rheumatoid arthritis, wherein the other therapeutic agent is administered together with the compound of the present invention.

[0214] The present invention also provides a method for treating a disease or condition mediated by BTK using a compound of the present invention. and the patient has not previously (e.g., within 24 hours) been treated with another therapeutic agent. are.

[0215] The present invention also provides another therapeutic agent for treating a disease or condition mediated by BTK. and wherein the patient has previously (e.g., within 24 hours) been treated with a compound of the invention. are.

[0216] The present invention also provides the use of another therapeutic agent to treat cancer, the other therapeutic agent being a compound of the present invention. It is administered together with the compound of interest.

[0217] The present invention also provides a compound of the present invention for use in a method of treating cancer, The compound is administered in conjunction with another therapeutic agent.

[0218] The present invention also provides other therapeutic agents for use in methods of treating cancer, is administered with a compound of the present invention.

[0219] The present invention also provides the use of a compound of the present invention to treat cancer, wherein the patient is receiving another treatment. have been previously treated (e.g., within 24 hours) with a therapeutic agent.

[0220] The present invention also provides the use of another therapeutic agent for treating cancer, wherein a patient is administered a compound of the present invention. have been previously treated (e.g., within 24 hours) with the compound.

[0221] In one embodiment, the other therapeutic agent is selected from: Apoptosis modulators, anti-CD20 antibodies, anti-CD22 antibodies, PI3K inhibitors, Tyrosine kinase inhibitors, immune checkpoint agents, CART therapeutic agents, immunomodulators , bispecific antibodies targeting CD20 and CD3, antibody-drug conjugates (ADCs), Loteasome inhibitor, epigenetic modifier, anti-CD38 mAb, anti SLAMF7 agents, XPO1 inhibitors as well as other agents such as chemotherapeutic agents.

[0222] In one embodiment, the apoptosis modulator is a Bcl2 inhibitor (e.g., amputees, obatoclax, venetoclax (Venclexta®) ), ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2- Oxoethyl)-4H-chromone-3-carboxylate (HA14-1), Obrimel Genasense (G3139, Genasense®), Bak BH3 peptide, (- )-Gossypol (AT-101, BL-193), Navitoclax (ABT-26 3)), Mcl1 inhibitors (e.g., AMG176, S63845, AZD5991, MIK665) and MDM2 / p53 inhibitors (e.g., NVP-HDM201, NV P-CGM-097, ALRN-6924, idasanutlin, AMG232 and DS-3 032B).

[0223] In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, ofatum The antibody is selected from the group consisting of umab, ocrelizumab and ublituximab.

[0224] In one embodiment, the anti-CD22 antibody is inotuzumab, epratuzumab, bectuzumab, The treatment is selected from the group consisting of rivaroxaban and moxetumomab.

[0225] In one embodiment, the PI3K inhibitor is duvelisib, umbralisib tosylar , INCB050465, apilimod mesylate (LAM-002), copanlisibhi Dolochloride (Aliqopa®), tenalisib, pictilisib (GDC 0 941), sonolisib (PX866), pilaralisib (SAR 245408 or XL 147), alpelisib (BYL719), and leniolisib (CDZ173). can be.

[0226] In one embodiment, the tyrosine kinase inhibitor is a BTK inhibitor, e.g., Eve Rutinib, acalabrutinib, zanubrutinib (BGB-3111), tirabrutinib ( ONO-4059), ARQ531, CC-292(AVL-292), CT-1530 , DTRMWXHS-12, GDC-0853, M7583 and becabrutinib (SNS -062), SYK inhibitors, such as entospletinib (GS9973), fosta Matinib and HMPL-523, SYK / JAK inhibitor cerduratinib (PRT0 62070), SYK / FLT inhibitors, e.g., TAK-659, FLT3 inhibitors FF-10101, FLT3 / BTK inhibitor (CG806), JAK inhibitor Vitabiotropin (e.g., itacitinib, INCB052793, BMS911543, fedracitinib) Nib, WP-1066, NS-018, and ruxolitinib (Jakavi®) etc.), erlotinib hydrochloride (Tarceva®), linifanib (A BT869), sunitinib malate (Sutent®), bosutinib (bos ulif®), dasatinib (Sprycel®), pazopanib (V otrient®), sorafenib (Nexavar®), Zac tima (ZD6474), imatinib or imatinib mesylate (Gilvec trademark) and Gleevec®) and tozasertib (VX680 or MK045 7) is selected.

[0227] In one embodiment, the immune checkpoint agent is an anti-PD-1 agent and an anti-PD-L1 The drugs are pembrolizumab, nivolumab, tislelizumab, atezolizumab, and ipilimumab. , cemiplimab, TLR4 agonist, CCR4 mAb mogamulizumab and CD47 mAb fusion protein (TTI-621).

[0228] In one embodiment, the CART therapy includes CD19, BCMA CART, CD20, C D79b, CD22, and CD30.

[0229] In one embodiment, the immunomodulator is lenalidomide (Revlimid®). )), thalidomide (Thalomid®), avadomide (CC-122) and and pomalidomide (Actimid®, Imnovid®, Poma lyst®).

[0230] In one embodiment, the bispecific antibody targeting CD20 and CD3 is REGN-197 9, XmAb-13676, BTCT-4465-A, CD20-TCB and 8RG-6 026 is selected.

[0231] In one embodiment, the ADC is the CD79 ADC polatuzumab vedotin, the CD30 ADC brentuximab vedotin, CD25 ADC camidanlumab tesirin and CD1 9 ADC loncastuximab tesirine.

[0232] In one embodiment, the proteasome inhibitor is bortezomib (Velcade Registered trademark), carfilzomib (Kyprolis®), marizomib (NP I-0052, ixazomib citrate (MLN-9708, Ninlaro (registered trademark) (target), delanzomib (CEP-18770) and oprozomib (ONX-0912) are selected.

[0233] In one embodiment, epigenetic modifiers, such as HDAC methylation inhibitors, Inhibitors and DNA methylation inhibitors include vorinostat (Zolinza® )), romidepsin (Istodax®), azacitidine (Mylosar® Registered Trademark), Vidaza®), Pyroxamide, Spiruchostatin A, Mirupu Selected from loin (valproic acid), entinostat and guadecitabine.

[0234] In one embodiment, the anti-CD38 mAb is selected from daratumumab and isatuximab. It is selected.

[0235] In one embodiment, the anti-SLAMF7 agent is elotuzumab.

[0236] In one embodiment, the XPO1 inhibitor is selected from the group consisting of selinexor and ertanexor. be selected.

[0237] In one embodiment, other drugs that can be combined with the compounds of the present invention, such as general chemical The chemotherapy agents include anastrozole (Arimidex®), bendamustine (T Reanda®), bicalutamide (Casodex®), bleoma isin sulfate (Blenoxane®), busulfan (Mylera n®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluoro Orocitidine, carboplatin (Paraplatin®), carmustine ( BiCNU®), chlorambucil (Leukeran®), cisplatin Platinol®, Cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®) )), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine vin liposome injection (DepoCyt®), dacarbazine (DTIC-Dom e®), dactinomycin (Actinomycin D, Cosmegan), Dow Norubicin hydrochloride (Cerubidine®), daunorubicin citrate Late liposome injection (DaunoXome®), dexamethasone, docetaxel Cell (Taxotere®), doxorubicin hydrochloride (Adriam ycin®, Rubex®), epirubicin (Ellence®), (Trademark), etoposide (Vepesid®), fludarabine phosphate ( Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezativir Gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea Registered Trademark), Idarubicin (Idamycin®), Ifosfamide (IF EX (registered trademark), irinotecan (Camptosar (registered trademark), L-asparagus ginase (ELSPAR®), leucovorin calcium, melphalan (Al keran®), 6-mercaptopurine (Purinethol®), ), methotrexate (Folex®), mitoxantrone (Novantr one®), Mylotarg, paclitaxel (Taxol®), n ab-paclitaxel (Abraxane®), Phoenix (yttrium 90 / MX-DTPA), pentostatin, and carmustine implants Losan 20 (Gliadel®), tamoxifen citrate (Nolvad ex (registered trademark), teniposide (Vumon (registered trademark)), 6-thioguanine, thio Tepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®) , vincristine (Oncovin®), vinorelbine (Navelbine (R), ROR mAb cirumutuzumab, dual PI3K / HDAC inhibitor (CUDC-907), Bet inhibitor (INCB357643), ALK inhibitor (crizotinib), EZH1 / 2 inhibitor (DS-3201b), MAPK inhibitor Aplidin, plitidepsin (eEF1A2 inhibitor), Wnt inhibitor, Radiopharmaceuticals, idiotype vaccines, pegfilgrastim (Neulasta and cytoplurikine (IRX-2).

[0238] In further embodiments, the other therapeutic agent is selected from: Venetoclax, oblimersen, navitoclax, MIK665, NVP-HD M201, rituximab, obinutuzumab, ofatumumab, ocrelizumab, ublitz Ximab, inotuzumab, epratuzumab, bectumomab, moxetumomab, Dubec Lisib, umbralisib tosylate, INCB050465, leniolisib (CDZ17 3), Apilimod mesylate (LAM-002), Copanlisib hydrochloride, Tenali Sib, pictilisib, alpelisib, ibrutinib, acalabrutinib, zanubrutinib (BGB-3111), tirabrutinib (ONO-4059), ARQ531, CC-2 92 (AVL-292), CT-1530, DTRMWXHS-12, GDC-0853 , M7583, becabrutinib (SNS-062), entospletinib (GS9973 ), fostamatinib, HMPL-523, celdulatinib (PRT062070), (TAK-659), FF-10101, FLT3 / BTK inhibitor (CG806), Itacitinib, INCB052793, BMS911543, fedratinib, WP-1 066, NS-018, ruxolitinib (Jakavi®), pembrolizumab bu, nivolumab, tislelizumab, atezolizumab, ipilimumab, cemiplimab, TL R4 agonist, CCR4 mAb mogamulizumab, CD47 mAb fusion protein ( TTI-621), CD19, BCMA CART, CD20, CD79b, CD22, CD30, lenalidomide, thalidomide, avadomide, pomalidomide, XmAb-13 676, CD79 ADC polatuzumab vedotin, CD30 ADC brentuximab vedotin Dotin, CD25 ADC Kamidan, lumabtesirin, CD19 ADC Loncastuximab Butecillin, carfilzomib, bortezomib, ixazomib, marizomib, oprozomib azacitidine, romidepsin, vorinostat, guadecitabine, daratumumab, ibuprofen Satuximab, elotuzumab, selinexor, ertanexor, fludarabine, calm cyclophosphamide, chlorambucil, bendamustine, melphalan, cladoxamic acid, Livin, dacarbazine, pentostatin, vincristine, etoposide, epirubicin, Doxorubicin, anthracyclines and antifolates.

[0239] In a further embodiment, the other therapeutic agent is selected from the group consisting of a Bcl2 inhibitor and a BTK inhibitor. are selected.

[0240] In a further embodiment, the other therapeutic agent is venetoclax, ibrutinib, and acaroxaban. brutinib.

[0241] Individual specific combinations that may provide particular treatment benefits include compounds selected from the following: nothing: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine 4-methoxybenzoyl)piperidin-1(2H)-yl)piperidin-4-yl)oxy )piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxide (ii)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)o 7H-pyrrolo[2,3-d]pyrimidin-1-yl)ethyl)phenyl)- (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyridine (2H)-(4-methoxybenzoyl)piperazin-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (4-fluorobenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, or its pharmaceutically acceptable salts (in combination with venetoclax);

[0242] Specific individual additional combinations that may provide particular treatment benefits include compounds selected from the following: Including: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine 4-methoxybenzoyl)piperidin-1(2H)-yl)piperidin-4-yl)oxy )piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxide (ii)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)o 7H-pyrrolo[2,3-d]pyrimidin-1-yl)ethyl)phenyl)- (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyridine (2H)-(4-methoxybenzoyl)piperazin-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (4-fluorobenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, or and pharmaceutically acceptable salts thereof (in combination with ibrutinib).

[0243] Specific individual additional combinations that may provide particular treatment benefits include compounds selected from the following: Including: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine 4-methoxybenzoyl)piperidin-1(2H)-yl)piperidin-4-yl)oxy )piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (xypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxide (ii)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)o 7H-pyrrolo[2,3-d]pyrimidin-1-yl)ethyl)phenyl)- (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) (hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyridine (2H)-(4-methoxybenzoyl)piperazin-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin (4-fluorobenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy cyclopropan-2-yl)benzamide, or and pharmaceutically acceptable salts thereof (in combination with acalabrutinib).

[0244] These combinations include a compound of the invention or a pharmaceutically acceptable salt thereof and venetoclax. It may be provided as a pharmaceutical composition containing LAXX, ibrutinib or acalabrutinib.

[0245] Alternatively, these combinations may comprise the compound of the present invention or a pharmaceutically acceptable salt thereof as described above. Treatment with venetoclax, ibrutinib, or acalabrutinib, either simultaneously, separately, or sequentially The compounds may be provided as a combined preparation for therapeutic use.

[0246] In particular, these combinations with ibrutinib are effective in the treatment of hematopoietic cancers, particularly CLL and DLBCL. It may be particularly effective in the treatment of

[0247] The activity of the compounds of the present invention was evaluated by the following in vitro methods described herein. It is possible.

[0248] The compounds of the present invention can be prepared as described in the following examples. [Example]

[0249] The following examples are illustrative of the present invention and should not be construed as limiting thereof. Temperatures are given in degrees Celsius. Abbreviations used are conventional in the art. These are listed below.

[0250] Starting materials, building blocks, reagents, acids, bases, decomposition products, etc. utilized in synthesizing the compounds of the present invention The solutions, solvents and catalysts are all commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Furthermore, the compounds of the present invention can be prepared by the following steps. They can be produced by organic synthesis methods known to those skilled in the art.

[0251] Abbreviation: ACN Acetonitrile OAc acetate AcOH acetic acid aq. Water-based BISPIN Bis(pinacolato)diboron BOC tert-butoxycarbonyl br Wide CHX Cyclohexane d doublet DCM dichloromethane dd Doublet of Doublets DEA Diethylamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMA N,N-dimethylacetamide DMEM Dulbecco's Modified Eagle's Medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide e.g. eq. equivalent amount ESI electrospray ionization Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol FCS calf serum h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethicone uronium hexafluorophosphate HPLC High Pressure Liquid Chromatography HV high vacuum iPrOH isopropanol LC-MS Liquid Chromatography and Mass Spectrometry m multiplet m / z mass-to-charge ratio MeOH Methanol mg milligram min ml milliliter mmol millimole MS mass spectrometry Ms2O methanesulfonic anhydride NaBH(OAc)3 Sodium triacetoxyborohydride NaBH3CN Sodium cyanoborohydride NaPyr. Sodium pyruvate NEAA Non-Essential Amino Acids NMM N-methylmorpholine NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PBS Phosphate-buffered saline PG protecting group Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]para Dium dichloride PdCl2(dppf)-CH2Cl2[1,1'-bis(diphenylphosphino)f [Erocene]palladium dichloride-dichloromethane adduct PdCl2(PPh3)2 Bis(triphenylphosphine)palladium dichloride ppm (parts per million) rac racemic RM reaction mixture Rt retention time RT room temperature s singlet sat. saturation SFC Supercritical Fluid Chromatography t triplet TBME tert-butyl methyl ether TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl Ionium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran

[0252] Analysis method General conditions: NMR: Bruker AVAN with ICON-NMR under TopSpin program control CE 400MHz, 500MHz or 600MHz NMR spectrometer, NM R spectra were recorded. Spectra were measured at 298 K unless otherwise stated. , and referenced to known solvent resonances.

[0253] LC-MS: LC-electrospray, chemical and mass spectra using electron impact ionization methods. MS, SFC-MS or GC-MS systems were acquired from a wide range of instruments in the following configurations: Waters Ac using a photodiode array detector and a single quadrupole mass detector A quity UPLC / SQD system or G 6110 series mass spectrometer equipped Gilent 1200 system. [M+H] + is the protonated molecular ion of the species. This refers to the

[0254] Method A: Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 60℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM) B: ACN containing formic acid (0.04%) Flow rate: 1.0ml / min Gradient: 5% to 98% B in 1.4 min

[0255] Method B: Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 60℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM) B: ACN containing formic acid (0.04%) Flow rate: 0.8ml / min Gradient: 5% to 98% B in 9.4 minutes

[0256] Method C: Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 50℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM) B: ACN containing formic acid (0.04%) Flow rate: 1.2ml / min Gradient: 2% to 98% B in 1.4 min

[0257] Method D: Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%) B: Acetonitrile containing TFA (0.01%) Flow rate: 2.0ml / min Gradient: 5% to 95% B in 1.4 min

[0258] Method E: Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%) B: Acetonitrile containing TFA (0.01%) Flow rate: 2.0ml / min Gradient: 5% to 95% B in 1.2 min, 95% B in 1.3 min

[0259] Method F: Column: Phenomenex, 3.0 x 30 mm, 5 μm Column temperature: 50°C Eluent: A: aq. ammonium bicarbonate (10 mM) B: Acetonitrile Flow rate: 1.5ml / min Gradient: 5% to 95% B in 1.5 min, 95% B in 0.7 min

[0260] Method G: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM) B: Acetonitrile Flow rate: 2.0ml / min Gradient: 5% to 95% B in 1.5 min

[0261] Method H: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. ammonium bicarbonate (10 mM) B: Acetonitrile Flow rate: 1.8ml / min Gradient: 5% to 95% B in 1.5 min, 95% B in 1.5 min

[0262] Method I: Column: SunFire C18, 3 x 30 mm, 2.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%) B: Acetonitrile containing TFA (0.01%) Flow rate: 1.5ml / min Gradient: 5% to 95% B in 1.5 min

[0263] Method J: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM) B: Acetonitrile Flow rate: 1.8ml / min Gradient: 5% to 95% B in 1.4 min, 95% B in 1.6 min

[0264] Chiral analytical HPLC method: Method K: Equipment: Agilent 1200 system Column: Chiralpak ID 5μm 4.6×250mm Column temperature: RT Eluent: Hept:DCM:MeOH(40:35:25)+DEA(0.1%) Flow rate: 1.0mL / min Gradient: Isocratic Detection: UV at 254 nm

[0265] Preparative Chromatography Normal and reversed phase flash chromatography purification was performed using CombiFlash® The purification was performed on an Rf200 or Rf+ system. Alternatively, chromatographic purification on reversed phase was performed. Interchim Puriflash 4250 system or Biotage system The analysis was performed on a Waters 2998 photodiode with MeOH as a modifier. Waters spectrometry with a diode array detector or Waters MS single quadrupole detection Supercritical fluid chromatography (SFC) separation was performed using a preparative SFC-100-MS system. Typically, the back pressure was 120 bar and the flow was 100 g CO2 / min. The column temperature was 40°C. Reverse-phase HPLC purification was performed using a Waters 2998 phosphatase. Waters MS single quadrupole detection with a Waters 1000 ohm diode array detector or a Waters MS single quadrupole detector s Performed on a preparative HPLC system.

[0266] Achiral Preparative HPLC Method: Method L: Equipment: Gilson GX-281 Column: SunFire C18 Column temperature: RT Mobile phase: ACN in water containing TFA (0.1%) Flow: 40ml / min Detection: UV@254nm

[0267] Chiral preparative chromatography method: Method M: Equipment: Gilson Trilution I HPLC System Column: ChiralPak ID, 5μM, 250×20mm Column temperature: RT Mobile phase: heptane / DCM / MeOH (40:35:2) containing DEA (0.05%) 5) Flow: 10ml / min Detection: UV@254nm

[0268] Materials used for solid phase extraction: The following solid phase extraction (SPE) cartridges were used according to the manufacturer's instructions to extract various salts: The corresponding free base was prepared from PL-HCO3 MP SPE cartridges. ent StratosPhere (reference: PL-HCO3 MP resin, 1 0.8mmol / g, 100A, 150-300μm, 500mg, 6ml). SCX Car The cartridge was purchased from Agilent (reference: HF Mega DE-SCX, 2g, 12ml).

[0269] Synthesis of intermediates Intermediate 1 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde Do [ka] Step 1: (4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl (Nil)methanol Ethyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6- (10.2 g, 33.8 mmol) in THF (100 ml) As described in published U.S. Patent No. 6,140,332, column 45, Example 30 (which can be prepared according to the procedure) to a solution of lithium aluminum hydride (1M) in THF (50. 7 ml, 50.7 mmol) was slowly added at 0-5°C. During the addition, RM was dissolved in THF (5 ml After addition, the RM was stirred at 0°C for 10 min and then warmed to RT. After stirring for 3 h at RT, the RM was dissolved in a mixture of water and an aqueous solution of NaOH (15%). The mixture was quenched at 0° C. The mixture was filtered through Hyflo® and the solids were removed by filtration. After washing with HF, the combined filtrates were concentrated to give the title compound (9.32 g). Method A: Rt=0.78min;[M+H] + =260.1.

[0270] Step 2: 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benz aldehyde (4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl) Methanol (9.32 g, 32.7 mmol) and manganese dioxide (28.4 g, 327 A suspension of 1 mmol) in THF (250 ml) was stirred overnight at RT. Manganese (8.52 g, 98 mmol) was added to the RM and stirring was continued at RT for another night. The RM was filtered through Hyflo® and the solids were washed with THF. The filtrate was concentrated, rediluted with THF, and again filtered through Hyflo® to concentrate. Concentration gave the title compound as a solid (5.68g). Method A: Rt=0.88min;[M+H] + =258.1.

[0271] Intermediate 2 2-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydroxypropane (2-phenyl)benzamide [ka] 2-Fluoro-4-(2-hydroxypropan-2-yl)benzoic acid (6.35 g, 3 2.0 mmol), HATU (17.06 g, 44.9 mmol) and DIPEA (16 A mixture of 0.79 ml, 96 mmol) in DMF (100 ml) was stirred at RT for 30 min. Next, 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)aniline (International Publication No. 2013 / 008095A1 (This compound can be prepared according to the procedure described in the pamphlet, page 37, intermediate 5) (8.47 g, 32.0 mmol) was added and the RM was stirred at 50° C. overnight. The mixture was diluted with EtOAc and the organic phase was washed with a sat. aq. solution of NaHCO3 and brine. The combined aqueous phases were again extracted with EtOAc, and the combined organic phases were washed with N Dry over a2SO4, filter, concentrate, and eluate with MeOH in DCM (0-10%). The resulting solid was purified by silica gel chromatography eluting with Et 20, filtered, the solid washed with diisopropyl ether and dried. The title compound was obtained as a solid (9.28 g). Method A: Rt=1.28min;[M+H] + =432.3.

[0272] Note: An alternative preparation of intermediate 2 is described in WO 2013 / 008095 A1. , p. 81, Intermediate 35.

[0273] Intermediate 3 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyrrolidone 2-hydroxy-[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxy- Cypropan-2-ylbenzamide [ka] 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde Hydroxide (Intermediate 1, 150 mg, 0.553 mmol), 2-fluoro-N-(5-fluoro- 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (medium Intermediate 2, 328 mg, 0.608 mmol), aq. solution of Na2CO3 (2 M) (0. 553 ml, 1.106 mmol) and PdCl2(PPh3)2 (19.41 mg, 0 A 1-propanol suspension (4 ml) of 1.028 mmol of 1-propanol was subjected to microwave irradiation. The suspension was heated at 40° C. for 15 minutes. The suspension was filtered and the solid was dissolved in 1-propanol, water and The resulting solid was dried and the title compound was obtained as a solid (178 mg ) was obtained. Method A: Rt=0.99min;[M+H] + =527.2.

[0274] Intermediate 4 rac-2-fluoro-N-(5-fluoro-3-(6-(4-((7-(hydroxymethyl) methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2 (hydroxypropan-2-yl)benzamide [ka] Step 1: rac-tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro)-2-methyl-2-propanol)) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1-(hydroxymethyl) (ethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (2-xypropan-2-yl)benzamide (Intermediate 3, 300 mg, 0.570 mmol) , rac-tert-butyl 1-(hydroxymethyl)-3,9-diazaspiro[5.5 ]undecane-3-carboxylate (219 mg, 0.684 mmol) and TEA ( ZnCl2 (0.5 A solution of M) in THF (1.197 ml, 0.598 mmol) was added. The RM was stirred under argon at RT for 3 h before adding solid NaBHCN (71.6 mg , 1.140 mmol) was added. The RM was stirred overnight at RT and then diluted with DCM. The organic phase was dried over MgSO4, concentrated and diluted with Me. Purify by silica gel chromatography eluting with 0-20% OH in DCM. This gave the title compound as a solid (273 mg). Method A: Rt=0.87min;[M+H] + =795.6.

[0275] Step 2: rac-2-fluoro-N-(5-fluoro-3-(6-(4-((7-(hydro) (hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)- 4-(2-hydroxypropan-2-yl)benzamide rac-tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4 -(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H -pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1-(hydroxymethyl) -3,9-diazaspiro[5.5]undecane-3-carboxylate (273 mg, 0 0.343 mmol) and TFA (0.794 ml, 10.30 mmol) in DCM ( 3 ml) was stirred at RT for 2 h, concentrated and dried to give the title compound in solid TFA Obtained as a salt (288 mg). Method A: Rt=0.63min;[M+H] + =695.5.

[0276] Intermediate 5 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate Zozoic acid [ka] 3-Amino-4-methoxybenzoic acid (5.0 g, 29.3 mmol) was dissolved in acrylic acid (8 The resulting suspension was heated to 100°C. The mixture was stirred at RT for 3 h and then cooled to RT. AcOH (33 ml) was added and the mixture was stirred. The suspension was heated at 100°C for 10 minutes, and then urea (11.00 g, 183 mmol) was added and the RM was stirred overnight at 120° C. The solution was diluted with water and concentrated aqueous HCl (37% After stirring, the resulting suspension was stored in a refrigerator at 5°C. After storing overnight, it was filtered, the solid was washed with water and dried to give a solid. Cl (0.05M), filtered, and the solid was washed with TBME. Drying under reduced pressure at 40° C. gave the title compound as a solid (6.29 g). Method A: Rt=0.48min;[M+H] + =265.2.

[0277] Intermediate 6 N-(3-(6-(4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl )phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2 -methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benz amide [ka] Step 1: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-3,9-diazaspiro[5. 5]Undecane-3-carboxylate 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (2-xypropan-2-yl)benzamide (Intermediate 3, 510 mg, 0.969 mmol) , tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (271mg, 1.065mmol), TEA (0.135ml, 0.969mmol) and ZnCl2 (0.5M) in THF (2.325 ml, 1.162 mmol) The mixture was stirred in MeOH (10 ml) at RT for 6 h. 0.0 mg, 1.065 mmol) was added and the RM was stirred at RT overnight. Diluted with tOAc, the organic phase was washed with a saturated aqueous solution of NaHCO3 and brine. The mixture was dried over Na2SO4, concentrated, and dissolved in MeOH in DCM (0-50%). The title compound was purified by silica gel chromatography to give a solid (550 mg). was obtained as. Method A: Rt=4.60min;[M+H] + =765.4.

[0278] Step 2: N-(3-(6-(4-(3,9-diazaspiro[5.5]undecane-3-yl) (phenylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro (2-hydroxypropan-2-yl)-2-fluoro-4-(2-hydroxy-2-methylphenyl)- ) Benzamide tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)benzyl)-3,9-diazaspiro[5.5] A solution of 4-benzophenone-3-carboxylate (0.55 g, 0.683 mmol) in DCM To the resulting solution (1.00 ml) was added TFA (1.053 ml, 13.66 mmol) at RT. The resulting RM was stirred at RT overnight, evaporated and reconstituted in a mixture of ACN and water. Dissolution and lyophilization gave the title compound as a solid TFA salt (0.76 g). Method B: Rt=2.84min;[M+H] + =665.6.

[0279] Intermediate 7 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]piperidin Lymidine [ka] Step 1: 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin gin Mineral oil (1.563 g, 39.1 ml) was placed in a flame-dried flask under argon. 60% NaH in 1000 mol) was suspended in 60 ml of DMF and the mixture was cooled to 0°C. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (4 g, 26.0 mmol) A solution of RM in DMF (20 ml) was added slowly over 10 min to The mixture was stirred for 10 minutes until the mixture was dissolved. l) was added and the RM was stirred at RT for 1 h. Water was added and the resulting precipitate The solid was filtered and dried to give the title compound as a solid (7.418 g). Method C: Rt=1.01min;[M+H] + =294.1.

[0280] Step 2: 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3 -d]pyrimidine 4-chloro-7-(phenylsulfonyl)-7H-pyrrolidone under argon atmosphere at -78°C A stirred solution of 2,3-d-pyrimidine in dry THF (80 ml) was added to lithium diisopropyl ether. A solution of 1.5M tetrahydrofuran in CHX (5.22 ml, 7.83 After 1 h, iodine (1.987 g, 7.83 mmol) was added over 15 min. A solution of 1) in THF (20 ml) was added dropwise over 15 minutes at -78°C. The resulting solution was stirred at -78°C for 3 h. Water (2 ml) was added and the mixture was brought to RT. The mixture was diluted with DCM and the organic phase was washed with brine and dried over Na2SO4. The resulting solid was triturated with ACN, filtered, and Drying gave the title compound as a solid (1.513g). Method C: Rt=1.12min;[M+H] + =419.9.

[0281] Intermediate 8 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzo Aromatic acid [ka] Step 1: 3-((2-carboxyethyl)amino)-4-methylbenzoic acid 3-Amino-4-methylbenzoic acid (15.12 g, 100 mmol) in toluene (25 ml) was heated to reflux. Acrylic acid (27.5 ml, 400 mmol) and Toluene (10 ml) was added, and the mixture began to become a homogeneous solution. The mixture was stirred at rt for 3 h and then cooled to RT. The separated solid was collected by filtration and the solid The body was washed with toluene and dried to give the title compound as a solid (17.87 g). Method A: Rt=0.61min;[M+H] + =224.1.

[0282] Step 2: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrimidin methyl benzoate 3-((2-carboxyethyl)amino)-4-methylbenzoic acid (893 mg, 4 mm ol) and urea (601 mg, 10 mmol) in AcOH (12 ml) were heated at 120°C. The RM was cooled to RT and poured onto crushed ice, and the resulting The resulting mixture was acidified to pH 0 with an aqueous solution of HCl (1M). The solid was collected by filtration. Collected, washed with cold water and dried to give the title compound as a solid (661 mg). Method A: Rt=0.51min;[M+H] + =249.1.

[0283] Intermediate 9 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoate Zozoic acid [ka] Step 1: 3-(2-carboxyethylamino)-4-fluorobenzoic acid 3-amino-4-fluorobenzoic acid (9.3 g, 60 mmol) and acrylic acid at 25 °C A mixture of acid (13.0 g, 180 mmol) with AcOH (40 ml) and concentrated H2SO4 ( 0.5 ml) was added, and the mixture was stirred at 100°C for 5.5 hours. The resulting crude mixture (13.6 g) was used directly in the next step without further purification. Method D: Rt=1.298min;[M+H] + =228.

[0284] Step 2: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-pyrimidin Fluorobenzoic acid AcOH (60 ml) and urea (18.0 g, 300.0 mmol) were dissolved in 3-(2-calcium chloride) Crude mixture of (4-hydroxyethylamino)-4-fluorobenzoic acid (13.6 g, 60.0 mmol) l), and the resulting RM was stirred at 120° C. for 26 h and evaporated. Ice and water were added, followed by a concentrated aqueous solution of HCl (37%). The liquid was filtered, and the filtrate was saturated with solid NaCl and allowed to stand at 15°C for 20 hours. The filtrate was evaporated and the residue was The resulting mixture was allowed to stand at 15°C for 20 h. The precipitate was filtered off. The combined crops (9 g) were added to Ac OH was added and the mixture was sonicated for 10 minutes. TBME was added and the TBME phase was decanted. This was repeated once more. The residue was evaporated and AcOH and TBME were added. The mixture was sonicated. Additional TBME was added and the TBME phase was decanted. The above procedure was repeated once more. TBME was added, and the mixture was left standing at 15°C for 20 hours. The BME phase was decanted. The mixture was evaporated to dryness and resuspended in an aqueous solution of HCl (0.001M). The mixture was filtered and the solid was washed with an aqueous solution of HCl (0.001M) and ACN. Washing and drying gave the title compound as a solid (4.0 g). Method D: Rt=1.164min;[M+H] + =253.1. 1 H NMR(500MHz,DMSO-d6)δ13.16(brs,1H),10 .54(s,1H),8.02(dd,J=7.4,2.0Hz,1H),7.93(d dd,J=8.3,4.7,2.1Hz,1H),7.44(dd,J=9.8,8.9 Hz,1H),3.77(t,J=6.6Hz,2H),2.74(t,J=6.6Hz ,2H).

[0285] Intermediate 10 tert-Butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate to [ka] Step 1: tert-Butyl 4-(pyridin-4-yloxy)piperidine-1-carboxylate Silat In a 500 ml round-bottom flask, pyridin-4-ol (5 g, 52.6 mmol), THF (200 ml), tert-butyl 4-hydroxypiperidine-1-carboxylate ( 13.3g, 65.8mmol) and triphenylphosphine (18g, 68.4mmol) DEAD (12 g, 68.4 mmol) was added dropwise at RT. The RM was stirred at RT for 3 h. The RM was concentrated and diluted with methanol in DCM (1:3 0) to give the title compound as a solid (10 g). Method E:Rt=1.35min;MSm / z[M+H] + 279.

[0286] Step 2: tert-Butyl 4-(piperidin-4-yloxy)piperidine-1-carbohydrate Xylate In a 500 ml round bottom flask purged and maintained under an inert atmosphere, tert-butyl 4- (Pyridin-4-yloxy)piperidine-1-carboxylate (2g, 7.2mmol l), EtOH (100 ml), AcOH (5 ml) and Pd / C (10%) (0.4 g ) was added. The RM was stirred under a hydrogen atmosphere (4 MPa) at 80°C for 16 h. was filtered through Celite® and the filtrate was concentrated and diluted with MeOH in DCM (1: The title compound was purified by silica gel chromatography eluting with 0.10 ml of hexane to give the title compound as an oil (0. 5g). Method D: Rt=1.32min;MSm / z[M+H] + 285.3.

[0287] Intermediate 11 N-(3-(6-(4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl )phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2 -methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benz amide [ka] Step 1: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-3,9-diazaspiro[5. 5]Undecane-3-carboxylate tert-butyl 3,9-diazaspiro[5.5]undecane in a 25 ml round-bottom flask -3-carboxylate (118 mg, 0.450 mmol), TEA (0.100 ml , 0.717 mmol), 2-fluoro-N-(5-fluoro-3-(6-(4-formyl) (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 3, 220 mg , 0.409 mmol) and MeOH (4 ml) were added. HF solution (1 ml, 0.500 mmol) was added and the resulting RM was stirred at RT. Solid NaBH3CN (30 mg, 0.477 mmol) was added and the mixture was stirred overnight. The mixture was stirred at RT for 5 h, evaporated and the residue was dissolved in MeOH (DCM) (0-50 The title compound was purified by silica gel chromatography eluting with 35% CO₂O to give the title compound as a solid (35%). 4 mg). Method A: Rt=0.96min;[M+H] + =765.4.

[0288] Step 2: N-(3-(6-(4-(3,9-diazaspiro[5.5]undecane-3-yl) (phenylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro (2-hydroxypropan-2-yl)-2-fluoro-4-(2-hydroxy-2-methylphenyl)- ) Benzamide tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)benzyl)-3,9-diazaspiro[5.5] A solution of 1,3-dichlorobenzofuran-3-carboxylate (354 mg, 0.407 mmol) in MeOH ( HCl (4 M) in 1,4-dioxane (2 ml, 8.00 mmol) was added to the The RM was then stirred at RT for 1 h. The RM was concentrated and co-evaporated with DCM to dryness. This afforded the title compound as a solid HCl salt (340 mg). Method A: Rt=0.65min;[M+H] + =665.5.

[0289] Intermediate 12 2-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl )ethanol [ka] 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 4.2 9mmol), 4-(2-hydroxyethyl)phenylboronic acid (750mg, 4.29 mmol), aq. solution of Na2CO3 (2.0 M) (4.72 ml, 9.45 mmol ), PdCl2(PPh3)2 (154 mg, 0.215 mmol) and 1-propanol A 100 ml round-bottom flask containing a mixture of 10 ml of ethanol (36 ml) was purged with N2 at RT. The mixture was then stirred at 105° C. overnight. The mixture was concentrated to dryness and Purify by silica gel chromatography eluting with 40-100% HCl (in X). The title compound was obtained as a solid (762 mg). Method A: Rt=0.82min;[M+H] + =274.0.

[0290] Intermediate 13 4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane-2- (yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine -6-yl)phenethyl methanesulfonate [ka] Step 1: 2-Fluoro-N-(5-fluoro-3-(6-(4-(2-hydroxyethyl) )phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide At RT, 2-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6 -yl)phenyl)ethanol (Intermediate 12, 888 mg, 2.60 mmol) and 2- Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydroxypropane- 2-yl)benzamide (Intermediate 2, 1567 mg, 3.63 mmol) in 1-propanol A solution of 12 ml of ethanol and 2.0 M Na2CO3 in water (2.60 ml, 5.19 mm Argon was passed through the RM for 2 minutes to give a suspension of PdCl2(PPh 3) 2 (91 mg, 0.130 mmol) was added. The mixture was heated under microwave irradiation. The RM was diluted with EtOAc, water and brine and heated at 140° C. for 20 min. The phases were separated and the organic phase was dried over MgSO4 and purified with Isolute® HM- Dry by adsorption onto N. Elution with MeOH in DCM (0-20%) was performed on silica gel. Purification by column chromatography gave the title compound as a solid (863 mg). Method A: Rt=0.92min;[M+H] + =543.3.

[0291] Step 2: 4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropanediol) (2-methylphenyl)-7H-pyrrolo[2,3-d]piperidin-2-ylbenzamido Rimidin-6-yl)phenethyl methanesulfonate At RT and under argon, 2-fluoro-N-(5-fluoro-3-(6 -(4-(2-hydroxyethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)benzoate Diazolamide (89 mg, 0.164 mmol) was dissolved in dry THF (2 ml) and TEA (0.1 14 ml, 0.820 mmol) and the mixture was cooled to 0°C. 57.1 mg, 0.328 mmol) was added, and the RM was stirred at 0°C for 30 minutes. After quenching with ice water, DCM was added and the phases were separated. The aqueous phase was extracted with DCM and the resulting mixture was The combined organic phases were dried over MgSO4. Evaporation gave the title compound as a solid (94 mg ) was obtained. Method A: Rt=1.01min;[M+H] + =621.2.

[0292] Intermediate 14 tert-Butyl 4-((4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- 6-yl)benzyl)oxy)piperidine-1-carboxylate [ka] 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (84 8 mg, 3.03 mmol) and (4-(((1-(tert-butoxycarbonyl)pyridinyl) Peridine-4-yl)oxy)methyl)phenyl)boronic acid (1.068 g, 3.19 m mol) in 1-propanol (20 ml) to PdCl2(PPh3)2 (106 m g, 0.152 mmol), followed by an aqueous solution of Na2CO3 (2.0 M) (3.03 ml , 6.07 mmol) was added. The RM was stirred at 100° C. overnight, then added with EtOAc. The organic phase was separated, washed with water and brine, and dried over MgSO4. After evaporation, the residue was purified by silica gel chromatography eluting with EtOAc in CHX (0-100%). Purification by chromatography gave the title compound (844 mg). Method A: Rt=1.29min;[M+H] + =443.3.

[0293] Intermediate 15 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H -Pyrrolo[2,3-d]pyrimidine [ka] 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 3 A solution of 5.8 mmol) in DMF (120 ml) was added to mineral oil (1.7 g, 42.5 m NaH (60%) in 1000 ml of HCl was added in small portions under argon. Stir at 0°C for 30 minutes to obtain 2-(trimethylsilyl)ethoxymethyl chloride (7 0.5 ml, 42.3 mmol) was added and the RM was warmed to RT for 1 h. M was carefully poured into ice water and extracted with Et 2 O. The combined organic phase was washed with brine. The residue was diluted with ACN and the resulting mixture was filtered and The title compound was obtained as a solid (8.052 g). The filtrate was concentrated and triturated in cold MeOH to give and filtered to give a second crop of the title compound as a solid (3.120 g). Method A: Rt=1.48min;[M+H] + =410.1.

[0294] Intermediate 16 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidine-4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl )-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: 4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7 H-Pyrrolo[2,3-d]pyrimidin-6-yl)phenol 4-Chloro-6-iodobenzoate in a mixture of 1,4-dioxane (15 ml) and water (15 ml) 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (intermediate 15, 1333 mg, 3.254 mmol), Cs2CO3(2 0.651g, 11.33mmol) and 4-hydroxyphenylboronic acid (840mg, A solution of PdCl2(dppf)-CHCl (2.67 mmol) was degassed with argon. 2 adduct (266 mg, 0.325 mmol) was added, and the RM was heated to 100°C for 1.5 The RM was filtered through Hyflo® and the solid was washed with MeOH. The combined filtrate was concentrated and partitioned between EtOAc and water. The phases were separated and the organic phase was The title compound was obtained as a solid (575 mg) by washing with HCl, drying over MgSO4 and evaporation. ) was obtained. Method A: Rt=1.30min;[M+H] + =376.

[0295] Step 2: 2-fluoro-N-(5-fluoro-3-(6-(4-hydroxyphenyl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]piperidin (2-hydroxypropane-2-yl)-4-(2-methylphenyl-4-imidin-4-yl)-2-methylphenyl benzamide 4-(4-chloro-)-2-(4-chloro-)-2-(2-methyl-2-propanol) in a mixture of 1,4-dioxane (10 ml) and water (10 ml) 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]piperidin rimidin-6-yl)phenol (1635 mg, 2.044 mmol), K2CO3 ( 1119 mg, 8.1 mmol) and 2-fluoro-N-(5-fluoro-2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 2, 1811 A solution of PdCl2(dppf) (238 mg, 4.2 mmol) was degassed with argon. mg, 0.325 mmol) was added, and the RM was stirred at 100°C for 1.5 h. was filtered through Hyflo® and the solids were washed with MeOH. The mixture was concentrated and partitioned between EtOAc and water. The phases were separated and the organic phase was washed with brine and Dry over gSO4, evaporate and elute with MeOH in DCM (0-7.5%). The title compound was purified by silica gel chromatography using And got it. Method A: Rt=1.35min;[M+H]+=645.3.

[0296] Step 3: tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin (6-phenyl)phenoxy)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-3-(6-(4-hydroxyphenyl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin (2-hydroxypropan-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)phenyl amide (749 mg, 0.999 mmol), 1-Boc-4-hydroxypiperidin phenanthroline (221 mg, 1.099 mmol) and triphenylphosphine (365 mg, 1. A THF solution (10 ml) of DEAD (40%) in toluene (0. 550 ml, 1.390 mmol) was added dropwise under argon at RT. The combined RM was stirred at RT overnight. Additional 1-Boc-4-hydroxypiperidine ( 79 mg, 0.393 mmol) was added, and the RM was stirred at RT for 2 h. The solvent was removed. The residue was dissolved in ACN (aq. solution of TFA (0.1%)) (2-100%). The product was purified by Redisep® C18 column chromatography to obtain the product. The title compound was obtained as a solid (421 mg). Method A: Rt=1.64min;[M+H] + =828.5.

[0297] Step 4: 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidinyl) (2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydro (2-xypropan-2-yl)benzamide tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-((2- (Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -yl)phenoxy)piperidine-1-carboxylate (416.6 mg, 0.503 A solution of 12.98 mmol) and TFA (1 ml, 12.98 mmol) in DCM (5 ml) was added to RT. The mixture was stirred for 2 h, concentrated, and then purified by distillation with ACN (aq. solution of TFA (0.1%)) (2-1 00% elution was performed by reversed-phase chromatography on a Redisep® C18 column. to give the title compound as a solid TFA salt (101 mg). Method A: Rt=0.77min;[M+H] + =598.4.

[0298] Intermediate 17 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine-1- (ylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl )-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazine-1-carboxylate Route 1-Boc-piperazine (95 mg, 0.500 mmol), TEA (0.100 ml , 0.717 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-chloro- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 3, 250m g, 0.465 mmol) was dissolved in MeOH (4 ml) at RT. A solution of 2 (0.5 M) in THF (1 ml, 0.500 mmol) was added, and the resulting The mixture was stirred at RT for 3 days. Solid NaBH3CN (32 mg, 0.509 m mol) was added and the RM was stirred at RT overnight, the solvent was removed and the residue was treated with AC Elute Redisep (in aq. solution of TFA (0.1%)) (2-100%). The title compound was purified by reverse phase chromatography on a C18 column to give a solid TF Obtained as salt A (370 mg). Method A: Rt=0.94min;[M+H] + =697.5.

[0299] Step 2: 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine) (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (phenyl)-4-(2-hydroxypropan-2-yl)benzamide tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)benzyl)piperazine-1-carboxylate ( 360 mg, 0.431 mmol) in MeOH (2 ml) with 1,4 M HCl -Dioxane solution (2 ml, 8.00 mmol) was added and the RM was stirred at RT for 4 h. The RM was concentrated and dried to give the title compound as a solid HCl salt (281 mg). Ta. Method A: Rt=0.76min;[M+H] + =597.5.

[0300] Intermediate 18 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine-1- (ylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl )-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazine-1-carboxylate Route 1-Boc-piperazine (170 mg, 0.912 mmol), TEA (0.300 m 1, 2.152 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-fluoro- (pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (phenyl)-4-(2-hydroxypropan-2-yl)benzamide (Intermediate 3, 400 mg, 0.760 mmol) was dissolved in MeOH (6 ml) at RT. A solution of 12 (0.7 M) in THF (1.2 ml, 0.840 mmol) was added, resulting in The resulting mixture was stirred at RT for 5 h. Solid NaBH3CN (50 mg, 0.79 6 mmol) was added and the RM was stirred at RT for 3 days, the solvent was evaporated and the residue The column was eluted with ACN (aq. solution of TFA (0.1%)) (2-100%). The title compound was purified by reverse phase chromatography on a Sep® C18 column. Obtained as a solid TFA salt (328 mg). Method A: Rt=0.94min;[M+H] + =697.5.

[0301] Step 2: 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine) (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (phenyl)-4-(2-hydroxypropan-2-yl)benzamide tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)benzyl)piperazine-1-carboxylate ( A solution of 328 mg of HCl (0.360 mmol) in MeOH (2.0 ml) was added to 1 M of HCl (4 M). ,4-dioxane solution (2 ml, 8.00 mmol) was added, and the RM was stirred at RT for 4 h. The RM was concentrated and the residue was dissolved in ACN (aq. solution of TFA (0.1%)) Redisep® C18 column reversed-phase chromatograph eluting with 2-100% Purification by HPLC gave the title compound as a solid TFA salt (278 mg). Method A: Rt=0.74min;[M+H] + =597.4.

[0302] Intermediate 19 tert-Butyl 4-(2-oxoethoxy)piperidine-1-carboxylate [ka] Step 1: tert-butyl 4-(allyloxy)piperidine-1-carboxylate NaH (60%) in mineral oil (964 mg, 24.10 mmol) was dissolved in 1-Boc A solution of 4-hydroxypiperidine (1000 mg, 4.82 mmol) in anhydrous THF (4 5 ml) was added in small portions at RT under argon and stirring was continued for 30 min. Romide (0.500 ml, 5.78 mmol) was added dropwise and the RM was stirred at RT for 40 h. After stirring, the mixture was quenched with ice water. The mixture was extracted with EtOAc and the combined organic layers were The phase was dried over Na2SO4, concentrated and washed with EtOAc in CHX (0-20%). The title compound was purified by silica gel chromatography eluting with HCl to give a colorless liquid (11 30 mg). Method A: Rt=1.13min;[M-tBu+H] + =186.1.

[0303] Step 2: tert-Butyl 4-(2-oxoethoxy)piperidine-1-carboxylate to tert-Butyl 4-(allyloxy)piperidine-1-carboxylate (1120 mg, 4.64 mmol) in anhydrous DCM (40 ml) was cooled to -78°C and ozone The RM was warmed to RT and the polymer-bound triphenylphosphine was added. Finn (5 g, 16.00 mmol) was added. The RM was stirred at RT for 30 min. The solid was filtered through Celite® and washed with DCM. The combined filtrate was evaporated Evaporation to dryness gave the title compound as a colorless oil (1147 mg) without further purification. It was widely used.

[0304] Intermediate 20 rac-1-(5-(7-(hydroxymethyl)-3,9-diazaspiro[5.5]un) Decane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H ,3H)-dione [ka] Step 1: rac-tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidinyl)methyl) benzoyl)-1-(hydroxymethyl)-3, 9-Diazaspiro[5.5]undecane-3-carboxylate rac-tert-butyl 1-(hydroxymethyl)-3,9-diazaspiro[5.5 ]undecane-3-carboxylate (200 mg, 0.703 mmol), 3-(2, 4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (medium Intermediate body 5 (204 mg, 0.774 mmol) and NMM (0.387 ml, 3.52 mmol) HATU (401 mg, 1.055 mmol) was added to a DMF solution (3 ml). The RM was stirred at RT for 2 h, then poured into water and filtered. The filtrate was extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4 and evaporated. and purified by silica gel chromatography eluting with MeOH in DCM (0-20%). The product was purified by HCl to give the title compound as a solid (241 mg). Method A: Rt=0.77min;[M+H] + =531.3.

[0305] Step 2: rac-1-(5-(7-(hydroxymethyl)-3,9-diazaspiro[5. 5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2, 4(1H,3H)-dione rac-tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3,9-di Azaspiro[5.5]undecane-3-carboxylate (241 mg, 0.454 mm ol) and TFA (1.050 ml, 13.63 mmol) in DCM (4 ml) were added to R The mixture was stirred at RT for 2 h, concentrated, and the residue was diluted with ACN (aq. solution of TFA (0.1% The elution was performed by reversed-phase chromatography on a Redisep® C18 column with Purification by HCl gave the title compound as a solid TFA salt (228 mg). Method A: Rt=0.38min;[M+H] + =431.2.

[0306] Intermediate 21 1-(2-Methoxy-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl) (1H,3H)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: tert-Butyl 9-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undeca Benzene-3-carboxylate tert-Butyl 3,9-diazaspiro[5.5]undecane-3 at RT under argon -carboxylate (432 mg, 1.698 mmol) and NMM (0.392 ml, 3.57 mmol) in DMF (4 ml) 471 mg, 1.78 mg of benzoic acid (Intermediate 5) 3 mmol) followed by HATU (743 mg, 1.953 mmol). After stirring at RT for 2.5 h, a saturated aqueous solution of NaHCO3 was added. EtOAc was added. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and and brine, dried over MgSO4, and concentrated to give the title compound as a solid (90 0 mg). Method A: Rt=0.91min;[M+H] + =501.4.

[0307] Step 2: 1-(2-methoxy-5-(3,9-diazaspiro[5.5]undecane-3- (carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione tert-Butyl 9-(3-(2,4-dioxotetrahydropyrimidine-1(2H) -yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecane-3 -carboxylate (805 mg, 1.415 mmol) in DCM (19 ml) FA (3.27 ml, 42.5 mmol) was added. The RM was stirred at RT for 1 h. The residue was concentrated and purified with ACN (aq. solution of TFA (0.1%)) (5-100%). Purified by reversed-phase chromatography on a Redisep® C18 column eluting with This gave the title compound as a solid TFA salt (767 mg). Method A: Rt=0.40min;[M+H] + =401.3.

[0308] Intermediate 22 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro- 4-Methylbenzoic acid [ka] Step 1: 5-amino-2-fluoro-4-methylbenzoic acid RT methyl 5-amino-2-fluoro-4-methylbenzoate (250 mg, 1. A stirred solution of 365 mmol of lithium hydroxide monohydrate (128 ml) in THF (5.4 ml) was added. g, 3.02 mmol) was added to an aqueous solution (1.35 ml). The resulting RM was The mixture was stirred overnight at T. The RM was concentrated, rediluted with water (5 ml) and diluted with HCl (2 M). (1.5 ml) was added until the mixture reached a pH of 4. The mixture was placed in an ice-water bath. Cool in rt, filter, wash the solid with water and Et2O, dry the solid, and The mixture was obtained as a solid (217 mg). Method A: Rt=0.46min;[M+H] + =170.1.

[0309] Step 2: 5-((2-carboxyethyl)amino)-2-fluoro-4-methylbenzoic acid 5-Amino-2-fluoro-4-methylbenzoic acid (216 mg, 1.277 mmol) and a mixture of acrylic acid (0.354 ml, 5.11 mmol) in toluene (0.5 ml). The mixture was flushed with N2 and stirred at 100 °C for 3.5 h. The RM was concentrated to give the title compound. The mixture was obtained as a solid (352 mg). Method A: Rt=0.58min;[M+H] + =242.1.

[0310] Step 3: 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-pyrimidin Fluoro-4-methylbenzoic acid 5-((2-carboxyethyl)amino)-2-fluoro-4-methylbenzoic acid (35 0mg, 1.277mmol) and urea (460mg, 7.66mmol) in AcOH The mixture (1 ml) was stirred at 120° C. overnight and cooled to RT. The resulting oil was diluted with water (1-2 ml) and the mixture was poured onto crushed ice. Aq. solution was added and stirring was continued until all the ice had melted. The liquid was filtered, the solid was washed with ACN and dried to give the title compound as a solid (250 mg). was obtained as. Method A: Rt=0.48min;[M+H] + =267.1

[0311] Intermediate 23 Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidine-1(2H)- (yl)-4-methoxybenzoate [ka] In a 250 ml round-bottom flask, add 3-(2,4-dioxotetrahydropyrimidine-1(2H) )-yl)-4-methoxybenzoic acid (Intermediate 5, 28 g, 106 mmol), pentafluoro Orophenyl 2,2,2-trifluoroacetate (36 g, 127 mmol) and DM F (50 ml) was added. DIPEA (76 ml, 424 mmol) was added at 0°C. The RM was stirred at RT for 2 h and diluted with water. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column eluting with EtOAc in petroleum ether (10-30%). Purification by column chromatography gave the title compound as a solid (40 g). Method H:Rt=1.51min,[M+H] + =432.

[0312] Intermediate 24 tert-Butyl 9-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[5.5] Undecane-3-carboxylate [ka] Step 1: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)ethan-1-ol 2-(4-Bromophenyl)ethan-1-ol (60 g, 300 mmol), BIS PIN (84 g, 330 mmol), KOAc (90 g, 900 mmol) and PdCl 2(dppf) (6.6 g, 9 mmol) in 1,4-dioxane (600 ml) Stirred under N2 at 85 °C for 16 h. Cooled the RM to RT, filtered and concentrated the filtrate. The residue was then purified by silica gel chromatography eluting with EtOAc in petroleum ether (0-30%). Purification by chromatography gave the title compound as an oil (100 g). Method J:Rt=1.87min,[M+NH4] + =266.

[0313] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) (I) Phenethyl methanesulfonate 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) (phenyl)ethan-1-ol (100 g, 300 mmol) and TEA (240 g A mixture of 2400 mmol) and DCM (1300 ml) was stirred at 0° C. for 20 minutes. A solution of MsCl (136 g, 1200 mmol) in DCM (200 ml) was added dropwise to the reaction mixture. The mixture was stirred at RT for 16 h and water was added. The phases were separated and the organic phase was extracted with Na2SO4. Dry and concentrate, and the residue is eluted with EtOAc in DCM (0-50%). Purification by silica gel chromatography gave the title compound as an oil (87 g). Method E: Rt=1.92min,[M+H] + =327.

[0314] Step 3: tert-Butyl 9-(4-(4,4,5,5-tetramethyl-1,3,2-diphenyl ether) Oxaborolan-2-yl)phenethyl)-3,9-diazaspiro[5.5]undecane -3-carboxylate tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (34g, 133mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxide) (xaborolan-2-yl)phenethyl methanesulfonate (86 g, 172 mmol), AC of K2CO3 (47 g, 345 mmol) and KI (2.3 g, 13.8 mmol) The N mixture (1000 ml) was stirred at 60°C for 16 hours. The RM was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with MeOH in DCM (0-10%). Purification by chromatography gave the title compound as a solid (49g). Method I: Rt=1.47min,[M+H] + =485.

[0315] Step 4: tert-Butyl 9-(4-(4-chloro-7-(phenylsulfonyl)-7H) -pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[ 5.5]Undecane-3-carboxylate tert-Butyl 9 in a mixture (480 ml) of 1,4-dioxane and water (5:1) -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate(3 8g, 79mmol), 4-chloro-6-iodo-7-(phenylsulfonyl)-7H- Pyrrolo[2,3-d]pyrimidine (Intermediate 7, 37 g, 88 mmol), K2CO3(2 A mixture of PdCl2(dppf) (2g, 160mmol) and PdCl2(dppf) (5.8g, 8mmol) The mixture was stirred under N2 at 80 °C for 16 h. The RM was poured into EtOAc and the organic phase was separated. The residue was extracted with MgSO4, washed with water, dried over Na2SO4, filtered and concentrated. Purified by silica gel chromatography eluting with eOH in DCM (0-10%) This gave the title compound as a solid (34 g). Method I: Rt=1.99min,[M+H] + =650.

[0316] Synthesis of the final compound compound 1 rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] rac-2-fluoro-N-(5-fluoro-3-(6-(4-((7-(hydroxy Methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-( 2-hydroxypropan-2-yl)benzamide (Intermediate 4, 100 mg, 0.108 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- A mixture of 4-methoxybenzoic acid (Intermediate 5, 31.5 mg, 0.119 mmol) and HA TU (61.8 mg, 0.163 mmol) and NMM (0.060 ml, 0.542 m The RM was stirred at RT for 2 h, and the solution was poured into water and filtered. The solid was dried and then extracted with ACN (aq. solution of TFA (0.1%)) (10-100%). Purified by reversed-phase chromatography on a Redisep® C18 column eluting with The title compound was obtained as a solid TFA salt. The solid was dissolved in MeOH and purified by SCX chromatography. Filtration through a tray and concentration of the combined filtrate gave the title compound (19.6 mg). . Method B: Rt=3.41min;[M+H] + =941.6. 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),9.92( s,1H),9.62(d,J=3.1Hz,1H),8.85(s,1H),7.99 (s,2H),7.8-7.6(m,2H),7.50-7.25(m,6H),7.2 5-7.05(m,2H),6.81(s,1H),3.86(s,4H),3.75- 3.6(m,6H),3.29(s,3H),2.69(t,J=6.7Hz,4H), 2.19(s,4H),2.1-1.6(m,2H),1.6-1.4(m,11H), 1.4-1.25(m,3H).

[0317] Compound 2 and Compound 3: (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide, and (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] Heptane, DCM and MeOH (40:35:25) containing DEA (0.05%) A Chiralpak ID column (5μ) was eluted with a mixture of rac-N-(3-(6-(4-( (9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methyl ... (Hydroxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) chiral separation of (propan-2-yl)benzamide (7.7 mg, 7.9 μmol) The title compound was obtained as a single enantiomer in the following sequence:

[0318] First eluted enantiomer: 1.2 mg Method K: Rt=29.5min Method B: Rt=3.44min;[M+H] + =941.5 1 H NMR (400 MHz, DMSO-d6) confirmed the N Follow MR.

[0319] Second eluted enantiomer: 2.0 mg Method K: Rt=37.5min Method B: Rt=3.46min;[M+H] + =941.4 1 H NMR (400 MHz, DMSO-d6) confirmed the N Follow MR.

[0320] Compound 4: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5]undecanoate (3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl)- (pan-2-yl)benzamide [ka] Step 1: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-en Toxobenzoic acid 3-Amino-4-ethoxybenzoic acid (2.7 g, 14.90 mmol) was dissolved in acrylic acid ( 4.09 ml, 59.6 mmol), and the RM was stirred at 110°C for 1 h. Urea (5.37 g, 89 mmol) and AcOH (18 ml) were added to the RM. Stirred for 2 h at 0° C. The RM was quenched with water and added to a concentrated aq. solution of HCl (37% The mixture was acidified with HCl and extracted with EtOAc. The organic phases were combined and evaporated. Water was added. The mixture was filtered and the solid was washed with water and EtOAc to give the title compound as a solid (1.1 g). Method A: Rt=0.56min;[M+H] + =279.1.

[0321] Step 2: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Diazin-1(2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5 ]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (2-xypropan-2-yl)benzamide TBTU (38.4 mg, 0.119 mmol) followed by 2,4,6-collidine (0. 2 ml, 1.508 mmol) to 3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-ethoxybenzoic acid (33.2 mg, 0.119 mmol) in DMF The RM was stirred at RT for 15 min. (4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide (Intermediate 6 , 60 mg, 0.060 mmol) was added and the RM was stirred at RT for 3 days. Dilute with DMF (2 ml) and add to ACN (aq. solution of TFA (0.1%)) (5-1 HPLC (Method L) on a SunFire C18 column eluted with a 0.0000% linear gradient. The title compound was obtained as a solid TFA salt (32.8 mg). Method B: Rt=3.74min;[M+H] + =925.3. 1 H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.06 ( d,J=8.1Hz,2H),7.90(t,J=7.9Hz,1H),7.74-7. 68(m,1H),7.66(d,J=8.1Hz,2H),7.52-7.37(m, 4H),7.25(dd,J=8.5,2.7Hz,1H),7.19(d,J=8.5 Hz,1H),7.00(s,1H),4.41(s,2H),4.19(q,J=7. 0Hz,2H),3.8-3.5(m,6H),3.45-3.15(m,4H),2. 82(t,J=6.7Hz,2H),2.23(s,3H),2.07(m,2H),1 .9-1.4(m,6H),1.58(s,6H),1.45(t,J=7.0Hz,3 H).

[0322] Compound 5: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]un Decane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-ylbenzamide [ka] Step 1: tert-Butyl 9-(4-bromophenethyl)-3,9-diazaspiro[5. 5]Undecane-3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 3,9-diazasol in ACN (50 ml). Pyro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol), K2C O3 (4.07 g, 29.5 mmol) and 1-bromo-4-(2-bromoethyl)benzoate Zene (5.2 g, 17.6 mmol) was added. The RM was stirred under N2 at RT for 16 h. The RM was concentrated, diluted with water and extracted with DCM. The combined organic phases were concentrated. and purified by silica gel chromatography eluting with MeOH in DCM (1:100). The product was purified by HCl to give the title compound as a solid (4.8 g). Method F:Rt=1.91min;MSm / z[M+H] + 438.1.

[0323] Step 2: tert-Butyl 9-(4-(4,4,5,5-tetramethyl-1,3,2-diphenyl ether) Oxaborolan-2-yl)phenethyl)-3,9-diazaspiro[5.5]undecane -3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 9-(4-bromophenethyl)-3,9- Diazaspiro-[5.5]undecane-3-carboxylate (4.8 g, 11 mmol) ), BISPIN (3.4g, 13.2mmol), KOAc (2.2g, 22mmol) ), PdCl2(dppf) (0.8 g, 1.1 mmol) and DMSO (60 ml) The RM was stirred at 80° C. for 16 h and then diluted with water. The mixture was diluted with EtOAc The combined organic phase was washed with water and brine, concentrated, and extracted with EtOAc ( Purified by silica gel chromatography eluting with (0-100%) in petroleum ether This gave the title compound as a solid (4.0 g). Method E: Rt=1.67min;MSm / z[M+H] + 485.

[0324] Step 3: tert-Butyl 9-(4-(4-chloro-7-(phenylsulfonyl)-7H) -pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[ 5.5]Undecane-3-carboxylate In a 25 ml round-bottom flask, add tert-butyl 9-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenethyl)-3,9-diazaspiro[5 .5]undecane-3-carboxylate (889 mg, 1.83 mmol), 4-chloro 6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 7, 700 mg, 1.67 mmol), Na2CO3 (354 mg, 3.34 m mol) and PdCl(dppf) (124 mg, 0.17 mmol) were added. N (10 ml) and water (2 ml) were added and the RM was stirred under N at 80 °C for 16 h. The RM was diluted with EtOAc, the mixture was filtered, and the filtrate was concentrated and diluted with EtOAc ( Purify by silica gel chromatography eluting with 0-100% ethanol in ethyl ether. This gave the title compound as an oil (600 mg). Method F:Rt=1.85min;MSm / z[M+H] + 650.

[0325] Step 4: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-( Phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl )-3,9-diazaspiro[5.5]undecane-3-carboxylate In a 25 ml round-bottom flask, add tert-butyl 9-(4-(4-chloro-7-phenyl)sulfonyl) (7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9 -Diazaspiro[5.5]undecane-3-carboxylate (400 mg, 0.62 m mol), 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetrafluoroethane) tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydro (xypropan-2-yl)benzamide (Intermediate 2, 265 mg, 0.62 mmol), Na2CO3 (130 mg, 1.23 mmol) and PdCl2(dppf) (44 mg ACN (10 ml) and water (2 ml) were added to the RM. Stirred under N2 at 80 °C for 16 h. The RM was diluted with EtOAc and the mixture was filtered. The filtrate was concentrated and the silica gel was eluted with EtOAc in petroleum ether (0-100%). Purification by gel chromatography gave the title compound as a solid (200 mg). Method E:Rt=1.74min;MSm / z[M+H] + 919.

[0326] Step 5: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[5 .5]undecane-3-carboxylate In a 10 ml round-bottom flask, add tert-butyl 9-(4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6- (yl)phenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate The solution was added with 200 mg of dimethylformamide (0.22 mmol) and 2 ml of DMSO. A solution of 1 mg of RM in water (1 ml) was added at RT, and the RM was stirred at RT. The mixture was stirred for 1 h and diluted with EtOAc. The phases were separated and the organic phase was washed with water and brine. It was dried and concentrated to give the title compound as a solid (170 mg). Method E: Rt=1.64min;MSm / z[M+H] + 779.

[0327] Step 6: N-(3-(6-(4-(2-(3,9-diazaspiro[5.5]undecane- 3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide In a 10 ml round-bottom flask, add tert-butyl 9-(4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9- Diazaspiro[5.5]undecane-3-carboxylate (160 mg, 0.21 mm ol), EtOH (2 ml) and DCM (0.5 ml) were added. A solution of 4-dioxane (1.5 ml, 6 mmol) was added at 0°C. The RM was warmed to RT. The RM was concentrated to give the title compound as a solid HCl salt (130 mg). And got it. Method E: Rt=1.45min;MSm / z[M+H] + 679.

[0328] Step 7: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyridine) Rimidin-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5. 5]Undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (2-hydroxypropan-2-yl)benzamide In a 10 ml round-bottom flask, add N-(3-(6-(4-(2-(3,9 -diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro Oro-4-(2-hydroxypropan-2-yl)benzamide hydrochloride (100 mg, 0.13 mmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H )-yl)-4-methylbenzoic acid (Intermediate 8, 33 mg, 0.13 mmol), HATU (59 mg, 0.16 mmol) and DIPEA (34 mg, 0.27 mmol) were added. The RM was stirred at RT for 2 h, and the mixture was diluted with ACN (aqueous ammonium bicarbonate). Preparative HPLC was performed on an XBridge C18 column eluting with 10 mM NaCl. Purification gave the title compound as a solid (40 mg). Method G:Rt=1.92min;MSm / z[M+H] + 909. 1 H NMR(500MHz,DMSO-d6)δ12.72(br.s,1H),10 .37(br.s,1H),9.93(br.s,1H),8.80(s,1H),7. 89(d,J=8.1Hz,2H),7.73(t,J=7.9Hz,1H),7.7- 7.6(m,1H),7.5-7.4(m,2H),7.4-7.3(m,4H),7. 3-7.2(m,2H),6.77(s,1H),5.4-5.3(m,1H),3.9 -3.8(m,1H),3.6-3.5(m,3H),2.9-2.7(m,4H),2 .6-2.5(m,2H),2.4-2.3(m,4H),2.21(s,3H),2. 17(s,3H),1.7-1.3(m,16H).

[0329] Compound 6: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-(4-bromobenzyloxy)piperidine-1-carboxylate Silat DM of NaH (60%) in mineral oil (1.17 g, 29.25 mmol) at 5 °C F suspension (30 ml) was added to tert-butyl 4-hydroxypiperidine-1-carboxylate A solution of 4.03 g (20.0 mmol) of methylpropanol in 15 ml of DMF was added dropwise at 5°C. The RM was stirred at 5°C for 1 h, and then 1-bromo-4-(bromomethyl)benzene (7.0 g, 28.0 mmol) was added at 5° C. The RM was warmed to RT and stirring was continued for 1 The reaction was continued for 8 h. Ice-cold water (250 ml) was added and the mixture was diluted with EtOAc and petroleum ether. (2:1) mixture, and the combined organic phase was dried over MgSO4 and concentrated. and silica gel chromatography eluting with EtOAc in petroleum ether (0-20%). Purification by filtration gave the title compound as an oil (6.1 g). Method H:Rt=2.301min;[M-100+H] + =270.

[0330] Step 2: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-diphenyl ether) Oxaborolan-2-yl)benzyloxy)piperidine-1-carboxylate tert-Butyl-4-(4-bromobenzyloxy)piperidine under an inert atmosphere Zin-1-carboxylate (2.0 g, 5.4 mmol), BISPIN (2.7 g, 10.8 mmol), KOAc (1.59 g, 16.2 mmol) and PdCl2 (dp pf) (630 mg, 0.86 mmol) was added to 1,4-dioxane (45 mL). Additionally, the RM was stirred under N at 85° C. for 18 h. The RM was evaporated to EtOAc. Purified by silica gel chromatography eluting with (0-20%) in petroleum ether This gave the title compound as a solid (2.1 g). Method F: Rt=1.698min,[M-100+H] + =318.

[0331] Step 3: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzyloxy)piperidine tert-butyl-4-(4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)benzyloxy)piperidine-1-carboxylate(2 A solution of 1.1 g (5.0 mmol) of 1,4-dioxo-HCl (4 M) in DCM (10 ml) was The RM was warmed to 30°C and stirred for 2 hours. The RM was concentrated and the residue was dissolved in a mixture of petroleum ether and TBME (2:1). Triturate, filter and dry the solid to give the title compound as a solid HCl salt (1.2 g). Got it. Method E: Rt=1.743min,[M+H] + =318.2.

[0332] Step 4: tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperidine- 1-carboxylate tert-Butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (2 g, 8.72 mmol) and TEA (1.77 g, 17.44 mmol) in DCM To the combined solution (50 ml) was added dropwise methanesulfonyl chloride (1.2 g, 10.47 mmol). The RM was then stirred at RT for 16 h. The RM was diluted with DCM (100 ml) and and brine, dried over Na2SO4 and concentrated to give the title compound as a solid ( 2.6g). 1 H NMR(500MHz,DMSO-d6)δ4.24(t,J=6.3Hz,2H ),3.91(d,J=9.9Hz,2H),3.17(s,3H),2.68(s,2 H),1.71-1.48(m,5H),1.39(s,9H),1.07-0.94( m,2H).

[0333] Step 5: tert-Butyl 4-(2-(4-(4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)benzyloxy)piperidin-1-yl)ethy (I)piperidine-1-carboxylate 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa- (Borolan-2-yl)benzyloxy)piperidine (700 mg, 1.98 mmol), tert-Butyl-4-(2-(methylsulfonyloxy)ethyl)piperidine-1-carboxylate carboxilate (913 mg, 2.97 mmol), K2CO3 (821 mg, 5.94 A mixture of NaI (445 mg, 1.5 mmol) and ACN (20 ml) was added. Additionally, the RM was stirred under N at RT for 16 h. The RM was then dissolved in EtOAc (100 ml), filtered, and the filtrate was concentrated to give the title compound as a solid (1 g). Method I: Rt=1.527min;[M+H] + =529.

[0334] Step 6: tert-Butyl 4-(2-(4-(4-chloro-7-(phenylsulfo) (Nyl)-7H-pyrrolo[2,3d]pyrimidin-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperidine-1-carboxylate tert-Butyl-4-(2-(4-(4-(4,4,5,5-tetramethyl-2-methyl-4- ... (tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)piperidine-1 -yl)ethyl)piperidine-1-carboxylate (472 mg, 0.89 mmol) , 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d] Pyrimidine (Intermediate 7, 250 mg, 0.60 mmol), Na2CO3 (126 mg, Mixture of PdCl2(dppf) (1.19 mmol) and PdCl2(dppf) (49 mg, 0.06 mmol) ACN (5 ml) and water (1 ml) were added to the mixture, and the RM was stirred at 80°C for 16 h. The RM was diluted with EtOAc (100 ml), filtered, and the filtrate was concentrated and added to MeOH ( Purify by silica gel chromatography eluting with 0-15% DCM (in DCM) to obtain the table The title compound was obtained as an oil (500 mg). Method I: Rt=1.553min;[M+H] + =694.

[0335] Step 7: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl (phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl )benzyloxy)piperidin-1-yl)ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(2 -hydroxypropan-2-yl)benzamide (Intermediate 2, 149 mg, 1.2 mmol) l), tert-butyl-4-(2-(4-(4-chloro-7-(phenylsulfonyl) (7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyloxy)piperidinyl (1-methyl-1-yl)ethyl)piperidine-1-carboxylate (200 mg, 1 mmol) , Na2CO3 (92 mg, 0.86 mmol) and PdCl2(dppf) (24 mg ACN (5 ml) and water (1 ml) were added to the mixture of RM and N The mixture was stirred at 80°C for 16 h under 2. The RM was then diluted with EtOAc (100 ml). The silica gel was extracted with methanol in DCM (0-15%), filtered, and the filtrate was concentrated. Purification by column chromatography gave the title compound as an oil (260mg). Method G:Rt=2.875min,[M+H] + =694.

[0336] Step 8: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl (I)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperidine-1-carboxylate tert-Butyl-4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl (2-phenyloxy)piperidin-1-yl)ethyl)piperidine-1-carboxylate 00 mg, 0.21 mmol) in DMSO (2 ml) 3 mmol) was slowly added to an aqueous solution (1 ml) of RM at RT. The mixture was stirred for 1 h and diluted with ACN (aq. solution of ammonium bicarbonate (0.1%)) Purification was performed by reversed-phase HPLC on an XBridge C18 column eluting with 5–95% CO₂. The title compound was obtained as a solid (150 mg). Method J:Rt=2.419min,[M+H] + =823.

[0337] Step 9: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((1-( 2-(Piperidin-4-yl)ethyl)piperidin-4-yloxy)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydro (2-xypropan-2-yl)benzamide tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyloxy)piperidine-1- (yl)ethyl)piperidine-1-carboxylate (150 mg, 0.16 mmol) The DCM solution (4 ml) was cooled to 0° C. A solution of HCl (6 M) in 1,4-dioxane was added. (1 ml, 6 mmol) was added slowly. The RM was warmed to RT and stirring was continued for 2 h. The RM was concentrated to give the title compound as a solid HCl salt (115 mg). Method I: Rt=1.142min;[M+H] + =723.

[0338] Step 10: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxote tetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidine-4 -yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro Oro-4-(2-hydroxypropan-2-yl)benzamide 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((1-(2-( Piperidin-4-yl)ethyl)piperidin-4-yloxy)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropyl propan-2-yl)benzamide (80 mg, 0.11 mmol), 3-(2,4-diol 1(2H)-1-hexotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid (Intermediate 9, 31mg, 0.12mmol), HATU (50mg, 0.13mmol), DIPEA A mixture of (29 mg, 0.22 mmol) and DMF (2 ml) was stirred at RT for 2 h. The mixture was dissolved in ACN (aq. solution of ammonium bicarbonate (0.1%)) (5-9 XBridge C18 column (21.2 x 250 mm, 10 μm) eluted with 5% CO₂. Purification by phase HPLC gave the title compound as a solid (53 mg). Method D: Rt=1.319min,[M+H] + =957. 1 H NMR(500MHz,DMSO-d6)δ12.77(s,1H),9.94( s,1H),8.85(s,1H),7.96(d,J=8.2Hz,2H),7.73 (t,J=8.0Hz,1H),7.67-7.65(dd,J=9.2Hz,1H), 7.49(dd,J=7.6Hz,1H),7.44-7.36(m,6H),7.24 (dd,J=8.3,2.6Hz,1H),6.84(s,1H),5.30(s,1H ),4.53(s,2H),3.75(t,J=6.6Hz,2H),3.41-3.3 6(m,2H),2.99-2.93(m,1H),2.77-2.61(m,4H), 2.49-2.35(m,2H),2.28-2.24(m,2H),2.18(s,3 H),2.04-1.93(m,3H),1.92-1.79(m,2H),1.88- 1.85(m,2H),1.75-1.46(m,3H),1.45(s,6H),1. 39-1.31(m,2H),1.13-1.04(m,2H).

[0339] Compound 7: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine (2H)-diphenyl-4-methoxybenzoyl)piperidin-4-yl)methyl Piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide [ka] Step 1: tert-Butyl 4-(piperazin-1-ylmethyl)piperidine-1-carbohydrate Xylate In a 100 ml round-bottom flask, add tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. carboxilate (1.0 g, 3.59 mmol), piperazine (3.1 g, 31.95 mmol) mol) and ACN (20 ml) were added. The RM was stirred at 80°C for 16 h. The solution was concentrated and the residue was loaded onto a silica gel column eluting with MeOH in DCM (0-10%). Purification by chromatography gave the title compound as a solid (400 mg). Method G:Rt=1.56min;MSm / z[M+H] + 284.

[0340] Step 2: tert-Butyl 4-((4-(4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazin-1-yl )Methyl)piperidine-1-carboxylate In a 25 ml round-bottom flask, add tert-butyl 4-(piperazin-1-ylmethyl)piperazine. Zn-1-carboxylate (400 mg, 1.41 mmol), K2CO3 (585 m g, 4.23 mmol) and DMSO (5 ml) were added and the RM was incubated at RT for 30 min. The mixture was stirred. ZnCl2 (1.0 M) in THF (1.55 ml, 1.55 mmol) and and 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyridinyl)phenyl)- (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 3, 743 mg, 1.41 mmol) The RM was stirred at RT for 30 min to give solid NaBHCN (266 mg, 4. 23 mmol) and MeOH (5 ml) were added and the RM was stirred at RT for 16 h. The mixture was concentrated and the residue was diluted with ACN (aq. solution of ammonium bicarbonate (10 mM) Agela C18 column (spherical 20-35 μm, 100 Å, 120 g) eluted with Purification by chromatography gave the title compound as a solid (500 mg). Method G:Rt=2.44min;MSm / z[M+H]+ 794.

[0341] Step 3: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-( Piperidin-4-ylmethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrro 2-hydroxypropane-4-yl-[2,3-d]pyrimidin-4-yl)phenyl 2-yl)benzamide hydrochloride In a 25 ml round-bottom flask, tert-butyl 4-((4-(4-(4 -(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzyl)benzyl) (2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl benzyl)piperazin-1-yl)methyl)piperidine-1-carboxylate(1 50 mg, 0.19 mmol) was added. A solution of HCl (4 M) in 1,4-dioxane (3 The RM was stirred at RT for 3 h to give a concentrated solution. The residue was concentrated and used directly in the next step without further purification. Obtained as a salt (138 mg). Method G:Rt=1.98min;MSm / z[M+H] + 694.

[0342] Step 4: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydrochloride (4-methoxybenzoyl)piperidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) Methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyridine 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... Hydroxypropan-2-yl)benzamide In a 25 ml round-bottom flask, add 2-fluoro-N-(5-fluoro-2-methyl-3-(6- (4-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)phenyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxy (2-hydroxypropan-2-yl)benzamide hydrochloride (138 mg, 0.19 mmol) l), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-meth Dibenzoic acid (intermediate 5, 55 mg, 0.21 mmol), DIPEA (123 mg, 0 0.95 mmol) and DMF (3 ml) were added. Then, HATU (86 mg, 0.23 (mmol) was added and the RM was stirred at RT for 2 h. The mixture was concentrated to give a residue XBridge eluted with ACN (aq. solution of ammonium bicarbonate (10 mM)) The samples were purified by preparative HPLC using a C18 column (21.2 × 250 mm, 10 μm) and analyzed by the following method. The title compound was obtained as a solid (65 mg). Method J:Rt=1.76min;MSm / z[M+H] + 940. 1 H NMR(500MHz,DMSO-d6)δ12.77(s,1H),10.34 (s,1H),9.96(s,1H),8.84(s,1H),7.94(d,J=8. 2Hz,2H),7.81-7.58(m,2H),7.46-7.33(m,5H), 7.31(d,J=2.1Hz,1H),7.24(dd,J=8.8,2.7Hz,1 H),7.15(dd,J=8.6Hz,2.6Hz,1H),6.83(s,1H), 5.31(s,1H),3.84(s,3H),3.59(t,J=6.6Hz,2H) ,3.49(s,2H),3.20-2.70(m,4H),2.68(m,2H),2 .48-2.36(m,8H),2.22-2.10(m,5H),1.82-1.61 (m,3H), 1.45(s,6H), 1.04(m,2H).

[0343] Compound 8: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyridine (2H)-diphenyl-4-methoxybenzoyl)piperidin-4-yl)oxy Piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide [ka] Step 1: tert-Butyl 4-(1-(4-(4-(5-fluoro-3-(2-fluoro) -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-Pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperidin-4-yl (oxy)piperidine-1-carboxylate In a 100 ml round-bottom flask, add 2-fluoro-N-(5-fluoro-3-(6-(4-chloro-N-methyl ... (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 3, 4.35 g, 8.26 mmol) and tert-butyl 4-(piperidin-4-yloxy)piperidine Lysine-1-carboxylate (Intermediate 10, 2.35 g, 9.09 mmol) and DM SO (30 ml) was added. ZnCl2 (1 M) in THF (9.1 ml, 9.1 mm Solid NaBH3CN (1.5 mol) was added and the mixture was stirred at RT for 45 min. 6g, 24.8mmol) was added and the mixture was stirred at RT for 30 min. (20 ml) was added and stirring was continued for 16 h. The mixture was concentrated and the residue was diluted with ACN ( Agela C18 column eluted with ammonium bicarbonate (10 mM in aq. solution) (Spherical size 20-35 μm, 100 Å, 120 g) Purified by chromatography The compound was obtained as a solid (4.0 g). Method E: Rt=1.58min;MSm / z[M+H] + 795.

[0344] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-( Piperidin-4-yloxy)piperidin-1-yl)methyl)phenyl)-7H-pyrro 2-hydroxypropane-4-yl-[2,3-d]pyrimidin-4-yl)phenyl 2-yl)benzamide In a 50 ml round-bottom flask, add tert-butyl 4-(1-(4-(4-(5-fluoro-3 -(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (ethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperidine (4.5g, 5.66mmol)piperidine-1-carboxylate HCl (4M l), 1,4-dioxane (20 ml) and MeOH (2 ml) were added. A solution of 1,4-dioxane (4 ml, 16 mmol) of 1,4-dioxane (4 ml, 16 mmol) was slowly added. The mixture was heated at RT The mixture was stirred at rt for 1 h and then concentrated to give the title compound as a solid HCl salt (5.0 g). This material was used in the next step without further purification. Method F:Rt=1.27min;MSm / z[M+H] + 695.

[0345] Step 3: N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yloxy (B)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (2-hydroxypropan-2-yl)benzamide In a 100 ml round-bottom flask, add 3-(2,4-dioxotetrahydropyrimidine-1(2H) )-yl)-4-methoxybenzoic acid (Intermediate 5, 1.6 g, 6.23 mmol), DMF (25 ml) and HATU (2.58 g, 6.79 mmol) were added. The mixture was stirred for 0.5 h. 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-( 4-((4-(piperidin-4-yloxy)piperidin-1-yl)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydro (2-xypropan-2-yl)benzamide hydrochloride (5 g, 6.84 mmol) and DIPEA (2.19 g, 16.98 mmol) was added and the mixture was stirred at RT for 3 h. The mixture was stirred and eluted with ACN (aq. solution of ammonium bicarbonate (10 mM)). Agela C18 column (spherical 20-35 μm, 100 Å, 120 g) for chromatography Purification by chromatography gave the title compound as a solid (4.17g). Method J:Rt=1.78min;MSm / z[M+H] + 941. 1 H NMR(500MHz,DMSO-d6)δ12.77(s,1H),10.34 (s,1H),9.95(s,1H),8.85(s,1H),7.94(d,J=7. 5Hz,2H),7.73(t,J=7.9Hz,1H),7.66(d,J=9.1H z,1H),7.47-7.31(m,6H),7.24(dd,J=8.8,2.7H z,1H),7.15(d,J=8.6Hz,1H),6.83(s,1H),5.31 (s,1H),3.84(s,3H),3.74-3.38(m,8H),3.20(t ,J=9.7Hz,2H),2.68-2.57(m,4H),2.18(s,3H), 2.18-2.05(m,2H),1.84-1.74(m,4H),1.49-1.4 0(m,10H).

[0346] Compound 9: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecanoate (3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl)- (pan-2-yl)benzamide [ka] N-(3-(6-(4-(3,9-diazaspiro[5.5]undecane-3-ylmethyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro- 2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzene amide (Intermediate 11, 50 mg, 0.068 mmol), 3-(2,4-dioxotetyl) (17.9)-4-methoxybenzoic acid (Intermediate 5, 17.9) 1 mg, 0.068 mmol) and HBTU (30.8 mg, 0.081 mmol) D To the MF solution (3 ml) was added DIPEA (0.071 ml, 0.407 mmol). M was stirred under argon at RT for 2 h, water was added and the resulting suspension was filtered. The solid was filtered, washed with water, dried, and dissolved in MeOH (in CO2) (30-45%). Princeton PPU column (250 x 30 mm, 100 Å, 5 μm) Purification by HPLC gave the title compound (15 mg). Method B: Rt=3.67min,[M+H] + =911.6. 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),10.31 (s,1H),9.93(d,J=2.6Hz,1H),8.85(s,1H),7.9 4(d,J=8.2Hz,2H),7.74(t,J=7.9Hz,1H),7.66( m,1H),7.47-7.34(m,5H),7.32(d,J=2.1Hz,1H) ,7.24(dd,J=8.8,2.8Hz,1H),7.15(d,J=8.6Hz, 1H),6.82(s,1H),5.29(s,1H),3.85(s,3H),3.6 0(t,J=6.6Hz,2H),3.55-3.25(m,6H),2.68(t,J =6.4Hz,2H),2.42-2.28(m,4H),2.18(s,3H),1. 6-1.35(m,8H),1.46(s,6H).

[0347] Compound 10: N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydropyridine Rimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxy )piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro (2-xypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-((1-(4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)piperidin-4-yl (aryl)oxy)piperidine-1-carboxylate 4-(4-(5) in a mixture of ACN and DMF (4:1) at RT flushed with N -Fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzal (2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl Ethyl methanesulfonate (Intermediate 13, 334 mg, 0.538 mmol) and te rt-Butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate ( A mixture (13.5 ml) of intermediate 10 (306 mg, 1.076 mmol) and K2CO3 (446 mg, 3.23 mmol) was added. The resulting RM was heated at 50° C. for 3 The RM was cooled in an ice-water bath under stirring until the mixture reached a pH of 3-4. The resulting mixture was allowed to warm to RT and partially and adsorbed onto Isolute® and dissolved in ACN (aq. solution of TFA). Redisep® C18 column reversed-phase chromatograph eluted with 0.1% ethanol (in 0.1%). Purification by filtration gave the title compound as a TFA salt (225 mg). Method A: Rt=0.99min;[M+H]+ =809.6.

[0348] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(2-(4 -(piperidin-4-yloxy)piperidin-1-yl)ethyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropanediol) (2-phenyl)benzamide tert-Butyl 4-((1-(4-(4-(5-fluoro-3-(2-fluoro- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)piperidin-4-yl ((223 mg, 0.194 mmol) of 1-( ... To the DCM solution (3.7 ml) was added TFA (0.447 ml, 5.81 mmol). The resulting solution was stirred at RT for 1 h and diluted with a mixture of DCM and ACN. The resin was redissolved in a mixture of ACN and water to give a resin. Lyophilization gave the title compound as a solid TFA salt (225 mg). Method A: Rt=0.67min;[M+H] + =709.5.

[0349] Step 3: N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetramethyl) Hydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl )oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pi rimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 (hydroxypropan-2-yl)benzamide N2 flushed 2-fluoro-N-(5-fluoro-2-methyl-3-(6-( 4-(2-(4-(piperidin-4-yloxy)piperidin-1-yl)ethyl)phenyl (2-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-phenyl (hydroxypropan-2-yl)benzamide (120 mg, 0.114 mmol), 3- (2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid (Intermediate 8, 29.8 mg, 0.120 mmol) and HBTU (46.4 mg, 0.1 20 mmol) in dry DMF (2.25 ml) was added to DIPEA (140 μl, 0.7 99 mmol) was slowly added. The resulting solution was stirred at RT for 1.5 h. It was then diluted with ACN and adsorbed onto Isolute® to obtain a TF Elute with Redisep (registered trademark) in an aq. solution of A (0.1%) (10-100%). Purified by reversed-phase chromatography on a C18 column, PL-HCO3MP SP After filtration and lyophilization of the fractions containing the pure target compound through E cartridges, the The mixture was obtained as a solid (66 mg). Method B: Rt=3.85min;[M+H] + =939.6. 1 H NMR(400MHz,DMSO-d6)δ12.70(s,1H),10.36 (s,1H),9.91(s,1H),8.76(s,1H),7.89(d,J=8. 07Hz,2H),7.73(t,J=7.89Hz,1H),7.63(d,J=9. 05Hz,1H),7.37-7.46(m,2H),7.31-7.36(m,2H) ,7.16-7.31(m,4H),6.73(s,1H),5.29(s,1H),3 .96(m,1H),3.81(m,1H),3.68(m,1H),3.38-3.5 9(m,3H),3.20(m,2H),2.69-2.83(m,6H),2.52- 2.55(m,2H),2.21(s,3H),2.17(s,3H),2.11(t, J=10.15Hz,2H),1.62-1.94(m,4H),1.32-1.51( m,10H).

[0350] Compound 11: N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]urethane 7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide [ka] Step 1: 3-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl) (phenyl)propan-1-ol 4-(3-hydroxypropyl)benzeneboronic acid (2.511 g, 13.95 mmol) l) and 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.44 g , 12.31 mmol) was dissolved in 1-propanol (100 ml) at RT To the mixture was added an aq. solution of Na2CO3 (2M) (13.54 ml, 27.1 mmol). Argon was bubbled through the mixture for 5 min to obtain PdCl2(PPh3)2 (0.432 g, The RM was stirred at 105 °C for 22 h and then cooled to RT. The solvent was removed and the residue was sonicated in a mixture of water and THF (3:2). The mixture was filtered, the solid was washed with water and dried to give the title compound as a solid (2. 4g). Method A: Rt=0.86min;[M+H] + =288.2.

[0351] Step 2: 2-Fluoro-N-(5-fluoro-3-(6-(4-(3-hydroxypropyl) (phenyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl (2-hydroxypropan-2-yl)benzamide 3-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl (5-fluoro-N-(2-fluoro-N-methyl ... -fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa (Borolan-2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzal Dissolve the intermediate (Intermediate 2, 2.1 g, 4.87 mmol) in 1-propanol (36 ml) in R The mixture was suspended in 100 ml of an aq. solution of Na2CO3 (2 M) (5.1 ml, 10.20 ml mol) was added. Argon was bubbled through the mixture for 1 minute to give PdCl2(PPh3) 2 (0.180 g, 0.256 mmol) was added. RM was converted to 1 using microwave irradiation. Heated at 40° C. for 20 min. The RM was diluted with EtOAc and added to Hyflo® The filtrate was evaporated and rediluted with a mixture of THF and H2O (1:1) to give Extraction with EtOAc was performed. The combined organic phases were dried over MgSO4 and evaporated. The residue was triturated in a mixture of DCM and MeOH, filtered and the solid was washed with DCM. and dried to give the title compound as a solid (1.696 g). Method A: Rt=0.95min;[M+H] + =557.4.

[0352] Step 3: 3-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)phenyl)propyl methanesulfonate 2-Fluoro-N-(5-fluoro-3-(6-(4-(3-hydroxypropyl) (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl -4-(2-hydroxypropan-2-yl)benzamide (1032 mg, 1.539 (mmol) was dissolved in dry THF (16 ml) under argon at RT to give TEA (0.858 ml, 6.16 mmol) was added. The mixture was cooled to 0°C and MsO( 536 mg, 3.08 mmol) was added and the RM was stirred at 0° C. for 40 minutes. The mixture was quenched with ice water, extracted with DCM, and the combined organic phases were dried over MgSO4. The mixture was evaporated and concentrated to give the title compound as a solid (1.33 g). Method A: Rt=1.03min;[M+H] + =635.3.

[0353] Step 4: tert-Butyl 9-(3-(4-(4-(5-fluoro-3-(2-fluoro) -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-Pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)propyl)-3,9-di Azaspiro[5.5]undecane-3-carboxylate 3-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropanediol) (2-methylphenyl)-7H-pyrrolo[2,3-d]piperidin-2-ylbenzamido (Irimidin-6-yl)phenyl)propyl methanesulfonate (0.977g, 1.53 9 mmol) in a mixture of dry DMF (4 ml) and ACN (16 ml) under argon. K2CO3 (1.063 g, 7.70 mmol) and 3,9- Diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0. The RM was stirred at 60°C for 13.5 hours. The combined solution was evaporated to dryness and the resulting residue was taken up in a mixture of EtOAc and water. The phases were separated. The aq. layer was extracted with EtOAc and the combined organic phases were washed with lithium bromide. aq. solution, a mixture of brine and water (1:1), and washed with brine, followed by MgSO 4, concentrated and dried to give the title compound as a solid (1.76 g) . Method A: Rt=1.00min;[M+H] + =793.5.

[0354] Step 5: N-(3-(6-(4-(3-(3,9-diazaspiro[5.5]undecane- 3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-yl)benzamide tert-Butyl 9-(3-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)propyl)-3,9-diaza Pyro[5.5]undecane-3-carboxylate (1.545 g, 1.539 mmol) A solution of 3) in DCM (10 ml) and TFA (4 ml, 51.9 mmol) was stirred at RT. The mixture was stirred for 10 minutes, evaporated, and adsorbed onto Isolute® HM-N. Red eluted with ACN (aq. solution of TFA (0.1%)) (5-100%) Purification by reverse phase chromatography on an isep® C18 column gave the title compound was obtained as a solid TFA salt (1.337 g). Method A: Rt=0.75min;[M+H] + =693.5.

[0355] Step 6: N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyridine) Rimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5 .5]undecan-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrrol 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... Hydroxypropan-2-yl)benzamide N-(3-(6-(4-(3-(3,9-diazaspiro[5.5]undecane-3-yl) (phenyl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5- Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2- Dry (200 mg, 0.193 mmol) benzamide trifluoroacetate DIPEA (0.270 ml) was dissolved in DMF (3 ml) under argon at RT. l, 1.546 mmol) and 3-(2,4-dioxotetrahydropyrimidine-1(2 followed by (H)-yl)-4-methoxybenzoic acid (Intermediate 5, 58 mg, 0.220 mmol). HBTU (86 mg, 0.227 mmol) was added to the RM. The RM was stirred at RT for 20 min. Stir, dilute with ACN, adsorb onto Isolute® HM-N and dry Elute with ACN (aq. solution of TFA (0.1%)) (5-100%). The compound was purified by reversed phase chromatography on a disep® C18 column. Obtained as the TFA salt. Freezing followed by filtration through a PL-HCO3 MP SPE cartridge. Drying gave the title compound as a solid TFA salt (100 mg). 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),10.33 (s,1H),9.95(s,1H),9.0-9.25(m,1H),8.85(s, 1H),7.95(d,J=8.1Hz,2H),7.73(t,J=7.9Hz,1H ),7.65(d,J=10.0Hz,1H),7.48-7.28(m,6H),7. 25-7.21(m,1H),7.16(d,J=8.6Hz,1H),6.84(s, 1H),5.30(s,1H),3.84(s,3H),3.6-3.3(m,7H), 3.2-2.9(m,4H),2.75-2.6(m,4H),2.17(s,3H), 2.1-1.9(m,2H),1.9-1.8(m,2H),1.7-1.25(m,1 2H). Method B: Rt=3.91min[M+H] + =939.7.

[0356] Compound 12: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5- Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2- Il)benzamide [ka] Step 1: tert-Butyl 9-(4-bromophenethyl)-3,9-diazaspiro[5. 5]Undecane-3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 3,9-diazasol in ACN (50 ml). Pyro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol), K2C O3 (4.07 g, 29.5 mmol) and 1-bromo-4-(2-bromoethyl)benzoate Zene (5.2 g, 17.6 mmol) was added. The RM was stirred under N2 at RT for 16 h. The mixture was concentrated and rediluted in a mixture of water and DCM. The phases were separated and the aq. phase was diluted with DCM. The combined organic phases were concentrated and extracted with MeOH in DCM (1:100). Purification by silica gel chromatography eluting with hexane gave the title compound as a solid (4.8 g). was obtained as. Method F:Rt=1.91min;MSm / z[M+H] + 438.1.

[0357] Step 2: tert-Butyl 9-(4-(4,4,5,5-tetramethyl-1,3,2-diphenyl ether) Oxaborolan-2-yl)phenethyl)-3,9-diazaspiro[5.5]undecane -3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 9-(4-bromophenethyl)-3,9- Diazaspiro[5.5]undecane-3-carboxylate (4.8 g, 11 mmol) , BISPIN (3.4g, 13.2mmol), KOAc (2.2g, 22mmol) Add PdCl2(dppf) (0.8 g, 1.1 mmol) and DMSO (60 ml). The RM was stirred at 80°C for 16 h, diluted with water, and extracted with EtOAc. The combined organic phase was washed with water and brine, concentrated and diluted with EtOAc (petroleum ether ) (0-100%) to give the title compound. The product was obtained as a solid (4.0 g). Method E: Rt=1.67min;MSm / z[M+H] + 485.

[0358] Step 3: tert-Butyl 9-(4-(4-chloro-7-(phenylsulfonyl)-7H) -pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[ 5.5]Undecane-3-carboxylate In a 25 ml round-bottom flask, add tert-butyl 9-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenethyl)-3,9-diazaspiro[5 .5]undecane-3-carboxylate (889 mg, 1.83 mmol), 4-chloro 6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 7, 700 mg, 1.67 mmol), Na2CO3 (354 mg, 3.34 m mol) and PdCl(dppf) (124 mg, 0.17 mmol) were added. N (10 ml) and water (2 ml) were added and the RM was stirred under N at 80 °C for 16 h. The RM was diluted with EtOAc, filtered, and the filtrate was concentrated to give EtOAc (petroleum ether). Purification was performed by silica gel chromatography eluting with 0 to 100% ethanol (in a 100% aqueous solution). The compound was obtained as an oil (600 mg). Method F:Rt=1.85min;MSm / z[M+H] + 650.

[0359] Step 4: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-( Phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl )-3,9-diazaspiro[5.5]undecane-3-carboxylate In a 25 ml round-bottom flask, add tert-butyl 9-(4-(4-chloro-7-phenyl)sulfonyl) (7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9 -Diazaspiro[5.5]undecane-3-carboxylate (400 mg, 0.62 m mol), 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetrafluoroethane) tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydro (xypropan-2-yl)benzamide (Intermediate 2, 265 mg, 0.62 mmol), Na2CO3 (130 mg, 1.23 mmol) and PdCl2(dppf) (44 mg ACN (10 ml) and water (2 ml) were added to the RM. Stirred under N2 at 80 °C for 16 h. The RM was diluted with EtOAc and filtered, and the filtrate The mixture was concentrated and purified by silica gel chromatography eluting with EtOAc in petroleum ether (0-100%). Purification by chromatography gave the title compound as a solid (200 mg). Method E:Rt=1.74min;MSm / z[M+H] + 919.

[0360] Step 5: tert-Butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9-diazaspiro[5 .5]undecane-3-carboxylate In a 10 ml round-bottom flask, add tert-butyl 9-(4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6- (yl)phenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate The solution was added with 200 mg of dimethylformamide (0.22 mmol) and 2 ml of DMSO. A solution of 1 mg of 1H 2 O in water (1 ml) was added at RT and the RM was stirred for 1 h. It was then diluted with EtOAc, the phases were separated and the organic phase was washed with water and brine and dried. Drying and concentration gave the title compound as a solid (170 mg). Method E: Rt=1.64min;MSm / z[M+H] + 779.

[0361] Step 6: N-(3-(6-(4-(2-(3,9-diazaspiro[5.5]undecane- 3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide In a 10 ml round-bottom flask, add tert-butyl 9-(4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3,9- Diazaspiro[5.5]undecane-3-carboxylate (160 mg, 0.21 mm ol), EtOH (2 ml) and DCM (0.5 ml) were added. A solution of 4-dioxane (1.5 ml, 6 mmol) was added at 0°C and the RM was warmed to RT. The RM was concentrated to give the title compound as a solid HCl salt (130 mg). And got it. Method E: Rt=1.45min;MSm / z[M+H] + 679.

[0362] Step 7: 3-(2-carboxyethylamino)benzoic acid In a 500 ml round-bottom flask, add 3-aminobenzoic acid (10 g, 72.92 mmol), Add acrylic acid (6.83 g, 94.79 mmol) and toluene (200 ml) to RM The mixture was stirred at 120°C for 48 h, cooled to RT and filtered. The solid was washed with toluene. After stirring and drying, the title compound was obtained as a solid (14.0 g). Method D: Rt=1.19min;MSm / z[M+H] + 210.

[0363] Step 8: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid In a 50 ml round-bottom flask, add 3-(2-carboxyethylamino)benzoic acid (2 g, 9.5 6mmol), AcOH (25ml) and urea (1.72g, 28.68mmol) were added. The RM was then stirred at 120°C for 16 h. The solvent was evaporated and water (20 ml) was added. The mixture was then filtered, and the solid was washed with water and dried to give a solid. The mixture was stirred at RT for 2 h, filtered, and the solid was washed with water. and dried to give the title compound as a solid (800 mg). Method D: Rt=1.13min;MSm / z[M+H] + 235. 1 H NMR(500MHz,DMSO-d6)δ13.12(s,1H),10.46 (s,1H),7.89(s,1H),7.80(d,J=7.6Hz,1H),7.5 9(d,J=8.6Hz,1H),7.53(t,J=7.8Hz,1H),3.84( t,J=6.6Hz,2H),2.73(t,J=6.6Hz,2H).

[0364] Step 9: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyridine) Rimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undeca (phenyl-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-phenyl)benzamide N-(3-(6-(4-(2-(3,9-diazaspiro[5.5]undecane-3-yl) (phenyl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-phenyl (fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2-yl) (2,4-dioxotetyl)benzamide (137 mg, 0.182 mmol) of 1(2H)-hydroxypyrimidin-1(2H)-yl)benzoic acid (43 mg, 0.182 mmol) DIPEA (141 mg, 1.09 mmol) and HATU (73 mg, 0.191 mmol) were added at 5°C. The RM was stirred at 25°C for 1 h, filtered, and the filtrate was concentrated and diluted with ACN (hydrogen carbonate). XBridge C18 column (eluted with ammonium hydroxide solution (10 mM) The title compound was purified by preparative HPLC (250 x 21.2 mm, 10 μm) to give the solid ( 50 mg). Method G:Rt=2.003min,MSm / z[M+H] + 895. 1 H NMR(500MHz,DMSO-d6)δ12.72(s,1H),10.42 (s,1H),9.94(s,1H),8.83(s,1H),7.89(d,J=8. 1Hz,2H),7.73(t,J=7.6Hz,1H),7.65(d,J=10.7 Hz,1H),7.50-7.35(m,5H),7.31(d,J=8.2Hz,2H ),7.25-7.20(m,2H),6.79(s,1H),5.30(s,1H), 3.82(t,J=6.7Hz,2H),3.65-3.50(m,2H),2.76( t,J=7.6Hz,2H),2.71(t,J=6.6Hz,2H),2.60-2. 50(m,2H),2.45-2.35(m,6H),2.17(s,3H),1.55 -1.45(m,6H),1.45(s,6H),1.40-1.30(m,2H).

[0365] Compound 13: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydro pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-((4-(4-(5-fluoro-3-(2-fluoro-4 -(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H -pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)oxy)piperidine-1-carboxylate Ruboxylate tert-Butyl 4-((4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine (6-yl)benzyl)oxy)piperidine-1-carboxylate (Intermediate 14, 56 0 mg, 1.264 mmol), 2-fluoro-N-(5-fluoro-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )-4-(2-hydroxypropan-2-yl)benzamide (Intermediate 2, 709 mg, 1.0644 mmol) and a solution of Na2CO3 (2 M) in 1-propanol (10 ml) q. A mixture of PdCl2(PPh3)2(8 The resulting RM was heated to 100°C for 1 hour using microwave irradiation. The mixture was filtered through Hyflo® and heated at 140° C. for 15 minutes. The filtrate was concentrated and purified by silica chromatography eluting with EtOAc in CHX (0-95%). Purification by filtration gave the title compound as a solid (526 mg). Method A: Rt=1.29min;[M+H] + =712.5.

[0366] Step 2: 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((piperidinyl) (4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide tert-Butyl 4-((4-(4-(5-fluoro-3-(2-fluoro-4-(2 -hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyro 2,3-d]pyrimidin-6-yl)benzyl)oxy)piperidine-1-carboxylate The sylate (526 mg, 0.739 mmol) was dissolved in dry DCM (4 ml) TFA (1.708 ml, 22.17 mmol) was added and the resulting mixture was stirred at RT The mixture was stirred at T for 2 h. The RM was evaporated to dryness to give the title compound as the TFA salt and as an oil. The obtained product was (536 mg). Method A: Rt=0.79min;[M+H] + =612.5.

[0367] Step 3: tert-Butyl 4-(2-(4-((4-(4-(5-fluoro-3-(2- Fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphen (7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)oxy)piperidin Di-1-yl)ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((piperidine- 4-yloxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (phenyl)-4-(2-hydroxypropan-2-yl)benzamide (536 mg , 0.739 mmol), tert-butyl(2-oxoethyl)carbamate (201 mg, 0.886 mmol) and TEA (0.309 ml, 2.216 mmol) The OH mixture (5 ml) was mixed with ZnCl2 (0.5 M) in THF (1.625 ml, 0.8 12 mmol) was added and the RM was stirred under argon at RT for 3 h. 3CN (20.06 mg, 0.319 mmol) was added and the RM was stirred at RT overnight. The RM was diluted with EtOAc and the aq. phase was washed with an aq. solution of NaHCO3 and brine. The organic phase was dried over MgSO4 and absorbed onto Isolute® Allow to dry and elute with ACN (aq. solution of TFA (0.1%)). The title compound was purified by reverse phase chromatography on a ep® C18 column. The compound was obtained as a TFA salt (400 mg). Method B: Rt=4.90min;[M+H] + =823.6.

[0368] Step 4: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(((1- (2-(piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phen (2-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-phenyl Hydroxypropan-2-ylbenzamide tert-Butyl 4-(2-(4-((4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)oxy)piperidine- 1-yl)ethyl)piperidine-1-carboxylate (400 mg, 0.427 mmol) A solution of 1) in DCM (10 ml) and TFA (0.987 ml, 12.81 mmol) was The mixture was stirred under argon at RT for 2 h. The RM was concentrated to give the title compound as a solid TFA salt (5 00mg). Method A: Rt=0.70min;[M+H] + =723.6.

[0369] Step 5: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetate (1(2H)-yl)-4-methoxybenzoyl)piperidine-4- yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro 4-(2-hydroxypropan-2-yl)benzamide 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(((1-(2- (Piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxy Cypropan-2-yl)benzamide trifluoroacetate (120 mg, 0.102 mmol), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4 -methoxybenzoic acid (Intermediate 5, 27.0 mg, 0.102 mmol) and HBTU (4 A solution of 6.5 mg of DIPEA (0.107 mmol) in DMF (3 ml) was added. Water (1, 0.613 mmol) was added and the RM was stirred under argon at RT for 2 h. The resulting white precipitate was filtered, washed with water, dried and Reprospher PEI column (2) eluted with 22-55% OH (in CO2). 50 × 30 mm, 100 Å, 5 μm) purified by SFC and then diluted with ACN (a XBridge C18 OBD eluted with 18-48% q. solution (0.1%) Purification was performed by reverse-phase HPLC on a column (100 × 30 mm, 5 μm) to obtain PL-HCO3 After filtration through an MP SPE cartridge and lyophilization, the title compound was obtained as a solid (35.9 mg ) was obtained. Method B: Rt=4.11min;[M+H] + =970.5. 1 H NMR(400MHz,DMSO-d6)δ12.73(s,1H),10.35 (s,1H),9.95(s,1H),8.79(s,1H),7.98(d,J=8. 0Hz,2H),7.80-7.56(m,2H),7.52-7.12(m,9H), 6.79(s,1H),5.32(s,1H),4.54(s,2H),4.35(m, 1H),3.85(s,3H),3.61(t,J=6.7Hz,2H),3.10-2 .60(m,6H),2.28(t,J=7.4Hz,2H),2.19(s,3H), 2.02(t,J=10.6Hz,2H),1.95-1.82(m,2H),1.69 (m,2H),1.47(m,10H),1.39(m,2H),1.10(m,2H) .

[0370] Compound 14: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-fluorobenzoyl)-3,9-diazaspiro[5.5]undecanoate (3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl)- (pan-2-yl)benzamide [ka] RT of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorouracil A solution of fluorobenzoic acid (Intermediate 9, 8.89 mg, 0.035 mmol) in DMA (0.5 ml) was treated with HATU (15.46 mg, 0.041 mmol) followed by DIPEA (0.0 47 ml, 0.271 mmol) was added. After 15 minutes, N-(3-(6-(4-(3,9 -diazaspiro[5.5]undecan-3-ylmethyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro 4-(2-hydroxypropan-2-yl)benzamide (Intermediate 6, 31 mg, 0 0.027 mmol) was added and the RM was stirred at RT overnight. The RM was diluted with EtOAc. The organic phase was washed with aqueous solutions of NaHCO3 and brine, and then evaporated over Na2SO4. Dry, concentrate, and dilute the 10-100% ACN in aq. solution of TFA (0.1%). The mixture was purified by reversed-phase HPLC on a Reprosil® C18 column eluted with 1000 kJ / ml. The fractions containing the pure compound were combined and basified with an aqueous solution of NaHCO3. The combined organic phases were dried over Na2SO4 and concentrated. The residue was dissolved in a mixture of water and ACN and lyophilized to give the title compound as a solid. (18.5 mg). Method B: Rt=3.64min;[M+H] + =899.8. 1 H NMR(600MHz,DMSO-d6)δ12.79(s,1H),10.55 (s,1H),9.98(s,1H),8.87(s,1H),8.08-7.90(m ,2H),7.74(t,J=7.8Hz,1H),7.67(d,J=10.9Hz, 1H),7.51(d,J=6.6Hz,1H),7.46-7.35(m,6H),7 .25(dd,J=8.7,2.6Hz,1H),6.85(br.s,1H),5.3 2(s,1H),3.76(t,J=6.6Hz,2H),3.67-3.44(m,4 H),3.42-3.32(m,2H),2.73(t,J=6.6Hz,2H),2. 55-2.51(m,2H),2.42-2.31(m,2H),2.18(s,3H) ,1.57-1.35(m,8H),1.46(s,6H).

[0371] Compound 15: N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydropyridine Rimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)pro Pyr)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxybenzoyl) Hydroxypropan-2-ylbenzamide [ka] Step 1: tert-Butyl 4-(3-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl (I)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1 -yl)propyl)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidine-4 -yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 16, 101m g, 0.142 mmol), TEA (0.060 ml, 0.430 mmol) and ter t-Butyl 4-(3-oxopropyl)piperidine-1-carboxylate (45 mg, 0.186 mmol) was dissolved in MeOH (1.5 ml) at RT. A 0.7 M solution of 2 in THF (0.250 ml, 0.175 mmol) was added to the RM. Stirred overnight at RT under argon. Solid NaBHCN (11 mg, 0.175 m mol) was added and the RM was stirred at RT overnight. The solvent was removed and the resulting The residue was used directly in the next step without further purification (134 mg). Method A: Rt=1.05min;[M+H] + =823.5.

[0372] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((1-( 3-(piperidin-4-yl)propyl)piperidin-4-yl)oxy)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxy (propan-2-yl)benzamide Crude tert-butyl 4-(3-(4-(4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl (propyl)piperidine-1-carboxylate (117 mg, 0.142 mmol) A solution of DCM (1.5 ml) and TFA (0.150 ml, 1.947 mmol) was heated at RT After stirring at RT for 2.5 h, the solvent was removed and the residue was dissolved in ACN (aq. solution of TFA ( 0.1%) in water (2-100%). The title compound was purified by phase chromatography to give the solid TFA salt (135 mg). Got it. Method A: Rt=0.72min;[M+H] + =723.6.

[0373] Step 3: N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetramethyl) Hydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl propyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy A solution of benzoic acid (Intermediate 5, 45 mg, 0.170 mmol) in DMF (1 ml) was added to NMM. (0.050 ml, 0.455 mmol) followed by HATU (65 mg, 0.170 mm The RM was stirred for 30 minutes, and then 2-fluoro-N-(5-fluoro-2- Methyl-3-(6-(4-((1-(3-(piperidin-4-yl)propyl)piperidinyl) (phenyl-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )phenyl)-4-(2-hydroxypropan-2-yl)benzamide trifluoroacetate acetate (0.142 mmol) and NMM (0.050 ml, 0.455 mmol). The DMF solution (0.5 ml) was added dropwise and the RM was stirred at RT for 2.5 h. Concentrate and dissolve in ACN (aq. solution of NH4HCO3 (0.1%)) (2-100%). Purified by reversed phase chromatography on a Redisep® C18 column. The title compound was obtained as a solid (93 mg). Method B: Rt=3.99min;[M+H] + =969.7. 1 H NMR(400MHz,DMSO-d6)δ12.64(s,1H),10.31 (s,1H),9.92(s,1H),8.80(s,1H),7.89(d,J=8. 3Hz,2H),7.72(t,J=7.9Hz,1H),7.68-7.57(m,1 H),7.47-7.26(m,4H),7.26-7.18(m,1H),7.13( d,J=8.5Hz,1H),7.02(d,J=8.4Hz,2H),6.70(s, 1H),5.29(s,1H),4.45(m,1H),3.82(s,3H),3.5 8(t,J=6.8Hz,2H),3.00-2.63(m,6H),2.21(m,7 H),1.93(m,2H),1.63(m,4H),1.44(m,10H),1.2 2(m,3H),1.15-0.97(m,2H).

[0374] Compound 16: N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydropyridin (2H)-imidine-4-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl (I)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate A stirred solution of oxalyl chloride in anhydrous DCM (10 ml) at -78 °C (0.380 ml, 4. DMSO (0.538 ml, 7.58 mmol) was added to the RM. After stirring for 1 min, 1-Boc-4-(2-hydroxyethyl) pyridine was dissolved in DCM (10 ml). Perazine (500 mg, 2.106 mmol) was added. The RM was incubated at -78°C for 30 minutes. After stirring for 1 hour, TEA (2.4 ml, 17.22 mmol) was added and stirring was continued for 1.5 hours. The RM was then warmed to RT. The RM was then cooled by adding a saturated aqueous solution of NaHCO3. The mixture was quenched with HCl and extracted with DCM. The combined organic phases were dried over Na2SO4. The residue was purified by elution with EtOAc and MeOH (4:1) in EtOAc. The title compound was purified by silica chromatography eluting with a mixture of 2,4-dimethyl-3,5-dichloro-2 ... The product was obtained as a solid (371 mg). 1 H NMR(400MHz,DMSO-d6)δ9.57(d,J=1.5Hz,1H ),3.31(dd,J=10.0,5.0Hz,4H),3.18(d,J=1.5H z,2H),2.38(t,J=5.1Hz,4H),1.38(s,9H).

[0375] Step 2: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazine-1- (yl)ethyl)piperazine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine-1 -ylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl (2-hydroxypropan-2-yl)benzamide hydrochloride (intermediate 17, 265mg, 0.384mmol), TEA (0.200ml, 1.435mmol) l) and tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate (96 mg, 0.399 mmol) was dissolved in MeOH (2 ml) at RT. Add ZnCl2 (0.5 M) in THF (0.850 ml, 0.425 mmol) The RM was stirred at RT for 7 h. Solid NaBH3CN (27 mg, 0.430 mmol) was added. l) was added and the RM was stirred at RT overnight, concentrated and the residue was diluted with ACN (TFA Redisep® C18 column reversed phase eluted with an aq. solution (0.1%) of Purification by chromatography gave the title compound as a solid TFA salt (259 mg). Ta. Method D: Rt=0.58min;[M+H] + =809.6.

[0376] Step 3: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-( 2-(piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropyl propan-2-ylbenzamide tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazin-1-yl) Ethyl)piperazine-1-carboxylate (259 mg, 0.109 mmol) OH solution (2 ml) in 1,4-dioxane solution (2 ml, 8.00 mm) of HCl (4 M) ol) was added and the RM was stirred at RT for 1 h, concentrated and the residue was diluted with ACN (TF Elute with Redisep (registered trademark) (2-100%) in an aq. solution of A (0.1%). ) C18 column reverse phase chromatography to give the title compound as a solid TFA salt (9 1 mg). Method A: Rt=0.65min;[M+H] + =709.6.

[0377] Step 4: N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetramethyl) Hydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl (ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Benzoic acid (Intermediate 5, 20 mg, 0.074 mmol) was dissolved in DMF (0.5 ml) at RT NMM (0.050 ml, 0.455 mmol) and HATU (3 0 mg, 0.077 mmol) was added and the RM was stirred at RT for 30 min. Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-(2-piperazine) (phenyl-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropane-2-yl) (I)benzamide trifluoroacetate (91 mg, 0.059 mmol) and NMM (0.050 ml, 0.455 mmol) in DMF (0.5 ml) was added dropwise to The mixture was stirred at RT for 2.5 h. The mixture was concentrated and diluted with ACN (aq. solution of TFA (0 Redisep® C18 column reversed phase eluted with (2-100%) 0.1% Purified by chromatography and purified by PL-HCO3 MP SPE cartridges Torus 2P filtered, lyophilized, and eluted with MeOH (in CO2) (22-52%) After further purification by SFC on an IC column (250 × 30 mm, 130 Å, 5 μm), the title The compound was obtained as a solid (34 mg). Method B: Rt=3.07min;[M+H] + =955.5. 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),10.31 (s,1H),9.92(s,1H),8.83(s,1H),7.92(m,2H), 7.68(m,2H),7.36(m,6H),7.19(m,2H),6.81(s, 1H),5.28(s,1H),3.82(s,3H),3.75-2.85(m,14 H),2.64(m,8H),2.16(m,6H),1.44(m,6H).

[0378] Compound 17: N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydropyridine (Irimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl (I)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazine-1- yl)ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperazine-1 -ylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl (2-hydroxypropan-2-yl)benzamide trifluoroacetate (Intermediate 18, 200 mg, 0.228 mmol), TEA (0.100 ml, 0.71 7 mmol) and N-Boc-4-piperidineacetaldehyde (70 mg, 0.293 ZnCl (0.7 M) was dissolved in MeOH (2 ml) at RT. A THF solution (0.370 ml, 0.259 mmol) of The mixture was stirred at RT for 5 h. Solid NaBH3CN (16 mg, 0.255 mmol) was added. The RM was stirred at RT overnight, the solvent was removed, and the residue was dissolved in ACN (a Redisep® C1 eluted in 2-100% q. solution (0.1%) The title compound was purified by 8-column reverse phase chromatography to give the solid TFA salt (236m g). Method A: Rt=0.96min;[M+H] + =808.5.

[0379] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-( 2-(Piperidin-4-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropyl propan-2-ylbenzamide tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazin-1-yl) Ethyl)piperidine-1-carboxylate (230 mg, 0.249 mmol) OH solution (2 ml) and HCl (4 M) in 1,4-dioxane (1.5 ml, 6.00 (mmol) was added and the RM was stirred at RT for 2 h. The RM was concentrated to give the title compound. Obtained as a solid HCl salt (234 mg). Method A: Rt=0.68min;[M+H] + =708.5.

[0380] Step 3: N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetramethyl) Hydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl (ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Benzoic acid (Intermediate 5, 41 mg, 0.155 mmol) was dissolved in DMF (1 ml). NMM (0.050 ml, 0.455 mmol) and HATU (58 mg, 0.15 3 mmol) was added and the RM was stirred at RT for 30 min. -fluoro-2-methyl-3-(6-(4-((4-(2-(piperidin-4-yl)ethyl) (methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (2-hydroxypropan-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide Hydrochloride (100 mg, 0.122 mmol) and NMM (0.050 ml, 0. A solution of 455 mmol) in DMF (0.5 ml) was added dropwise and the RM was stirred at RT overnight. The mixture was concentrated and eluted with ACN (aq. solution of NH4HCO3 (0.1%)). The product was purified by reversed phase chromatography on a Redisep® C18 column. The title compound was obtained as a solid (78 mg). Method B: Rt=3.77min;[M+H] + =954.5. 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),10.32 (s,1H),9.94(s,1H),8.85(s,1H),7.94(d,J=7. 6Hz,2H),7.82-7.60(m,2H),7.53-7.06(m,8H), 6.83(s,1H),5.30(s,1H),3.83(s,3H),3.53(m, 4H),3.00-2.3(m,16H),2.17(s,3H),1.91-0.91 (m,13H).

[0381] Compound 18: rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-dioxoteto (1(2H)-yl)-4-methoxybenzoyl)piperidine-4- yl)oxy)-3-hydroxypropyl)piperidin-4-yl)oxy)phenyl) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphen (2-hydroxypropan-2-yl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: rac-tert-butyl 4-((1-(4-(4-(4-(5-fluoro-3 -(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (ethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine Lysin-1-yl)-3-hydroxypropan-2-yl)oxy)piperidine-1-carboxylate Ruboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidine-4 -yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl (2-hydroxypropan-2-yl)benzamide trifluoroacetate (intermediate 16, 124 mg, 0.171 mmol), TEA (0.100 ml, 0.71 7mmol) and tert-butyl 4-(2-oxoethoxy)piperidine-1-carbohydrate xylate (Intermediate 19, 60 mg, 0.222 mmol) in MeOH (2 ml) ZnCl2 (0.7 M) in THF (0.300 ml, 0.2 10 mmol) was added and the RM was stirred overnight at RT under argon. 3CN (13 mg, 0.207 mmol) was added and the RM was stirred at RT overnight, After concentration, the residue was purified with ACN (aq. solution of TFA (0.1%)) (2-100%). Purified by reversed-phase chromatography on a Redisep® C18 column eluting with This gave the title compound as a solid TFA salt (78 mg). Method A: Rt=0.94min;[M+H] + =855.5.

[0382] Step 2: rac-2-fluoro-N-(5-fluoro-3-(6-(4-((1-(3- Hydroxy-2-(piperidin-4-yloxy)propyl)piperidin-4-yl)o (oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (phenyl)-4-(2-hydroxypropan-2-yl)benzamide rac-tert-butyl 4-((1-(4-(4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine -1-yl)-3-hydroxypropan-2-yl)oxy)piperidine-1-carbox Silane trifluoroacetate (75 mg, 0.079 mmol) in DCM (1 ml) and TFA (0.100 ml, 1.3 mmol) solution was stirred at RT for 2 h and concentrated. The residue was then eluted with ACN (aq. solution of TFA (0.1%)) (2-100%). The product was purified by reversed phase chromatography on a Redisep® C18 column. The title compound was obtained as a solid TFA salt (67 mg). Method A: Rt=0.67min;[M+H] + =755.5.

[0383] Step 3: rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-dihydro- ... 1(2H)-1-(4-methoxybenzoyl)-1(2H)-pyrimidin-1(2H)-yl (3-hydroxypropyl)piperidin-4-yl)oxy) (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methyl (2-hydroxyphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzaminium Do 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy To a solution of benzoic acid (Intermediate 5, 20 mg, 0.076 mmol) in DMF (0.5 ml), MM (0.050 ml, 0.455 mmol) and HATU (30 mg, 0.079 mm ol) was added and the RM was stirred at RT for 30 min. 5-Fluoro-3-(6-(4-((1-(3-hydroxy-2-(piperidin-4-yl) (peroxy)propyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropanediol (2-phenyl-2-yl)benzamide (65 mg, 0.065 mmol) and NMM (0.050 A DMF solution (0.5 ml) of 0.455 mmol (1 ml) was added dropwise, and the RM was stirred at RT. The solvent was removed and the residue was dissolved in an aq. solution of ACN (NH4HCO3) (0 Reversed-phase chromatography on a Redisep® C18 column eluted with 0.1% HCl (in a 0.1% ethanol solution) Purified by Torus 2P eluting with MeOH in CO2 (22-55%) After further purification by SFC on an IC column (250 × 30 mm, 130 Å, 5 μm), the title The mixture was obtained as a solid (30 mg). Method B: Rt=3.77min;[M+H] + =1001.6. 1 H NMR(600MHz,DMSO-d6)δ13.99(s,1H),10.31 (s,1H),10.08(s,1H),9.22(s,1H),8.04(m,2H) ,7.86(d,J=9.9Hz,1H),7.72(t,J=7.8Hz,1H),7 .44-7.38(m,3H),7.36(m,1H),7.32(s,1H),7.1 5(m,4H),4.75-4.35(m,1H),3.94(m,1H),3.82( m,4H),3.75-3.50(m,6H),3.50-3.32(m,2H),3. 32-3.07(m,5H),2.66(t,J=6.8Hz,2H),2.28(m, 1H),2.19(s,3H),2.14-2.01(m,2H),2.00-1.77 (m,3H),1.63-1.45(m,3H),1.44(s,6H).

[0384] Compound 19: N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyridine (2H)-diphenyl-4-methoxybenzoyl)piperidin-4-yl)methyl Piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide [ka] Step 1: tert-Butyl 4-((4-(4-(4-(5-fluoro-3-(2-fluoro) (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl -7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl (methyl)piperidine-1-carboxylate 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidine-4 -yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl (2-hydroxypropan-2-yl)benzamide trifluoroacetate (intermediate 16, 127 mg, 0.170 mmol), TEA (0.075 ml, 0.53 8 mmol) and 1-Boc-piperidine 4-carboxaldehyde (40 mg, 0.18 2 mmol) was dissolved in MeOH (2 ml) at RT and ZnCl2 (0.7 M A THF solution (0.300 ml, 0.210 mmol) of ) was added and the RM was stirred under argon. The mixture was stirred at RT for 7 h. Solid NaBH3CN (13 mg, 0.207 mmol) was added. The RM was then stirred at RT for 4 days, the solvent was removed and the residue was dissolved in ACN (TFA Redisep® eluted in an aq. solution (0.1%) (2-100%) The title compound was purified by reverse phase chromatography on a C18 column to give the solid TFA salt (17 4 mg). Method D: Rt=0.75min;[M+H] + =795.5.

[0385] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((1-( Piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrro 2-hydroxypropane-4-yl-[2,3-d]pyrimidin-4-yl)phenyl 2-yl)benzamide tert-Butyl 4-((4-(4-(4-(5-fluoro-3-(2-fluoro-4 -(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H -pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl)methyl (ethyl) piperidine-1-carboxylate trifluoroacetate (170 mg, 0.1 90 mmol) in DCM (2 ml) and TFA (0.100 ml, 1.298 mmol) The solution was stirred at RT for 1 h and the RM was concentrated to give the title compound as a solid TFA salt (202 mg). Method D: Rt=0.52min;[M+H] + =695.6.

[0386] Step 3: N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydrochloride (4-methoxybenzoyl)piperidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl) Methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyridine 4-(2-(2-(2-(2-(4-(4-yl-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 ... Hydroxypropan-2-yl)benzamide RT of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrimidin-1-yl To a solution of benzoic acid (Intermediate 5, 60 mg, 0.227 mmol) in DMF (1 ml) NMM (0.050 ml, 0.455 mmol) and HATU (87 mg, 0.042 m 2-Fluoro-N-(5-fluoro-N-methyl ... Fluoro-2-methyl-3-(6-(4-((1-(piperidin-4-ylmethyl)piperidine) (4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl (phenyl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide trifluoro acetate (0.190 mmol) and NMM (0.050 ml, 0.455 mmol) A solution of (1 ml) in DMF was added dropwise and the RM was stirred at RT for 2.5 h. The solvent was removed. The residue was then dissolved in ACN (aq. solution of NH4HCO3 (0.1%)) (2-100% Purification was performed by reversed-phase chromatography on a Redisep® C18 column eluting with Prepare the column and elute with ACN (aq. solution of NH4OH (0.1%)) (30-65%). After further purification by reversed-phase HPLC on an XBridge column (50 × 250 mm, 5 μm) The title compound was obtained as a solid (47 mg). Method B: Rt=3.95min;[M+H] + =941.8. 1 H NMR(600MHz,DMSO-d6)δ12.69(s,1H),10.36 (s,1H),9.97(s,1H),8.83(s,1H),7.92(d,J=8. 4Hz,2H),7.74(m,1H),7.66(d,J=10.2Hz,1H),7 .46-7.39(m,2H),7.37(m,1H),7.33(m,1H),7.2 4(m,1H),7.16(m,1H),7.05(d,J=8.3Hz,2H),6. 76-6.70(s,1H),5.33(s,1H),4.48(m,1H),3.85 (s,3H),3.61(t,J=6.6Hz,2H),3.20-2.75(m,4H ),2.18(m,7H),1.97(m,2H),1.80-1.55(m,5H), 1.46(s,6H),1.08(m,2H).

[0387] Compound 20: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydrochloride) 3,9-diazaspiro(4-methoxybenzoyl)-1(2H)-yl-4-pyrimidin-1(2H)-yl [5.5]Undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro Oro-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-Butyl 9-(2-(4-bromophenyl)acetyl)-3,9-diazomethane Zaspiro[5.5]undecane-3-carboxylate 3,9-Diaza-spiro[5.5]undecane-3-carboxylic acid at RT under argon A solution of ert-butyl ester (1269 mg, 4.99 mmol) in dry DMF (12 m l) with DIPEA (1.743 ml, 9.98 mmol), 4-bromophenylacetic acid (1 073 mg, 4.99 mmol) and dry DMF (6 ml) were added. 081 mg, 5.49 mmol) was added, and the RM was stirred at RT for 1 h and poured into water. The resulting mixture was stirred for 1 h. The liquid was decanted and water was added and mixed. The liquid was again decanted and the residue was dissolved in DCM and dissolved. The liquor was dried over MgSO4 and evaporated to give the title compound as an oil (2.2 g). Method A: Rt=1.22min;[M+H] + =451.2.

[0388] Step 2: tert-Butyl 9-(1-(4-bromophenyl)-2-methylpropane-2 -yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-Butyl 9-(2-(4-bromophenyl)acetyl)- )-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.9g, 4 A solution of 0.21 mmol) of ZrCl4 (1.0 mL) in dry THF (15 mL) was added to oven-dried ZrCl4 (1.0 mL). 0.079g, 4.63mmol) was added, and the RM was stirred at -50°C to -45°C for 30 minutes. Methylmagnesium bromide (3M) in Et2O (8.42 ml, 25.3 mm ol) was added dropwise over 10 minutes while maintaining the reaction temperature at -45°C to -40°C. M was warmed to -20 °C and then stirred in an ice bath for 15 min and then at RT for 2 h. A sat. aq. solution of HCl and EtOAc was added and the phases were separated. The aqueous phase was diluted with EtO Extract with Ac, dry the combined organic phases over MgSO4, evaporate and give a residue Red is eluted with ACN (aq. solution of TFA (0.1%)) (10-100%). Purification by reverse phase chromatography on an isep® C18 column gave the title compound was obtained as a solid TFA salt (70 mg). Method A: Rt=0.95min;[M+H] + =465.2.

[0389] Step 3: tert-Butyl 9-(2-methyl-1-(4-(4,4,5,5-tetramethyl)methyl) (phenyl)-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-3, 9-Diazaspiro[5.5]undecane-3-carboxylate tert-Butyl 9-(1-(4-bromophenyl)-2-methylpropan-2-yl )-3,9-diazaspiro[5.5]undecane-3-carboxylate (70 mg, 0 KOAc (35.6 mg) in a dry 1,4-dioxane solution (2 ml) , 0.362 mmol) and BISPIN (36.8 mg, 0.145 mmol) were added. Argon was then passed through the mixture for 5 minutes. The mixture was heated at 35°C to remove PdCl2 (dppf) (4.42 mg, 6.04 μmol) was added and the RM was again purged with argon. After flashing, the mixture was stirred at 90° C. for 6 h. The solvent was removed and the residue was precipitated on silica. Absorbed in EtOAc (in CHX) (10-100%) followed by MeOH (in DCM) ( The title compound was purified by silica gel chromatography eluting with 0-20% ethanol. (94 mg). Method A: Rt=1.09min;[M+H] + =513.4.

[0390] Step 4: tert-Butyl 9-(1-(4-(4-chloro-7H-pyrrolo[2,3-d] Pyrimidin-6-yl)phenyl)-2-methylpropan-2-yl)-3,9-diaza Spiro[5.5]undecane-3-carboxylate tert-Butyl 9-(2-methyl-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-3,9-di Azaspiro[5.5]undecane-3-carboxylate (94 mg, 0.182 mmol) l) and 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (51 mg, 0.182 mmol) in 1-propanol (5 ml) and Na2CO3 (2 M) aq. The mixture was suspended in a solution (0.182 ml, 0.365 mmol) at RT. PdCl2(PPh3)2 (12.81 mg, 0.018 mcg) was added to the mixture. mol) was added and the RM was stirred at 100°C under an argon atmosphere for 23 h. A solution of propyl alcohol (3 ml) and an aq. solution of Na2CO3 (2 M) (0.540 ml, 1.0 8 mmol) was added, and argon was passed through the RM for 5 min to obtain PdCl2(PPh3)2( 15 mg, 0.021 mmol) was added, and the RM was stirred at 110°C for 7 h. The mixture was diluted with EtOAc and dried over MgSO4 and purified by Isolute® The target was adsorbed onto HM-N, dried, and then dissolved in ACN (aq. solution of TFA (0.1%)). Redisep® C18 column reversed-phase chromatograph eluting with 5-100% Purification by filtration gave the title compound as a solid TFA salt (33 mg). Method A: Rt=0.94min;[M+H] + =538.3.

[0391] Step 5: tert-Butyl 9-(1-(4-(4-(5-fluoro-3-(2-fluoro) -4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-methylpropane- 2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate RT tert-Butyl 9-(1-(4-(4-chloro-7H-pyrrolo[2,3-d] Pyrimidin-6-yl)phenyl)-2-methylpropan-2-yl)-3,9-diaza Spiro[5.5]undecane-3-carboxylate (33 mg, 0.019 mmol) In a 1-propanol solution (1 ml) of 2-fluoro-N-(5-fluoro-2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 2, 36 mg , 0.083 mmol), 1-propanol (1.5 ml) and Na2CO3 (2 M) Aq. solution (0.08 ml, 0.160 mmol) was added. Argon was passed through the mixture. PdCl2(PPh3)2 (1.330 mg, 1.895 μmol) was added and the RM The mixture was heated at 140° C. for 20 min using microwave radiation. The RM was diluted with EtOAc. The mixture was then dried over MgSO4 and absorbed onto Isolute® HMN. The mixture was dried and then soaked in ACN (aq. solution of TFA (0.1%)) (5-100%). Purified by reversed-phase chromatography on a Redisep® C18 column eluting with This gave the title compound as a solid TFA salt (9 mg). Method A: Rt=1.00min;[M+H] + =807.4.

[0392] Step 6: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyridine) Rimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5 .5]undecan-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide tert-Butyl 9-(1-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-methylpropan-2-yl 3,9-diazaspiro[5.5]undecane-3-carboxylate (9 mg, 8 A solution of 0.70 μmol) in DCM (0.8 ml) and TFA (0.8 ml) was added at RT. The mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in DMF (0.8 ml) and NMM (0. 0.22 ml, 0.200 mmol) of 3-(2,4-dioxotetrahydrofuran) 4-Methoxybenzoic acid (Intermediate 5, 4.60 mg, 0.017 mmol) and HATU (6.61 mg, 0.017 mmol) were added, and R M was stirred under argon at RT for 15 h. The mixture was then placed on Isolute® The mixture was adsorbed onto ACN (aq. solution of TFA (0.1%)) and dried, and then purified by filtration. Purification was performed by reversed-phase chromatography on a Redisep® C18 column eluting with This gave the title compound as a solid TFA salt (6.5 mg). Method B: Rt=3.91min;[M+H] + =953.7. 1 H NMR(400MHz,DMSO-d6)δ12.83(s,1H),10.34 (s,1H),9.95(s,1H),8.88(s,1H),7.99(d,J=8. 2Hz,2H),7.73(t,J=7.9Hz,1H),7.70-7.50(m,1 H),7.50-7.25(m,6H),7.25(d,J=8.8Hz,1H),7. 17(d,J=8.7Hz,1H),6.89(s,1H),3.85(s,3H),3 .70-3.40(m,6H),3.20-3.00(m,2H),2.70-2.60 (m,2H),2.18(s,3H),2.1-1.9(m,3H),1.75-1.5 5(m,4H),1.45(s,6H),1.45-1.20(m,12H).

[0393] Compound 21: N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl) ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate In a 250 ml round-bottom flask, add tert-butyl piperazine-1-carboxylate (10 g, 53.7 mmol), ACN (100 ml) and K2CO3 (11.1 g, 80.6 1-Bromo-2-chloroethane (15. mmol) was added and the mixture was cooled to 5° C. 0 g, 104 mmol) was added slowly at 5°C, and the RM was warmed to RT and stirred for 1 The RM was filtered and the filtrate was concentrated and diluted with EtOAc (in petroleum ether) (0-5 The title compound was purified by silica gel chromatography eluting with 4.0% ethanol to give the title compound as an oil (4. 2g). Method J:Rt=1.93min,MSm / z[M+H] + 249.

[0394] Step 2: tert-Butyl 4-(4-bromobenzyloxy)piperidine-1-carboxylate Silat In a 250 ml round-bottom flask, add mineral oil (1.17 g, 29.25 mmol) and D NaH (60%) in MF (30 ml) was added and the mixture was cooled to 5°C. ethyl 4-hydroxypiperidine-1-carboxylate (4.03 g, 20.0 mmol) A DMF solution (15 ml) of ) was added dropwise at 5°C, and the RM was stirred at 5°C for 1 h. 1-Bromo-4-(bromomethyl)benzene (7.0 g, 28.0 mmol) was heated to 5°C. The RM was stirred at 30°C for 18 h and then diluted with ice water. The aq. phase was extracted with a mixture of EtOAc and petroleum ether (2:1) and combined. The organic phase was dried, concentrated and eluted with EtOAc in petroleum ether (0-20%). The title compound was purified by silica gel chromatography to give the title compound as an oil (6.1 g). Got it. Method H:Rt=2.30min,MSm / z[M-100+H] + 270.

[0395] Step 3: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-diphenyl ether) Oxaborolan-2-yl)benzyloxy)piperidine-1-carboxylate In a 100 ml round bottom flask purged and maintained under an inert atmosphere, tert-butyl 4- (4-Bromobenzyloxy)piperidine-1-carboxylate (2.0 g, 5.4 m mol), BISPIN (2.7g, 10.8mmol), KOAc (1.59g, 16 0.2 mmol) and PdCl2(dppf) (630 mg, 0.86 mmol) were added. 1,4-Dioxane (45 ml) was added and the RM was stirred under N2 at 85 °C for 18 h. The RM was evaporated and the residue was dissolved in EtOAc in petroleum ether (0–20%). The title compound was purified by silica gel chromatography to give the title compound as a solid (2.1 g). And got it. Method F:Rt=1.70min,MSm / z[M-100+H] + 318.

[0396] Step 4: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzyloxy)piperidine In a 50 ml round-bottom flask, add tert-butyl 4-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzyloxy)piperidine-1-carbo Xylate (2.1 g, 5.0 mmol) and DCM (10 ml) were added and the solution was heated to 5°C. The mixture was cooled to rt. A solution of HCl (4 M) in 1,4-dioxane (5 ml, 20 mmol) was slowly added. The RM was added again and stirred at 30° C. for 2 h. The mixture was concentrated to give petroleum ether and The title compound was obtained by triturating with a mixture of TBME (2:1) and filtering the solid to give the title compound as solid HCl Obtained as a salt (1.2 g). Method E: Rt=1.74min,MSm / z[M+H] + 318.

[0397] Step 5: 4-((1-(2-(4-(tert-butoxycarbonyl)piperazine-1- 4-(4-(4-(2 ... In a 100 ml round-bottom flask, add 4-(4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)benzyloxy)piperidine hydrochloride (530m g, 1.5 mmol), K2CO3 (518 mg, 3.75 mmol), NaI (80 m g, 0.53 mmol), ACN (30 ml) and tert-butyl 4-(2-chloroethene) (ethyl)piperazine-1-carboxylate (374 mg, 1.5 mmol) was added. M was stirred at 30°C for 24 h, concentrated, and rediluted in DMF (9 ml) to give 60 C. for 6 h and filtered to give the title compound as a solid (670 mg). Method I: Rt=1.02min, MSm / z[M+H] + 448.

[0398] Step 6: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl (phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl )benzyloxy)piperidin-1-yl)ethyl)piperazine-1-carboxylate In a 100 ml round-bottom flask purged and maintained under an inert atmosphere, 4-((1-(2-( 4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)piperidine-4 (-yloxy)methyl)phenylboronic acid (604 mg, 1.35 mmol) in DMF Solution (9 ml), 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[ 2,3-d]pyrimidine (Intermediate 7, 680 mg, 1.62 mmol), Na2CO3( 300 mg, 2.83 mmol) and PdCl2(dppf) (120 mg, 0.16 m ACN (25 ml) and water (7 ml) were added and the RM was heated under N2 for 95 min. The mixture was stirred at 5°C for 1 hour. 2-Fluoro-N-(5-fluoro-2-methyl-3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl (2-hydroxypropan-2-yl)benzamide (Intermediate 2, 815 mg , 1.89 mmol), Na2CO3 (520 mg, 4.9 mmol) and PdCl2 ( dppf) (80 mg, 0.11 mmol) was added, and the RM was heated at 100 °C under N The mixture was stirred for 16 h. The mixture was concentrated, water was added, filtered, and the solid was extracted with EtOAc (petroleum Purify by silica gel chromatography eluting with 0-50% hexane in ether The title compound was obtained as a solid (1.3 g). Method I: Rt=1.51min, MSm / z[M+H] + 965.

[0399] Step 7: tert-Butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro) Fluoro-4-(2-hydroxypropan-2-yl)benzamido-2-methylphenyl (I)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperazine-1-carboxylate In a 100 ml round-bottom flask, add tert-butyl 4-(2-(4-(4-(4-(5-furan) Fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamide )-2-Methylphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d] Pyrimidin-6-yl)benzyloxy)piperidin-1-yl)ethyl)piperazine- A DMSO solution (12 ml) of 1-carboxylate (1.3 g, 1.35 mmol) was added. In addition, an aqueous solution (2.6 ml) of NaOH (630 mg, 15.75 mmol) was added at 0°C. The RM was stirred at 30°C for 1 h, and then ice water was added. The solid was filtered and Upon redissolution in DCM, the solution was dried over Na2SO4 and concentrated to give a residue Purification was performed by silica gel chromatography eluting with ethanol in DCM (0-60%). The title compound was obtained as a solid (600 mg). Method I: Rt=1.34min, MSm / z[M+H] + 825.

[0400] Step 8: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-((1-( 2-(Piperazin-1-yl)ethyl)piperidin-4-yloxy)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydro (2-xypropan-2-yl)benzamide In a 100 ml round-bottom flask, add tert-butyl 4-(2-(4-(4-(4-(5-fulv) Oro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamide) -2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl Oxy)piperidin-1-yl)ethyl)piperazine-1-carboxylate (200m g, 0.24 mmol), DCM (1.5 ml) and EtOH (4.5 ml) were added. A solution of HCl (4 M) in 1,4-dioxane (1.8 ml, 7.2 mmol) was added at 5°C. The RM was stirred at 30°C for 4 h. The RM was concentrated and diluted with petroleum ether. and TBME (1:1) mixture, TBME and DCM and TBME (1:2) mixture Trituration with liquor and filtration gave the title compound as a solid HCl salt (160 mg). Method I: Rt=1.15min, MSm / z[M+H] + 725.

[0401] Step 9: N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetate (2H)-pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1- yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro 4-(2-hydroxypropan-2-yl)benzamide In a 100 ml round-bottom flask, add 2-fluoro-N-(5-fluoro-2-methyl-3-(6 -(4-((1-(2-(piperazin-1-yl)ethyl)piperidin-4-yloxy )methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl) -4-(2-hydroxypropan-2-yl)benzamide hydrochloride (160mg , 0.21 mmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H)- (2-methyl-4-methoxybenzoic acid (Intermediate 5, 63 mg, 0.24 mmol), DMF (2 0.5ml) and DIPEA (163mg, 1.26mmol) were added and the mixture was cooled to 5°C. HATU (90 mg, 0.24 mmol) was added, and the RM was stirred at 5°C for 1 h. The mixture was filtered and the filtrate was diluted with ACN (aq. solution of ammonium bicarbonate (1 0 mM) in an XBridge C18 column (21.2 × 250 mm, 10 μL) m) Purification by preparative HPLC gave the title compound as a solid (79 mg). Method G:Rt=1.95min,MSm / z[M+H] + 970. 1 H NMR(500MHz,DMSO-d6)δ12.78(s,1H),10.34 (s,1H),9.95(s,1H),8.85(s,1H),7.96(d,J=8. 2Hz,2H),7.73(t,J=8.0Hz,1H),7.66(dd,J=9.8 ,1.7Hz,1H),7.45-7.39(m,4H),7.37(dd,J=8.4 ,2.1Hz,1H),7.33(d,J=2.0Hz,1H),7.24(dd,J= 8.8,2.7Hz,1H),7.15(d,J=8.6Hz,1H),6.85(s, 1H),5.31(s,1H),4.53(s,2H),3.84(s,3H),3.5 9(t,J=6.6Hz,2H),3.54-3.40(m,4H),3.39-3.3 6(m,1H),2.74-2.64(m,4H),2.45-2.36(m,8H), 2.17(s,3H),2.07(t,J=9.3Hz,2H),1.89-1.80( m,2H),1.54-1.47(m,2H),1.45(s,6H).

[0402] Compound 22: N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidin (2H)-benzoyl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazine (1-hydroxyl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) propan-2-ylbenzamide [ka] Step 1: tert-Butyl 4-(piperazine-1-carbonyl)piperazine-1-carbonyl Xylate Di(1H-imidazol-1-yl)methanone (1.95 g, 12.0 mmol) tert-butylpiperazine into a 100 ml round-bottom flask containing HF solution (35 ml) HCl (1.863 g, 10.0 mmol) was added at 0°C. The resulting solution was stirred at 0°C for 2 h and then added piperazine (2.59 g, 30. 0 mmol) was added and the RM was stirred at 65 °C for 16 h before adding additional piperazine ( 0.86 g, 10.0 mmol) was added and the RM was stirred at 65°C for 24 h. The residue was redissolved in H2O, Na2CO3 was added, and the mixture was diluted with DCM The combined organic phases were dried over Na2SO4 and the solvent was removed. The material was triturated with TBME, the mixture was filtered, the solid was washed with TBME and dried. The title compound was obtained as a solid (2.0 g). 1 H NMR(500MHz,DMSO-d6)δ3.30(s,4H),3.11-3 .02(m,8H),2.67-2.61(m,4H),2.36(s,1H),1.4 0(s,9H).

[0403] Step 2: tert-Butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazine Zin-1-carboxylate 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Benzoic acid (Intermediate 5, 555 mg, 2.1 mmol) and HATU (783 mg, 2.0 DIPEA was added to a 100 ml round-bottom flask containing a DMF solution (8 ml) of (6 mmol). (517 mg, 4.0 mmol), RM was stirred at 15° C. for 5 minutes, and then t ert-Butyl 4-(piperazine-1-carbonyl)piperazine-1-carboxylate (587 mg, 2.0 mmol) was added. The solution was stirred at 15 °C for 1 h and KH The mixture was extracted with DCM. The combined organic phase was washed with N Drying over a2SO4 and evaporation gave the title compound as a solid (1.1 g). Method F: Rt=1.113min, MSm / z[M+Na] + 567.

[0404] Step 3: 1-(2-methoxy-5-(4-(piperazine-1-carbonyl)piperazine- 1-Carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione tert-Butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazine- A solution of 1-carboxylate (1.1 g, 2.0 mmol) in DCM (10 ml) was To a 100 ml round-bottom flask was added anisole (1 ml) and TFA (3.5 ml). The RM was stirred at 15°C for 3 h, the solvent was removed, and the residue was triturated with TBME to give The mixture was filtered and the solid was dried to give the title compound as a solid TFA salt (1.0 g). Got it. Method F:Rt=0.750min,MSm / z[M+Na] + 445.

[0405] Step 4: N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carbonyl (I)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin (phenyl-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyphenyl) (2-hydroxypropan-2-yl)benzamide 1-(2-Methoxy-5-(4-(piperazine-1-carbonyl)piperazine-1-carbonyl) (1H,3H)-dihydropyrimidine-2,4(1H,3H)-trifluorocarbonylphenyl acetate (440 mg, 0.788 mmol) and DIPEA (70 mg, 0.542 In a 50 ml round-bottom flask containing a solution (5 ml) of 2-fluoro- N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropane-2 -yl)benzamide (Intermediate 3, 206 mg, 0.391 mmol) in DMSO ( 5 ml) was added at 10°C and the mixture was stirred for 5 min. F solution (0.41 ml, 0.41 mmol) was added and the RM was stirred at 22°C for 2 h. Solid NaBH3CN (30 mg, 0.477 mmol) was added and stirring was continued at 22 °C. The mixture was then filtered and the reaction mixture was stirred for 18 h. The solvent was removed, and ice water and KH2PO4 were added. The filtrate was eluted with ACN (aq. solution of ammonium bicarbonate (0.0075M)). Reversed phase chromatography on an Agela C18 column (spherical 20-35 μm, 100 Å, 40 g) Purification by chromatography gave the title compound as a solid (63 mg). Method D: Rt=1.223min, MSm / z[M+H] + 955. 1 H NMR(500MHz,DMSO-d6)δ12.78(s,1H),10.36 (s,1H),9.96(s,1H),8.85(s,1H),7.96(d,J=8. 1Hz,2H),7.73(m,1H),7.66(d,J=9.9Hz,1H),7. 44-7.36(m,6H),7.24(dd,J=8.7,2.7Hz,1H),7. 16(d,J=8.4Hz,1H),6.84(s,1H),5.31(s,1H),3 .84(s,3H),3.60(t,J=6.6Hz,2H),3.53(s,2H), 3.49-3.41(m,2H),3.31(s,2H),3.24-3.13(m,8 H),2.68(t,J=6.5Hz,2H),2.40-2.34(m,4H),2. 18(s,3H),1.45(s,6H).

[0406] Compound 23: rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (2-xypropan-2-yl)benzamide (Intermediate 3, 200 mg, 0.380 mmol) , rac-1-(5-(7-(hydroxymethyl)-3,9-diazaspiro[5.5]u 2,4(1-octyl-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine H,3H)-dione trifluoroacetate (Intermediate 20, 228 mg, 0.418 mm ol) and TEA (0.079 ml, 0.570 mmol) in THF (3 ml) A solution of ZnCl2 (0.5 M) in THF (0.798 ml, 0.399 mmol) was added. The RM was stirred under argon at RT for 3 h to give solid NaBHCN (47.7 mg, 0.760 mmol) was added and the RM was stirred at RT for 4 h. The mixture was diluted with DCM. The organic phase was washed with water, concentrated and the residue absorbed onto Isolute®. The mixture was collected, dried, and purified by filtration using ACN (aq. solution of TFA (0.1%)) (10-100%). Purified by reversed-phase chromatography on a Redisep® C18 column eluting with The title compound was obtained after filtration through a PL-HCO3 MP SPE cartridge and lyophilization. The product was obtained as a solid (161 mg). Method B: Rt=3.53min;[M+H] + =942.3. 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),10.33 (s,1H),9.95(s,1H),8.85(s,1H),8.2-7.85(m, 2H),7.73(t,J=8Hz,1H),7.66(d,J=8.8Hz,1H), 7.57-7.28(m,6H),7.24(dd,J=8.8,2.5Hz,1H), 7.14(d,J=8.6Hz,1H),6.84(s,1H),5.30(s,1H) ,4.38(br.s,1H),3.84(s,3H),3.7-3.40(m,6H) ,3.3-3.0(m,4H),2.75-2.55(m,3H),2.35-2.25 (m,2H),2.18(s,3H),2.0-1.7(m,2H),1.58-1.1 5(m,6H),1.45(s,6H).

[0407] Compound 24 and Compound 25: (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide, and (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Dibenzoyl-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyro (2,3-d)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] Heptane, DCM and MeOH (40:35:25) containing DEA (0.05%) A Chiralpak ID column (5μ) was eluted with a mixture of rac-N-(3-(6-(4-( (9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methyl ... (Hydroxybenzoyl)-1-(hydroxymethyl)-3,9-diazaspiro[5.5]un Decane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (2-hydroxypropyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Chiral separation of (propan-2-yl)benzamide (50 mg, 50.6 μmol) The title compound was obtained as a single enantiomer in the following sequence:

[0408] First eluted enantiomer: 14.7 mg; Method K:Rt=30.8min; Method B: Rt=3.45min;[M+H] + =941.5. 1 H NMR (400 MHz, DMSO-d6) confirmed the N Follow MR.

[0409] Second eluted enantiomer: 12.7 mg; Method K:Rt=42.3min; Method B: Rt=3.48min;[M+H] + =941.5. 1 H NMR (400 MHz, DMSO-d6) confirmed the N Follow MR.

[0410] Compound 26: N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidin (2H)-4-methoxybenzamido)butyl)piperazin-1-yl) Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro 2-fluoro-4-(2-hydroxypropan-2-yl)-2-methylphenyl benzamide [ka] Step 1: tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-4-methoxybenzamido)butyl)piperazine-1-carboxamide Silat 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Benzoic acid (Intermediate 5, 150 mg, 0.539 mmol), 4-(4-amino-butyl) -Piperazine-1-carboxylic acid tert-butyl ester (146 mg, 0.539 mmol) l), HATU (293 mg, 0.755 mmol) and NMM (0.300 ml, 2. A solution of A (70 mmol) in DMF (5 ml) was stirred at RT for 3 h. Redisep eluted with CN (aq. solution of TFA (0.1%)) (2-100%) The title compound was purified by reverse phase chromatography on a C18 column to give solid T Obtained as the FA salt (348 mg). Method A: Rt=0.98min;[M+H] + =504.3.

[0411] Step 2: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrimidin Toxoxy-N-(4-(piperazin-1-yl)butyl)benzamide tert-Butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methoxybenzamido)butyl)piperazine-1-carboxylate A solution of 305 mg (0.469 mmol) of benzophenone in MeOH (2 ml) and 4 M HCl A solution of 1,4-dioxane (4 ml, 16 mmol) was stirred at RT for 1.5 h. The solvent was removed and the residue was redissolved in a mixture of ACN and water and freeze-dried to give the title compound. The compound was obtained as a solid HCl salt (249 mg). Method A: Rt=0.70min;[M+H] + =404.4.

[0412] Step 3: N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydro Pyrimidin-1(2H)-yl)-4-methoxybenzamido)butyl)piperazine-1 -yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5 -fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2 -yl)benzamide 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy -N-(4-(piperazin-1-yl)butyl)benzamide hydrochloride (136m g, 0.303 mmol), TEA (0.100 ml, 0.717 mmol) and 2- Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropyl (2-phenyl-2-yl)benzamide (Intermediate 3, 163 mg, 0.303 mmol) was dissolved in MeO ZnCl2 (0.5 M) in THF (0. 75 ml, 0.375 mmol) was added and the RM was stirred overnight at RT. BHCN (22 mg, 0.350 mmol) was added and the RM was stirred overnight at RT. The solvent was removed. The residue was dissolved in ACN (aq. solution of TFA (0.1%)) (2-1 00% elution was performed by reversed-phase chromatography on a Redisep® C18 column. After purification by filtration through a PL-HCO3MP SPE cartridge and lyophilization, A solid was obtained. Reprospherol was eluted with MeOH in CO2 (33-50%). Further purification of this material by SFC on a PEI column (250 x 30 mm, 100 Å, 5 μM) Preparation gave the title compound as a solid (95 mg). Method B: Rt=3.68min;[M+H] + =914.5. 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),10.33 (s,1H),9.93(s,1H),8.84(s,1H),8.33(t,J=5. 6Hz,1H),7.93(d,J=7.8Hz,2H),7.83(dd,J=8.7 ,2.3Hz,1H),7.78-7.68(m,2H),7.64(d,J=9.7H z,1H),7.39(m,4H),7.22(dd,J=8.9,2.8Hz,1H) ,7.15(d,J=8.7Hz,1H),6.81(s,1H),5.28(s,1H ),3.84(s,3H),3.57(t,J=6.7Hz,2H),3.48(s,2 H),3.25-3.18(m,2H),2.67(t,J=6.6Hz,2H),2. 43-2.24(m,10H),2.16(s,3H),1.45(m,10H).

[0413] Compound 27: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undeca (phenyl-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (2-phenyl)benzamide [ka] Step 1: tert-Butyl 9-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecane -3-carboxylate In a 100 ml round-bottom flask, add 3-(2,4-dioxotetrahydropyrimidine-1(2H) )-yl)-4-methylbenzoic acid (Intermediate 8, 195 mg, 0.787 mmol), TE A (0.33 ml, 2.36 mmol), THF (8 ml) and HATU (420 mg, 1.1 mmol) was added. The RM was stirred at RT for 5 min; tert-butyl 3, 9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 0.78 7 mmol) was added in small portions at 0°C and the mixture was stirred at RT for 1 h. The solution was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc. The title compound was obtained as a solid (350 mg). Method J:Rt=1.77min;MSm / z[M+H] + 485

[0414] Step 2: 1-(2-methyl-5-(3,9-diazaspiro[5.5]undecane-3-yl) (1H,3H)-dihydropyrimidine-2,4(1H,3H)dione In a 100 ml round-bottom flask, add tert-butyl 9-(3-(2,4-dioxotetrahydrofuran) 3,9-diazaspiro[4-methylbenzoyl-1(2H)-yl]-pyrimidin-1(2H)-yl 5.5]undecane-3-carboxylate (0.35 g, 0.723 mmol) and D CM (5 ml) was added and the mixture was cooled to 0° C. 1,4-dioxaHCl (4 M) A solution of ethanol (20 ml, 80 mmol) was added dropwise, the RM was warmed to RT and stirring was continued for 3 h. The RM was concentrated and used directly in the next step without further purification to give the title compound as solid HCl. Obtained as the l salt (0.32 g). Method D: Rt=1.62min;MSm / z[M+H] + 384.

[0415] Step 3: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyridine) Zin-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy Cypropan-2-ylbenzamide In a 100 ml round-bottom flask, add 1-(2-methyl-5-(3,9-diazaspiro[5.5 ]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H) -dione hydrochloride (0.32 g, 0.723 mmol), 2-fluoro-N-(5 -fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidinyl) (2-hydroxypropan-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl) Benzamide (intermediate 3, 0.25 g, 0.462 mmol), MeOH (10 ml) and A solution of ZnCl2 (1M) in THF (1.38 ml, 0. 462 mmol) was added at 0° C., the RM was warmed to RT and stirring was continued for 2 h. NaBH3CN (87 mg, 1.38 mmol) was added and the RM was stirred at RT for 16 h. The mixture was filtered, the solid was washed with MeOH (10 ml), and the combined filtrate The residue was concentrated. Elution: XBridge C18 column (21.2 x 250 mm, 10 μm) preparative HPLC Purification by HPLC gave the title compound as a solid (109 mg). Method I: Rt=1.28min;MSm / z[M+H] + 896. 1 H-NMR(500MHz,DMSO-d6)δ12.75(s,1H),10.37 (s,1H),9.95(s,1H),8.85(s,1H),7.94(d,J=8. 0Hz,2H),7.75(t,J=8.0Hz,1H),7.67(d,J=9.0H z,1H),7.43-7.30(m,6H),7.24(d,J=7.5Hz,2H) ,6.82(s,1H),5.3(s,1H),3.85-3.75(m,1H),3. 56-3.49(m,5H),3.37-3.27(m,2H),2.77-2.6(m ,2H),2.39-2.29(m,4H),2.21(s,3H),2.17(s,3 H),1.49-1.37(m,8H),1.45(s,6H).

[0416] Compound 28: 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzaldehyde Mido [ka] Step 1: tert-Butyl (5-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-2-fluoro-N,4-dimethylbenzamido)pentyl)carbama Route 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl) under N2 atmosphere -2-fluoro-4-methylbenzoic acid (Intermediate 22, 80 mg, 0.300 mmol), 5-(methylamino)-N-Boc-pentanamine (73.7 mg, 0.331 mmol) l) and HBTU (128 mg, 0.331 mmol) in dry DMF (3 ml) IPEA (210 μl, 1.202 mmol) was added and the resulting RM was cooled to RT. The RM was diluted with DCM and added to a citrate buffer (pH 4, Sigma-Aldrich) a-Aldrich 33643) was added. The phases were separated and the aq. phase was extracted with DCM. The combined organic phases were dried over MgSO4 and evaporated to give a residue containing iPrO Purification by silica chromatography eluting with H in DCM (1-6%) gave the title compound. The compound was obtained as a solid (124 mg). Method A: Rt=0.88min;[M+H]+ =465.4.

[0417] Step 2: N-(5-aminopentyl)-5-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-2-fluoro-N,4-dimethylbenzamide HCl (4 M) in 1,4-dioxane (1.827 ml, 7.31 mmol) ert-butyl(5-(5-(2,4-dioxotetrahydropyrimidine-1(2H)- (2-fluoro-N,4-dimethylbenzamido)pentyl)carbamate (123 The suspension of RM was stirred at RT for 2 h under a N2 atmosphere. Concentration, redissolution in a mixture of ACN and water, and lyophilization gave the title compound as a solid. Obtained as the HCl salt (116 mg). Method A: Rt=0.46min;[M+H] + =365.3.

[0418] Step 3: 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-pyrimidin Fluoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-fluoro) Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethyl benzamide 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (xypropan-2-yl)benzamide (Intermediate 3, 60 mg, 0.114 mmol), N-(5-aminopentyl)-5-(2,4-dioxotetrahydropyrimidine-1(2 H)-yl)-2-fluoro-N,4-dimethylbenzamide hydrochloride (59.8 mg, 0.125 mmol) and TEA (0.017 ml, 0.125 mmol) The OH mixture (2.1 ml) was mixed with ZnCl2 (0.5 M) in THF (0.251 ml, 0 The resulting mixture was stirred at RT under N2 atmosphere for 3 min. Solid NaBH3CN (8.29 mg, 0.125 mmol) was added and the RM The mixture was stirred at RT for 18 h. The RM was diluted with ACN and added to Isolute® Adsorb onto HCl, dry, and elute with ACN (in an aq. solution of TFA (0.1%)). Purification was carried out by reversed phase chromatography on an edisep® C18 column to give PL- The title compound was obtained as a solid (7%) after filtration through a HCO3 MP SPE cartridge and lyophilization. 7 mg). Method A: Rt=0.81min;[M+H] + =875.4. 1 H NMR(400MHz,DMSO-d6)δ12.71(s,1H),10.35 (s,1H),9.92(s,1H),8.83(s,1H),7.91(m,2H), 7.72(t,J=7.89Hz,1H),7.64(m,J=9.70Hz,1H), 7.44-7.35(m,4H),7.31(dd,J=6.48,2.81Hz,1H ),7.24-7.18(m,2H),6.81(s,1H),5.28(s,1H), 3.80-3.62(m,3H),3.51-3.40(m,2H),3.11(m,1 H),2.93(s,1H),2.80(s,3H),2.64-2.77(m,2H) ,2.52(m,1H),2.39(m,1H),2.17(d,J=7.34Hz,6 H),1.41-1.57(m,9H),1.25-1.36(m,2H),1.02- 1.14(m,1H).

[0419] Compound 29: 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)benzyl)amino)pentyl)-4-methylbenzamide [ka] Step 1: tert-Butyl (5-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-2-fluoro-4-methylbenzamido)pentyl)carbamate 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl) under N2 atmosphere -2-fluoro-4-methylbenzoic acid (Intermediate 22, 80 mg, 0.300 mmol), N-Boc-cadaverine (0.071 ml, 0.331 mmol) and HBTU (128 A solution of 1 mg of 1000 kJ / kg ... DMF (3 ml) was added to 1000 kJ / kg of DIPEA (210 μl, 1.2 mg, 0.331 mmol). 02 mmol) was added. The resulting RM was stirred at RT for 2.5 h to give RM DCM and citrate buffer (pH = 4, Sigma-Aldrich 33643) The aqueous phase was extracted with DCM and the combined organic phases were washed with MgS Drying over O4, filtering, and evaporating affords the residue, which is then purified by distillation with iPrOH (in DCM) (1- The title compound was purified by silica gel chromatography eluting with 1000 mL of ethyl acetate (6%) to give the title compound as a solid (1 17 mg). Method A: Rt=0.86min;[M+H] + =451.3.

[0420] Step 2: N-(5-aminopentyl)-5-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-2-fluoro-4-methylbenzamide A solution of HCl (4 M) in 1,4-dioxane (1.753 ml, 7.01 mL) under N2 atmosphere was tert-Butyl (5-(2,4-dioxotetrahydropyrimidine) (mmol) -1(2H)-yl)-2-fluoro-4-methylbenzamido)pentyl)carbamate The suspension of RM (117 mg, 0.234 mmol) was stirred at RT for 2 h. The title compound was then redissolved in a mixture of ACN and water and lyophilized to give the title compound as solid HCl. Obtained as the l salt (106 mg). Method A: Rt=0.43min;[M+H] + =351.2.

[0421] Step 3: 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-pyrimidin Fluoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-fluoro) Hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-4-methylbenz amide 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (xypropan-2-yl)benzamide (Intermediate 3, 53 mg, 0.101 mmol), N-(5-aminopentyl)-5-(2,4-dioxotetrahydropyrimidine-1(2 H)-yl)-2-fluoro-4-methylbenzamide hydrochloride (50.4 mg, 0.111mmol) and TEA (0.015ml, 0.111mmol) in MeOH The combined solution (2 ml) was diluted with ZnCl2 (0.5 M) in THF (0.221 ml, 0.111 m mol) was added. The RM was stirred at RT under N2 atmosphere for 3 h. Solid NaBH3C N (7.32 mg, 0.111 mmol) was added and the RM was stirred at RT for 18 h. The mixture was diluted with ACN and dried by adsorption onto Isolute®. Redissolve in ACN (aq. solution of TFA (0.1%)) (10-100%) Purification was performed by reversed-phase chromatography on an ep® C18 column to obtain PL-HCO3 After filtration through an MP SPE cartridge and lyophilization, the title compound was obtained as a solid (65 mg). was obtained as. Method A: Rt=0.80min;[M+H] + =861.5. 1 H NMR(400MHz,DMSO-d6)δ12.71(s,1H),10.35 (s,1H),9.92(s,1H),8.83(s,1H),8.18-8.24(m ,1H),7.90(d,J=8.19Hz,2H),7.72(t,J=7.95Hz ,1H),7.64(d,J=10.51Hz,1H),7.50(d,J=6.97H z,1H),7.37-7.43(m,4H),7.17-7.24(m,2H),6. 80(s,1H),5.28(s,1H),3.67-3.80(m,4H),3.45 -3.52(m,1H),3.21(m,2H),2.67-2.80(m,2H),2 .43-2.47(m,2H),2.17(d,J=7.46Hz,6H),1.40- 1.52(m,10H),1,29-1.38(m,2H).

[0422] Compound 30: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-(( 4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane-2- (yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine -6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide [ka] Step 1: tert-Butyl (5-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-N,4-dimethylbenzamido)pentyl)carbamate 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylammonium Benzoic acid (Intermediate 8, 125 mg, 0.504 mmol), 5-(methylamino)-NB oc-pentanamine (124 mg, 0.554 mmol) and HBTU (214 mg, A solution of DIPEA (352 μl, 2.01 4 mmol) was added and the resulting RM was stirred at RT under N2 atmosphere for 1 h. RM was dissolved in DCM and citrate buffer (pH = 4, Sigma-Aldrich 33 643), the phases were separated, the aq. phase was extracted with DCM, and the combined organic phases were was dried over MgSO4, concentrated, and the residue was purified by distillation with iPrOH (in DCM) (2-10 The title compound was purified by silica gel chromatography eluting with 18% HCl to give the title compound as a solid (18%). 8 mg). Method A: Rt=0.86min;[M+H] + =447.4.

[0423] Step 2: N-(5-aminopentyl)-3-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-N,4-dimethylbenzamide HCl (4 M) in 1,4-dioxane (2.89 ml, 11.56 mmol) ert-butyl(5-(3-(2,4-dioxotetrahydropyrimidine-1(2H)- (yl)-N,4-dimethylbenzamido)pentyl)carbamate (187 mg, 0.3 A suspension of 85 mmol) was stirred at RT under N atmosphere for 1 h. The RM was concentrated to give The residue was redissolved in a mixture of ACN and water and lyophilized to give the title compound as a solid H Obtained as the Cl salt (171 mg). Method A: Rt=0.43min;[M+H] + =347.3.

[0424] Step 3: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-( 5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropanediol (2-methylphenyl)-7H-pyrrolo[2,3-d]piperidin-2-ylbenzamido Rimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide 2-Fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)phenyl)-7H-pyridinyl) (2-hydroxybenzoyl)-4-(2-methylphenyl)-4-(2-hydroxybenzoyl)-2-methylphenyl (xypropan-2-yl)benzamide (Intermediate 3, 90 mg, 0.171 mmol), N-(5-aminopentyl)-3-(2,4-dioxotetrahydropyrimidine-1(2 H)-yl)-N,4-dimethylbenzamide hydrochloride (90 mg, 0.171 m mol) and TEA (0.026 ml, 0.188 mmol) in MeOH (3.5 ml) in a THF solution of ZnCl2 (0.5 M) (0.376 ml, 0.188 mmol) The RM was stirred at RT under N2 atmosphere for 3 h. Solid NaBH3CN (12 0.44 mg, 0.188 mmol) was added and stirring was continued at RT for 18 h. was diluted with ACN and adsorbed onto Isolute® to dryness, and the residue was , Redisep® eluted with ACN (in an aq. solution of TFA (0.1%)) Purification was performed by reversed-phase chromatography on a C18 column, and the PL-HCO3MP SPE column After filtration through a cartridge and lyophilization the title compound was obtained as a solid (110 mg). Method A: Rt=0.80min;[M+H] + =857.6. 1 H NMR(400MHz,DMSO-d6)δ12.72(s,1H),10.34 (s,1H),9.92(s,1H),8.83(s,1H),7.91(d,J=8. 07Hz,2H),7.68-7.76(m,1H),7.64(d,J=9.78Hz ,1H),7.35-7.45(m,4H),7.25-7.32(m,2H),7.2 2(m,2H),6.80(s,1H),5.28(s,1H),3.63-3.81( m,3H),3.46-3.53(m,1H),3.39(m,2H),3.16(m, 1H),2.88(m,3H),2.64-2.76(m,2H),2.52-2.61 (m,1H),2.38(m,1H),2.18(s,3H),2.16(s,3H), 1.44(m,10H),1.31(m,1H),1.09(m,1H).

[0425] Compound 31: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]urethane (3-indecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy (propan-2-yl)benzamide [ka] 1-(2-Methoxy-5-(3,9-diazaspiro[5.5]undecane-3-carbo (1H,3H)-dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 21, 9 4 mg, 0.182 mmol) in dry ACN (2 ml) at RT under an argon atmosphere. Dissolve K2CO3 (144 mg, 1.042 mmol) in dry DMF (1 ml) and dry ACN (1 ml) in a mixture of 4-(4-(5-fluoro-3-(2 -fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl (phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethylmethanesulfonate A solution of methyl ester (Intermediate 13, 94 mg, 0.151 mmol) was added. The RM was heated to 55°C. After stirring for 24 h, the mixture was cooled to 0 °C and TFA (0.198 ml, 2.57 ml) was added. The mixture was dried by adsorption onto Isolute® HMN. The residue was eluted with ACN (aq. solution of TFA (0.1%)) (5-100%). The product was purified by reversed-phase chromatography on a Redisep® C18 column. The title compound was obtained as a solid after filtration through a L-HCO3 MP SPE cartridge and lyophilization. (21.2 mg). Method B: Rt=3.69min;[M+H] + =925.5. 1 H NMR(400MHz,DMSO-d6)δ12.71(s,1H),10.31 (s,1H),9.92(s,1H),8.83(s,1H),7.88(d,J=7. 8Hz,2H),7.72(t,J=7...

Claims

1. A compound represented by the following formula (XXIa): 【Chemistry 1】 (In the formula, R 6 is H or F; R 7 is H, F, Cl, —CH 3 , —OCH 3 , or —OCH 2 CH 3 ). A compound represented by the formula: or a salt thereof.

2. The compound or salt thereof according to claim 1, wherein R 6 is H.

3. The compound or salt thereof according to claim 1, wherein R 6 is F.

4. The compound or salt thereof according to claim 1, wherein R 7 is Cl or F.

5. The compound or salt thereof according to claim 1, wherein R 7 is —CH 3 .

6. The compound or salt thereof according to any one of claims 1 to 3, wherein R 7 is -OCH 3 .

7. The compound or salt thereof according to claim 1, wherein R 7 is —OCH 2 CH 3 .

8. The compound or salt thereof according to any one of claims 1 to 3, 6 and 7, wherein R 7 is —OCH 3 or —OCH 2 CH 3 .

9. The compound or salt thereof according to any one of claims 1 to 3 and 6 to 8, wherein R 6 is H and R 7 is —OCH 3 or —OCH 2 CH 3 .

10. The following formula: 【Chemistry 2】 The compound according to any one of claims 1 to 9, or a salt thereof, represented by:

11. A compound of the following formula: 【Transformation 3】 or a salt thereof, The following formula: 【Chemistry 4】 Use of a compound represented by the formula (I) or a salt thereof.

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