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

Abstract

This invention provides compounds used to treat symptoms, diseases, and disorders mediated by Bruton's tyrosine kinases. [Solution] Formula (I) TIFF2026082817000131.tif67170 This relates to the compound or its pharmaceutically acceptable salt, intermediates in the preparation of the compound, pharmaceutical compositions containing the compound, and the use of the compound in the treatment of diseases.

Description

[Technical Field]

[0001] This invention relates to N-(3-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl ) Benzamide derivatives, preparations thereof, pharmaceutical compositions containing the same, and Bruton's type tyrosine Regarding its use in the treatment of symptoms, diseases, and disorders mediated by -ase. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is involved in B cell receptor (BCR) signaling. It is a critical node in cancer and an important target within cancer. Many cancers and lymphomas are BT It expresses K and is dependent on BTK function. Furthermore, BCR signaling in tumor-infiltrating B cells The ng was related to the tumor-promoting microenvironment of solid tumors (JABurger and A. Wiestner, Nat Rev Cancer 2018, 18, 148). Using a vita inhibitor, particularly one that irreversibly binds to BTK via cysteine-481. Pharmacological inhibition of BTK has been established as a strategy, and BTK is the main target of molecular ibrutinib. It is a target (JABurger and JJBuggy, Leukemia) and Lymphoma (2013, 54, 2385). This is the treatment of several cancers. The location is shown (CS Lee et al., J. Oncol. Phar m.Practice 2016,22,92-104.V.Kaur&A.Swami ,Ann.Hematol.2017,96,1175), and at least one prior Acalabrutinib is indicated for the treatment of patients with mantle cell lymphoma who have received treatment. This has also been shown (Wang M et al, Lancet 2018, 391) (Issue 10121, 659-667).

[0003] Furthermore, BTK plays an essential role in autoimmune diseases. (BTK-deficient mouse) This is chronic rheumatoid arthritis (L. Jansson and R. Holmdahl, Clin). ical and experimental immunology 1993,94 ,459;LENyhoff et al,Arthritis Rheumatoid 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.) In a standard preclinical model of Med. 1998, 187, 1235-1247) Therefore, pharmacological inhibition of BTK may be useful in treating immunodeficiency.

[0004] In light of the above, the modulator of BTK is used in proliferative disorders such as cancer and immune disorders (e.g., autoimmune disorders). It may be useful in treating disease-related disorders.

[0005] BTK-dependent disorders, particularly those involving resistance to or insufficient response to currently available medications. A new drug is needed to treat this condition.

[0006] Reduce or remove BTK protein by inducing its degradation. The molecule designed to do this (hereinafter referred to as "BTK degrader") is a broad B It may be effective in treating TK-mediated diseases, such as proliferative disorders (cancer, etc.) and immunodeficiency. Furthermore, the BTK degrader is irreversible to the BTK inhibitor (which covalently bonds to BTK). This may be effective in situations of resistance to the substance. Resistance to the substance is, for example, cysteine-481 to serine. It can result from a mutation (or substitution of other amino acids).

[0007] Potential indicators of BTK degrader include, but are not limited to, hematopoietic origin. Cancer, e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, hair cells Leukemias, histiocytic neoplasms, dendritic neoplasms, B-cell neoplasms, such as chronic lymphocytic leukemia (C LL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldensian Threm's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma, Burkitt lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter syndrome, precursor B lymphoblastic lymphoma, primary multiple myeloma and secondary multiple myeloma Myeloma, B-cell pre-lymphocytic 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 effusion lymphoma, lymphoma granulomatosis, and acute lymphoblastic leukemia.

[0008] Furthermore, potential indicators for the BTK degrader include, but are not limited to, the following: Immune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, allergic diseases, and anaphylactic acid Symptoms include irritation and inflammation. Furthermore, potential indicators of BTK degradation. These include chronic graft-versus-host disease (cGvHD) and immunoglobulin light chain amyloidosis (A L) is one example.

[0009] The principle of induced degradation of protein targets as a potential therapeutic approach is, for example, C .M.Crews,2018,J.Med.Chem.,61(2),403-404 and It is stated in the cited references within the biography. The ibrutinib substructure is the BTK binding site. Recruitment of target proteins to the E3 ubiquitin ligase IAP for integration and degradation. Therefore, the BTK degrader molecule incorporating the E3 ligase IAP binding site was published in International Publication No. 2. It is described on page 12 of pamphlet number 016 / 169989. Two structural Two further BTK degrader molecules incorporating different parts as BTK binding components. Huang et al., 2018, Cell Chemical Biolog It is described in y 25,88-99. The molecules described in that publication are ubiquitinated. And for the breakdown thereof, B to the E3 ligase complex containing cereblon (CRBN) To mobilize TK, incorporate the immunomodulatory imide (IMiD) portion (pomalidomide). Furthermore, Huang et al. describes how multiple targets, including BTK, are separated. It causes the zinc finger DNA-binding protein IKZF1 (Ikaros) to dissolve and also the zinc finger DNA-binding protein IKZF1 (Ikaros) A miscellaneous kinase binder that has been reported to degrade certain non-kinase targets, including This is a molecule (TL12-186) based on IKZF1 and related proteins IKZF3. Aiolos is known to be broken down 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 Problems

[0010] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbelow. Since the compound of formula (I) is a BTK degrader, it is potentially useful for the treatment of symptoms, diseases and disorders mediated by BTK .

[0011] In one aspect of the present invention, formula (I)

Chemical formula

Chemical formula

[0012] The present invention relates to a novel N-(3-(7H-pyrrolo[2,3-d]pyrimidine-4 of formula (I). -Iyl(phenyl)benzamide compounds, which are Bruton-type tyrosine kinases ( This leads to the degradation of BTK. The compound is BTK (BTK mutant, especially BTK Although it confers resistance to inhibitors, especially irreversible BTK inhibitors such as ibrutinib, By mobilizing (including) into E3 ligase, the decomposition of BTK is induced, Designed to promote the theasome's ubiquitination and subsequent degradation of BTK. The compound of the present invention is a novel compound that binds to E3-ligase cereblon (CRBN). It includes a novel BTK-binding domain portion bound to Gand.

[0013] Therefore, the compounds of the present invention are mediated by proliferative autoimmune diseases, particularly BTK. Disorders and diseases (e.g., mutations of cysteine-481 to serine (or other amino acid mutations)) Potentially useful in treating a wide range of diseases and disorders, including those that have developed resistance due to exchange. The compounds of the present invention may include IMiDs, such as thalidomide, lenalidomide, and po It is degraded by maridomide and also by the aforementioned protein degradation molecule TL12-186. It has been shown that other proteins, particularly other tyrosine kinase proteins, and / Or the (non-tyrosine kinase) IKZF1 and / or IKZF3 proteins. The compounds of the present invention may further demonstrate selectivity for BTK degradation against the ZF family. Ze-selectivity and / or other off-target proteins, such as ion channels and G-tanks. This may further demonstrate selectivity for protein-binding receptors (GPCRs).

[0014] Therefore, compounds of formula (I) (including their pharmaceutically acceptable salts) are BTK Symptoms, diseases and disorders mediated by, in particular, proliferative symptoms, diseases and disorders, such as cancer, This includes hematopoietic cancers (B-cell neoplasms, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma). MCL (mammary leukoma), small lymphocytic lymphoma (SLL), Waldenström macroglobulin Lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt Lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter syndrome, precursor B lymphoma Lymphoblastic lymphoma, primary multiple myeloma and secondary multiple myeloma, B-cell prolymphoblastic Leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytosis myeloma, plasmacytoma Extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma Cystic lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, lymphoma granuloma It is considered suitable for use in the treatment of tumors (including acute lymphoblastic leukemia). .

[0015] In another embodiment, the present invention treats, prevents or treats symptoms, diseases or disorders mediated by BTK. This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in methods of improvement. ru.

[0016] In another embodiment, the present invention relates to a compound of formula (I) or (for example, a therapeutically effective amount) A composition comprising the pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers is proposed. To provide.

[0017] In another embodiment, the present invention relates to a compound of formula (I) or (for example, a therapeutically effective amount) The present invention provides a combination comprising a pharmaceutically acceptable salt and one or more therapeutically active agents. [Modes for carrying out the invention]

[0018] Various embodiments of the present invention are described herein. The features specified in each embodiment are: It is recognized that, in combination with other specified features, further embodiments of the present invention may be provided. It will be. Furthermore, various (listed) embodiments of the present invention are described herein. .

[0019] The definition of substituents is, where applicable, formulas (I), (I'), (I''), (I''') and This corresponds to compound (Ia).

[0020] The definition of substituent applies to the final product and its corresponding intermediate.

[0021] Therefore, the present invention relates to formula (I) [ka] (In the formula, R 1 , R 1a , R 2 and R 2a In each existence, H and F are independently selected; R 6 is either H or F; R 7 It is selected from H, F, Cl, -CH3, -OCH3, and -OCH2CH3; X 1 is equation (A) or (B): [ka] It is the basis of, and in the formula, * X 1a teeth, * -(CH2) 1~3 -and * Selected from -CH2C(CH3)2-, Here, * X in equation (I) 1a Shows the attachment site of the group to the phenyl ring; * X 1b is selected from * -O-, * -OCH2- and * -CH2O-, where * is the attachment point of X in formula (I) 1b to the phenyl ring of the group; X 2a is selected from formulas (C), (D), (E), (F) and (G):

Chemical formula

Chemical formula

[0022] Unless otherwise specified, the terms "multiple compounds of the present invention" or "one compound of the present invention" are used interchangeably. Formula (I), compounds of its subformulas and exemplary compounds, and their salts, and all of the formulas Isomers (including diastereoisomers and enantiomers), rotational isomers, tautomers, and Compounds labeled with isotopes (including deuterium substitution), and moieties formed endogenously .

[0023] Unless otherwise specified, the expressions used in the present invention have the following meanings. In this specification The term -(CH2) 1~3 - consists solely of carbon and hydrogen atoms, contains no unsaturation has 1 to 3 carbon atoms, and refers to a (particularly) linear hydrocarbon chain biradical attached to other molecules at each end by a single bond . For such groups, the ends attached to other molecules at specific positions can be specified by an indicator symbol * or ** . Similar terms, such as -(CH2)2O-, -(CH2) 2~3 NH-, -(CH2) 3~4 NH(CH2)2- and -(CH2)4NH- incorporated groups should be interpreted accordingly .

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

[0025] Embodiment 2. A compound of formula (I) according to Embodiment 1 wherein R<00> 1 is H, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 3. A compound of formula (I) according to Embodiment 1 or 2 wherein R<00> 1a is F, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 4. A compound of formula (I) according to any one of Embodiments 1 to 3 wherein R<00> 2 is H, or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 5.R 2a F is the chemical formula of formula (I) according to any one of embodiments 1 to 4. Compounds or pharmaceutically acceptable salts thereof.

[0029] Embodiment 6.R 6 is a compound of formula (I) according to any one of embodiments 1 to 5, wherein H is A substance or its pharmaceutically acceptable salt.

[0030] Embodiment 7.R 7 This is selected from F, -CH3 and -OCH3, according to Embodiments 1 to 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof that follows any one of the following conditions.

[0031] Embodiment 8.R 7 F is a compound of formula (I) according to any one of embodiments 1 to 7. A substance or its pharmaceutically acceptable salt.

[0032] Embodiment 9.R 7 is -CH3, according to formula (I) according to any one of embodiments 1 to 7 A compound of or a pharmaceutically acceptable salt thereof.

[0033] Embodiment 10.R 7 is -OCH3, according to one of the embodiments 1 to 7 ( I) The compound or a pharmaceutically acceptable salt thereof.

[0034] Embodiment 11.X 1 Equation (A): [ka] A compound of formula (I) according to any one of embodiments 1 to 10, which is the base of, or pharmaceutically Allowable salt.

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

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

[0037] Embodiment 14. X 2a is of formula (C), (E) and (F):

Chemical formula

[0038] Embodiment 15. X 2a is of formula (C) and (E):

Chemical formula

[0039] Embodiment 16. R 4 is H, a compound of formula (I) according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt thereof. I) or a pharmaceutically acceptable salt thereof.

[0040] Embodiment 17. R 5 is H, a compound of formula (I) according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof. I) or a pharmaceutically acceptable salt thereof.

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

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

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

[0044] Embodiment 21.X 5 and X 6 Both are CH, one of any 1 of Embodiments 1 to 20 A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 22.X 5 and X 6 Both are N, one of Embodiments 1 to 20 A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 23.Z 1 teeth, * -O- is an expression that follows any one of embodiments 1 to 21 ( I) The compound or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 24.Z 1 teeth, * The chemical formula (I) according to Embodiment 22 is -(CH2)2- Compounds or pharmaceutically acceptable salts thereof.

[0048] Embodiment 25.Z 2a is -NH(CH2)4- ** The embodiments 1 to 24 are A compound of formula (I) or a pharmaceutically acceptable salt thereof that follows any one of the following conditions.

[0049] Embodiment 26.Z 2a is -NH(CH2)4- **The formula according to Embodiment 13 is ( I) The compound or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 27.Z 3 Formula (I) is absent, according to any one of embodiments 1 to 26. A compound of or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 28.Z 3 is absent, the compound of formula (I) according to Embodiment 1 or its pharmaceutical A generally acceptable salt.

[0052] Embodiment 29. Formula (Ia) [ka] (In the formula, R 6 is either H or F; R 7 It is selected from H, F, Cl, -CH3, -OCH3, and -OCH2CH3; X 1 is equation (A) or (B): [ka] It is the basis of, and in the formula, * X 1a teeth, * -(CH2) 1~3 -and * Selected from -CH2C(CH3)2-, Here, * This is X in equation (Ia). 1a Shows the attachment site of the group to the phenyl ring; * X 1b teeth, * -O-, * -OCH2- and * Selected from -CH2O-, where, * This is X in equation (Ia). 1bShows the attachment site of the group to the phenyl ring; X 2a These are equations (C), (D), (E), (F), and (G): [ka] Selected from, in the formula, ** X 1a It shows the attachment point; X 2b These are equations (E1) and (F1): [ka] Selected from, in the formula, ** X 1b It shows the attachment point; X 5 is either CH or N; X 6 is either CH or N; R 3 is H or -CH3; R 4 is either H or -CH2OH; R 5 is either H or -CH2OH; Z is absent or * -(CH2) 2~3 It is NH-, and here, * This is in equation (C) This shows the attachment site of Z to the N atom; Z 1 teeth, * -O-, * -C(O)-, * -(CH2) 1~3 -, * -(CH2)2O- and * Selected from -CH2CH(CH2OH)O-, where, * is equation (E) and equation ( Z in E1) 1 X 5 It shows the attachment point; Z 2a is absent or NH(CH2)4- ** and; Z 2b is, -(CH2) 3~4 NH(CH2)2- ** and; Z 3 is absent or ** It is -(CH2)4NH- and Z 2a and Z 3 Both are simultaneous Not absent; Here, Z 2a , Z 2b and Z 3 In each of the ** This is based on equations (F) and (F1). This shows the attachment points to each N atom; q is 0 or 1; and n and p are independently either 0 or 1; (i) Z in equation (E) or equation (E1) 1 but * If it is -O-, then X 5 and X 6 teeth, (ii) Z in equation (E) or equation (E1) 1 but * -(CH2)2-O - or * If it is -CH2CH(CH2OH)O-, then X 6 (is not N) A compound of or a pharmaceutically acceptable salt thereof.

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

[0054] Embodiment 31.R 4H is the formula (Ia) according to Embodiment 29 or Embodiment 30 A compound or a pharmaceutically acceptable salt thereof.

[0055] Embodiment 32.R 5 H is the formula (Ia) according to any one of embodiments 29 to 31. A compound of ) or a pharmaceutically acceptable salt thereof.

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

[0057] Embodiment 34.n is formula (Ia) which follows any one of Embodiments 29 to 33, where 1 is the formula A compound of or a pharmaceutically acceptable salt thereof.

[0058] Embodiment 35.p is formula (Ia) which follows any one of Embodiments 29 to 34, where 1 is the formula A compound of or a pharmaceutically acceptable salt thereof.

[0059] Embodiment 36.Z is a compound of formula (Ia) according to Embodiments 29-35, or The pharmaceutically acceptable salt.

[0060] Embodiment 37.X 5 and X 6 Both are CH, one of embodiments 29 to 36. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof that follows one of the following.

[0061] Embodiment 38.X 5 and X 6 Both are N, one of the embodiments 29 to 36 A compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

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

[0063] Embodiment 40.Z 1 teeth, * -O- and * -(CH2)2- selected, Embodiment 3 A compound of formula (Ia) according to 9, or a pharmaceutically acceptable salt thereof.

[0064] Embodiment 41.X 1 teeth, [ka] (In the formula, * (wherein this 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 according to Embodiment 29, selected from the above. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0065] Embodiment 42.X 1 teeth, [ka] (In the formula, * (wherein this indicates the atom attached to the phenyl ring in formula (I) or formula (Ia)) A compound of formula (I) or formula (Ia) according to Embodiment 41, selected from the above, or pharmaceutically thereof Allowable salt.

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

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

[0068] Embodiment 45.R 4 and R 5 Both are H, one of any one of embodiments 41 to 44 A compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof.

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

[0070] Embodiment 47.Z is absent from any one of Embodiments 41-46, which follows formula (I). or the compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0071] Embodiment 48.X 1 teeth, [ka] [ka] [ka] [ka] (In the formula, * (wherein this indicates the atom attached to the phenyl ring in formula (I) or formula (Ia)) Formula (I) according to one of embodiments 1 to 10, 29 and 30 selected from (Ia) is a compound or a pharmaceutically acceptable salt thereof.

[0072] Embodiment 49.X 1 teeth, [ka] (In the formula, * (wherein this indicates the atom attached to the phenyl ring in formula (I) or formula (Ia)) A compound of formula (I) or formula (Ia) according to Embodiment 48, selected from the above, or pharmaceutically thereof Allowable salt.

[0073] Embodiment 50.rac-N-(3-(6-(4-((9-(3-(2,4-dioxote Trahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydro Xymethyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)phen (Lu)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methyl Phenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Roro[2,3-d]pyrimidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium N-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]u Ndecane-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-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-fluorobenzoyl)piperidine-4-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl Piperazine-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-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy )piperidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Loxypropan-2-yl)benzamide, N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidium 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-dioxotetrahydropyrimidium n-1(2H)-yl)benzoyl)-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-hydroxypropane-2) -Il)benzamide, N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Pyro)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-Dioxote Trahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4 -yl)oxy)-3-hydroxypropyl)piperidine-4-yl)oxy)phenyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methyl Enyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-((1-((3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl )piperidine-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-dioxotetrahydropyrimidium 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrim (Zin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-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, rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)butyl)piperazin-1-yl )methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-full Oro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl) ) Benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]unde Can-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (L)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Pan-2-yl)benzamide, 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3 -d] Pyrimidine-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenz Amido, 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3 -d] Pyrimidine-6-yl)benzyl)amino)pentyl)-4-methylbenzamide , 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-N-(5-( (4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane-2 -yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl N-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-2,7-diazaspiro[3.5]nona (-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl)benzamide, N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydropyrim (Di-1(2H)-yl)-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,8-diazaspi Ro[4.5]decane-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Midine-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)amino)butoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-i (L)-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 Hydropyrimidine-1(2H)-yl)benzamide)ethyl)-1-oxa-4,9- Diazaspiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-1-oxa-4,9 -Diazapiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu Oro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-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-Gioki Sotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, 4-Chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-yl)benzyl)amino)pentyl)-N-methylbenzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyryl Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-3,9-diazaspi Ro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((3-((2-(4-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) Ethyl)amino)propoxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((1r,4r)-4-((1-(3(2,4-dioxo Tetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-((4-(3-(4-chloro-3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)benzamide)propyl)-1-oxa-4,9 -Diazapiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu 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 (2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy) Piperidine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperidine-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyryl Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,7-diazaspi Ro[3.5]nonan-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,8-diazaspi Ro[4.5]decane-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Midine-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 Tetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-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 (-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl)benzamide, N-(3-(6-(4-((((1r,4r)-4-((1-(3-(2,4-Gioki Sotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(4-chloro-3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)benzamide)propyl)-3,9-diazaspi Ro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-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-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Oxy)ethyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide A compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 51. N-(3-(6-(4-((4-((1-(3-(2,4-dioxote Trahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4 -yl)oxy)piperidine-1)yl)methyl)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Loxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 5-Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydrox Cypropan-2-yl)benzamide A compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt thereof.

[0075] Embodiment 52. Compound N-(3-(6-(4-((4-((1-(3-(2,4-Geo Xotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine (-4-yl)oxy)piperidine-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable Salt.

[0076] Embodiment 53. Compound N-(3-(6-(4-((9-(3-(2,4-dioxoteto Lahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3,9-diaza Spiro[5,5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3- d] Pyrimidine-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- Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl)piper Zin-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu Oro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable Salt.

[0078] Embodiment 55. Compound N-(3-(6-(4-((4-(2-(4-(3-(2,4- Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl) pipette Radin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form Salt.

[0079] Embodiment 56. Compound N-(3-(6-(4-(2-(9-(3-(2,4-dioxo Tetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3,9-di Azaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2, 3-d]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable salt.

[0080] Embodiment 57. Compound N-(3-(6-(4-(2-(4-((1-(3-(2,4- Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl) pipette Lysine-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form Salt.

[0081] Embodiment 58. Compound N-(3-(6-(4-(((4-(4-(3-(2,4-Geo Xotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazi 1-Il)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrrolo Midine-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 Tetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)-3,9-di Azaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[2, 3-d]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable salt.

[0083] Depending on the selection of starting materials and procedures, the compound may take one possible form of stereoisomer. or mixtures of stereoisomers, for example, pure optical isomers or mixtures of stereoisomers, for example It can exist as a racemic mixture and a mixture of diastereoisomers (depending on the number of chiral carbon atoms) (determined). The present invention relates to racemic mixtures, diastereomer mixtures and optically pure forms. It is intended to include all conceivable stereoisomers. Optically active -(R) stereoisomer Isomers and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents. Alternatively, it can be divided using conventional techniques. If the compound contains a double bond, the substituent is It may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, cyclo Alkyl substituents may have a cis configuration or a trans configuration. Also, all tautomorphisms It is intended that the forms of the opposite sex be included.

[0084] Compounds of formula (I) or formula (Ia) may exist in various tautomeristic forms. The present invention encompasses all tautomeristic forms of compounds of formula (Ia). For example, formula Compound (I) is given by formulas (I') and (I''). [ka] (In the formula, R 1 , R 1a , R 2 , R 2a , X 1 , R 6 and R 7 is equation (I) or equation (Ia) (As defined according to the law) It may exist in tautomeristic forms that follow [a specific pattern].

[0085] As used herein, the terms "one salt" or "multiple salts" refer to the acid-treated compounds of the present invention. This refers to salts with added salt or base. Specifically, "pharmaceutically acceptable salts" are often cited as an example of "salt." .

[0086] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the compound of the present invention. Furthermore, it typically refers to a salt that is not undesirable, either biologically or otherwise. The compound of the present invention The presence of an amino group and / or a carboxyl group or a similar group results in an acid salt. And / or base salts may be formed.

[0087] The pharmaceutically acceptable salts of the present invention are obtained by conventional chemical methods, either by the basic or acidic portion. Such salts can be synthesized from the free acid form of the compound using an appropriate base. By reacting it with a stoichiometric amount, or by converting the free base form of the compound into an appropriate acid It can be prepared by reacting it with a stoichiometric quantity. Such reactions are typically This is carried out in water, an organic solvent, or a mixture of the two. Usually, if feasible, Tel, ethyl acetate, ethanol, isopropanol, acetonitrile or tetrahydrof The use of a non-aqueous medium such as R is desired. A list of suitable further salts is, for example, “R emington's Pharmaceutical Sciences”,20th ed., Mack Publishing Company, Easton, Pa., (1985) and “Handbook of Pharmaceutical Salt s:Properties,Selection,and Use”(Stahl an d Wermuth)(Wiley-VCH,Weinheim,Germany,20 02) It can be found inside.

[0088] Furthermore, when both a basic group and an acidic group are present in the same molecule, the compound of the present invention is internal Salts, such as zwitterionic molecules, can be formed.

[0089] The compound of the present invention contains at least one basic group, for example, an amino group. Therefore, it is particularly suitable for forming acid addition salts.

[0090] Pharmacologically acceptable acid addition salts can be formed from inorganic and organic acids.

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

[0092] Examples of organic acids that can be derived from salts include acetic acid, propionic acid, glycolic acid, oxalic acid, and ma 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. It is possible.

[0093] pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. .

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

[0095] Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, and naturally occurring ones. Examples include substituted amines containing substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, corinate, and diethanol. Examples include amines, diethylamine, lysine, meglumine, piperazine, and tromethamine. ru.

[0096] In another embodiment, the present invention relates to the compound of the present invention as an acetate, ascorbate, adipine Salts, aspartates, benzoates, besilates, bromides / hydrobroms, bicarbonates / Carbonates, bisulfates / sulfates, camphor sulfonates, caprinates, chlorides / hydrochlorides, Chlortheophyllonate, citrate, ethanedisulfonate, fumarate, Glucept Salts, glucuronides, gluconates, glutamates, glutarates, glycolates Hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, Lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methyl sulfate, mucoates, naphthoates, napsylates, nicotinates, nitrates, octades Canate, oleate, oxalate, palmitate, pamoate, phosphate / hydrophosphate Raw salt / dihydrogen phosphate, polygalacturate, propionate, sebacinate, stearyl Sulfates, succinates, sulfosalicylates, sulfates, tartrates, tosylates, triphenates Provided in the form of trifluoroacetate, trifluoroacetate, or xinafoate.

[0097] All formulas given herein refer to the unlabeled and isotope-labeled forms of compounds. It is also intended to represent that one or more atoms are selected in an isotope-labeled compound. Other than being substituted by an atom having the given atomic weight or mass number, as given herein It has a structure represented by the formula shown. Examples of isotopes that can be incorporated into the compound of the present invention are And then there are isotopes of hydrogen.

[0098] In another embodiment of the present invention, formula (I''') [ka] (In the formula, R 1 , R 1a , R 2 , R 2a , R 6 This is defined for equation (I) or equation (Ia). As stated above, R 7 -C(R 10 )3, -OC(R 10 )3 or -OC(R 10 ) 2C(R 10 )3, X 1 teeth, [ka] Selected from, Each R 8 , R 9 and R 10 In each existence, it is independently selected from H or deuterium, and described Number # is independently substituted by H or deuterium in each presence. (Indicates the position where it is shown to be The compound is provided.

[0099] Specific isotopes, especially deuterium (i.e.) 2 Incorporation of H or D) leads to greater metabolic stability For example, by extending the in vivo half-life, relaxing the drug requirements, or improving the therapeutic index or tolerability. It may provide certain therapeutic benefits. Deuterium, in relation to this, is involved in formulas (I) and (I). It is understood that (Ia) is a substituent of the compound. The concentration of deuterium is an isotopic enrichment. It can be defined by a coefficient. The term "isotope enrichment coefficient" as used herein refers to the isotope This refers to the ratio between the abundance and the natural abundance of a specified isotope. In the compounds of the present invention... When the substituent is expressed as deuterium, the compound is an isotopic of each specified deuterium atom. The material concentration factor is at least 3500 (52.5% deuterium in each specified deuterium atom). (Integrated), at least 4000 (60% deuterium embedded), at least 4500 (67. (5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 55 00 (82.5% deuterium content), at least 6000 (90% deuterium content), little At least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium) (Hydrogen incorporated), at least 6600 (99% deuterium incorporated), or at least 6633. It is 3 (99.5% deuterium incorporated). The term "isotope enrichment factor" is used for deuterium. It should be understood that, just as it is listed, it can be applied to any isotope. be.

[0100] Other examples of isotopes that can be incorporated into the compound of the present invention include hydrogen, carbon, nitrogen, Isotopes of oxygen, fluorine, and chlorine, for example, 3 H, 11 C, 13 C, 14 C, 15 N , 18 F, 35 S, 36 Cl and 125 I is one example. Therefore, the present invention is, for example, , radioactive isotopes, for example 3 H and 14 Incorporate one or more of the above-mentioned isotopes containing C Compounds or non-radioactive isotopes, for example 2 H and 13 It is understood that this includes those in which C exists. Such isotope-labeled compounds should be used in metabolic studies. 14 (by C), opposite Research on response dynamics (for example, 2 H or 3 (by H), detection or imaging techniques, such as positron emission. Tomography (PET) or single-photon emission computed tomography (SPECT) (tissue of drug or substrate) It is useful for distribution assays or for radioactive treatment of patients. In particular, 18 F-labeled compounds, This may be particularly desirable for PET or SPECT studies. The isotope-labeled compound of formula (I). Typically, this involves using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent. or similar to the process described in the appended examples, by the prior art known to those skilled in the art or by the process described in the appended examples. It can be prepared by the following process.

[0101] As used herein, the term “pharmaceutical composition” refers to at least one pharmaceutically acceptable The compound of the present invention in a form suitable for oral or parenteral administration, together with a carrier, or This refers to a pharmaceutically acceptable salt of [the substance].

[0102] As used herein, the term "pharmaceutically acceptable carrier" refers to the preparation of a pharmaceutical composition or This refers to a substance useful for use, for example, a suitable diluent, solvent, or dispersion known to those skilled in the art. System media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drugs Physical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes and These combinations include (for example, Remington's Pharmaceut ical Sciences,18th Ed.Mack Printing Comp See any, 1990, pp. 1289–1329.

[0103] In this invention, the term "therapeutably effective amount" of a compound refers to the amount that induces a biological or medical response in the target. For example, to reduce or inhibit enzyme or protein activity, or to improve disease symptoms. To treat, alleviate symptoms, slow or delay the progression of the disease, or prevent the disease. This refers to the amount of the compounds of the present invention, such as those mentioned above. In one embodiment, the term "therapeutably effective amount" means When administered to the target, (1)(i) mediated by BTK, or (ii) BTK activity (iii) related to, or characterized by BTK activity (normal or abnormal) To alleviate, prevent, and / or improve the symptoms, disorders, or diseases that are present. (2) reduce or inhibit BTK activity; or (3) express BTK This refers to the amount of the compound of the present invention that is effective in reducing or inhibiting these effects. The result can be achieved, for example, by reducing the amount of BTK through decomposition of BTK. It is possible. In another embodiment, the term “therapeutably effective amount” can refer to cells, tissues, or non-cells. When administered to biomaterials or culture media, it at least partially reduces the activity of BTK or Alternatively, inhibit it; or reduce BTK expression by, for example, degrading BTK. This also refers to the amount of the compound of the present invention that is effective in partially reducing or inhibiting it.

[0104] As used herein, the term "subject" refers to primates (e.g., humans, males or females), i This refers to animals, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, Elephants are primates. In one embodiment, the subject is a human.

[0105] As used herein, the terms "inhibit" or "to inhibit" refer to a specific symptom, sign, or disorder. Alternatively, disease reduction or suppression, or baseline of biological activity or biological process. This refers to a significant decrease in activity.

[0106] As used herein, the terms "decompose" or "decompose" refer to the biological activity of BTK ( The cellular proteasome system reduces or eliminates abnormal activity. This refers to the partial or complete degradation of a target protein, such as BTK. Degradation is performed by E3 ligases. This can be achieved, in particular, through the mediation of an E3 ligase complex containing the protein cereblon. The terms "regulation of BTK activity" or "to regulate BTK activity" used in this document refer to BTK This means altering the activity, particularly reducing, suppressing, or removing it. This involves degrading BTK. This can be achieved by the following: The amount of decomposed BTK is measured before treatment with the compound of the present invention. The initial amount or level of BTK present and the BTK after treatment with the compound of the present invention. It can be measured by comparing it with the residual amount. In one embodiment, the initial Compared to the Bell, at least about 30% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 40% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 50% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 60% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 70% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 80% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 90% of the BTK is decomposed. In one embodiment, the initial Compared to the Bell, at least about 95% of the BTK is decomposed. In one embodiment, the initial Compared to Bell, over 95% of BTK is decomposed. In one embodiment, compared to the initial level. This decomposes at least approximately 99% of BTK.

[0107] In one embodiment, BTK is reduced in amount by approximately 30% to approximately 99% compared to the initial level. Understood. In one embodiment, BTK is approximately 40% to approximately 99% compared to the initial level. The quantity decomposes. In one embodiment, BTK is reduced by about 50% to about 9% compared to the initial level. 9% of the amount decomposes. In one embodiment, BTK is about 60% compared to the initial level. Approximately 99% of the amount decomposes. In one embodiment, BTK is approximately compared to the initial level. Approximately 70% to 99% of the amount decomposes. In one embodiment, BTK is compared to the initial level. Approximately 80% to 99% of the amount is decomposed. In one embodiment, BTK is at an initial level Compared to that, approximately 90% to 99% of the amount is decomposed. In one embodiment, BTK is the initial Approximately 95% to 99% of the amount is decomposed compared to the level. In one embodiment, BTK is Approximately 90% to 95% of the amount is broken down compared to the initial level.

[0108] As used herein, the term "BTK selectivity" means, for example, that the compound of the present invention is BTK This means that it will be broken down preferentially to or to a greater extent than other proteins. It tastes good.

[0109] The terms used herein, "to treat" or "to treat" any disease or disorder "Treatment" of a disease or disability means alleviating or improving the disease or disability (that is, To slow down or suppress the progression of the disease or at least one of its clinical symptoms. and); or related to a disease or disorder (including those that may not be identifiable to the patient) To alleviate or improve at least one related physical parameter or biomarker It refers to doing something.

[0110] The terms used herein, "prevent" or "prevent" any disease or disorder "Prevention" of disease or disability means preventive measures for disease or disability; or disease or disability This refers to delaying the onset or progression of a condition.

[0111] The subjects used herein refer to subjects that are biological, medical, or subject to such treatment. If the treatment is beneficial to the quality of life, then the treatment is "necessary."

[0112] The terms used herein in relation to the present invention (particularly in relation to the claims) The terms "one (a)", "one (an)", "that", and similar terms are, Unless otherwise specified in the details or unless the context clearly contradicts it, singular and plural. It should be interpreted as encompassing both.

[0113] All methods described herein, unless otherwise specified herein or in context, As long as there is no obvious contradiction, it can be performed in any appropriate order. The use of any example or illustrative wording provided (e.g., "etc." or "for example") The purpose is solely to better illustrate the present invention and, unless otherwise claimed, This does not impose any limitations on the scope of the present invention.

[0114] Any asymmetric atom (e.g., carbon) of the compound of the present invention is racemic or enantiomer. It can be concentrated organically and exist in configurations such as (R)-, (S)-, or (R,S)-. In this embodiment, each asymmetric atom has an enantiomer excess of (R)-configuration or (S)-configuration. At least 50%, at least 60% extra enantiomers, at least 70% extra enantiomers , at least 80% have extra enantiomers, at least 90% have extra enantiomers, and extra enantiomers At least 95% or at least 99% enantiomerity is present. It has an unsaturated double bond. In atoms, substituents exist in cis (Z) form or trans (E) form, where possible. -It can exist in a specific form.

[0115] Therefore, the compounds of the present invention used herein have possible stereoisomers, rotations Isomers, atropisomers, tautomers, or mixtures thereof in one form, for example, substantially Pure geometric (cis or trans) stereoisomers, left-right isomers, optical isomers (opposites) It may be in the form of a racemic mixture or a mixture thereof.

[0116] Any mixture in which stereoisomers are formed is determined based on the physicochemical differences of its constituent components, for example. Chromatography and / or fractional crystallization reveal pure or substantially pure geometric isomers or It can be separated into optical isomers, diastereoisomers, and racemates.

[0117] Any racemic mixture resulting from the compound or intermediate of the present invention can be prepared by known methods, for example. For example, by separating the diastereomer salt obtained with an optically active acid or optically active base, By releasing optically active acidic compounds or optically active basic compounds, they are separated into enantiomers. It can be divided. Therefore, the basic portion is particularly suitable for optically active acids, such as tartaric acid. Dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluyl tartaric acid, man By fractional crystallization of salts formed with delic acid, malic acid, or camphor-10-sulfonic acid Furthermore, the present invention can be used to split the compound into enantiomers. Compounds or racemic intermediates are analyzed using chiral chromatography, for example, high-pressure liquid chromatography with a chiral adsorbent. It can be separated by whole-body chromatography (HPLC).

[0118] The compounds of this application were synthesized organically using commercially available starting materials and compounds known in the literature. In some methods well known to those skilled in the art, or from easily prepared intermediates, Standard synthesis that is either described or will be apparent to those skilled in the art in consideration of the teachings herein. It can be prepared by using the methods and procedures. For all examples, potential For example, Protective Groups in Orthogonal Protective Groups (ORG) anic Synthesis, 3 rdedition, John Wiley & So ns: New York, 1999 or Protecting Groups, 3 rd Standards such as those described in edition, Thieme, Stuttgart, 2004 It can be used in accordance with the knowledge of typical textbooks. Those skilled in the art will know that it is disclosed herein. They will be able to recognize whether a stereocenter exists in the compound.

[0119] The compounds of the present invention can be synthesized according to the following scheme. The compounds are related to The reaction procedure is used in a modular manner that allows for various reaction sequences to construct the final molecule. It can be assembled in various ways. Some reaction types are particularly useful for producing the compound. Useful. All of the compounds of the present invention are coupling reagents in solvents such as DMF or DMA. (e.g., HATU or HBTU) and a base (e.g., DIPEA or NMM) are used. amide functionalities typically formed by amide coupling reactions between amines and carboxylic acids. It contains the group. Instead, the carboxylic acid first contains its pentafluorophenol ester. It can be converted to an amine in the presence of a base such as TEA in a solvent such as DMF. The amide can be formed by a simple subsequent reaction. This product contains a carbon-nitrogen bond. The compounds in question often undergo reductive amination, starting with amines and aldehydes or ketones. It can be produced using a reaction. The reaction involves N in a solvent mixture such as THF and MeOH. This occurs under conditions such as aBH3CN, ZnCl2, and TEA. Furthermore, the carbon-nitrogen bond... Typically, alkyl halides or A are used in the presence of a base (such as TEA) in a solvent such as THF. Nucleophilic substitution reaction of amines with suitable reaction partners containing leaving groups such as lucylmesylate. It can be formed by [method]. Furthermore, compounds containing ether can be formed by nucleophilic substitution reactions. In this case, the alcohol is subjected to a halo reaction in the presence of a base (such as TEA) in a solvent such as THF. It is produced by reacting it with a suitable partner containing a leaving group, such as benzyl genate. It is possible. Another generally useful method for producing the ether-containing compounds of the present invention is: This is the Mitsunobu reaction. In this reaction, phenol and another alcohol are used as solvents such as THF. In the case of phosphine (triphenylphosphine, etc.) and azodicarboxylic acid ester (diethi (in the presence of azodicarboxylic acid ester or diisopropylazodicarboxylic acid ester, etc.) They react with each other. Another reaction that is highly useful for the synthesis of the compounds of the present invention is the reaction of two aromatic compounds. This is a palladium (Pd) catalyzed cross-coupling reaction that bonds group groups to each other. Particularly useful This is because the catalyst in a solvent mixture such as dioxane / water (e.g., PdCl2(dppf)) and Aromatic halides and fragrances using a base (e.g., Na2CO3 or Cs2CO3) This is a Suzuki coupling reaction with a boronic acid or ester.

[0120] Specifically, the compound of formula (I) is R 1 , R 1a , R 2 , R 2a , X 1 , R 6 , R 7 , X 1a and X 2a Manufactured as shown in Scheme 1, which is as previously defined. It is possible. M is defined as H or as a protecting group such as -SO2Ph or -SEM. , and LG are defined as leaving groups such as mesylate (OM).

[0121] Therefore, the compound of formula (I) is used in a solvent such as DMF or DMA as a coupling reagent (e.g. For example, amines and carbohydrates using HATU and a base (e.g., DIPEA or NMM) The amide coupling between the ions leads to the formation of the compound of formula (II) and the compound of formula (III). It can be produced from. Alternatively, the compound of formula (I) is treated with TEA in a solvent such as DMF. By processing, the amine of formula (II) and the acid (IIIa) pentafluorophenyl ester It can be produced by amide coupling with tel. Compounds of formula (II) are of formula (I It can be produced from the compound in V). Compound of formula (IV) in which M is a protecting group such as -SO2Ph. Regarding deprotection, the base (e.g., DMSO, THF, and water) in a solvent mixture (e.g., DMSO, THF, and water) is used. This can be achieved using NaOH; if M is a SEM protecting group, in a solvent such as DCM Deprotection using acids such as TFA can be used, and should be combined with subsequent amine deprotection steps as much as possible. They can be combined. t-butoxycarb using an acid (e.g., TFA) in a solvent such as DCM. Further deprotection of the nyl (Boc) group yields the compound of formula (II). [ka]

[0122] The compound of formula (IV) is found in a solvent mixture (e.g., DMF and ACN) with a base (e.g., Using K2CO3, for example, in a nucleophilic substitution reaction, the compound of formula (VI) is used with formula (V) It can be provided by the reaction of the compound of formula (IV), THF and M For example, under conditions using NaBH3CN, ZnCl2, and TEA in a solvent mixture such as eOH. In a reductive amination reaction, the reaction of the compound of formula (VI) with the compound of formula (VII) Therefore, it may be provided.

[0123] The compound of formula (V) is R 1 , R 1a , R 2 , R 2a , X 1 , M and LG were previously defined It can be manufactured according to scheme 2 as described above. Base-B(OR x )2 is boronic acid or Boronic acid ester functional groups (cyclic boronates, including boron pinacol ester, for example) Define. Therefore, Pd-catalyzed coupling, for example, solvent mixture (e.g., dioxane / A catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2CO3) are used in water. The second reaction follows the Suzuki reaction between the compound of formula (VIII) and the compound of formula (IX). For example, in the process, by mesylation using Ms2O and TEA in a solvent such as THF, X 1a The conversion of the linked alcohol functional group to the leaving group LG provides the compound of formula (V). The compound of formula (VIII) is a Pd-catalyzed coupling agent, for example, a solvent mixture (for example, di A catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2) are used in an oxane / water mixture. It is produced by the Suzuki reaction between the compound of formula (X) and the compound of formula (XI) using CO3. It is possible. [ka]

[0124] By analogy, the compound of formula (VII) is R 1 , R 1a , R 2 , R 2a , M, LG and - B(OR x )2 may be manufactured according to scheme 3, as previously defined.

[0125] Therefore, Pd-catalyzed coupling, for example in a solvent mixture (e.g., dioxane / water) Formulas using a catalyst (e.g., PdCl2(dppf)) and a base (e.g., Cs2CO3) The Suzuki reaction between compound (XII) and compound (IX) results in compound (VII) Provided. Also, the compound of formula (XII) is used in Pd-catalyzed coupling, for example, in solvent mixtures. For example, a catalyst (e.g., PdCl2(dppf)) and a base (e.g., dioxane / water) in which a catalyst (e.g., PdCl2(dppf)) and a base (e.g., The Suzuki reaction between the compound of formula (X) and the compound of formula (XIII) using Cs2CO3) It can be manufactured by response. [ka]

[0126] Furthermore, the compound of formula (II) can be prepared according to scheme 4. For example, M When H is present, NaBH3CN, ZnCl2 and The reductive amination between compounds of formula (XIV) and formula (XV) using conditions such as TEA follows Furthermore, the deprotection of amines with an acid (e.g., TFA) in a solvent such as DCM is given by formula (II). The compound of formula (XIV) is a similar sequence starting from the compound of formula (VII). Manufactured by Kens, the compound of formula (VII) is a solvent mixture such as THF and MeOH. N-(t-butoxycarb) Reductive amination with (nyl)piperazine followed by acid (e.g., TF) in a solvent such as DCM. Deprotection of the amine by A) may provide (XIV). [ka]

[0127] The compound of formula (IV) is obtained from the compound of formula (XVI) according to scheme 5, using a Pd catalyst cut. Pulling, for example, in a solvent mixture (e.g., dioxane / water), catalyst (e.g., PdCl2 Using the Suzuki reaction with (dppf) and a base (e.g., Cs2CO3), formula (IX It can be produced by reacting it with the compound of formula (XVI). Therefore, from the compound of formula (XVII), Pd-catalyzed coupling, for example, solvent mixture (e.g. For example, a catalyst (e.g., PdCl2(dppf)) and a base (e.g., dioxane / water) in a dioxane / water mixture. It can be produced by a Suzuki reaction with the compound of formula (X) using Cs2CO3. [ka]

[0128] The compound of formula (XVII) is obtained by ferroventing a solvent such as dioxane, as shown in Scheme 6. Ronic acid ester dimer (e.g., bis(pinacolate)diborone), PdCl2(dp Using Pd catalysts such as pf and bases such as KOAc, compounds starting with (XVIII) It can be produced by a hydroxyl-boron exchange reaction. Compounds where Hal represents halogen ( XVIII) For example, when both Hal and LG in formula (XIX) are bromine, Compounds can be compounded using nucleophilic substitution reactions with bases such as K2CO3 in solvents such as acetonitrile. It can be accessed from compound (XIX) and compound (VI).

[0129] Furthermore, certain compounds of formula (XVII) undergo a two-step process (firstly hydroxyl Nucleophilic substitution by the compound of formula (VI), following the conversion of a group to a leaving group, such as mesylate. It can be accessed from the compound of formula (XI) via a reaction. Compound type (XI) is a halogen. It can be derived from compound form (XIXa) using a boron exchange reaction.

[0130] A specific subset of compound (XVIII) described by formula (XVIIIa) is: From the halophenylacetic acid derivative (XX) and the compound of formula (VI), a two-step procedure (DM Coupling reagents (e.g., HATU) and bases (e.g., D) in a solvent such as F or DMA. A catalyst in a solvent such as THF, following an amide coupling reaction using IPEA or NMM. This includes the addition of Grignard reagents such as MeMgBr in the presence of (for example, ZrCl4). Compound (XVIIIa) can be synthesized using the formula (XVIII). Compound (XVIIIa) is described in relation to compound (XVIII). It is converted to compound (XVII) by halogen-boron exchange in a manner similar to the conversion shown. obtain. [ka]

[0131] The compound of formula (I) is, according to scheme 7, the compound of formula (XXI) and the compound of formula (VIIa) From the compound (a specific embodiment of compound type (VII) when M=H), for example, THF and Reductive amine using NaBH3CN, ZnCl2, and TEA in a solvent mixture such as MeOH It can be produced using a ionization coupling. Alternatively, the compound of formula (I) is prepared using a solvent mixture ( For example, in nucleophilic substitution reactions using a base (e.g., K2CO3) in DMF and ACN And, the compound of formula (Va) (a specific embodiment of compound type (V) when M=H) of formula (X It can be produced by reaction with the compound of XI). [ka]

[0132] The compound of formula (XXI) is obtained from the compound of formula (VI) and the compound of formula (III) as DMF Alternatively, a coupling reagent (e.g., HATU) and a base (e.g., DI) in a solvent such as DMA. A amide coupling reaction using PEA or NMM followed by an acid in a solvent such as DCM (e.g., For example, by deprotecting the t-butoxycarbonyl (Boc) group of an amine using TFA They are combined.

[0133] Compounds of formula (I) in which Z is not absent include, for example, N in a solvent mixture such as THF and MeOH. In reductive amination coupling using aBH3CN, ZnCl2, and TEA, the formula It can be produced by reacting compound (XXII) with compound (XXIII). ru (Z, R 1 , R 1a , R 2 , R 2a , X 1a , R 4 , R 5 , R 6 , R 7 , n, p and q (as previously defined). By analogy, compound (XXIV) and compound (XX III) under similar conditions, the reaction may yield the compound of formula (I) according to scheme 8. ru. [ka]

[0134] The compound of formula (XVI) can be coupled with a Pd catalyst according to scheme 9, for example, by solvent mixing. A catalyst (e.g., PdCl2(dppf)) and a base in a liquid (e.g., dioxane / water) For example, using the Suzuki reaction with Cs2CO3, the compound of formula (X) and the compound of formula (XXV) It can be synthesized from compounds. [ka]

[0135] The compound of formula (XXV) is prepared using various procedures under the reaction conditions previously described. Obtain. For example, in scheme 10, a common boronic acid / ester starting material (XXVII Starting from I), the deprotection following the Mitsunobu reaction using the compound of structure (XXIX) is given by formula (X This provides an intermediate of formula (XVI), which is then subjected to a nucleophilic substitution reaction by the compound of formula (XXVII). In response, a compound of formula (XXV) may be supplied. In some cases, (XXVIII), The Mitsunobu reaction with the compound of formula (XXX) can directly provide (XXV). [ka]

[0136] Furthermore, the compound of formula (XXV) is derived from the common starting material 4-bromobenzyl bromide (XXX It can be synthesized from I). In this case, as shown in scheme 11, soluble THF, etc. In a nucleophilic substitution reaction using a compound (XXX) with a base such as potassium t-butoxide in the reaction medium, The subsequent halogen-boron exchange using the previously described conditions can directly lead to (XXV). In other cases, a halogen-boron exchange follows a nucleophilic substitution reaction by compound (XXXII). Boc deprotection gives a new intermediate (XXXIII), which is of type (XXVII). The compound reacts in further nucleophilic substitution reactions, resulting in reactions similar to those previously described. Under these conditions, (XXV) can be reached. [ka]

[0137] As is well known to those skilled in the art, reaction sequence orders are often similar, though they may vary. This can lead to the compound (I An alternative method for constructing compound V) is shown. For example, Pd-catalyzed coupling, Catalyst (e.g., PdCl2(dppf)) in a solvent mixture (e.g., dioxane / water) and A bell using compound (X) and compound (XXVIII) as a base (e.g., Cs2CO3) The wood reaction gives intermediate (XXXIV), which is due to the compound of formula (XXXII) by Mitsunobu The reaction may provide an intermediate (XXXV). Next, compound (XXXV) further During the Suzuki coupling reaction, the compound of formula (IX) and the subsequent deprotection sequence are affected. A compound of formula (XXXVI) may be given. The compound of formula (XXXVI) is of formula (XX Reductive amination with the compound of formula (XVII) may yield the compound of formula (IV). [ka]

[0138] Furthermore, the compound of formula (XXXVI) undergoes reductive amine by the compound of formula (XXXVIII). The compound of formula (IV) can be obtained by ionization. In this case, as shown in scheme 13. Two products (either Q is H or Q is CH2OH) can be formed. For compound (IV) where Q is H, instead of (XXXVIII), the masked A It can be prepared using rudehyde (XXXIX). [ka]

[0139] Scheme 14 presents a further approach to providing a compound of formula (IV). Therefore, The intermediate of formula (XL) is, for example, between compound (XXVIII) and compound (XXIX). It can be produced by the Mitsunobu reaction. Alternatively, (XL) is formula (XXXI) and formula (XXX II) The following two-step reaction is produced from a halogen-boron exchange reaction following nucleophilic substitution between compounds. It is possible. The reaction of intermediate (XL) in the Pd-catalyzed coupling reaction with the compound of formula (X) The response yields the compound of formula (XLI), which further catalyzes Pd catalysis with the compound of formula (IX). The compound ( ) may undergo deprotection following a coupling reaction to obtain the compound of formula (XLII). XLII) undergoes a reductive amination reaction with the compound of formula (XXXVII), (IV ) may be able to provide. [ka]

[0140] The compound of formula (I) was prepared from the intermediate of formula (XLIV), as shown in Scheme 15. It can be produced, which in itself, by direct analogy, in scheme 14, compound (XL) It can be manufactured in (XLIV). Therefore, the intermediate (XLIV) is combined with (XLIII). It is derived from XXVIII) or (XXXI). Next, compound (XLIV) is a Pd catalyst. The compound (XLV) is supplied after undergoing two reactions: a plucking reaction and a deprotection sequence. XLV) reacts with the compound of formula (XLVI) in a reductive amination reaction, (I) It can supply. Compound (XLVI) is an a compound with N-(2-hydroxyethyl)piperazine. Oxidation reactions such as Swarn oxidation following the Mido coupling reaction (e.g., oxalyl chloride and Using the addition of TEA in a solvent such as DCM following DMSO, equation (III) It is manufactured from a compound. [ka]

[0141] The dihydrouracil molecule of formula (III) reacts with urea in acetic acid heated to approximately 120°C. It can be prepared by cyclization of the molecule of formula (XLVII) used. Compound (XLVII) is Therefore, heating in acrylic acid at a temperature of approximately 100°C is typical (Scheme 16) It is synthesized from the corresponding aniline derivative (XLVIII). Formula (IIIa The compounds of ) are pentafluoro in the presence of a base such as DIPEA in a solvent such as DMF. Reaction with nyl-2,2,2-trifluoroacetate yields the compound of formula (III) It can be synthesized. [ka]

[0142] The compound of formula (IX) is obtained according to scheme 17, between the compounds of formulas (XLIX) and (L). Amide coupling reaction, coupling reagent (e.g., HATU), and DMF or DMA It is produced using a base in a solvent such as DIPEA or NMM. [ka]

[0143] In the experimental section, we will describe the specific preparation of intermediates and examples using the general methods described above. I will describe it in detail.

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

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

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

[0147] In further embodiments, compounds or salts thereof selected from the group consisting of the following are provided. ru. 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy Benzoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylammonium Zozoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluoro Benzoic acid: [ka] 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-ethoxy Benzoic acid: [ka] tert-butyl9-(4-bromophenethyl)-3,9-diazaspiro[5.5]u Ndecan-3-carboxylate: [ka] 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro -4-methylbenzoic acid: [ka] 4-Chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl) Zozoic acid: [ka] Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidine-1(2H) -Il)-4-methoxybenzoate: [ka] and 1-(2-methoxy-5-(3,9-diazaspiro[5.5]undecane-3-cal Bonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione: [ka]

[0148] The compounds of these embodiments are useful for preparing the compounds of the present invention.

[0149] The present invention further includes any variation of the process, wherein any stage In this process, an intermediate available in the region is used as the starting material, and the remaining steps are carried out. Alternatively, the starting materials are formed in situ under the reaction conditions, or the reaction components are It is used in the form of a salt or an optically pure material. Also, the compounds and intermediates of the present invention This involves, for example, the reduction of the resulting compound, according to methods generally known to those skilled in the art. Any protecting group present by oxidation and / or other functionalization, and / or optionally. Alternatively, by cutting the linker portion and recovering the compounds obtained in that way, It can be converted to this.

[0150] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt thereof and pharmaceutical The present invention provides a pharmaceutical composition containing a suitably acceptable carrier.

[0151] In another embodiment, the present invention relates to a therapeutically effective amount of the compound of the present invention or a pharmaceutically effective amount thereof. The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0152] In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, For example, those described herein. Pharmaceutical compositions may be administered via a specific route, such as orally. Administration, parenteral administration (e.g., by injection, intravenous infusion, transdermal administration or local administration) and rectal administration It can be formulated for this purpose. Local administration may also be by inhalation or intranasal administration. The pharmaceutical composition may be in solid form (but not limited to capsules, tablets, pills, granules, powders or Manufactured in the form of suppositories (including suppositories) or in liquid form (but not limited to solutions, suspensions, or emulsions). The tablets may be manufactured in a manner known in the art. Therefore, it can be film-coated or enterically coated.

[0153] Typically, a pharmaceutical composition is a tablet or gel containing an active ingredient together with one or more of the following: These are latin capsules. a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol Toll, cellulose, and / or glycine; b) Lubricants, such as silica, talc, stearic acid, and its magnesium or calcium Umium salts and / or polyethylene glycol; also, for tablets, c) Binder, e.g., magnesium aluminum silicate, starch paste, gelatin N, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary, d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or boiling Sexual mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

[0154] Compounds of formula (I) or formula (Ia) or their pharmaceutically acceptable salts are valuable pharmacologically. Characteristics such as regulating BTK activity by acting as a BTK degrader. This is shown, for example, in the BTK or BTK C481S mutation described herein. By using a modified cell line that overexpresses the synthetic protein for fluorescent readout, This can be determined in vitro in cells and in cell lines that express endogenous BTK. Furthermore, the pharmacological usefulness of the compound of the present invention can be demonstrated, for example, in tumors such as TMD8 tumors. When the compound of the present invention is administered to animals such as mice, the tumor tissue resulting from the administration of the compound is... This can be determined in vivo by measuring the decrease in BTK and tumor volume. Yes, it is possible. Therefore, compounds of formula (I) or formula (Ia) are mediated by BTK. It may be useful in treating the patient.

[0155] Compounds of formula (I) or formula (Ia) are examples for the study of BTK-mediated diseases. For example, it could be useful as a tool compound.

[0156] The compounds of the present invention, in free form or in the form of pharmaceutically acceptable salts, are effective against cancer, for example, solid cancer. It may be useful in the prevention or treatment of cancers selected from cytoplasmic tumors and hematopoietic cancers.

[0157] Examples of solid tumor cancers include central nervous system cancers, brain cancers, breast cancers, head and neck cancers, lung cancers; esophageal cancers and esophageal cancers. Gastric junction cancer, gastric cancer, colorectal cancer, rectal cancer, anal cancer, hepatobiliary tract cancer, pancreatic cancer, non-melanoma skin cancer, black Ichthyophthoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, bone cancer, neuroendocrine cancer, Examples include mesothelioma, 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 lymphoma. , non-Hodgkin lymphoma, post-transplant lymphoproliferative disorders, hairy cell leukemia, histiocytic neoplasms and Dendritic neoplasms are one example.

[0159] Examples of B-cell neoplasms include chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (M). CL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter syndrome, precursor B lymphoblasts Multiple lymphoma, primary multiple myeloma and secondary multiple myeloma, B-cell prelymphocytic leukemia, Lymphoid plasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytosis myeloma, plasmacytoma, extranodal Marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma Parkinson's disease, including peritoneum, intravascular large B-cell lymphoma, primary exudative lymphoma, and lymphoma-granulomatosis. Acute lymphoblastic leukemia is one example.

[0160] In certain embodiments, cancer is chronic lymphocytic leukemia (CLL), diffuse large cell type B Cellular lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma The diagnosis is selected from (SLL) and Waldenström 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). ru.

[0163] The compounds of the present invention are cancers (e.g., CLL, DLBCL, MCL, SLL and Waldensian Treatment of patients with strom macroglobulinemia who have developed resistance to ibrutinib For example, a mutation of cysteine-481 to serine (i.e., mutation C) In cancers that have developed resistance to 481S), there may be specific applications. Such targets are: For example, the patient may have already been treated with ibrutinib or may continue to be treated with ibrutinib. Elephants have a reduced or no longer respond to ibrutinib treatment. No. Therefore, the compounds of the present invention are effective against ibrutinib-resistant cancers, particularly ibrutinib-resistant cancers. CLL, DLBCL, MCL, SLL, and Waldenström macroglots exhibiting nib resistance It may be useful in treating robulinemia, particularly in CLL that shows resistance to ibrutinib.

[0164] In another embodiment, the compound of the present invention is in free form or in the form of a pharmaceutically acceptable salt. In this context, autoimmune disorders, inflammatory disorders, allergic diseases, anaphylaxis, allergies - It may be useful for the prevention or treatment of asthma and airway diseases, as well as for transplantation. For example, the present invention The compound, in its free form or in the form of a pharmaceutically acceptable salt, is effective for asthma; chronic obstructive pulmonary disease ( COPD; transplant rejection; abnormal antibody production, antigen presentation, cytokine production, or lymphatic organ formation. A chronic or undesirable disease; chronic rheumatoid arthritis; systemic juvenile idiopathic arthritis (S OJIA; Gout; Pemphigus; Idiopathic Thrombocytopenic Purpura; Systemic Lupus Erythematosus; Multiple Stigma Myasthenia gravis; Sjögren's syndrome; Autoimmune hemolytic anemia; Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis; cryoglobulinemia; thrombotic thrombocytopenic purpura; chronic autoimmune disease Epidemic urticaria; allergies (atopic dermatitis, contact dermatitis, allergic rhinitis); atero Crohn's disease; Type 1 diabetes; Type 2 diabetes; Inflammatory bowel disease; Ulcerative colitis; Crohn's disease Pancreatitis; glomerulonephritis; Goodpasture syndrome; Hashimoto's disease; Graves' disease; antibody-mediated transplant refusal Antimicrobial Respiratory Mixed Reality (AMR); Graft-versus-Host Disease (GvHD); Chronic Graft-versus-Host Disease (cGvHD); B-cell Transplant-mediated hyperacute; acute and chronic transplant rejection; thromboembolic disorders; myocardial infarction; angina pectoris; stroke; ischemic Disorders; pulmonary embolism; polycythemia vera; essential thrombocythemia; and myelofibrosis due to myelogenesis. It may be useful for prevention or treatment.

[0165] In another embodiment, the compound of the present invention is in free form or in the form of a pharmaceutically acceptable salt. In this context, it may be useful for the prevention or treatment of immunoglobulin light chain amyloidosis (AL).

[0166] In a further embodiment, the present invention relates to the therapeutic use of the compound of the present invention or a pharmaceutically acceptable salt thereof. To provide use in medicine. In one embodiment, the present invention provides the compound of the present invention or the drug thereof. The use of scientifically acceptable salts in the prevention or treatment of BTK-mediated diseases is proposed. Provided. In another embodiment, the present invention relates to the compound of the present invention or its pharmaceutically acceptable equivalent. The use of salt in the prevention or treatment of cancer is provided. In a further embodiment, cancer is hematopoiesis It is a hematopoietic cancer. In a further embodiment, hematopoietic cancer is chronic lymphocytic leukemia (CLL), and Diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small Lymphoid lymphoma (SLL) and Waldenström macroglobulinemia, in particular It is either CLL or DLBCL.

[0167] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl )piperidine-4-yl)oxy)piperidine-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt that is permissible.

[0168] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-di Oxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form It is a type of salt.

[0169] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl Piperidine-4-yl Oxy(piperidine-1-yl) Ethyl(phenyl)-7H -Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl) -2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceuticals It is a generally acceptable salt.

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

[0171] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0172] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzo Il)piperidine-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or the drug thereof It is a scientifically acceptable salt.

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

[0174] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0175] In a further embodiment, the present invention relates to the compounds of the present invention or their pharmaceutically appropriate for use in therapeutic purposes. Provides a salt that is acceptable. In one embodiment, the present invention provides a salt mediated by BTK The present invention provides compounds or pharmaceutically acceptable salts thereof for use in the prevention or treatment of diseases. Provided. In one embodiment, the present invention is for use in the prevention or treatment of cancer. The present invention provides a compound or a pharmaceutically acceptable salt thereof. In a further embodiment, cancer is hematopoietic It is cancer. In a further embodiment, hematopoietic cancer is chronic lymphocytic leukemia (CLL), biliary tract cancer. Large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphoma Lymphoma cysticum (SLL) and Waldenström macroglobulinemia, particularly C It is either LL or DLBCL.

[0176] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl )piperidine-4-yl)oxy)piperidine-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt that is permissible.

[0177] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-di Oxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form It is a type of salt.

[0178] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl Piperidine-4-yl Oxy(piperidine-1-yl) Ethyl(phenyl)-7H -Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl) -2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceuticals It is a generally acceptable salt.

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

[0180] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0181] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzo Il)piperidine-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or the drug thereof It is a scientifically acceptable salt.

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

[0183] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0184] In a further embodiment, the present invention relates to a method for treating a disease mediated by BTK. Therefore, a therapeutically acceptable amount of this to patients who require treatment for BTK-mediated diseases. The present invention provides a method comprising administering the compound of the invention or a pharmaceutically acceptable salt thereof. In terms of application, the present invention is a method for treating cancer, which provides treatment to patients who require treatment for cancer. This includes administering a therapeutically acceptable amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. A method is provided. In a further embodiment, the cancer is a hematopoietic cancer. In a further embodiment, In this context, hematopoietic cancers include chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphocytes. Lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL) and This includes Waldenström macroglobulinemia, particularly CLL or DLBCL.

[0185] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl )piperidine-4-yl)oxy)piperidine-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt that is permissible.

[0186] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-di Oxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form It is a type of salt.

[0187] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl Piperidine-4-yl Oxy(piperidine-1-yl) Ethyl(phenyl)-7H -Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl) -2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceuticals It is a generally acceptable salt.

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

[0189] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0190] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzo Il)piperidine-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or the drug thereof It is a scientifically acceptable salt.

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

[0192] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0193] In a further embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt thereof, To provide use for the manufacture of pharmaceuticals. In one embodiment, the present invention provides a compound or The pharmaceutically acceptable salt of the BTK for the prevention or treatment of diseases mediated by BTK. To provide use for the manufacture of pharmaceuticals. In one embodiment, the present invention provides a compound or Providing the use of the pharmaceutically acceptable salt for the manufacture of medicines for the prevention or treatment of cancer. In a further embodiment, the cancer is a hematopoietic cancer. Organizational cancers include chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBC). L), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and Waldensian This is strom macroglobulinemia, particularly CLL or DLBCL.

[0194] In one embodiment, the compound is N-(3-(6-(4-((4-((1-(3-(2 ,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl )piperidine-4-yl)oxy)piperidine-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)- 2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutical It is a salt that is permissible.

[0195] In one embodiment, the compound is N-(3-(6-(4-((9-(3-(2,4-di Oxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3, 9-Diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo [2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-f Luoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically acceptable form It is a type of salt.

[0196] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl Piperidine-4-yl Oxy(piperidine-1-yl) Ethyl(phenyl)-7H -Pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl) -2-Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceuticals It is a generally acceptable salt.

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

[0198] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0199] In one embodiment, the compound is N-(3-(6-(4-(2-(4-((1-(3- (2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzo Il)piperidine-4-yl)oxy)piperidine-1-yl)ethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl )-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide or the drug thereof It is a scientifically acceptable salt.

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

[0201] In one embodiment, the compound is N-(3-(6-(4-(2-(9-(3-(2,4 -Dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)- 3,9-Diazaspiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide or its pharmaceutically It is an acceptable salt.

[0202] The pharmaceutical composition or combination of the present invention is used to deliver approximately 1 to 1000 m³ of material to a target weighing approximately 50 to 70 kg. g of active ingredient or approximately 1-500 mg, approximately 1-250 mg, approximately 1-150 mg, approximately 0.5 mg The unit dose of the active ingredient may be 100 mg or approximately 1 to 50 mg. The therapeutically effective dosage of the drug or its combination depends on the species, weight, age, and individual symptoms of the subject. It depends on the disability or disease being treated and its severity. If you are a physician, clinician, or veterinarian, it is essential to prevent, treat, or inhibit the course of a disorder or disease. The effective amount of each active ingredient can be easily determined.

[0203] The dosage characteristics cited above apply to mammals, e.g., mice, rats, dogs, monkeys, or isolated organisms. This can be demonstrated in in vitro and in vivo studies using the organs, tissues, and their preparations in an advantageous manner. It is possible. The compounds of the present invention can be used in vitro and in the form of a solution, for example, an aqueous solution. For example, administer enterally, parenterally, or preferably intravenously in vivo as a suspension or aqueous solution. It may be used. The in vitro dosage is approximately 10 -6 moles ~10-10 It can be expressed as a molar concentration. The therapeutically effective in vivo dose is approximately 0.1 to 500 mg / kg or approximately 1 It can reach 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 by other routes. The therapeutic agent may be administered together in the same pharmaceutical composition as the drug. For example, the compound of the present invention and When administered in combination to a patient, the compounds are either therapeutically active or enhance therapeutic activity. It is a substance, peptide, antibody, antibody fragment, or nucleic acid.

[0205] In one embodiment, the present invention provides the compound of the present invention and at least one other therapeutic agent. Simultaneously, we provide products that include a combination of preparations used separately or sequentially in treatment. In one embodiment, treatment is the treatment of a disease or symptom mediated by BTK. In another embodiment, the treatment is the treatment of cancer as described herein. Combination As a product provided as a prepared preparation, the compound of the present invention and other therapeutic agents have the same pharmaceutical composition. The compounds of the present invention in a composition contained together in a substance or in a separate form, for example, in the form of a kit, and other A therapeutic agent is one example.

[0206] In one embodiment, the present invention proposes a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Provides. In another embodiment, the present invention provides a therapeutically effective amount of the compound of the present invention and another The present invention provides a pharmaceutical composition containing a therapeutic agent.

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

[0208] In one embodiment, the present invention provides two or more compounds containing at least one of the compounds of the present invention. A kit is provided which comprises a separate pharmaceutical composition. In one embodiment, the kit comprises the composition Means for holding items separately, such as containers, divided bottles, or divided foil packets. This includes, for example, tablets, capsules, etc., which are typically packaged together. There are blister packs used for packaging.

[0209] The kit of the present invention administers different compositions at various dosing intervals or different compositions For administering various oral and parenteral dosage forms to gradually increase the amount of substances relative to each other. It can be used. To aid in compliance, the kit of the present invention is typically used for administration Includes instructions.

[0210] In the combination therapy of the present invention, the compound of the present invention and other therapeutic agents are from the same manufacturer or different manufacturers. It can be manufactured and / or formulated by manufacturers. Furthermore, the compounds of the present invention and other therapeutics The drug (i) before the release of the combination product to the physician (for example, the compound and (ii) Immediately before administration by the physician himself (or physician) (iii) under the guidance of the present invention and other therapeutic agents during sequential administration, for example, the compound of the present invention and other therapeutic agents The patient may categorize these treatments as combination therapies.

[0211] Therefore, the present invention is a different method for treating diseases or symptoms mediated by BTK. The use of therapeutic agents is also provided, and other therapeutic agents are administered together with the compounds of the present invention.

[0212] Furthermore, the present invention is used in methods for treating diseases or symptoms mediated by BTK. The present invention provides a compound that is administered together with another therapeutic agent.

[0213] Furthermore, the present invention is used in methods for treating diseases or symptoms mediated by BTK. The present invention provides another therapeutic agent, which is administered together with the compound of the present invention.

[0214] Furthermore, the present invention relates to the treatment of diseases or symptoms mediated by BTK. The use of the compound is provided, and the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. It is.

[0215] Furthermore, the present invention relates to another therapeutic agent for treating diseases or symptoms mediated by BTK. The use of the compound of the present invention is provided, and the patient has been previously treated (e.g., within 24 hours) with the compound of the present invention. It is.

[0216] Furthermore, the present invention provides the use of another therapeutic agent for treating cancer, and the other therapeutic agent is the present invention It is administered together with the compound for light.

[0217] Furthermore, the present invention provides compounds for use in methods of treating cancer, and the present invention The compound is administered together with another therapeutic agent.

[0218] Furthermore, the present invention provides another therapeutic agent for use in methods of treating cancer, and other therapeutic agents It is administered together with the compound of the present invention.

[0219] Furthermore, the present invention provides the use of the compounds of the present invention for treating cancer, and patients can receive another treatment. The patient has been treated with medication previously (for example, within the last 24 hours).

[0220] Furthermore, the present invention provides the use of another therapeutic agent for treating cancer, and patients can utilize the present invention. It has been treated with a compound previously (for example, within the last 24 hours).

[0221] In one embodiment, other therapeutic agents are selected from the following: Apoptosis modulator, anti-CD20 antibody, anti-CD22 antibody, PI3K inhibitor, Tyrosine kinase inhibitors, immune checkpoint agents, CART treatment agents, immunomodulators Bispecific antibody-targeted CD20 and CD3, antibody-drug conjugate (ADC), Roteasome inhibitor, epigenetic modifier, anti-CD38 mAb, anti SLAMF7 agents, XPO1 inhibitors, and other drugs, such as chemotherapeutic agents.

[0222] In one embodiment, the apoptosis modulator is a Bcl2 inhibitor (for example, A Nthymycin, ovatocrax, venetocrax (Venclexta (registered trademark)) ), ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2- Oxoethyl)-4H-chromone-3-carboxylate (HA14-1), Oblimel Sen (G3139, Genasense®), Bak BH3 peptide, (- )- Gossipole (AT-101, BL-193), Navitoclax (ABT-26 3)), Mcl1 inhibitor (e.g., AMG176, S63845, AZD5991, MIK665) and MDM2 / p53 inhibitors (e.g., NVP-HDM201, NV P-CGM-097, ALRN-6924, Idasanutrin, AMG232 and DS-3 Selected from 032B).

[0223] In one embodiment, the anti-CD20 antibody is rituximab, obinutuzumab, or ofatum The following are selected from mab, ocrelizumab, and ublituximab.

[0224] In one embodiment, the anti-CD22 antibody is inotuzumab, epratuzumab, or vectumoma. Selected from Bu and Moxetumomabupath.

[0225] In one embodiment, the PI3K inhibitor is dubellicib, umbralicib tosyllar INCB050465, Apilimodo mesylate (LAM-002), Copanlisibhi Dichloride (Aliqopa®), tenaliciv, pictiliciv (GDC 0 941), sonolicib (PX866), piralalisib (SAR 245408 or XL 147) Select from alpericib (BYL719) and reniolisib (CDZ173) It can be done.

[0226] In one embodiment, the tyrosine kinase inhibitor is a BTK inhibitor, for example, ibuprofen. 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, e.g., entospretinib (GS9973), fossa Matinib and HMPL-523, SYK / JAK inhibitors, dulatinib (PRT0 62070), SYK / FLT inhibitors, e.g., TAK-659, FLT3 inhibitors For example, FF-10101, FLT3 / BTK inhibitor (CG806), JAK inhibitor Vita (e.g., itacitinib, INCB052793, BMS911543, fedor) Nib, WP-1066, NS-018, and ruxolitinib (Jakavi®) (etc.), Erlotinib hydrochloride (Tarceva®), Linifanib (A BT869), Sunitinib Marat (Sutent®), Bosutinib (bos ulif(registered trademark), dasatinib (Sprycel(registered trademark)), pazopanib (V otrient®), sorafenib (Nexavar®), Zac tima (ZD6474), imatinib or imatinib mesylate (Gilvec (Registered (Trademark) and Gleevec (Registered Trademark) and Tozacelltive (VX680 or MK045) Selected from 7).

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

[0228] In one embodiment, CART treatment involves CD19, BCMA CART, CD20, C Select from D79b, CD22, and CD30.

[0229] In one embodiment, the immunomodulatory substance is lenalidomide (Revlimid (registered trademark)). )), thalidomide (Thalomid®), abadomide (CC-122) and Pomalidomide (Actimid®, Imnovid®, Poma) Selected from lyst(registered trademark).

[0230] In one embodiment, bispecific antibody-targeted CD20 and CD3 are REGN-197 9, XmAb-13676, BTCT-4465-A, CD20-TCB and 8RG-6 Selected from 026.

[0231] In one embodiment, the ADC is CD79 ADC polatuzumab vedotin, CD30 ADC brentuximab vedotin, CD25 ADC camidan lumab tecilin and CD1 9. Select from ADCs (longacustuximab tesirin).

[0232] In one embodiment, the proteasome inhibitor is bortezomib (Velcade( (Registered Trademark), Carfilzomib (Kyprolis (Registered Trademark)), Marizomib (NP I-0052), Ixazomibushitrato (MLN-9708, Ninlaro (Registered Trademark) (Standard), delanzomib (CEP-18770) and oprozomib (ONX-0912) It will be selected.

[0233] In one embodiment, an epigenetic modifier, for example, HDAC methylation Inhibitors and DNA methylation inhibitors are manufactured by Zolinza (a registered trademark). )), Romidepsin (Istodax(registered trademark)), Azacitidine (Mylosar( (Registered Trademark), Vidaza (Registered Trademark), Pyroxamide, Spircostatin A, Milp The following are selected: loin (valproic acid), entinostat, and guadecitabine.

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

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

[0236] In one embodiment, the XPO1 inhibitor is derived from selinexol and ertanexol. Selected.

[0237] In one embodiment, other agents that can be combined with the compound of the present invention, for example, general chemicals Therapeutic agents include anastrozole (Arimidex®) and bendamustine (T reanda(registered trademark), bicalutamide (Casodex(registered trademark)), bleoma Icinsulfate (Blenoxane®), Busulfan (Mylera n(registered trademark), Busulfex(registered trademark) injection, Capecitabine (Xeloda(registered trademark)), N4-pentoxycarbonyl-5-deoxy-5-full Orocitidine, Carboplatin (Paraplatin®), Carmustine BiCNU (registered trademark), chlorambucil (Leukeran (registered trademark)), sysp Latin (Platinol (registered trademark)), Cladribine (Leustatin (registered trademark) (Registered trademark), cyclophosphamide (Cytoxan® or Neosar®) )), cytarabine, cytosine arabinoside (Cytosar-U(registered trademark)), cytarabine Binliposome injection (DepoCyt®), dacarbazine (DTIC-Dom e(registered trademark), dactinomycin (actinomycin D, Cosmegan), Dow Norbicin hydrochloride (Cerubidine®), daunorbicin cytochloride Latliposome injection (DaunoXome®), dexamethasone, docetaxel Cell (Taxotere®), Doxorubicin Hydrochloride (Adriam Ycin (registered trademark), Rubex (registered trademark), Epirubicin (Ellence (registered trademark) (Registered Trademark), Etoposide (Vepesid (Registered Trademark)), Fludarabine Phosphate ( Fludara (registered trademark), 5-fluorouracil (Adrucil (registered trademark)), Efudex®, Flutamide (Eulexin®), Tezacichibi Gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea Idamycin (registered trademark), Ifosfamide (IF) EX (registered trademark), Irinotecan (Camptosar (registered trademark)), L-asparagus Ginase (ELSPAR®), leucovorin calcium, melphalan (Al keran (registered trademark), 6-mercaptopurine (Purinethol (registered trademark)) ), methotrexate (Folex®), mitoxantrone (Novantr one(registered trademark), Mylotarg, Paclitaxel (Taxol(registered trademark)), n ab-Paclitaxel (Abraxane®), Phoenix (Yttrium) Polyfeb with 90 / MX-DTPA, pentostatin, and carmustine implants. Losan 20 (Gliadel (registered trademark)), Tamoxifen citrate (Nolvad ex(registered trademark), teniposide (Vumon(registered trademark)), 6-thioguanine, thio Tepa, Tirapazamine (Tirazone®), Topotecan Hydrochloride for Injection Hycamptin (registered trademark), Vinblastine (registered trademark) , vincristine (Oncovin®), vinorelbine (Navelbine (Registered Trademark), ROR mAb silmutuzumab, dual PI3K / HDAC inhibitor Ta (CUDC-907), Bet inhibitor (INCB357643), ALK inhibitor Ta (crizotinib), EZH1 / 2 inhibitor (DS-3201b), MAPK inhibitor Aplidin, Pritidepsin (eEF1A2 inhibitor), Wnt inhibitor, Radiopharmaceuticals, idiotype vaccines, pegfilgrastim (Neulasta ( The registered trademark is selected from SitePurullikin (IRX-2).

[0238] In further embodiments, other therapeutic agents are selected from the following: Benetocrax, Oblimersen, Navitocrax, MIK665, NVP-HD M201, rituximab, obinutuzumab, ofatumumab, ocrelizumab, ubritz Ximab, Inotuzumab, Epratuzumab, Vectumomab, Moxetumomab Pas, Dube Lysib, Umbralisibtosylart, INCB050465, Leniolysib (CDZ17) 3) Apilimodo mesylate (LAM-002), Copanlisib hydrochloride, Tenali Sibu, 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), Entosupretinib (GS9973) ), fostamatinib, HMPL-523, celduratinib (PRT062070), (TAK-659), FF-10101, FLT3 / BTK inhibitor (CG806), Itacitinib, INCB052793, BMS911543, Fedratinib, WP-1 066, NS-018, Ruxolitinib (Jakavi®), Pembrolizma B, nivolumab, tislerizumab, atezolizumab, ipilimumab, semiprimab, TL R4 agonist, CCR4 mAb mogamulizumab, CD47 mAb fusion protein ( TTI-621), CD19, BCMA CART, CD20, CD79b, CD22, CD30, lenalidomide, thalidomide, abadomide, pomalidomide, XmAb-13 676, CD79 ADC polatuzumab vedotin, CD30 ADC brentuximab vedotin Dotin, CD25 ADC camidan lumabutecillin, CD19 ADC loncustuximin Butecillin, carfilzomib, bortezomib, ixazomib, marizomib, oprozomib Bu, azacitidine, romidepsin, vorinostat, guadecitabine, daratumumab, I Satuximab, elotuzumab, selinexol, ertanexol, fludarabine, calm Stine, cyclophosphamide, chlorambucil, bendamustine, melphalan, clad Livin, dacarbazine, pentostatin, vincristine, etoposide, epirubicin, Doxorubicin, anthracyclines, and antifolic acid agents.

[0239] In a further embodiment, other therapeutic agents may be Bcl2 inhibitors and BTK inhibitors. It will be selected.

[0240] In further embodiments, other therapeutic agents include venetoclax, ibrutinib, and acala. The choice will be made from brutinib.

[0241] Each specific combination that may provide a particular therapeutic benefit includes compounds selected from the following: nothing: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy )piperidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Loxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 5-Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydrox Cypropan-2-yl)benzamide, or The pharmaceutically acceptable salt (in combination with venetoclax).

[0242] Specific individual further combinations that may provide a particular treatment benefit are selected from the following compounds Includes objects: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy )piperidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Loxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 5-Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydrox Cypropan-2-yl)benzamide, or The pharmaceutically acceptable salt (in combination with ibrutinib).

[0243] Specific individual further combinations that may provide a particular treatment benefit are selected from the following compounds Includes objects: N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyriol) Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy )piperidine-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 Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Loxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydrox Cypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)- 5-Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane- 2-yl)benzamide, and N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydrox Cypropan-2-yl)benzamide, or The pharmaceutically acceptable salt (in combination with acalabrutinib).

[0244] These combinations include the compounds of the present invention described above or their pharmaceutically acceptable salts and benetoc It may be provided as a pharmaceutical composition containing Lux, ibrutinib, or acalabrutinib.

[0245] Instead, these combinations use the compounds of the present invention described above or their pharmaceutically acceptable salts. Venetoclax, ibrutinib, or acalabrutinib can be used simultaneously, separately, or sequentially to treat It may be provided as a combined preparation for use in medical treatment.

[0246] In particular, these combinations with ibrutinib are effective for hematopoietic cancers, especially CLL and DLBCL. It may be particularly effective in treating this condition.

[0247] The activity of the compounds of the present invention is 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. [Examples]

[0249] The following examples illustrate the present invention and should be construed as limitations of the present invention. No. The temperature is given in degrees Celsius. The abbreviations used are conventional in this field. Therefore, they are listed below.

[0250] Starting materials, building blocks, reagents, acids, bases, and dehydrogenases used to synthesize the compounds of the present invention. The aqueous solution, solvent, and catalyst are all commercially available or are used in organic synthesis methods known to those skilled in the art. Therefore, it can be produced. Furthermore, the compound of the present invention can be produced as shown in the following examples. It can be produced by organic synthesis methods known to the industry.

[0251] Abbreviation: ACN Acetonitrile OAc Acetate Acetic acid (ACOH) aq. Water-based BISPIN Bis (Pinacolato) Diboron BOC tert-butoxycarbonyl br Wide CHX Cyclohexane d doublet DCM Dichloromethane dd doublet doublet DEA (Diethylamine) DEAD Diethylazodicarboxylate DIAD Diisopropylazodicarboxylate DIPEA Diisopropylethylamine DMA N,N-dimethylacetamide DMEM Dulbecco's Modified Eagle Medium DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) e.g., for example eq. equivalent weight ESI Electrospray Ionization Et2O Diethyl ether HCl 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-tetramethyl Luuronium hexafluorophosphate HPLC (High-Pressure Liquid Chromatography) HV high vacuum iPrOH Isopropanol LC-MS (Liquid Chromatography and Mass Spectrometry) m multiplex m / z mass-to-charge ratio MeOH methanol mg milligrams min ml (milliliter) mmol millimol MS mass spectrometry Ms2O Methanesulfonic acid anhydride NaBH(OAc)3 sodium triacetoxyborohydride NaBH3CN Sodium cyanobolohydride 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)4Tetrakis(triphenylphosphine)palladium PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]para Dium dichloride PdCl2(dppf)-CH2Cl2[1,1'-bis(diphenylphosphinol)f [Erocene] Palladium dichloride-dichloromethane adduct PdCl2(PPh3)2-bis(triphenylphosphine)palladium dichloride ppm (parts per million) rac racemi RM reaction mixture Rt retention time RT room temperature s singlet sat. saturation SFC Supercritical Fluid Chromatography t triplet TBME tert-butylmethyl ether TBTU O-(benzotriazol-1-yl)-N,N,N',N'tetramethyl Rhonium tetrafluoroborate TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran)

[0252] Analysis method General conditions: NMR: Bruker AVAN using ICON NMR under TopSpin program control CE 400MHz, 500MHz or 600MHz NMR spectrometer, NM The R spectrum was recorded. Unless otherwise specified, the spectrum was measured at 298K. Furthermore, known solvent resonances were referenced.

[0253] LC-MS: Mass spectra obtained using electrospray, chemical, and electron impulse ionization methods are obtained by LC- Acquired from a wide range of equipment in the following configurations using MS, SFC-MS, or GC-MS systems: Waters Acoustics using photodiode array detectors and single quadrupole mass detectors A equipped with a quity UPLC / SQD system or G 6110 series mass spectrometer Gilent 1200 system. [M+H] + is a protonated molecule of a chemical species io It refers to n.

[0254] Method A: Column: Waters Acquity HSS T3 1.8μm 2.1×50mm 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 over 1.4 minutes

[0255] Method B: Column: Waters Acquity HSS T3 1.8μm 2.1×50mm 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 over 9.4 minutes

[0256] Method C: Column: Waters Acquity HSS T3 1.8μm 2.1×50mm 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 over 1.4 minutes

[0257] Method D: Column: SunFire C18, 4.6 × 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 over 1.4 minutes

[0258] Method E: Column: SunFire C18, 4.6 × 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 over 1.2 minutes, 95% B over 1.3 minutes

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

[0260] Method G: Column: XBridge C18, 4.6 × 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 over 1.5 minutes

[0261] Method H: Column: XBridge C18, 4.6 × 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 over 1.5 minutes, 95% B over 1.5 minutes

[0262] Method I: Column: SunFire C18, 3×30mm, 2.5μm 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 over 1.5 minutes

[0263] Method J: Column: XBridge C18, 4.6 × 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 over 1.4 minutes, 95% B over 1.6 minutes

[0264] Chiral analysis using 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 254nm

[0265] Preparative chromatography Normal-phase and reverse-phase flash chromatography purification using CombiFlash (registered trademark). Performed on an Rf200 or Rf+ system. Alternatively, reverse-phase chromatographic purification was performed. Interchim Puriflash 4250 system or Biotage system I performed the operation using MeOH as a modifier. (Waters 2998 photodactyl) Waters fraction detection by an iodine array detector or Waters MS single quadrupole detection. Using the SFC-100-MS system, supercritical fluid chromatography (SFC) separation is performed. The procedure was performed. Normally, the back pressure is 120 bar and the flow is 100 g CO2 / min. The column temperature was 40°C. Reverse-phase HPLC purification was performed using a Waters 2998 filter. Waters MS single quadrupole detection by tridiode array detector or Waters MS The procedure was performed using an HPLC preparative 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 rate: 40 ml / min Detection: UV@254nm

[0267] Chiral preparative chromatography: 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 rate: 10 ml / min Detection: UV@254nm

[0268] Materials used for solid-phase extraction: The following solid-phase extraction (SPE) cartridges can be used in accordance with the manufacturer's instructions to extract various salts. The corresponding free base was generated. The PL-HCO3 MP SPE cartridge was used by Agil. Purchased from ent StratosPhere (Reference: PL-HCO3 MP resin, 1 (0.8 mmol / g, 100A, 150-300 μm, 500 mg, 6 ml). SCX Car I purchased the cartridge from Agilent (see: HF Mega DE-SCX, 2g, 12ml).

[0269] Synthesis of intermediates Intermediate 1 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzaldehyde Do [ka] Step 1: (4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl) (Nyl)methanol Ethyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-) under argon THF suspension (100ml) of benzoate (10.2g, 33.8mmol) As described in U.S. Patent No. 6,140332, column 45, example 30, which has been published. (Can be prepared according to the procedure) THF solution of lithium aluminum hydride (1M) (50. 7 ml (50.7 mmol) was slowly added at 0-5°C. During the addition, RM was added to THF (5m Diluted with 1). After addition, RM was stirred at 0°C for 10 minutes and then heated to RT. After stirring for 3 hours, RM is used with a mixture of water and aq. solution of NaOH (15%). The mixture was quenched at 0°C. The mixture was filtered with Hyflo® and the solid was extracted. The compound was washed with HF, and the combined filtrate was concentrated to obtain 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]pyrimidine-6-yl)benz aldehyde (4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl) Methanol (9.32 g, 32.7 mmol) and manganese dioxide (28.4 g, 327 mmol) A THF suspension (250 ml) of mmol was stirred overnight in RT. Additional carbon dioxide Add manganese (8.52g, 98mmol) to RM and stir, then leave in RT overnight. The RM was filtered with Hyflo® and the solid was washed with THF. Combination The filtrate is concentrated, re-diluted with THF, and then filtered again with Hyflo(registered trademark) to concentrate it. The compound was reduced to obtain the title compound as a solid (5.68 g). 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 (N-2-yl)benzamide [ka] 2-Fluoro-4-(2-hydroxypropan-2-yl)benzoic acid (6.35g, 3 2.0 mmol), HATU (17.06 g, 44.9 mmol) and DIPEA (16 Mix 0.79 ml and 96 mmol of DMF (100 ml) in RT for 30 minutes. Next, 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)aniline (International Publication No. 2013 / 008095A1) (It can be prepared according to the procedure described in the pamphlet, page 37, Intermediate 5.) (8.47g, 32.0 mmol) was added, and the RM was stirred overnight at 50°C. Dilute with ELISA and wash the organic phase with a sat.aq. solution of NaHCO3 and brine. The combined aqueous phase was extracted with SiO2, and the combined organic phase was treated with N2. Dry on a2SO4, filter, concentrate, and obtain MeOH (in DCM) (0-10%) The resulting solid was purified by silica gel chromatography using elution. Grind with 2O, filter, wash the solid with diisopropyl ether, and dry. 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 for intermediate 2 is available in International Publication No. 2013 / 008095A1. This is described on page 81, under intermediate 35.

[0273] Intermediate 3 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydroxyl) Cypropan-2-yl)benzamide [ka] 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzaldehyde Hyd (intermediate 1, 150 mg, 0.553 mmol), 2-fluoro-N-(5-fluorinated Ro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide ( Intermediate (2,328 mg, 0.608 mmol), aq. solution of Na2CO3 (2M) (0. 553 ml, 1.106 mmol) and PdCl2(PPh3)2 (19.41 mg, 0 A 1-propanol suspension (4 ml) of 0.028 mmol was subjected to microwave irradiation. The suspension was heated at 40°C for 15 minutes. The suspension was filtered, and the solid was mixed with 1-propanol, water, and Washed with 1-propanol. The remaining solid was dried, and the title compound was removed from the solid (178 mg). ) was obtained as follows. Method A: Rt=0.99min;[M+H] + =527.2.

[0274] Intermediate 4 rac-2-fluoro-N-(5-fluoro-3-(6-(4-((7-(hydroxymethyl (Tyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2 -Hydroxypropan-2-yl)benzamide [ka] Step 1: rac-tert-butyl9-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)-1-(hydroxymethyl (Tyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydro Xypropan-2-yl)benzamide (intermediate 3, 300 mg, 0.570 mmol) rac-tert-butyl1-(hydroxymethyl)-3,9-diazaspiro[5.5 Undecane-3-carboxylate (219 mg, 0.684 mmol) and TEA ( ZnCl2 (0.5) is added to a THF mixture (3 ml) of 0.119 ml and 0.855 mmol. The THF solution (1.197 ml, 0.598 mmol) of M) was added. The resulting After stirring RM under argon in RT for 3 hours, solid NaBH3CN (71.6 mg) was used. (1,140 mmol) was added. The RM was stirred overnight in the RT, then diluted with DCM. Then, it was washed with water and brine. The organic phase was dried on MgSO4 and concentrated, and Me Purified by silica gel chromatography that elutes with OH (in DCM) (0-20%). The title compound was then obtained 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-(Hyd Roxymethyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)fe (Nyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl)- 4-(2-hydroxypropan-2-yl)benzamide rac-tert-butyl9-(4-(4-(5-fluoro-3-(2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H -Pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)-1-(hydroxymethyl) -3,9-diazaspiro[5.5]undecane-3-carboxylate (273mg, 0 DCM solution of 0.343 mmol) and TFA (0.794 ml, 10.30 mmol) Stir 3 ml of the solution in RT for 2 hours, concentrate, and dry to obtain the title compound as solid TFA. It was obtained as salt (288 mg). Method A: Rt=0.63min;[M+H] + =695.5.

[0276] Intermediate 5 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxyammonium Zozoic acid [ka] 3-amino-4-methoxybenzoic acid (5.0g, 29.3 mmol) is mixed with acrylic acid (8 Suspend in 0.05 ml (117 mmol), and then heat the resulting suspension at 100°C. Stirred for 3 hours, then cooled RM to RT. Add AcOH (33 ml) and stir. The turbid liquid was heated at 100°C for 10 minutes, then urea (11.00 g, 183 mmol) was added. Adding this, the RM was stirred overnight at 120°C. The solution was then mixed with water and concentrated aqueous HCl (37%). It was added to the ice-cold mixture. After stirring, the resulting suspension was left in a refrigerator at 5°C. After being stored overnight, the solid was filtered, washed with water, dried, and a solid was obtained. The solid was then heated to H The solid was ground in a solution of Cl (0.05 M), filtered, and washed with TBME. The title compound was dried under reduced pressure at 40°C to obtain 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]undecane-3-ylmethyl )phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2 -Methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benz Amido [ka] Step 1: tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)-3,9-diazaspiro[5. 5] Undecane-3-carboxylate 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydro 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 a mixture of ZnCl2 (0.5M) THF solution (2.325 ml, 1.162 mmol) The mixture was stirred in MeOH (10 ml) at RT for 6 hours. Solid NaBH3CN(67 Add 0.0 mg (1.065 mmol) to RM and stir overnight in RT. RM was then transferred to E Diluted with tOAc, the organic phase was washed with a sat.aq. solution of NaHCO3 and brine. Then, it is dried on Na2SO4, concentrated, and dissolved in MeOH (in DCM) (0-50%). The compound was purified by silica gel chromatography to obtain the title compound as a solid (550 mg). It was obtained as such. Method A: Rt=4.60min;[M+H] + =765.4.

[0278] Step 2: N-(3-(6-(4-(3,9-diazaspiro[5.5]undecan-3-i (Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-full Oro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl) ) Benzamide tert-butyl9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidine-6-yl)benzyl)-3,9-diazaspiro[5.5]u DCM solution of ndecane-3-carboxylate (0.55 g, 0.683 mmol) (4 TFA (1.053 ml, 13.66 mmol) was added to 0 ml of RT. Results The resulting RM was stirred overnight in RT to evaporate, and then rehydrated in a mixture of ACN and water. The compound was dissolved and freeze-dried to obtain 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]pyrrolo[2,3-d] Limijin [ka] Step 1: 4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrim gin Mineral oil (1.563g, 39.1ml) in a flame-drying flask placed under argon. Suspend 60% NaH (mol) in 60 ml of DMF, and cool the mixture to 0°C. 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4g, 26.0 mmol) Slowly add 20 ml of DMF solution over 10 minutes, and continue adding RM until hydrogen release is complete. Stirred for 10 minutes until dissolved. Benzenesulfonyl chloride (3.36 ml, 26.0 mmol) l) was added and RM was stirred in RT for 1 hour. Water was added and the resulting precipitate was The mixture was filtered, and the solid was dried to obtain 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-pyro under an argon atmosphere at -78°C Lithium diisopropyl alcohol is added to a dry THF-stirred solution (80 ml) of r[2,3-d]pyrimidine. CHX solution of Luamido mono-tetrahydrofuran (1.5M) (5.22 ml, 7.83 Iodine (1.987g, 7.83mO) was added over 15 minutes. After 1 hour, iodine (1.987g, 7.83mO) was added. l) The THF solution (20 ml) was added dropwise over 15 minutes at -78°C. The results were as follows: The resulting solution was stirred at -78°C for 3 hours. Water (2 ml) was added, and the mixture was turned into RT. The mixture was heated. The mixture was diluted with DCM, the organic phase was washed with brine, and the mixture was dried over Na2SO4. It was dried and evaporated to dryness. The resulting solid was ground together with ACN and filtered. The compound was dried to obtain the title compound as a solid (1.513 g). Method C: Rt=1.12min;[M+H] + =419.9.

[0281] Intermediate 8 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzo Aromatic acid [ka] Step 1: 3-((2-carboxyethyl)amino)-4-methylbenzoic acid Toluene suspension of 3-amino-4-methylbenzoic acid (15.12 g, 100 mmol) (25 ml) was heated and refluxed. Acrylic acid (27.5 ml, 400 mmol) and When toluene (10 ml) is added, the mixture begins to become a homogeneous solution, and RM is 100°C. The mixture was stirred for 3 hours and then cooled to RT. The separated solid was collected by filtration. The body was washed with toluene and dried to obtain the title compound as a solid (17.87 g). Method A: Rt=0.61min;[M+H] + =224.1.

[0282] Step 2: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl Chilbenzoic acid 3-((2-carboxyethyl)amino)-4-methylbenzoic acid (893 mg, 4 mm A 12 ml AcOH suspension of 0.4 ol) and urea (601 mg, 10 mmol) was heated at 120°C. It was stirred overnight. The RM was cooled to RT and poured over crushed ice, resulting in raw The mixed solution was acidified to pH 0 with HCl (1M) solution. The solid was collected by filtration. The sample was collected, washed with cold water, and dried to obtain the title compound as a solid (661 mg). Method A: Rt=0.51min;[M+H] + =249.1.

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

[0284] Step 2: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-f Luorobenzoic acid AcOH (60 ml) and urea (18.0 g, 300.0 mmol) are mixed in 3-(2-calcium carbonate). Crude mixture of benzoethylamino-4-fluorobenzoic acid (13.6g, 60.0mmo) In addition to l), the resulting RM was evaporated by stirring at 120°C for 26 hours. Following ice and water, a concentrated aq. solution of HCl (37%) was added. The resulting mixture The liquid was filtered, the filtrate was saturated with solid NaCl, and allowed to stand at 15°C for 20 hours. Precipitate The material was collected and dried to obtain the first harvest (5g). The filtrate was evaporated, and the residue was H The solution was diluted with 2O, and the resulting mixture was allowed to stand at 15°C for 20 hours. The precipitate was filtered. After drying, a second harvest (4g) was obtained. Acrylic acid was added to the combined harvest (9g). OH was added, and the mixture was sonicated for 10 minutes. TBME was added, and the TBME phase was degraded. This was repeated once more. The residue was evaporated, and AcOH and TBME were added. The mixture was then ultrasonically treated. Additional TBME was added to decant the TBME phase, and this The process was repeated once more. TBME was added, and the mixture was left to stand at 15°C for 20 hours. The BME phase was decanted. The mixture was evaporated to dryness, and aq. dissolved in HCl (0.001M). Add the liquid, filter the mixture, and remove the solid in aq. HCl (0.001M) solution and ACN. The compound was washed and dried to obtain 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-(piperidine-4-yloxy)piperidine-1-carboxylate to [ka] Step 1: tert-butyl 4-(pyridine-4-yloxy)piperidine-1-carboc Syrah Pyridine-4-ol (5g, 52.6 mmol), THF in a 500ml round-bottom flask. (200ml), tert-butyl 4-hydroxypiperidine-1-carboxylate ( (13.3g, 65.8 mmol) and triphenylphosphine (18g, 68.4 mmol) l) was added. DEAD (12g, 68.4 mmol) was added dropwise in RT, and after addition... RM was stirred in RT for 3 hours. RM was concentrated and mixed with methanol (in DCM) (1:3 The title compound is purified by silica gel chromatography eluting at 0) and obtained as a solid (10 It was obtained as g). Method E: Rt=1.35min;MSm / z[M+H] + 279.

[0286] Step 2: tert-butyl 4-(piperidine-4-yloxy)piperidine-1-carb Xylart In a 500 ml round-bottom flask purged and maintained under an inert atmosphere, tert-butyl 4- (Pyridine-4-yloxy)piperidine-1-carboxylate (2g, 7.2mO) l) EtOH (100 ml), AcOH (5 ml), and Pd / C (10%) (0.4 g) ) was added. RM was stirred at 80°C for 16 hours under a hydrogen (4 MPa) atmosphere. Mixture The filtrate is filtered with Celite (registered trademark), and the filtrate is concentrated to obtain MeOH (in DCM) (1: 10) Purified by silica gel chromatography eluting the title compound into oil (0. It was obtained as 5g. Method D: Rt=1.32min;MSm / z[M+H] + 285.3.

[0287] Intermediate 11 N-(3-(6-(4-(3,9-diazaspiro[5.5]undecane-3-ylmethyl )phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2 -Methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benz Amido [ka] Step 1: tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)-3,9-diazaspiro[5. 5] Undecane-3-carboxylate Add tert-butyl3,9-diazaspiro[5.5]undecane to 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-hormone (Luphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl (Lu)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 3, 220 mg) 0.409 mmol) and MeOH (4 ml) were added. T of ZnCl2 (0.5 M) Add HF solution (1 ml, 0.500 mmol), and the resulting RM is refracted in RT. It was stirred overnight. Solid NaBH3CN (30 mg, 0.477 mmol) was added, and RM Stir in RT for 5 hours, evaporate, and remove the residue from MeOH (in DCM) (0-50 The title compound was purified by silica gel chromatography eluting at %), and the solid (35 It was obtained as 4 mg. Method A: Rt=0.96min;[M+H] + =765.4.

[0288] Step 2: N-(3-(6-(4-(3,9-diazaspiro[5.5]undecan-3-i (Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-full Oro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl) ) Benzamide tert-butyl9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo [2,3-d]pyrimidine-6-yl)benzyl)-3,9-diazaspiro[5.5]u MeOH solution of ndecane-3-carboxylate (354 mg, 0.407 mmol) Add 2 ml of HCl (4M) 1,4-dioxane solution (2 ml, 8.00 mmol) to 2 ml of HCl. Then, RM was stirred in RT for 1 hour. RM was concentrated and evaporated together with DCM, and dried. The title compound was then obtained 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]pyrimidine-6-yl)phenyl )ethanol [ka] 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.2g, 4.2 9 mmol), 4-(2-hydroxyethyl)phenylboronic acid (750 mg, 4.29 mmol), aq. solution of Na2CO3 (2.0M) (4.72 ml, 9.45 mmol) ), PdCl2(PPh3)2 (154 mg, 0.215 mmol) and 1-propano A 100 ml round-bottom flask containing a mixture (36 ml) was purged with N2 at RT. Then, the mixture was stirred overnight at 105°C. The mixture was concentrated to dryness and then ԅ(CH Purified by silica gel chromatography (40-100%) in X, and then presented. The compound in question 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- Il)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine -6-yl)phenethylmethanesulfonate [ka] Step 1: 2-Fluoro-N-(5-Fluoro-3-(6-(4-(2-hydroxyethyl )phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl (Lu)-4-(2-hydroxypropan-2-yl)benzamide In RT, 2-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6 -Iyl(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) is converted to 1-propano A solution of Na2CO3 (2.0M) (12 ml) and 5.19 ml of Na2CO3 (2.0 M) The mixture of ol) was suspended. Argon was passed through the RM for 2 minutes, and PdCl2(PPh 3) Add 2 (91 mg, 0.130 mmol). The mixture was then heated using microwave radiation. It was heated at 140°C for 20 minutes. RM was diluted with ethyl acetate, water and brine, The phases are separated, and the organic phase is dried on MgSO4 to obtain Isolute(registered trademark) HM- It was adsorbed onto nitrogen and dried. Silica gelatin elutes in MeOH (in DCM) (0-20%). The title compound was obtained as a solid (863 mg) by purification using chromatography. Method A: Rt=0.92min;[M+H] + = 543.3.

[0291] Step 2: 4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane (-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrrolo[2,3-d] Limidine-6-yl)phenethylmethanesulfonate In 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-hydroxypropane-2-yl)ben Suamide (89 mg, 0.164 mmol) mixed with dried THF (2 ml) and TEA (0.1 It was dissolved in 14 ml (0.820 mmol) and the mixture was cooled to 0°C. Ms2O( Add 57.1 mg (0.328 mmol) and stir RM at 0°C for 30 minutes. Quenched with ice water, DCM was added, and the phases were separated. The aqueous phase was extracted with DCM and assembled. The combined organic phase was dried on MgSO4. By evaporation, the title compound was converted into a solid (94 mg). ) was obtained as follows. Method A: Rt=1.01min;[M+H] + =621.2.

[0292] Intermediate 14 tert-butyl4-((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 under argon (84 8 mg, 3.03 mmol) and (4-(((1-(tert-butoxycarbonyl) pi Peridine-4-yl(oxy)methyl(phenyl)boronic acid (1.068g, 3.19mg) 1-propanol suspension (20 ml) of mol) with PdCl2(PPh3)2(106 ml) 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 overnight at 100°C, and then siRNA was added. It was diluted with [a specific solution]. The organic phase was separated, washed with water and brine, and dried on MgSO4. After evaporation, the residue is eluted with silica gel using butyl (in CHX) (0-100%). The title compound (844 mg) was obtained by purification using electromagnetism. Method A: Rt=1.29min;[M+H] + =443.3.

[0293] Intermediate 15 4-Chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H -pyrololo[2,3-d]pyrimidine [ka] 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (10g, 3°C) 5.8 mmol) DMF solution (120 ml) with mineral oil (1.7 g, 42.5 ml) NaH (60%) in a mol (mol) solution was added in small amounts under argon. The resulting suspension was then... 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 heated to RT for 1 hour. Next, R M was carefully poured into ice water and extracted with Et2O. The combined organic phase was washed with brine. Then, it was evaporated. The residue was diluted with ACN, and the resulting mixture was filtered and presented. The compound in question was obtained as a solid (8.052 g). The filtrate was concentrated and ground in cold MeOH. The mixture was then filtered to obtain the second harvest 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- Iloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-6-yl)phenol 4-chloro-6-dioxane 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, 11.33 mmol) and 4-hydroxyphenylboronic acid (840 mg, A 2.67 mmol solution was degassed with argon. PdCl2(dppf)-CH2Cl Add the adduct (266 mg, 0.325 mmol) and leave RM at 100°C until 1.5 The mixture was stirred. RM was filtered with Hyflo® and the solid was washed with MeOH. The combined filtrate was concentrated and partitioned into SiO2 and water. The phases were separated, and the organic phase was bleached. Wash with water, dry on MgSO4, evaporate, and the title compound is converted into a solid (575 mg). ) was obtained as follows. 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]pyrrolo Limidine-4-yl)-2-methylphenyl)-4-(2-hydroxypropane-2-yl) Benzamide 4-(4-chloro- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrrolo Limidine-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) (Nyl)-4-(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 RM was stirred at 100°C for 1.5 hours. RM The mixture was filtered with Hyflo® and the solid was washed with MeOH. The combined filtrate The solution was concentrated and partitioned into dimethyl hydroxide and water. The phases were separated, and the organic phase was washed with brine. Dry on gSO4, evaporate, and elute with MeOH (in DCM) (0-7.5%). The title compound was purified by silica gel chromatography to obtain a solid (1.214 g) and I obtained it by doing so. 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)benzamide)-2-methylphenyl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidyl (6-yl)phenoxy)piperidine-1-carboxylate 2-Fluoro-N-(5-Fluoro-3-(6-(4-hydroxyphenyl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidyl (4-yl)-2-methylphenyl)-4-(2-hydroxypropane-2-yl) Nzuamide (749 mg, 0.999 mmol), 1-Boc-4-hydroxypiperidiamide (221 mg, 1.099 mmol) and triphenylphosphine (365 mg, 1. 10 ml of 392 mmol) THF solution is mixed with 0 ml of DEAD (40%) toluene solution. 550 ml (1,390 mmol) was added dropwise under argon in RT. As a result, The RM was stirred overnight in RT. Additional 1-Boc-4-hydroxypiperidine ( Add 79 mg (0.393 mmol) and stir RM in RT for 2 hours to remove the solvent. Removed. Dissolve the residue in ACN (in aq. TFA solution (0.1%)) (2-100%). The product is purified using Redisep(registered trademark) C18 column chromatography and then presented. The compound in question 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-(Piperidol (4-yloxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydro Xypropan-2-yl)benzamide tert-butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7-((2- (trimethylsilyl)ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -yl(phenoxy)piperidine-1-carboxylate (416.6 mg, 0.503 Add a DCM solution (5 ml) of mmol) and TFA (1 ml, 12.98 mmol) to RT. Stir for 2 hours, concentrate, and add ACN (in aq. TFA solution (0.1%)) (2-1 Redisep® C18 column reversed-phase chromatography elutes at 00% The compound was then purified to obtain 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- Ilmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-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)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1-carboxylate te 1-Boc-piperazine (95 mg, 0.500 mmol), TEA (0.100 ml) , 0.717 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-fluoro) Milphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl (Nyl)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 3, 250m) (g, 0.465 mmol) was dissolved in MeOH (4 ml) at RT. ZnCl Add 2 (0.5M) THF solution (1 ml, 0.500 mmol), and the result The mixture was stirred in RT for 3 days. Solid NaBH3CN (32 mg, 0.509 mg) Add (mol), stir RM in RT overnight, remove the solvent, and the residue is AC Redisep elutes in N (TFA aq. solution (0.1%)) (2-100%) The title compound was purified by C18 column reversed-phase chromatography (registered trademark) and obtained in solid TF. It was 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-(piperazi (1-ylmethyl)phenyl)-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)benzamide)-2-methylphenyl)-7H-pyrrolo [2,3-d] Pyrimidine-6-yl)benzyl)piperazine-1-carboxylate ( 360 mg (0.431 mmol) of MeOH solution (2 ml) with HCl (4 M) added. - Add dioxane solution (2 ml, 8.00 mmol) and stir RM in RT for 4 hours. The RM was concentrated and dried to obtain 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- Ilmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-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)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1-carboxylate te 1-Boc-piperazine (170 mg, 0.912 mmol), TEA (0.300 mg) l, 2.152 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-fluoro Lumilphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl (enyl)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 3,400 (mg, 0.760 mmol) was dissolved in MeOH (6 ml) in RT. ZnC Add 1.2 ml (0.840 mmol) of l2 (0.7 M) THF solution to obtain the result. The resulting mixture was stirred in RT for 5 hours. Solid NaBH3CN (50 mg, 0.7g) Add 6 mmol) and stir RM in RT for 3 days to evaporate the solvent and remove the residue. Elute Redi with ACN (in aq. solution of TFA (0.1%)) (2-100%). The title compound was purified by reverse-phase chromatography using sep(registered trademark) C18 column. It was 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-(piperazi (1-ylmethyl)phenyl)-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)benzamide)-2-methylphenyl)-7H-pyrrolo [2,3-d] Pyrimidine-6-yl)benzyl)piperazine-1-carboxylate ( 328 mg of MeOH solution (0.360 mmol) in 2.0 ml of HCl (4M) Add 4-dioxane solution (2 ml, 8.00 mmol) and leave RM at RT for 4 hours. Stirred. The RM was concentrated, and the residue was mixed with ACN (in aq. solution of TFA (0.1%)). Redisep® C18 column reversed-phase chromatography eluting at 2-100% The title compound was purified using [method / method] to obtain 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 In mineral oil (964 mg, 24.10 mmol), NaH (60%) is 1-Boc -4-hydroxypiperidine (1000 mg, 4.82 mmol) in anhydrous THF solution (4 (5 ml) was added little by little under argon light in RT mode, and stirring was continued for 30 minutes. Add romidol (0.500 ml, 5.78 mmol) dropwise to RM and leave at RT for 40 hours. After stirring, the mixture was quenched with ice water. The mixture was extracted with dimethyl and combined organic compounds. The phase was dried over Na2SO4, concentrated, and treated with siRNA (in CHX) (0-20%). The title compound was purified by eluting silica gel chromatography to obtain a colorless liquid (11 It was obtained as 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 A 40 ml solution of anhydrous DCM (mg, 4.64 mmol) was cooled to -78°C to remove ozone. The mixture was passed through RM for 70 minutes and foamed. The RM was heated in RT and polymer-bound triphenyl phosphate was used. Finn (5g, 16.00 mmol) was added. The RM was stirred in RT for 30 minutes. The solid was filtered with Celite® and washed with DCM. The combined filtrate was then steamed. The compound was dried to obtain the title compound as a colorless oil (1147 mg), and then further purified. It was 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)-Zeon [ka] Step 1: rac-tert-butyl9-(3-(2,4-dioxotetrahydropyrimid n-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3, 9-Diazaspiro[5.5]undecane-3-carboxylate rac-tert-butyl1-(hydroxymethyl)-3,9-diazaspiro[5.5 Undecane-3-carboxylate (200 mg, 0.703 mmol), 3-(2, 4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoic acid ( Intermediate 5, 204 mg, 0.774 mmol) and NMM (0.387 ml, 3.52 ml) Add HATU (401 mg, 1.055 mmol) to DMF solution (3 ml) The RM was stirred in RT for 2 hours, then poured into water and filtered. The filtrate was extracted with DCM. Then, the combined organic phases are washed with brine, dried on MgSO4, and evaporated. And, by silica gel chromatography that elutes with MeOH (in DCM) (0-20%) The compound was purified to obtain 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)-Zeon rac-tert-butyl9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3,9-di Azaspiro[5.5]undecane-3-carboxylate (241 mg, 0.454 mg) A DCM solution (4 ml) of 1.050 ml and 13.63 mmol of TFA is added to R Stir in water for 2 hours, concentrate, and the residue is converted to an aq. solution of ACN (TFA) (0.1%). By reverse-phase chromatography using Redisep(registered trademark) C18 column, which elutes in the middle of the process... The compound was purified to obtain 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-carbony Phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: tert-butyl9-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undeca n-3-carboxylate tert-butyl3,9-diazaspiro[5.5]undecane-3 under argon RT -Carboxylates (432 mg, 1.698 mmol) and NMM (0.392 ml, 3.57 mmol) DMF solution (4 ml) contains 3-(2,4-dioxotetrahydropyroxide). Midine-1(2H)-yl)-4-methoxybenzoic acid (intermediate 5, 471 mg, 1.78 3 mmol) was followed by HATU (743 mg, 1.953 mmol). RM was changed to R The mixture was stirred in T for 2.5 hours, and then a saturated solution of NaHCO3 was added. siRNA was added. Then, both phases were separated. The aqueous phase was extracted with SiO2, and the combined organic phase was treated with water. Wash with brine, dry on MgSO4, concentrate, and solidify the title compound (90°F). It was obtained as 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-butyl9-(3-(2,4-dioxotetrahydropyrimidine-1(2H) -yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecane-3 - Add T to carboxylate (805 mg, 1.415 mmol) in a DCM solution (19 ml) FA (3.27 ml, 42.5 mmol) was added. RM was stirred in RT for 1 hour. Concentrate the residue and use ACN (in aq. TFA solution (0.1%)) (5-100%) Purified by eluting Redisep® C18 column reverse-phase chromatography. The title compound was then obtained as a solid TFA salt (767 mg). Method A: Rt=0.40min;[M+H] + =401.3.

[0308] Intermediate 22 5-(2,4-dioxotetrahydropyrimidine-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. 365 mmol) of stirred THF solution (5.4 ml) to which lithium hydroxide monohydrate (128 ml) is added. A 1.35 ml aqueous solution of (g, 3.02 mmol) was added. The resulting RM was R The mixture was stirred overnight in T. RM was concentrated and re-diluted with water (5 ml), and HCl (2 M) was added. Add 1.5 ml of solution Aq. to the mixture until the pH reaches 4. The mixture was then placed in an ice bath. Cooled inside, filtered, the solid washed with water and Et2O, the solid dried, and then titled. 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 toluene mixture (0.5 ml) of acrylic acid (0.354 ml, 5.11 mmol). The mixture was flushed with N2 and stirred at 100°C for 3.5 hours. The RM was concentrated and then labeled. The mixture was obtained as a solid (352 mg). Method A: Rt=0.58min;[M+H] + =242.1.

[0310] Step 3: 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-f Luoro-4-methylbenzoic acid 5-((2-carboxyethyl)amino)-2-fluoro-4-methylbenzoic acid (35 AcOH mixture of 0 mg, 1.277 mmol) and urea (460 mg, 7.66 mmol) The mixture (1 ml) was stirred overnight at 120°C and then cooled to RT. The resulting oil Dilute with water (1-2 ml) and pour the mixture onto crushed ice. HCl (1M) Add the aq. solution and continue stirring until all the ice has melted. The resulting mixture The liquid was filtered, the solid was washed with ACN, and dried to obtain the title compound as a solid (250 mg). It was obtained as such. Method A: Rt=0.48min;[M+H] + =267.1

[0311] Intermediate 23 Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidine-1(2H)- Il-4-methoxybenzoate [ka] 3-(2,4-dioxotetrahydropyrimidine-1(2H) )-yl)-4-methoxybenzoic acid (intermediate 5, 28g, 106mmol), Pentaful Olophenyl 2,2,2-trifluoroacetate (36g, 127mmol) and DM F (50 ml) was added. DIPEA (76 ml, 424 mmol) was added at 0°C. Then, RM was stirred in RT for 2 hours and diluted with water. The mixture was extracted with ethyl acetate. The combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated. It shrank. The residue was eluted with phosphate (in petroleum ether) (10-30%). The title compound was purified by chromatography to obtain it as a solid (40 g). Method H:Rt=1.51min,[M+H] + = 432.

[0312] Intermediate 24 tert-butyl9-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo [2,3-d]pyrimidine-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)ethane-1-ol 2-(4-bromophenyl)ethane-1-ol (60g, 300mmol), BIS PIN (84g, 330mmol), KOAc (90g, 900mmol), and PdCl A 1,4-dioxane mixture (600 ml) of 2 (dppf) (6.6 g, 9 mmol) The mixture was stirred at 85°C for 16 hours under N2. The RM was cooled to RT, filtered, and the filtrate was concentrated. Then, the residue is eluted with silica gel using HCl (in petroleum ether) (0-30%). The title compound was purified by chromatography to obtain oil (100g). Method J:Rt=1.87min,[M+NH4] + =266.

[0313] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-i) Phenethylmethanesulfonate 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-i Phenylethane-1-ol (100g, 300mmol) and TEA (240g) A 1300 ml mixture of 2400 mmol DCM was stirred at 0°C for 20 minutes. Add dropwise, a DCM solution (200 ml) of MsCl (136 g, 1200 mmol) is added, R Mixture M was stirred in RT for 16 hours, and then water was added. The phases were separated, and the organic phase was placed on Na2SO4. The solution is dried, concentrated, and the residue is eluted with ethyl(in DCM) (0-50%). The title compound was purified by silica gel chromatography to obtain 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-di 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-diole) Xaborolan-2-yl)phenethylmethanesulfonate (86g, 172mmol), AC of K2CO3 (47g, 345 mmol) and KI (2.3g, 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 silica gel chromatograph shrinks and elutes the residue with MeOH (in DCM) (0-10%). The title compound was purified by Graph to obtain it as a solid (49 g). Method I: Rt=1.47min,[M+H] + = 485.

[0315] Step 4: tert-butyl9-(4-(4-chloro-7-(phenylsulfonyl)-7H -pyrolo[2,3-d]pyrimidine-6-yl)phenethyl)-3,9-diazaspiro[ 5.5] Undecane-3-carboxylate tert-butyl 9 in a mixture of 1,4-dioxane and water (5:1) (480 ml) -(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, 37g, 88mmol), K2CO3(2 A mixture of 2g, 160 mmol of (2 g, 160 mmol) and PdCl2 (dppf) (5.8 g, 8 mmol). The mixture was stirred at 80°C for 16 hours under N2. RM was poured into SiO4 to separate the organic phase. Then, wash with water, dry on Na2SO4, filter, concentrate, and the residue is M Purification by silica gel chromatography using eOH (in DCM) (0-10%). The title compound was then obtained 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-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-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]undecane-3-yl)methyl)phenyl) -7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-( 2-Hydroxypropan-2-yl)benzamide (intermediate 4, 100 mg, 0.108 mmol) and 3 (2,4-dioxotetrahydropyrimidine-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 ml) (mol) was added. RM was stirred in RT for 2 hours, the solution was poured into water, filtered, Dry the solid and soak it in ACN (in aq. TFA solution (0.1%)) (10-100%). Purified by eluting Redisep® C18 column reverse-phase chromatography. The title compound was obtained as a solid TFA salt. The solid was dissolved in MeOH and SCX carbide was used. The compound was filtered through a tinder, and the combined filtrate was concentrated to obtain 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-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide, and (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-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%) Elute Chiralpak ID column (5μ) with a mixture at a flow rate of 10 ml / min. rac-N-(3-(6-(4-( (9-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl Toxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]un Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Chiral separation of ropan-2-yl)benzamide (7.7 mg, 7.9 μmol) revealed that The title compound was obtained as a single enantiomer in the following order.

[0318] First eluted enantiomer: 1.2 mg Method K:Rt=29.5min Method B: Rt=3.44min;[M+H] + =941.5 1 The 1H NMR (400 MHz, DMSO-d6) for the racemic mixture reported previously showed N Follow the MR (Medical Representative).

[0319] Second eluting enantiomer: 2.0 mg Method K: Rt=37.5min Method B: Rt=3.46min;[M+H] + =941.4 1 The 1H NMR (400 MHz, DMSO-d6) for the racemic mixture reported previously showed N Follow the MR (Medical Representative).

[0320] Compound 4: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5]unde Can-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (L)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Pan-2-yl benzamide [ka] Step 1: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-e Toxybenzoic acid 3-amino-4-ethoxybenzoic acid (2.7g, 14.90 mmol) is mixed with acrylic acid ( Suspend in 4.09 ml (59.6 mmol) and stir RM at 110°C for 1 hour. Then, urea (5.37g, 89mmol) and AcOH (18ml) were added, and RM was 13 The mixture was stirred at 0°C for 2 hours. RM was quenched with water to obtain a 37% concentrated solution of HCl. The solution was acidified with ) and extracted with ÃO. The organic phase was combined and evaporated. Water was added. Then, the mixture is filtered, and the solid is washed with water and SiO2 to obtain the title compound as a solid (1.1 It was obtained as g). Method A: Rt=0.56min;[M+H] + =279.1.

[0321] Step 2: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-ethoxybenzoyl)-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-hydro Xypropan-2-yl)benzamide Following TBTU (38.4 mg, 0.119 mmol), 2,4,6-colidine (0. 2 ml, 1.508 mmol) to 3-(2,4-dioxotetrahydropyrimidine-1( DMF of 2H)-yl)-4-ethoxybenzoic acid (33.2 mg, 0.119 mmol) It was added to the solution (0.5 ml). The RM was stirred in RT for 15 minutes. N-(3-(6- (4-(3,9-diazaspiro[5.5]undecane-3-ylmethyl)phenyl)-7 H-pyrrolo[2,3-d]pyrimidine-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 in RT for 3 days. Dilute with DMF (2 ml) and add ACN (in aq. solution of TFA (0.1%)) (5-1 Elution is performed using SunFire C18 column HPLC (Method L) with a linear gradient of 00%. The compound was then purified to obtain the title compound as a solid TFA salt (32.8 mg). Method B: Rt=3.74min;[M+H] + =925.3. 1 ¹H 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- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide [ka] Step 1: tert-butyl9-(4-bromophenethyl)-3,9-diazaspiro[5. 5] Undecane-3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 3,9-diazas in ACN (50 ml). Pyro[5.5]undecane-3-carboxylate (5g, 19.7mmol), K2C O3 (4.07g, 29.5 mmol) and 1-bromo-4-(2-bromoethyl)bene Zen (5.2g, 17.6 mmol) was added. The RM was stirred under N2 in the RT for 16 hours. The RM was concentrated, diluted with water, and extracted with DCM. The combined organic phase was concentrated. And, by silica gel chromatography eluting with MeOH (in DCM) (1:100) The compound was purified to obtain the title compound as a solid (4.8 g). Method F:Rt=1.91min;MSm / z[M+H] + 438.1.

[0323] Step 2: tert-butyl9-(4-(4,4,5,5-tetramethyl-1,3,2-di 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 (4.8g, 11mmol) ), BISPIN (3.4g, 13.2mmol), KOAc (2.2g, 22mmol) ), PdCl2 (dppf) (0.8g, 1.1mmol) and DMSO (60ml) Added. RM was stirred at 80°C for 16 hours, then diluted with water. The mixture was acetone. Extracted, the combined organic phase is washed with water and brine, concentrated, and .''( Purification by silica gel chromatography (eluting in petroleum ether) (0-100%). The title compound was then obtained as a solid (4.0 g). Method E: Rt=1.67min;MSm / z[M+H] + 485.

[0324] Step 3: tert-butyl9-(4-(4-chloro-7-(phenylsulfonyl)-7H -pyrolo[2,3-d]pyrimidine-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-chlorocarboxylate Ro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 7, 700 mg, 1.67 mmol), Na2CO3 (354 mg, 3.34 m AC was added (mol) and PdCl2 (dppf) (124 mg, 0.17 mmol). Add N (10 ml) and water (2 ml), and stir RM under N2 at 80°C for 16 hours. RM was diluted with ethyl acetate, the mixture was filtered, and the filtrate was concentrated to obtain ethyl acetate (stone). Purified by silica gel chromatography (eluting in oil ether) (0-100%). The title compound was then obtained as 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)benzamide)-2-methylphenyl)-7-( Phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-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 Rufonyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)-3,9 - Diazaspiro[5.5]undecane-3-carboxylate (400mg, 0.62mg) mol), 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl Tramethyl-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) (0.06 mmol) was added. ACN (10 ml) and water (2 ml) were added, and RM was added. The mixture was stirred at 80°C for 16 hours under N2. RM was diluted with ethyl acetate, and the mixture was filtered. Then, the filtrate is concentrated and silica is eluted with siRNA (in petroleum ether) (0-100%). The title compound was purified by gel chromatography to obtain it 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)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-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)benzamide)-2-methyl Phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Il(phenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate NaOH (35 Add an aqueous solution (1 ml) of mg (0.87 mmol) to RT, and then add RM to RT. The mixture was stirred for 1 hour and then diluted with SiO2. The phases were separated, and the organic phase was washed with water and brine. The compound was then dried and concentrated to obtain 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]pyrimidine-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)benzamide)-2-methyl Phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)-3,9- Diazaspiro[5.5]undecane-3-carboxylate (160 mg, 0.21 mm) 0.5 ml of HCl (4M) was added. 4-dioxane solution (1.5 ml, 6 mmol) was added at 0°C. RM was warmed to RT. Then, stirring was continued for 2 hours. RM was concentrated, and the title compound was obtained as a solid HCl salt (130 mg) and I obtained it by doing so. Method E:Rt=1.45min;MSm / z[M+H] + 679.

[0328] Step 7: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydrop Limidine-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5. 5]Undecane-3-yl(ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Roxypropan-2-yl)benzamide In a 10 ml round-bottom flask, add 2 ml of DMF containing N-(3-(6-(4-(2-(3,9 -Diazapiro[5.5]undecane-3-yl)ethyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu 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 mixture was stirred in RT for 2 hours, and the mixture was converted to ACN (ammonium bicarbonate aq). Elution by XBridge C18 column preparative HPLC (in 10 mM solution) The title compound was purified to obtain it 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 Pyrimidine-1(2H)-yl)-4-fluorobenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-Hydroxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(4-bromobenzyloxy)piperidine-1-carbbox Syrah DM at 5°C in mineral oil (1.17g, 29.25 mmol) containing NaH (60%) Add tert-butyl 4-hydroxypiperidine-1-carboxylate to F suspension (30 ml). Add 4.03g (20.0 mmol) of DMF solution (15 ml) dropwise at 5°C. The RM was stirred at 5°C for 1 hour, and then 1-bromo-4-(bromomethyl)benzene was added. (7.0g, 28.0 mmol) was added at 5°C. The RM was warmed to RT and stirred for 1 minute. Continue for 8 hours. Add ice-cold water (250 ml) to the mixture and add butyl and petroleum ether. Extraction with a (2:1) mixture, the combined organic phase is dried on MgSO4, and concentrated. Then, silica gel chromatography elutes with SiO(in petroleum ether) (0-20%). The title compound was purified by Fi to obtain 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-di Oxaborolan-2-yl)benzyloxy)piperidine-1-carboxylate tert-butyl-4-(4-bromobenzyloxy)piper placed under an inert atmosphere Zin-1-carboxylate (2.0g, 5.4mmol), BISPIN (2.7g, 10.8 mmol), KOAc (1.59 g, 16.2 mmol) and PdCl2 (dp Add 1,4-dioxane (45 ml) to a mixture of pf) (630 mg, 0.86 mmol) In addition, RM was stirred at 85°C for 18 hours under N2. RM was evaporated, and toluene was added. Purification by silica gel chromatography (which elutes at a concentration of 0-20% in petroleum ether). The title compound was then obtained 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- at 5℃ Dioxaborolan-2-yl)benzyloxy)piperidine-1-carboxylate(2 1,4-dioxide solution of HCl (4M) in 10 ml of DCM solution (0.1 g, 5.0 mmol) The Sun solution (5 ml, 20 mmol) was slowly added. The RM was warmed to 30°C and stirred for 2 minutes. The process continued. The RM was concentrated, and the residue was mixed with a mixture of petroleum ether and TBME (2:1). The compound was ground, filtered, and the solid was dried to obtain the title compound as a solid HCl salt (1.2 g). I 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 DCM mixture of (2g, 8.72 mmol) and TEA (1.77g, 17.44 mmol) Add methanesulfonyl chloride (1.2g, 10.47 mmol) dropwise to the combined solution (50 ml). Then, RM was stirred in RT for 16 hours. RM was diluted with DCM (100 ml) and water. Then, wash with brine, dry on Na2SO4, concentrate, and solidify the title compound ( It was obtained as 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)piperidine-1-yl)eth (Lu)piperidine-1-carboxylate 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa under an inert atmosphere Bororan-2-yl)benzyloxy)piperidine (700 mg, 1.98 mmol), tert-butyl-4-(2-(methylsulfonyloxy)ethyl)piperidine-1-ca Ruboxilate (913 mg, 2.97 mmol), K2CO3 (821 mg, 5.94 mmol) A mixture of mmol) and NaI (445 mg, 1.5 mmol) with ACN (20 ml) In addition, RM was stirred in RT under N2 for 16 hours. Next, RM was mixed with ethyl acetate (100%). The compound was diluted in ml, filtered, and the filtrate was concentrated to obtain 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-(4-chloro-7-(phenyl sulfon (Nyl)-7H-pyrrolo[2,3d]pyrimidine-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperidine-1-carboxylate tert-butyl-4-(2-(4-(4-(4,4,5,5-tert under an inert atmosphere Lamethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)piperidine-1 -Iyl)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, A mixture of 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 hours. Dilute RM with ELISA (100 ml), filter, concentrate the filtrate, and then add MeOH ( Purified by silica gel chromatography (0-15% elution in DCM), and then presented. The compound in question was obtained as 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- Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6yl )benzyloxy)piperidine-1-yl)ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-Fluoro-2-methyl-3-(4,4,5 under an inert atmosphere ,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-(4-chloro-7-(phenylsulfonyl (Nyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyloxy)piperidine (1-yl)ethyl)piperidine-1-carboxylate (200 mg, 1 mmol) , Na2CO3 (92 mg, 0.86 mmol) and PdCl2 (dppf) (24 mg Add ACN (5 ml) and water (1 ml) to a mixture of 0.03 mmol and RM to N The mixture was stirred at 80°C for 16 hours. Next, the RM was diluted with phenylethylamine (100 ml). Then, filter it, concentrate the filtrate, and elute the silica with methanol (in DCM) (0-15%). The title compound was purified by Kagel chromatography to obtain oil (260 mg). Method G:Rt=2.875min,[M+H] + =694.

[0336] Step 8: tert-butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperidine-1-carboxylate tert-butyl-4-(2-(4-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)be (2)(diyloxy)piperidine-1-yl)ethyl)piperidine-1-carboxylate(2 DMSO solution (2 ml) of 00 mg, 0.21 mmol) with NaOH (33 mg, 0.8 A 3 mmol aqueous solution (1 ml) was slowly added to RT. RM was then 2 h Stirring, the mixture is in an ACN (ammonium bicarbonate aq. solution (0.1%)) ( Purified by XBridge C18 column reversed-phase HPLC, which elutes at 5-95%. 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-(piperidine-4-yl)ethyl)piperidine-4-yloxy)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydro Xypropan-2-yl)benzamide tert-butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyloxy)piperidine-1- (Iyl)ethyl)piperidine-1-carboxylate (150 mg, 0.16 mmol) A 4 ml solution of DCM was cooled to 0°C. The 1,4-dioxane solution of HCl (6 M) was then dissolved. The liquid (1 ml, 6 mmol) was slowly added. The RM was heated to RT and stirred for 2 hours. RM was concentrated to obtain the title compound as a solid HCl salt (115 mg). Method I: Rt=1.142min;[M+H] + =723.

[0338] Process 10: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-Dioxote Trahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)piperidine-4 -yl)ethyl)piperidine-4)yl)oxy)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu Oro-4-(2-hydroxypropan-2-yl)benzamide 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-((1-(2-( Piperidine-4-yl)ethyl)piperidine-4-yloxy)methyl)phenyl)-7 H-Pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxyp Ropan-2-yl)benzamide (80 mg, 0.11 mmol), 3-(2,4-diode) Xotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoic acid (intermediate 9, 31mg, 0.12mmol), HATU (50mg, 0.13mmol), DIPEA Mixture of (29 mg, 0.22 mmol) and DMF (2 ml) was stirred in RT for 2 hours. The mixture was then prepared using ACN (aq. solution of ammonium bicarbonate (0.1%)) (5-9 XBridge C18 column (21.2 × 250 mm, 10 μm) eluting at 5% reverse The title compound was purified by phase HPLC to obtain it 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-dioxotetrahydropyrim Din-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl) Piperazine-1-yl(methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(piperazine-1-ylmethyl)piperidine-1-carb Xylart In a 100 ml round-bottom flask, add tert-butyl 4-(bromomethyl)piperidine-1-C. Ruboxilate (1.0g, 3.59 mmol), piperazine (3.1g, 31.95 mg) (mol) and ACN (20 ml) were added. The RM was stirred at 80°C for 16 hours. Mixing The liquid is concentrated, and the residue is eluted with silica gel. The title compound was purified by chromatography to obtain it 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-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1-yl Methyl)piperidine-1-carboxylate In a 25 ml round-bottom flask, add tert-butyl 4-(piperazine-1-ylmethyl)piper Zin-1-carboxylate (400 mg, 1.41 mmol), K2CO3 (585 mg) Add (g, 4.23 mmol) and DMSO (5 ml), and RM in RT for 30 minutes. Stirred. ZnCl2 (1.0M) THF solution (1.55 ml, 1.55 mmol) and 2-Fluoro-N-(5-Fluoro-3-(6-(4-Formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydro Xypropan-2-yl)benzamide (intermediate 3, 743 mg, 1.41 mmol) Added. Stir RM in RT for 30 minutes to obtain solid NaBH3CN (266 mg, 4. 23 mmol) and MeOH (5 ml) were added, and the RM was stirred in RT for 16 hours. The mixture is concentrated, and the residue is converted to ACN (ammonium bicarbonate aq. solution (10 mM)). Agela C18 column (spherical, 20-35 μm, 100 Å, 120 g) that elutes in the middle. The title compound was purified by chromatography to obtain it 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-( Piperidine-4-ylmethyl)piperazine-1-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxypropane- 2-yl)benzamide hydrochloride In a 25 ml round-bottom flask, add tert-butyl 4-((4-(4-(4 -(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)be (2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-6- (1) benzyl piperazine-1-yl methyl piperidine-1-carboxylate (1 50 mg (0.19 mmol) was added. HCl (4M) 1,4-dioxane solution (3 Slowly add 0.0 ml (12.0 mmol). Stir RM in RT for 3 hours to concentrate. The compound was reduced and used directly in the next step without further purification of the residue. The title compound was treated with solid HCl. It was obtained as 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-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-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-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)phen (Lu)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-Hyd Roxypropan-2-yl)benzamide hydrochloride (138 mg, 0.19 mmol) l), 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-meth Xybenzoic acid (intermediate 5, 55 mg, 0.21 mmol), DIPEA (123 mg, 0 0.95 mmol) and DMF (3 ml) were added. Next, HATU (86 mg, 0.23 mmol) was added, and RM was stirred in RT for 2 hours. The mixture was concentrated, and the residue was... XBridge elutes with ACN (in aq. solution of ammonium bicarbonate (10 mM)). Purified by preparative HPLC using a C18 column (21.2 × 250 mm, 10 μm), and then presented in the table. The compound in question 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-dioxotetrahydropyrim Din-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy) Piperidine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(1-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperidine-4-yl Xy)piperidine-1-carboxylate In a 100 ml round-bottom flask, add 2-fluoro-N-(5-fluoro-3-(6-(4-fluoro). Milphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl (Nyl)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 3, 4.35 (g, 8.26 mmol) and tert-butyl 4-(piperidine-4-yloxy) pipe Lysine-1-carboxylate (intermediate 10, 2.35 g, 9.09 mmol) and DM SO (30 ml) was added. ZnCl2 (1 M) THF solution (9.1 ml, 9.1 mm) Add (ol) and stir the mixture in RT for 45 minutes. Solid NaBH3CN(1.5 6g (24.8 mmol) was added, and the mixture was stirred in RT for 30 minutes. MeOH (20 ml) was added and stirring continued for 16 hours. The mixture was concentrated and the residue was extracted from ACN (carbon Agela C18 column eluted in ammonium oxyhydrogen aq. solution (10 mM). (Spherical 20-35 μm, 100 Å, 120 g) Purified by chromatography, Title 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-( Piperidine-4-yloxy)piperidine-1-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxypropane- 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)benzamide)-2-me Tylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piper (Zin-4-yloxy)piperidine-1-carboxylate (4.5g, 5.66mmo) l) 1,4-dioxane (20 ml) and MeOH (2 ml) were added. HCl (4M A 1,4-dioxane solution (4 ml, 16 mmol) was slowly added. The mixture was then RT After stirring for 1 hour, the mixture was concentrated to obtain the title compound as a solid HCl salt (5.0 g). This material was then used in the next process without further refinement. Method F:Rt=1.27min;MSm / z[M+H] + 695.

[0345] Step 3: N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-ylox (C)piperidine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Roxypropan-2-yl)benzamide Add 3-(2,4-dioxotetrahydropyrimidine-1(2H) to a 100 ml round-bottom flask. )-yl)-4-methoxybenzoic acid (intermediate 5, 1.6g, 6.23mmol), DMF (25ml) and HATU (2.58g, 6.79mmol) were added. RM to RT. Stirred for 0.5 hours. 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-( 4-((4-(piperidine-4-yloxy)piperidine-1-yl)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydro Xypropan-2-yl)benzamide hydrochloride (5g, 6.84 mmol) and Add DIPEA (2.19g, 16.98 mmol) and stir the mixture in RT for 3 hours. Mix the mixture and elute it with ACN (in aq. solution of ammonium bicarbonate (10 mM)). Agela C18 column (spherical 20-35 μm, 100 Å, 120 g) chromatography The title compound was purified using a raffia meter to obtain it as a solid (4.17 g). 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]unde Can-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (L)-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-ilmeth (Lu)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro- 2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)ben Zuamide (intermediate 11, 50 mg, 0.068 mmol), 3-(2,4-dioxoteto Lahydropyrimidine-1(2H)-yl)-4-methoxybenzoic acid (intermediate 5, 17.9 D of 1 mg, 0.068 mmol) and HBTU (30.8 mg, 0.081 mmol) MF solution (3 ml) was mixed with DIPEA (0.071 ml, 0.407 mmol). M was stirred under argon in RT for 2 hours, water was added, and the resulting suspension was filtered. After passing through the process, wash the solid with water, dry it, and dissolve it in MeOH (in CO2) (30-45%). Princeton PPU column (250×30mm, 100Å, 5μm) SF The compound was purified using C to obtain 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy )piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydro Xypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-((1-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)piperidine-4-yl (Lu)oxy)piperidine-1-carboxylate 4-(4-(5 -Fluoro-3-(2-Fluoro-4-(2-hydroxypropan-2-yl)benzur (Mido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl) Enemethylmethanesulfonate (intermediate 13, 334 mg, 0.538 mmol) and te rt-butyl 4-(piperidine-4-yloxy)piperidine-1-carboxylate ( A mixture of intermediates (10 mg, 306 mg, 1.076 mmol) (13.5 ml) is mixed with K2CO3 (446 mg, 3.23 mmol) was added. The resulting RM was left at 50°C for 3 The mixture was stirred for several days. The RM was cooled in an ice bath under stirring until the mixture reached a pH of 3-4. The mixture was slowly acidified with TFA until it reached a certain point. The resulting mixture was then heated in RT and partially... It is concentrated and adsorbed onto Isolute(registered trademark), and ACN (TFA aq. solution) Redisep® C18 column reversed-phase chromatography (in 0.1%) elutes at a concentration of 0.1%. The title compound was purified by Fi to obtain the 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 -(piperidine-4-yloxy)piperidine-1-yl)ethyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxypropane (N-2-yl)benzamide RT tert-butyl 4-((1-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)piperidine-4-yl (Lu)Oxy)piperidine-1-carboxylate (223 mg, 0.194 mmol) TFA (0.447 ml, 5.81 mmol) was added to DCM solution (3.7 ml). The resulting solution was stirred in RT for 1 hour and then diluted with a mixture of DCM and ACN. The mixture was concentrated and dried to obtain a resin. The resin was then redissolved in a mixture of ACN and water. The title compound was obtained as a solid TFA salt (225 mg) by freeze-drying. Method A: Rt=0.67min;[M+H] + =709.5.

[0349] Step 3: N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl )Oxy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pi Limidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2 -Hydroxypropan-2-yl)benzamide 2-fluoro-N-(5-fluoro-2-methyl-3-(6-( 4-(2-(4-(piperidine-4-yloxy)piperidine-1-yl)ethyl) (Nyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-H Droxypropan-2-yl)benzamide (120 mg, 0.114 mmol), 3- (2,4-Dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoic acid (Intermediate 8, 29.8 mg, 0.120 mmol) and HBTU (46.4 mg, 0.1 Add DIPEA (140 μl, 0.7) to a 2.25 ml dry DMF mixture (20 mmol). 99 mmol was slowly added. The resulting solution was stirred in RT for 1.5 hours. Then, dilute with ACN and adsorb onto Isolute(registered trademark), and ACN(TF Redisep (registered trademark) elutes in solution (0.1%) of A (10-100%). (Standard) Purified by C18 column reverse-phase chromatography, PL-HCO3MP SP After filtering and freeze-drying the fraction containing the pure target compound using an E cartridge, the title was created. 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]u Ndecane-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide [ka] Step 1: 3-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl) Phenyl)propan-1-ol 4-(3-hydroxypropyl)benzeneboronic acid (2.511g, 13.95mmo) l) and 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.44g Dissolve 12.31 mmol of this substance in 100 ml of 1-propanol in RT. Then, a solution of Na2CO3 (2M) aq. (13.54 ml, 27.1 mmol) was added. Pass argon through the mixture for 5 minutes to create bubbles, then extract PdCl2(PPh3)2(0.432g, (0.615 mmol) was added. RM was stirred at 105°C for 22 hours, then proceeded to RT. It was cooled overnight. The solvent was removed, and the residue was ultrasonically treated in a mixture of water and THF (3:2). The mixture was filtered, the solid was washed with water, and dried to obtain the title compound as a solid (2. It was obtained as 4g. Method A: Rt=0.86min;[M+H] + =288.2.

[0351] Step 2: 2-Fluoro-N-(5-Fluoro-3-(6-(4-(3-hydroxypropyl (Phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl Nyl)-4-(2-hydroxypropan-2-yl)benzamide 3-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phen (L) Propan-1-ol (1.5g, 4.85 mmol) and 2-fluoro-N-(5 -Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa Bororan-2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzur Mid (intermediate 2, 2.1g, 4.87 mmol) in 1-propanol (36ml) Suspend in T and add aq. solution of Na2CO3 (2M) (5.1 ml, 10.20 ml). (mol) was added. Argon was passed through the mixture for 1 minute to create bubbles, and PdCl2(PPh3) was added. 2 (0.180g, 0.256 mmol) was added. RM was subjected to microwave radiation. The mixture was heated at 40°C for 20 minutes. RM was diluted with ELISA and then mixed with Hyflo (registered trademark). The solution was filtered using ). The filtrate was evaporated and re-diluted with a mixture of THF and H2O (1:1). Extraction was performed with carboxylate. The combined organic phase was dried on MgSO4 and evaporated. The residue is ground in a mixture of DCM and MeOH, filtered, and the solid is washed with DCM. The compound was then dried to obtain 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)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-yl)phenyl)propylmethanesulfonate 2-Fluoro-N-(5-Fluoro-3-(6-(4-(3-hydroxypropyl) (phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methylphenyl) -4-(2-hydroxypropan-2-yl)benzamide (1032 mg, 1.539 mmol) is dissolved in dry THF (16 ml) under argon in RT, and TEA (0.858 ml, 6.16 mmol) was added. The mixture was cooled to 0°C and Ms2O( 536 mg (3.08 mmol) was added, and the RM was stirred at 0°C for 40 minutes. Quench with ice water, extract with DCM, and dry the combined organic phase on MgSO4. The compound was then concentrated to obtain 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)benzamide)-2-methylphenyl)- 7H-Pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)propyl)-3,9-di Azaspiro[5.5]undecane-3-carboxylate 3-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane (-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrrolo[2,3-d] Limidine-6-yl)phenyl)propylmethanesulfonate (0.977g, 1.53 9 mmol) in a mixture of dry DMF (4 ml) and ACN (16 ml) under argon. Dissolved in RT. K2CO3 (1.063g, 7.70 mmol) and 3,9- Diaza-spiro[5.5]undecane-3-carboxylate tert-butyl ester (0. Add 783g (3.08 mmol) and stir the RM at 60°C for 13.5 hours. The mixture is evaporated to dryness, and the resulting residue is taken into a mixture of SiO and water. The phases were separated. The aq. layer was extracted with HCl, and the combined organic phase was extracted with lithium bromide. A mixture of solution, brine, and water (1:1), and washed with brine, then MgSO The mixture was dried, concentrated, and dried again to obtain 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]pyrimidine-4-yl) -5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane -2-yl)benzamide tert-butyl9-(3-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)propyl)-3,9-diazas Pyro[5.5]undecane-3-carboxylate (1.545g, 1.539mmol) ) A solution of DCM (10 ml) and TFA (4 ml, 51.9 mmol) was tested in RT for 3 Stir for 0 minutes, evaporate the mixture, and allow it to be adsorbed onto Isolute(registered trademark) HM-N. Furthermore, Red elutes in ACN (in aq. TFA solution (0.1%)) (5-100%). The title compound was purified by isep(registered trademark) C18 column reversed-phase chromatography. This 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5 .5]Undecane-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrrolo Midine-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-i (L)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5- Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2- (Il)benzamide trifluoroacetate (200 mg, 0.193 mmol) dried Dissolve in DMF (3 ml) under argon in RT, then DIPEA (0.270 ml) (1,546 mmol) and 3-(2,4-dioxotetrahydropyrimidine-1(2 H)-yl)-4-methoxybenzoic acid (intermediate 5, 58 mg, 0.220 mmol) followed by Then HBTU (86 mg, 0.227 mmol) was added. RM was administered at RT for 20 minutes. Stir, dilute with ACN, adsorb onto Isolute(registered trademark) HM-N, and dry. Then, Re elutes in ACN (in aq. TFA solution (0.1%)) (5-100%). The compound was purified by disep(registered trademark) C18 column reversed-phase chromatography. Obtained as TFA salt, followed by freezing after filtration using a PL-HCO3 MP SPE cartridge. By drying, the title compound was obtained 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- Iyl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5- Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2- Il-benzamide [ka] Step 1: tert-butyl9-(4-bromophenethyl)-3,9-diazaspiro[5. 5] Undecane-3-carboxylate In a 250 ml round-bottom flask, add tert-butyl 3,9-diazas in ACN (50 ml). Pyro[5.5]undecane-3-carboxylate (5g, 19.7mmol), K2C O3 (4.07g, 29.5 mmol) and 1-bromo-4-(2-bromoethyl)bene Zen (5.2g, 17.6 mmol) was added. The RM was stirred under N2 in the RT for 16 hours. The solution was then concentrated and re-diluted in a mixture of water and DCM. The phases were separated, and phase aq. was converted to DC. Extracted with M, the combined organic phase was concentrated and then treated with MeOH (in DCM) (1:100). The title compound was purified by eluting silica gel chromatography to obtain a solid (4.8g). It was obtained as such. Method F:Rt=1.91min;MSm / z[M+H] + 438.1.

[0357] Step 2: tert-butyl9-(4-(4,4,5,5-tetramethyl-1,3,2-di 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 (4.8g, 11mmol) , BISPIN (3.4g, 13.2mmol), KOAc (2.2g, 22mmol) Add PdCl2 (dppf) (0.8g, 1.1 mmol) and DMSO (60 ml). The RM was stirred at 80°C for 16 hours, diluted with water, and extracted with pharmaceutically acceptable phosphate. The combined organic phases are washed with water and brine, concentrated, and then SiO2 (in petroleum ether). Purified by silica gel chromatography eluting at (0-100%), the title compound The substance was obtained as a solid (4.0g). Method E: Rt=1.67min;MSm / z[M+H] + 485.

[0358] Step 3: tert-butyl9-(4-(4-chloro-7-(phenylsulfonyl)-7H -pyrolo[2,3-d]pyrimidine-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-chlorocarboxylate Ro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 7, 700 mg, 1.67 mmol), Na2CO3 (354 mg, 3.34 m AC was added (mol) and PdCl2 (dppf) (124 mg, 0.17 mmol). Add N (10 ml) and water (2 ml), and stir RM under N2 at 80°C for 16 hours. RM was diluted with RINKAN, filtered, and the filtrate was concentrated with RINKAN (petroleum ether). Purified by silica gel chromatography (0-100%), Title The compound was obtained as 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)benzamide)-2-methylphenyl)-7-( Phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-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 Rufonyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)-3,9 - Diazaspiro[5.5]undecane-3-carboxylate (400mg, 0.62mg) mol), 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl Tramethyl-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) (0.06 mmol) was added. ACN (10 ml) and water (2 ml) were added, and RM was added. The mixture was stirred at 80°C for 16 hours under N2 conditions. RM was diluted with SiO2, filtered, and the filtrate was obtained. The silica gel is concentrated and eluted with dimethyl (in petroleum ether) (0-100%). The title compound was purified by matrixing to obtain it 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)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-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)benzamide)-2-methyl Phenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Il(phenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate NaOH (35 Add 1 ml of an aqueous solution (0.87 mmol / mg) to RT and stir RM for 1 hour. Then, it was diluted with dimethyl glycol. The phases were separated, and the organic phase was washed with water and brine and dried. The compound was dried and concentrated to obtain 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]pyrimidine-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)benzamide)-2-methyl Phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenethyl)-3,9- Diazaspiro[5.5]undecane-3-carboxylate (160 mg, 0.21 mm) 0.5 ml of HCl (6N) was added. Add 4-dioxane solution (1.5 ml, 6 mmol) at 0°C, and warm RM to RT. Then, stirring was continued for 2 hours. RM was concentrated, and the title compound was obtained as a solid HCl salt (130 mg) and I obtained it by doing so. Method E:Rt=1.45min;MSm / z[M+H] + 679.

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

[0363] Step 8: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzoic acid 3-(2-carboxyethylamino)benzoic acid (2g, 9.5g) in a 50ml round-bottom flask. Add 6 mmol of hydroxypropyl alcohol, 25 ml of AcOH, and 1.72 g of urea (28.68 mmol). Then, RM was stirred at 120°C for 16 hours. The solvent was evaporated, and water (20 ml) was added. The mixture was then filtered, the solid was washed with water, and dried to obtain a solid. The solid was then processed into DMF. Redissolve in the mixture, stir in RT for 2 hours, filter, and wash the solid with water. The compound was then dried to obtain 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-dioxotetrahydrop Limidine-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane (H-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (N-2-yl)benzamide N-(3-(6-(4-(2-(3,9-diazaspiro[5.5]undecane-3-i (L)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-f (2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2-) (L)benzamide (137 mg, 0.182 mmol) and 3-(2,4-dioxotetol) Lahydropyrimidine-1(2H)-yl)benzoic acid (43 mg, 0.182 mmol) A 25 ml round-bottom flask containing DMF solution (2.5 ml) is filled with DIPEA (141 mg, Add 1.09 mmol) and HATU (73 mg, 0.191 mmol) at 5°C. The RM was stirred at 25°C for 1 hour, filtered, and the filtrate was concentrated to obtain ACN (bicarbonate). XBridge C18 column elutes in ammonium aq. solution (10 mM) The title compound was purified by preparative HPLC (250 × 21.2 mm, 10 μm) to obtain a solid ( It was obtained as 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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-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)benzamide)-2-methylphenyl)-7H -Pyrro[2,3-d]pyrimidine-6-yl)benzyl)oxy)piperidine-1-ca Luboxylart 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 1-propanol (10 ml) containing Na2CO3 (2M) q. Add PdCl2(PPh3)2(8) to a mixture of solutions (1.26 ml, 2.53 mmol). 9 mg (0.126 mmol) was added. The resulting RM was then treated with microwave radiation. The mixture was heated at 140°C for 15 minutes. The mixture was filtered using Hyflo®. The filtrate is concentrated and eluted with ethyl(CHX) (0-95%) in silica chromatography. The title compound was purified by Fi to obtain it 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-((Piperi Zin-4-yloxy)methyl)phenyl)-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)benzamide)-2-methylphenyl)-7H-pyro [2,3-d]pyrimidine-6-yl)benzyl)oxy)piperidine-1-carboxy Dissolve sylart (526 mg, 0.739 mmol) in dry DCM (4 ml), Add TFA (1.708 ml, 22.17 mmol), and the resulting mixture is R The mixture was stirred in T for 2 hours. RM was evaporated to dryness, and the title compound was obtained as a TFA salt and oil. (536 mg) was obtained. 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)benzamide)-2-methylphenyl (Nyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)oxy)piper Zin-1-yl)ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-((piperidine- 4-Iyloxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-I Phenyl-4-(2-hydroxypropan-2-yl)benzamide (536mg) , 0.739 mmol), tert-butyl(2-oxoethyl)carbamate (201 Me (mg, 0.886 mmol) and TEA (0.309 ml, 2.216 mmol) OH mixture (5 ml) with ZnCl2 (0.5 M) THF solution (1.625 ml, 0.8 Add 12 mmol of solid NaBH2. Stir RM under argon in RT for 3 hours. Add 3CN (20.06 mg, 0.319 mmol) and stir RM overnight in RT. The RM was diluted with RINKAN to form the aq. phase, and the aq. phase was made from NaHCO3 and brine in an aq. solution. The washing was performed. The organic phase was dried on MgSO4 and absorbed onto Isolute®. After drying, the Redis is eluted with ACN (in aq. solution of TFA (0.1%)). The title compound was purified by reverse-phase chromatography using ep(registered trademark) C18 column. It was obtained as 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-(piperidine-4-yl)ethyl)piperidine-4-yl)oxy)methyl) ethyl)piperidine-4-yl) oxy)methyl) ethyl) (Nyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-H Droxypropan-2-yl)benzamide tert-butyl 4-(2-(4-((4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)oxy)piperidine- 1-Iyl)ethyl)piperidine-1-carboxylate (400 mg, 0.427 mmol) l) A solution of DCM (10 ml) and TFA (0.987 ml, 12.81 mmol) The mixture was stirred for 2 hours under Lugon conditions in RT. The RM was concentrated, and the title compound was obtained as a solid TFA salt (5 It was obtained as 00 mg. Method A: Rt=0.70min;[M+H] + =723.6.

[0369] Step 5: N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxoteto Lahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4- Iyl)ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-(((1-(2- (Piperidine-4-yl)ethyl)piperidine-4-yl)oxy)methyl)phenyl) -7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydrox Cypropan-2-yl)benzamide trifluoroacetate (120 mg, 0.102 mmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4 - Methoxybenzoic acid (intermediate 5, 27.0 mg, 0.102 mmol) and HBTU (4 6.5 mg (0.123 mmol) of DMF solution (3 ml) mixed with DIPEA (0.107 ml) (1 / 1, 0.613 mmol) was added, and the RM was stirred under argon in RT for 2 hours. Add the following, filter the resulting white precipitate, wash with water, dry, and Me Reprospher PEI column (2) elutes in OH (CO2) (22-55%) (50×30mm, 100Å, 5μm) Purified by SFC, then ACN (TFA a q. XBridge C18 OBD elutes in solution (0.1%) (18-48%) Purified by reverse-phase HPLC using a column (100 x 30 mm, 5 μm), PL-HCO3 After filtration and freeze-drying using an MP SPE cartridge, the title compound was solidified (35.9 mg). ) was obtained as follows. 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]unde Can-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (L)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Pan-2-yl benzamide [ka] RT's 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4- DMA solution of ruorobenzoic acid (intermediate 9, 8.89 mg, 0.035 mmol) (0.5 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 -Diazapiro[5.5]undecane-3-ylmethyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide (intermediate 6, 31 mg, 0 Add 0.027 mmol) and stir RM overnight in RT. Dilute RM with siRNA. After dissolving, the organic phase was washed with a solution of NaHCO3 and brine, and then on Na2SO4. Dry and concentrate, then add ACN (in aq. solution of TFA (0.1%)) (10-100%) Purified by reverse-phase HPLC of a Reprosil® C18 column eluted at ) The fractions containing the pure compound were combined and basicized with an aq. solution of NaHCO3. Then, it was extracted with SiO2. The combined organic phase was dried on Na2SO4 and concentrated. The residue is then dissolved in a mixture of water and ACN, freeze-dried, and the title compound is obtained as a solid. (18.5 mg) was obtained. 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)pro Pyr(piperidine-4-yl)oxy(phenyl)-7H-pyrrolo[2,3-d]pyrim (Zin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(3-(4-(4-(4-(5-fluoro-3-(2-fluoro Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-4-yl)pheni (Lu)-4-(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. ZnCl Add 2 (0.7M) THF solution (0.250 ml, 0.175 mmol) and RM The mixture was stirred overnight under argon in RT. Solid NaBH3CN (11 mg, 0.175 m) (mol) was added and RM was stirred overnight in RT. The solvent was removed, and the resulting The residue was used directly in the next process 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-(piperidine-4-yl)propyl)piperidine-4-yl)oxy)phenyl)- 7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxy Propan-2-yl benzamide Crude tert-butyl 4-(3-(4-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenoxy)piperidine-1-yl (Propyl)piperidine-1-carboxylate (117 mg, 0.142 mmol) The DCM (1.5 ml) and TFA (0.150 ml, 1.947 mmol) solutions were RT Stirring for 2.5 hours, remove the solvent, and the residue is ACN (TFA aq. solution ( Redisep® C18 column reverse elution (0.1%) (2-100%) The title compound was purified by phase chromatography and obtained as a solid TFA salt (135 mg). I got it. Method A: Rt=0.72min;[M+H] + =723.6.

[0373] Step 3: N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl (L)propyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-Hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy NMM added to DMF solution (1 ml) of benzoic acid (intermediate 5, 45 mg, 0.170 mmol) (0.050 ml, 0.455 mmol) followed by HATU (65 mg, 0.170 ml) ol) was added. After stirring RM for 30 minutes, 2-fluoro-N-(5-fluoro-2- Methyl-3-(6-(4-((1-(3-(piperidine-4-yl)propyl)piperidi (H-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )phenyl)-4-(2-hydroxypropan-2-yl)benzamide trifluoro Setart (0.142 mmol) and NMM (0.050 ml, 0.455 mmol) 0.5 ml of DMF solution was added dropwise, and the RM was stirred in RT for 2.5 hours. Concentrate and dissolve in ACN (in a 0.1% solution of NH4HCO3) (2-100%). The resulting product is purified by Redisep(registered trademark) C18 column reverse-phase chromatography. 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)eth Piperazine-1-yl methylphenyl-7H-pyrrolo[2,3-d]pyrimidyl (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Roxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate -78°C oxalyl chloride in a stirred anhydrous DCM (10 ml) solution (0.380 ml, 4. DMSO (0.538 ml, 7.58 mmol) was added to 25 mmol. RM was 30 After stirring for minutes, add 1-Boc-4-(2-hydroxyethyl) phosphate to DCM (10 ml). Perazine (500 mg, 2.106 mmol) was added. The RM was left at -78°C for 30 minutes. After stirring, add TEA (2.4 ml, 17.22 mmol) and continue stirring for 1.5 hours. Meanwhile, RM was heated to RT. RM was heated by adding a sat.aq. solution of NaHCO3. After quenching, the mixture was extracted with DCM. The combined organic phase was dried on Na2SO4. Then, evaporate to dryness, and the residue is divided into SiO and MeOH (4:1) (in SiO). Purified by silica chromatography using a (0-30%) mixture, the title compound The substance 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- Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1- Iyl(ethyl)piperazine-1-carboxylate 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-(piperazine-1 -Ilmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl (Lu)-4-(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) under RT conditions. Add ZnCl2 (0.5M) THF solution (0.850 ml, 0.425 mmol) The RM was stirred in RT for 7 hours. Solid NaBH3CN (27 mg, 0.430 mmol) Add (1), stir RM overnight in RT, concentrate, and remove the residue from ACN (TFA Elution in aq. solution (0.1%) using a reversed-phase Redisep® C18 column. The title compound was purified by chromatography to obtain 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]pyrimidine-4-yl)phenyl)-4-(2-hydroxyp Ropan-2-yl)benzamide tert-butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1-yl) Ethyl)piperazine-1-carboxylate (259 mg, 0.109 mmol) OH solution (2 ml) + HCl (4M) 1,4-dioxane solution (2 ml, 8.00 ml) Add ol) and stir RM in RT for 1 hour to concentrate, and the residue is ACN(TF) Redisep (registered trademark) elutes in solution (0.1%) of A (2-100%). The title compound was purified by C18 column reversed-phase chromatography to obtain a solid TFA salt (9 It was obtained as 1 mg. Method A: Rt=0.65min;[M+H] + =709.6.

[0377] Step 4: N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl (L)ethyl)piperazine-1)yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy Benzoic acid (intermediate 5, 20 mg, 0.074 mmol) is dissolved in DMF (0.5 ml) using RT. Dissolve in the following: NMM (0.050 ml, 0.455 mmol) and HATU (3 0 mg (0.077 mmol) was added, and the RM was stirred in RT for 30 minutes. 2-F Luoro-N-(5-fluoro-2-methyl-3-(6-(4-((4-(2-(piperaj (1-yl)ethyl)piperazine-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxypropane-2-yl) (L) Benzamide trifluoroacetate (91 mg, 0.059 mmol) and NMM Add 0.5 ml of DMF solution (0.050 ml, 0.455 mmol) dropwise, RM The mixture was stirred in RT for 2.5 hours. The mixture was concentrated and ACN(TFA aq. solution (0 Redisep® C18 column reversed phase elution at concentrations of 0.1% (2-100%) Purified by chromatography, and then processed using a PL-HCO3 MP SPE cartridge. Torus 2P elutes by filtration, freeze-drying, and MeOH (in CO2) (22-52%). Titled after additional purification by SFC using an IC column (250×30mm, 130Å, 5μm). The mixture 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)eth Piperazine-1-yl methylphenyl-7H-pyrrolo[2,3-d]pyrimidyl (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Roxypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1- Iyl(ethyl)piperidine-1-carboxylate 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-(piperazine-1 -Ilmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl (Lu)-4-(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 mmol) was dissolved in MeOH (2 ml) at RT, and ZnCl2 (0.7 M) Add the THF solution (0.370 ml, 0.259 mmol) and perform RM under argon. The mixture was stirred for 5 hours in T. Solid NaBH3CN (16 mg, 0.255 mmol) was added. Then, stir RM in RT overnight to remove the solvent, and the residue is ACN (TFA a q. Redisep® C1 elutes in solution (0.1%) (2-100%). The title compound was purified by 8-column reverse-phase chromatography to obtain a solid TFA salt (236m). It was obtained as 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-(piperidine-4-yl)ethyl)piperazine-1-yl)methyl)phenyl)-7 H-Pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxyp Ropan-2-yl)benzamide tert-butyl 4-(2-(4-(4-(4-(5-fluoro-3-(2-fluoro -4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl)piperazine-1-yl) Ethyl)piperidine-1-carboxylate (230 mg, 0.249 mmol) OH solution (2 ml) + 1.5 ml of HCl (4 M) 1,4-dioxane solution (6.00 mmol was added, and RM was stirred in RT for 2 hours. RM was concentrated to obtain the title compound. It was 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-dioxotetra Hydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl (L)ethyl)piperazine-1)yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-Hydroxypropan-2-yl)benzamide 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy Dissolve benzoic acid (intermediate 5, 41 mg, 0.155 mmol) 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 in RT for 30 minutes. 2-Fluoro-N-(5 -fluoro-2-methyl-3-(6-(4-((4-(2-(piperidine-4-yl)e (Tyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim Zin-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide Hydrochloride (100 mg, 0.122 mmol) and NMM (0.050 ml, 0. Add 0.5 ml of 455 mmol DMF solution dropwise, and stir RM overnight in RT. The mixture was concentrated and eluted with ACN (in a 0.1% solution of NH4HCO3). Purified by Redisep(registered trademark) C18 column reversed-phase chromatography, 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 Lahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4- Iyl)oxy)-3-hydroxypropyl)piperidine-4-yl)oxy)phenyl) -7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl Nyl)-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)benzamide)-2-me Tylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenoxy)pipette Lysine-1-yl)-3-hydroxypropane-2-yl)oxy)piperidine-1- Luboxylart 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-(piperidine-4 -yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)pheni (Lu)-4-(2-hydroxypropan-2-yl)benzamide trifluoroacetate (intermediate 16, 124 mg, 0.171 mmol), TEA (0.100 ml, 0.71 7 mmol) and tert-butyl 4-(2-oxoethoxy)piperidine-1-carb Xylate (intermediate 19, 60 mg, 0.222 mmol) in MeOH (2 ml) Dissolve in T, then in a THF solution of ZnCl2 (0.7M) (0.300 ml, 0.2 Add 10 mmol of solid NaBH2. The RM was stirred overnight under argon in the RT. Add 3CN (13 mg, 0.207 mmol), and stir the RM overnight in RT. Concentrate the residue and use ACN (in aq. TFA solution (0.1%)) (2-100%) Purified by eluting Redisep® C18 column reverse-phase chromatography. The title compound was then obtained 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-(piperidine-4-yloxy)propyl)piperidine-4-yl) Xy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-methyl Enyl)-4-(2-hydroxypropan-2-yl)benzamide rac-tert-butyl4-((1-(4-(4-(4-(5-fluoro-3-(2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methyl Phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenoxy)piperidine -1-yl)-3-hydroxypropan-2-yl)oxy)piperidine-1-carb Dimethyl chloride (DCM) of sylate trifluoroacetate (75 mg, 0.079 mmol) (1 ml) Then, the TFA (0.100 ml, 1.3 mmol) solution was stirred in RT for 2 hours and concentrated. Then, the residue is eluted with ACN (in aq. TFA solution (0.1%)) (2-100%). Purified by Redisep(registered trademark) C18 column reversed-phase chromatography, The title compound was obtained as a solid TFA salt (67 mg). Method A: Rt=0.67min;[M+H] + =755.5.

[0383] Process 3: rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-Geo Xotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine (Piperidin-4-yl)oxy)-3-hydroxypropyl)piperidine-4-yl)oxy) (enyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methyl Tylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide Do 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy N20mg of benzoic acid (intermediate 5, 0.076 mmol) in a DMF solution (0.5 ml) MM (0.050 ml, 0.455 mmol) and HATU (30 mg, 0.079 ml) Add ol) and stir RM in RT for 30 minutes. rac-2-fluoro-N-( 5-Fluoro-3-(6-(4-((1-(3-Hydroxy-2-(Piperidin-4-I (Oxy)propyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2, 3-d]Pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydroxypropane N-2-yl)benzamide (65 mg, 0.065 mmol) and NMM (0.050 Add 0.5 ml of DMF solution (0.455 mmol) dropwise to RM and RT. Stirred for 2 hours. Remove the solvent and the residue is aq. of ACN(NH4HCO3) solution (0 Redisep® C18 column reversed-phase chromatography eluting at 0.1%) Torus 2P is purified by [method] and eluted with MeOH (in CO2) (22-55%). Titled after additional purification by SFC using an IC column (250×30mm, 130Å, 5μm). 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-dioxotetrahydropyrim Din-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl) Piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydrox Cypropan-2-yl)benzamide [ka] Step 1: tert-butyl 4-((4-(4-(4-(5-fluoro-3-(2-fluorine Ro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl) -7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenoxy)piperidine-1-yl Methylpiperidine-1-carboxylate 2-Fluoro-N-(5-Fluoro-2-methyl-3-(6-(4-(piperidine-4 -yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)pheni (Lu)-4-(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 Dissolve 2 mmol of ZnCl2 in 2 ml of MeOH in RT, and prepare ZnCl2 (0.7M). Add the THF solution (0.300 ml, 0.210 mmol) and perform RM under argon. The mixture was stirred for 7 hours in RT. Solid NaBH3CN (13 mg, 0.207 mmol) was added. Then, stir RM in RT for 4 days to remove the solvent, and the residue is ACN(TFA Redisep (registered trademark) elutes in aq. solution (0.1%) (2-100%). The title compound was purified by C18 column reversed-phase chromatography to obtain the solid TFA salt (17 It was obtained as 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-( Piperidine-4-ylmethyl)piperidine-4-yl)oxy)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydroxypropane- 2-yl)benzamide tert-butyl 4-((4-(4-(4-(5-fluoro-3-(2-fluoro-4 -(2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H -Pyrrolo[2,3-d]pyrimidine-6-yl)phenoxy)piperidine-1-yl)me (Chill) Piperidine-1-carboxylate trifluoroacetate (170 mg, 0.1 DCM (2 ml) and TFA (0.100 ml, 1.298 mmol) of 90 mmol each. The solution was stirred in RT for 1 hour, and RM was concentrated to obtain the title compound as a solid TFA salt (202 It was obtained as mg. Method D: Rt=0.52min;[M+H] + =695.6.

[0386] Step 3: N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Methyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide RT's 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl Toxybenzoic acid (intermediate 5, 60 mg, 0.227 mmol) in a DMF solution (1 ml) NMM (0.050 ml, 0.455 mmol) and HATU (87 mg, 0.042 ml) Add (mol) and stir RM at RT for 30 minutes. 2-Fluoro-N-(5-F Luoro-2-methyl-3-(6-(4-((1-(piperidine-4-ylmethyl)piperidine-4-ylmethyl)piperidine Zin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl Phenyl-4-(2-hydroxypropan-2-yl)benzamidetrifluoro Acetate (0.190 mmol) and NMM (0.050 ml, 0.455 mmol) Add 1 ml of DMF solution dropwise, and stir RM in RT for 2.5 hours. Remove the solvent. Then, the residue is in an aq. solution of ACN (NH4HCO3 (0.1%)) (2-100%) ) elution is performed by reverse-phase chromatography of the Redisep(registered trademark) C18 column. Prepare the solution and elute it in a solution of ACN (NH4OH aq. (0.1%)) (30-65%). After further purification by reverse-phase HPLC using 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, 6 hours), 1.08 (m, 2 hours).

[0387] Compound 20: N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro [5.5] Undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu Oro-4-(2-hydroxypropan-2-yl)benzamide [ka] Step 1: tert-butyl9-(2-(4-bromophenyl)acetyl)-3,9-dia Zaspiro[5.5]undecane-3-carboxylate 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid under argon RT Dry DMF solution (12m³) of ert-butyl ester (1269 mg, 4.99 mmol) l) DIPEA (1.743 ml, 9.98 mmol), 4-bromophenylacetic acid (1 0.73 mg (4.99 mmol) and dried DMF (6 ml) were added. Solid HBTU (2 Add 0.81 mg (5.49 mmol), stir RM in RT for 1 hour, and pour into water. Then, the resulting mixture was stirred for 1 hour. The liquid was decanted, water was added, and mixed. The liquid was treated with ultrasound. The liquid was then decanted, and the residue was dissolved in DCM. The liquid was dried on MgSO4 and evaporated to obtain the title compound as oil (2.2 g). Method A: Rt=1.22min;[M+H] + =451.2.

[0388] Step 2: tert-butyl9-(1-(4-bromophenyl)-2-methylpropane-2 -yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl 9-(2-(4-bromophenyl)acetyl under argon at -50°C )-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.9g, 4 0.21 mmol) of dried THF solution (15 ml) is mixed with oven-dried ZrCl4 (1 Add 0.079g (4.63 mmol) and stir RM at -50°C to -45°C for 30 minutes. . Methylmagnesium bromide (3M) Et2O solution (8.42 ml, 25.3 mm The solution (ol) was added dropwise over 10 minutes while the reaction temperature was maintained at -45°C to -40°C. M was heated to -20°C, then stirred in an ice bath for 15 minutes, and then stirred in RT for 2 hours. The phases were separated by adding a sat.aq. solution of H4Cl and RINKAN. The aqueous phase was separated into EtO2. Extraction with Ac, the combined organic phase is dried on MgSO4 and evaporated, and the residue is Red is eluted with ACN (in aq. TFA solution (0.1%)) (10-100%). The title compound was purified by isep(registered trademark) C18 column reversed-phase chromatography. This 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 Lu-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-3, 9-Diazaspiro[5.5]undecane-3-carboxylate tert-butyl9-(1-(4-bromophenyl)-2-methylpropan-2-yl )-3,9-diazaspiro[5.5]undecane-3-carboxylate (70mg, 0 KOAc (35.6 mg) in a 2 ml solution of 0.121 mmol of dried 1,4-dioxane. Add 0.362 mmol) and BISPIN (36.8 mg, 0.145 mmol). Then, argon was passed through the mixture for 5 minutes. The mixture was heated at 35°C to form PdCl2 (dppf) (4.42 mg, 6.04 μmol) was added, and RM was again treated with argon. After flushing, the mixture was stirred at 90°C for 6 hours. The solvent was removed, and the residue was placed on silica. Absorbed into ethyl acetate (in CHX) (10-100%), then MeOH (in DCM) ( The title compound was purified by silica gel chromatography at 0-20% elution, and then extracted into oil. (94 mg) was obtained. Method A: Rt=1.09min;[M+H] + =513.4.

[0390] Step 4: tert-butyl9-(1-(4-(4-chloro-7H-pyrrolo[2,3-d] Pyrimidine-6-yl)phenyl)-2-methylpropan-2-yl)-3,9-diaza Spiro[5.5]undecane-3-carboxylate tert-butyl9-(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) is mixed with 1-propanol (5 ml) and Na2CO3 (2 M) aq. The solution (0.182 ml, 0.365 mmol) was suspended in RT. Lugon was passed through the mixture, and PdCl2(PPh3)2(12.81 mg, 0.018 m) was obtained. (mol) was added, and RM was stirred at 100°C for 23 hours under an argon atmosphere. 1-P Lopanol (3 ml) and Na2CO3 (2 M) aq. solution (0.540 ml, 1.0 Add 8 mmol) and pass argon through RM for 5 minutes, then PdCl2(PPh3)2( 15 mg (0.021 mmol) was added, and the RM was stirred at 110°C for 7 hours. Dilute with HCl, dry the mixture on MgSO4, and then use Isolute (registered trademark (Standard) Adsorb onto HM-N and dry, then add ACN (in aq. TFA solution (0.1%)) Redisep® C18 column reversed-phase chromatography eluting at 5-100% The title compound was purified by Fi to obtain 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)benzamide)-2-methylphenyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-methylpropane- 2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate RT's tert-butyl 9-(1-(4-(4-chloro-7H-pyrrolo[2,3-d] Pyrimidine-6-yl)phenyl)-2-methylpropan-2-yl)-3,9-diaza Spiro[5.5]undecane-3-carboxylate (33 mg, 0.019 mmol) 1 ml of 1-propanol solution of 2-fluoro-N-(5-fluoro-2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Nyl)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 2, 36 mg) (0.083 mmol), 1-propanol (1.5 ml) and Na2CO3 (2M) Aq. solution (0.08 ml, 0.160 mmol) was added. Argon was passed through the mixture. Then, add PdCl2(PPh3)2 (1.330 mg, 1.895 μmol) and RM The mixture was heated at 140°C for 20 minutes using microwave radiation. RM was diluted with ethyl acetate. After dissolving, the mixture was dried on MgSO4 and absorbed onto Isolute(registered trademark) HMN. Dress and dry, then use ACN (in aq. TFA solution (0.1%)) (5-100%) Purified by eluting Redisep® C18 column reverse-phase chromatography. The title compound was then obtained 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-dioxotetrahydrop Limidine-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5 .5]Undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2, 3-d]Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro -4-(2-hydroxypropan-2-yl)benzamide tert-butyl9-(1-(4-(4-(5-fluoro-3-(2-fluoro-4- (2-hydroxypropan-2-yl)benzamide)-2-methylphenyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-methylpropane-2-yl (Lu)-3,9-diazaspiro[5.5]undecane-3-carboxylate (9mg, 8 A solution of 0.70 μmol of DCM (0.8 ml) and TFA (0.8 ml) was tested in RT. Stirred for 10 minutes. Evaporate the solvent and add the residue to DMF (0.8 ml) and NMM (0. Dissolved in 0.22 ml (0.200 mmol). 3-(2,4-dioxotetrahydride Lopyrimidine-1(2H)-yl)-4-methoxybenzoic acid (intermediate 5, 4.60 mg, Add 0.017 mmol) and HATU (6.61 mg, 0.017 mmol) and R M was stirred under argon in RT for 15 hours. The mixture was then placed on Isolute®. Adsorb onto and dry, then ACN (in aq. TFA solution (0.1%)) (5-100%) ) elution is performed by reverse-phase chromatography of the Redisep(registered trademark) C18 column. The compound was prepared to obtain 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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-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 Dissolve tert-butylpiperazine-1-carboxylate (10) in a 250 ml round-bottom flask. g, 53.7 mmol), ACN (100 ml) and K2CO3 (11.1 g, 80.6 1-Bromo-2-chloroethane (15.5%) was added and the mixture was cooled to 5°C. Slowly add 0g (104 mmol) at 5°C, warm RM to RT, and stir 1 Continued for 8 hours. Filtered the RM, concentrated the filtrate, and added RINKAN (in petroleum ether) (0-5 The title compound was purified by silica gel chromatography eluting with 0% elution, and the oil (4. It was obtained as 2g. Method J:Rt=1.93min,MSm / z[M+H] + 249.

[0394] Step 2: tert-butyl 4-(4-bromobenzyloxy)piperidine-1-carbbox Syrah In a 250ml round-bottom flask, add mineral oil (1.17g, 29.25mmol) and D 60% NaH was added to MF (30 ml), and the mixture was cooled to 5°C. Tyl 4-hydroxypiperidine-1-carboxylate (4.03g, 20.0mmol) ) DMF solution (15 ml) was added dropwise at 5°C, and RM was stirred at 5°C for 1 hour. 1-Bromo-4-(bromomethyl)benzene (7.0g, 28.0 mmol) at 5°C In addition, RM was stirred at 30°C for 18 hours, and then diluted with ice water. The phases were separated. Then, the aq. phase is extracted with a mixture of SiO and petroleum ether (2:1) and combined The organic phase was dried, concentrated, and eluted with SiO2 (in petroleum ether) (0-20%). The title compound was purified by silica gel chromatography and obtained as oil (6.1g). I 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-di 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 (2.0g, 5.4mg) mol), BISPIN (2.7g, 10.8mmol), KOAc (1.59g, 16 (0.2 mmol) and PdCl2 (dppf) (630 mg, 0.86 mmol) were added. Add 1,4-dioxane (45 ml) and stir RM under N2 at 85°C for 18 hours. The RM was evaporated, and the residue was dissolved with ethyl acetate (in petroleum ether) (0-20%). The title compound was purified by silica gel chromatography to obtain a solid (2.1g) and I obtained it by doing so. 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-carb Add xylate (2.1g, 5.0 mmol) and DCM (10 ml), and leave the solution at 5°C. It was cooled to [temperature]. A 1,4-dioxane solution in HCl (4M) (5 ml, 20 mmol) was slowly added. The mixture was then stirred at 30°C for 2 hours. The mixture was concentrated and then treated with petroleum ether and The compound was ground with a mixture of TBME (2:1), the solid was filtered, and the title compound was obtained as solid HCl. It was obtained as salt (1.2g). Method E: Rt=1.74min,MSm / z[M+H] + 318.

[0397] Step 5: 4-((1-(2-(4-(tert-butoxycarbonyl)piperazine-1- Iyl(ethyl)piperidine-4-yloxy)methyl)phenylboronic acid In a 100 ml round-bottom flask, add 4-(4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)benzyloxy)piperidine hydrochloride (530ml) 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-chloroethylene) (Til) Piperazine-1-carboxylate (374 mg, 1.5 mmol) was added. Stir M at 30°C for 24 hours to concentrate, then re-dilute in DMF (9 ml) and 60 The mixture was stirred at °C for 6 hours, filtered, and the title compound was obtained 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- Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6yl )benzyloxy)piperidine-1-yl)ethyl)piperazine-1-carboxylate 4-((1-(2-( 4-(tert-butoxycarbonyl)piperazine-1-yl)ethyl)piperidine-4 - Iloxy)methyl)phenylboronic acid (604 mg, 1.35 mmol) dissolved in DMF Liquid (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 mg) (mol) was added. ACN (25 ml) and water (7 ml) were added, and RM was heated to 95 under N2. The mixture was stirred for 1 hour at °C. 2-fluoro-N-(5-fluoro-2-methyl-3) was added to the mixture. -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen (Lu)-4-(2-hydroxypropan-2-yl)benzamide (intermediate 2, 815 mg) , 1.89 mmol), Na2CO3 (520 mg, 4.9 mmol) and PdCl2 ( Add dppf) (80 mg, 0.11 mmol) and incubate RM under N2 conditions at 100°C. The mixture was stirred for 16 hours. The mixture was concentrated, water was added, and the solid was filtered. Purified by silica gel chromatography (eluting in ether at 0-50%), 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- Luoro-4-(2-hydroxypropan-2-yl)benzamide)-2-methylphenid (Lu)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyloxy)piperidine -1-yl)ethyl)piperazine-1-carboxylate In a 100 ml round-bottom flask, tert-butyl 4-(2-(4-(4-(4-(5-F Luoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamide) )-2-methylphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-yl)benzyloxy)piperidine-1-yl)ethyl)piperazine- Add 12 ml of DMSO solution containing 1-carboxylate (1.3 g, 1.35 mmol). Then, add an aqueous solution (2.6 ml) of NaOH (630 mg, 15.75 mmol) to 0°C. It was added. The RM was stirred at 30°C for 1 hour, then ice water was added. The solid was filtered, Redissolve in DCM, dry the solution over Na2SO4, concentrate, and remove the residue. Calculation by silica gel chromatography using elution with tanol (in DCM) (0-60%) The title compound was prepared and 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-(piperazine-1-yl)ethyl)piperidine-4-yloxy)methyl)phenyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl)-4-(2-hydro Xypropan-2-yl)benzamide In a 100 ml round-bottom flask, add tert-butyl 4-(2-(4-(4-(4-(5-full Oro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamide) -2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)benzyl Oxy)piperidine-1-yl)ethyl)piperazine-1-carboxylate (200ml) g, 0.24 mmol), DCM (1.5 ml), and EtOH (4.5 ml) were added. Prepare a 1,4-dioxane solution in HCl (4M) (1.8 ml, 7.2 mmol) at 5°C. The RM was slowly added and stirred at 30°C for 4 hours. The RM was concentrated and then petroleum ether was added. and a mixture of TBME (1:1), TBME and a mixture of DCM and TBME (1:2) The compound was ground together with the liquid, filtered, and the title compound was obtained as a solid HCl salt (160 mg). Method I: Rt=1.15min, MSm / z[M+H] + 725.

[0401] Process 9: N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxoteto Lahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1- Iyl)ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-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-(piperazine-1-yl)ethyl)piperidine-4-yloxy )methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)phenyl) -4-(2-hydroxypropan-2-yl)benzamide hydrochloride (160mg) , 0.21 mmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H)- (Iyl)-4-methoxybenzoic acid (intermediate 5, 63 mg, 0.24 mmol), DMF (2 Add 0.5 ml of (0.5 ml) and DIPEA (163 mg, 1.26 mmol), and bring the mixture to 5°C. Cooled. Add HATU (90 mg, 0.24 mmol) and leave RM at 5°C for 1 hour. Stirred. Filter the mixture and take the filtrate as an aq. solution of ACN (ammonium bicarbonate). XBridge C18 column (21.2 × 250 mm, 10 μm) that elutes at 0 mM. m) The title compound was purified by preparative HPLC to obtain it 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-dioxotetrahydropyrimidium (1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazine Radin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Ropan-2-yl)benzamide [ka] Step 1: tert-butyl4-(piperazine-1-carbonyl)piperazine-1-carbon Xylart Di(1H-imidazole-1-yl)methanone (1.95g, 12.0 mmol) Add tert-butylpiperazine to a 100 ml round-bottom flask containing HF solution (35 ml). -1-carboxylate (1.863 g, 10.0 mmol) was added at 0°C. The resulting solution was stirred at 0°C for 2 hours, then piperazine (2.59 g, 30. Add 0 mmol) and stir RM at 65°C for 16 hours, then add additional piperazine ( (0.86 g, 10.0 mmol) was added, and RM was stirred at 65°C for 24 hours. Solvent Remove the residue, redissolve the remaining material in H2O, add Na2CO3, and the mixture is converted to DCM. Extraction was performed using [method]. The combined organic phase was dried on Na2SO4 to remove the solvent. Residual The material is ground with TBME, the mixture is filtered, the solid is washed with TBME, and then dried. The title compound was then 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)piper Zin-1-carboxylate 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy Benzoic acid (intermediate 5, 555 mg, 2.1 mmol) and HATU (783 mg, 2.0 Add DIPEA to a 100 ml round-bottom flask containing 8 ml of 6 mmol DMF solution. In addition, (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 hour, and KH2 The mixture was poured into ice water containing PO4 and extracted with DCM. The combined organic phase was then converted to N The title compound was dried on a2SO4 and evaporated to obtain 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- Contains a DCM solution (10 ml) of 1-carboxylate (1.1 g, 2.0 mmol). Anisole (1 ml) and TFA (3.5 ml) were added to a 100 ml round-bottom flask. Stir RM at 15°C for 3 hours to remove the solvent, then grind the residue together with TBME. The mixture was filtered, the solid was dried, and the title compound was obtained as a solid TFA salt (1.0 g). I 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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carbon Piperazine-1-yl methylphenyl-7H-pyrrolo[2,3-d]pyrimidyl (4-I)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-Hyd Roxypropan-2-yl)benzamide 1-(2-methoxy-5-(4-(piperazine-1-carbonyl)piperazine-1-carbonyl) Rubonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoro Acetate (440 mg, 0.788 mmol) and DIPEA (70 mg, 0.542 A 50 ml round-bottom flask containing a 5 ml MeOH solution of mmol) is mixed with 2-fluoro- N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d Pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydroxypropane-2) - DMSO solution of (-yl)benzamide (intermediate 3, 206 mg, 0.391 mmol) Add 5 ml of ZnCl2 (1M) at 10°C and stir the mixture for 5 minutes. Add solution F (0.41 ml, 0.41 mmol) and stir RM at 22°C for 2 hours. Add solid NaBH3CN (30 mg, 0.477 mmol) and stir at 22°C. The mixture was left for 18 hours. The solvent was removed, ice water and KH2PO4 were added, and the mixture was filtered. The filtrate is eluted with ACN (aq. solution of ammonium bicarbonate (0.0075M)). Reverse-phase chromatography using an Agela C18 column (spherical, 20-35 μm, 100 Å, 40 g) The title compound was purified by Graph to obtain it 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-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydro Xypropan-2-yl)benzamide (intermediate 3, 200 mg, 0.380 mmol) rac-1-(5-(7-(hydroxymethyl)-3,9-diazaspiro[5.5]u (1) H,3H)-dione trifluoroacetate (intermediate 20, 228 mg, 0.418 mm) In a THF mixture (3 ml) of 0.079 ml and 0.570 mmol of TEA... A THF solution of ZnCl2 (0.5M) (0.798 ml, 0.399 mmol) was added. RM was stirred under argon in RT for 3 hours to obtain solid NaBH3CN (47.7 mg, Add 0.760 mmol) and stir RM in RT for 4 hours. Dilute the mixture with DCM. After dissolving, the organic phase is washed with water, concentrated, and the residue is absorbed onto Isolute®. After harvesting and drying, add ACN (in aq. TFA solution (0.1%)) (10-100%) Purification by reverse-phase chromatography using Redisep® C18 column elution. Then, after filtration and freeze-drying using a PL-HCO3 MP SPE cartridge, the title compound is added. The substance 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] Compounds 24 and 25: (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2- Fluoro-4-(2-hydroxypropan-2-yl)benzamide, and (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3 ,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyro Ro[2,3-d]pyrimidine-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%) Elute Chiralpak ID column (5μ) with a mixture at a flow rate of 10 ml / min. rac-N-(3-(6-(4-( (9-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl Toxybenzoyl)-1-(hydroxymethyl)-3,9-diazaspiro[5.5]un Decan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl) Chiral separation of ropan-2-yl)benzamide (50 mg, 50.6 μmol) The title compound was obtained as a single enantiomer in the following order.

[0408] First eluted enantiomer: 14.7 mg; Method K:Rt=30.8min; Method B: Rt=3.45min;[M+H] + =941.5. 1 The 1H NMR (400 MHz, DMSO-d6) for the racemic mixture reported previously showed N Follow the MR (Medical Representative).

[0409] Second eluted enantiomer: 12.7 mg; Method K:Rt=42.3min; Method B: Rt=3.48min;[M+H] + =941.5. 1 The 1H NMR (400 MHz, DMSO-d6) for the racemic mixture reported previously showed N Follow the MR (Medical Representative).

[0410] Compound 26: N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidium (1(2H)-yl)-4-methoxybenzamide)butyl)piperazine-1-yl) Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluor Ro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl) Benzamide [ka] Step 1: tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)-4-methoxybenzamide)butyl)piperazine-1-carbbox Syrah 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy Benzoic acid (intermediate 5, 150 mg, 0.539 mmol), 4-(4-amino-butyl) -Piperazine-1 carboxylate tert-butyl ester (146 mg, 0.539 mmol) l) HATU (293 mg, 0.755 mmol) and NMM (0.300 ml, 2. A 70 mmol DMF solution (5 ml) was stirred in RT for 3 hours. The reaction mixture was then prepared as A Redisep elutes in CN (in aq. TFA solution (0.1%)) (2-100%). The title compound was purified by (registered trademark) C18 column reversed-phase chromatography and obtained as a solid T It was obtained as FA salt (348 mg). Method A: Rt=0.98min;[M+H] + =504.3.

[0411] Step 2: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl Toxy-N-(4-(piperazine-1-yl)butyl)benzamide tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-Iyl)-4-methoxybenzamide)butyl)piperazine-1-carboxylate MeOH solution (2 ml) of 305 mg, 0.469 mmol and HCl (4 M) A 1,4-dioxane solution (4 ml, 16 mmol) was stirred in RT for 1.5 hours. The medium is removed, the residue is redissolved in a mixture of ACN and water, freeze-dried, and the title is printed. 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 Pyrimidine-1(2H)-yl)-4-methoxybenzamide)butyl)piperazine-1 -yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5 -Fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane-2) -Il)benzamide 3-(2,4-dioxotetrahydropyrimidine-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-F Luoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydroxypropyl) Pan-2-yl)benzamide (intermediate 3, 163 mg, 0.303 mmol) is converted to MeO2 Dissolve in H (2 ml) at RT to make a THF solution of ZnCl2 (0.5 M) (0. Add 75 ml (0.375 mmol) and stir RM overnight in RT. Solid Na Add BH3CN (22 mg, 0.350 mmol) and stir RM overnight in RT. Then, the solvent was removed. The residue was mixed with ACN (in a 0.1% solution of TFA) (2-1 Redisep® C18 column reversed-phase chromatography elutes at 00% After purification, filtration and freeze-drying using a PL-HCO3MP SPE cartridge are performed. A solid was obtained. Reprospher was eluted in MeOH (CO2) (33-50%). Further purification of this material by SFC using a PEI column (250×30mm, 100Å, 5μM) The title compound was obtained as a solid (95 mg) by this process. 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 (-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane (N-2-yl)benzamide [ka] Step 1: tert-butyl9-(3-(2,4-dioxotetrahydropyrimidine-1( 2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecane -3-carboxylate Add 3-(2,4-dioxotetrahydropyrimidine-1(2H) to a 100 ml round-bottom flask. )-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. RM was stirred in RT for 5 minutes; tert-butyl 3, 9-Diazaspiro[5.5]undecane-3-carboxylate (200 mg, 0.78 7 mmol) was added little by little at 0°C, and the mixture was stirred in RT for 1 hour. The liquid is concentrated, and the residue is purified by silica gel chromatography using dimethyl elution. The title compound was prepared and 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-ca Rubonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione In a 100 ml round-bottom flask, add tert-butyl 9-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[ 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. HCl (4 M) 1,4-dioxa Add solution (20 ml, 80 mmol) dropwise, warm RM to RT, and continue stirring for 3 hours. The RM is concentrated and used directly in the next step without further purification to obtain the title compound as solid HCl. It was obtained as a salt (0.32g). Method D: Rt=1.62min;MSm / z[M+H] + 384.

[0415] Step 3: N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrim 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-hydrox Cypropan-2-yl)benzamide In a 100 ml round-bottom flask, 1-(2-methyl-5-(3,9-diazaspiro[5.5 Undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H) -Dione hydrochloride (0.32g, 0.723mmol), 2-fluoro-N-(5 -Fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrim Zin-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl) Benzamide (intermediate 3, 0.25 g, 0.462 mmol), MeOH (10 ml) and THF (30 ml) was added. ZnCl2 (1 M) THF solution (1.38 ml, 0. (462 mmol) was added at 0°C, the RM was heated to RT, and stirring was continued for 2 hours. Solid Add NaBH3CN (87 mg, 1.38 mmol) and stir RM in RT for 16 hours. Mixed. Filter the mixture, wash the solid with MeOH (10 ml), and combine the filtrate. The solution was concentrated. The residue was treated with ACN (in a 10 mM solution of ammonium bicarbonate). Eluting XBridge C18 column (21.2 × 250 mm, 10 μm) with preparative HPL The title compound was purified using C to obtain 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-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzal Mido [ka] Step 1: tert-butyl(5-(5-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-2-fluoro-N,4-dimethylbenzamide)pentyl)carbama te 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl) under an 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 a dry DMF solution (3 ml) Add IPEA (210 μl, 1.202 mmol), and the resulting RM is added to RT. Stirred for 1 hour. Dilute RM with DCM and prepare citrate buffer (pH=4, Sigma). a-Aldrich 33643) was added. The phases were separated, and the aq. phase was extracted using DCM. Then, the combined organic phase is dried on MgSO4 and evaporated, and the residue is converted to iPrO Purified by silica chromatography eluting with H (in DCM) (1-6%), Title 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 In a 1,4-dioxane solution of HCl (4M) (1.827 ml, 7.31 mmol), t ert-butyl(5-(5-(2,4-dioxotetrahydropyrimidine-1(2H)- (Iyl)-2-fluoro-N,4-dimethylbenzamide)pentyl)carbamate (123 The (mg, 0.244 mmol) suspension was stirred in RT for 2 hours under an N2 atmosphere. The compound is concentrated, redissolved in a mixture of ACN and water, and freeze-dried to obtain the title compound as a solid. It was obtained as an HCl salt (116 mg). Method A: Rt=0.46min;[M+H] + =365.3.

[0418] Step 3: 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-f Luoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-H Droxypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[ [2,3-d]pyrimidine-6-yl)benzyl)amino)pentyl)-N,4-dimethyl Benzamide 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hydro 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 Me (mg, 0.125 mmol) and TEA (0.017 ml, 0.125 mmol) OH mixture (2.1 ml) + ZnCl2 (0.5 M) THF solution (0.251 ml, 0 (0.125 mmol) was added. The resulting mixture was refrigerated in an N2 atmosphere at RT for 3 minutes. h Stirred. Add solid NaBH3CN (8.29 mg, 0.125 mmol) and RM The mixture was stirred in RT for 18 hours. The RM was diluted with ACN and Isolute(registered trademark) was used. The R is adsorbed onto the surface, dried, and eluted with ACN (in a 0.1% solution of TFA). Purified by edisep(registered trademark) C18 column reverse-phase chromatography, PL- After filtration and freeze-drying using an HCO3 MP SPE cartridge, the title compound was solidified (7 It was obtained as 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-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-yl)benzyl)amino)pentyl)-4-methylbenzamide [ka] Step 1: tert-butyl(5-(5-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)2-fluoro-4-methylbenzamide)pentyl)carbamate 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl) under an 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 Add DIPEA (210 μl, 1.2 mg, 0.331 mmol) to DMF solution (3 ml) (0.2 mmol) was added. The resulting RM was stirred in RT for 2.5 hours, and RM DCM and citrate buffer (pH=4, Sigma-Aldrich 33643) The solution was diluted, the phases were separated, and the aq. phase was extracted with DCM. The combined organic phase was then extracted with MgS Dry on O4, filter, evaporate, and the residue is treated with iPrOH (in DCM) (1~ The title compound was purified by silica gel chromatography eluting at 6% to obtain a solid (1 It was obtained as 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 1,4-dioxane solution in HCl (4M) under an N2 atmosphere (1.753 ml, 7.01 tert-butyl(5-(5-(2,4-dioxotetrahydropyrimidine) mmol) -1(2H)-yl)-2-fluoro-4-methylbenzamide)pentyl)carbamate A suspension of (117 mg, 0.234 mmol) was stirred in RT for 2 hours. RM was concentrated. Then, it is redissolved in a mixture of ACN and water, freeze-dried, and the title compound is converted into solid HCl. It was obtained as a salt (106 mg). Method A: Rt=0.43min;[M+H] + =351.2.

[0421] Step 3: 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-f Luoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-H Droxypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-yl)benzyl)amino)pentyl)-4-methylbenzyl Amido 2-Fluoro-N-(5-Fluoro-3-(6-(4-formylphenyl)-7H-P Roro[2,3-d]pyrimidine-4-yl)-2-methylphenyl)-4-(2-hy...

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ , R １ａ , R ２ and R ２ａ In each existence, H and F are independently selected; R ６ is either H or F; R ７ is selected from H, F, Cl, -CH ３ , -OCH ３ and -OCH ２ CH ３ ; X １ is formula (A) or (B): 【Chemistry 2】 It is the basis of, and in the formula, ＊ X １ａ teeth, ＊ - (CH ２ ) １～３ - and ＊ -CH ２ C (CH ３ ) ２ - Selected from, Here, ＊ X in equation (I) １ａ It shows the attachment site of the group to the phenyl ring; ＊ X １ｂ teeth, ＊ -O-, ＊ - OCH ２ - and ＊ -CH ２ Selected from O-, here, ＊ X in equation (I) １ｂ It shows the attachment site of the group to the phenyl ring; X ２ａ These are equations (C), (D), (E), (F), and (G): 【Transformation 3】 Selected from, in the formula, ＊＊ is, X １ａ It indicates the attachment point; X ２ｂ These are equations (E1) and (F1): 【Chemistry 4】 Selected from, in the formula, ＊＊ is, X １ｂ It indicates the attachment point; X ５ is CH or N; X ６ is CH or N; R ３ is H or -CH ３ And; R ４ is H or -CH ２ It is OH; R ５ is H or -CH ２ It is OH; Z is absent or ＊ - (CH ２ ) ２～３ It is NH-, and here, ＊ This is in equation (C) This shows the attachment site of Z to the N atom; Z １ は、 ＊ -O-、 ＊ -C(O)-、 ＊ -(CH ２ ) １～３ -、 ＊ -(CH ２ ) ２ O- and ＊ -CH ２ CH (CH ２ Selected from OH)O-, here, ＊ Equations (E) and ( Z in E1) １ X ５ It indicates the attachment point; Z ２ａ is absent or NH(CH ２ ) ４ - ＊＊ And; Z ２ｂ is, -(CH ２ ) ３～４ NH(CH ２ ) ２ - ＊＊ And; Z ３ is absent or ＊＊ - (CH ２ ) ４ NH- and Z ２ａ and Z ３ Both are simultaneous Not absent; Here, Z ２ａ Z ２ｂ and Z ３ In each of the ＊＊ This is given by equation (F) and equation (F1) The attachment points to each N atom are shown; q is 0 or 1; and n and p are independently either 0 or 1; (i) Z in equation (E) or equation (E1) １ but ＊ If it is -O-, then X ５ and X ６ teeth, not N, and (ii) Z in formula (E) or formula (E1) １ is ＊ -(CH ２ ) ２ -O - or ＊ -CH ２ CH (CH ２ If it is OH)O-, then X ６ (is not N) A compound of or a pharmaceutically acceptable salt thereof.

2. Equation (Ia) 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ６ is a compound according to claim 1 or 2 which is H or a pharmaceutically acceptable salt thereof.

4. R ７ is, -OCH ３ The compound or the pharmaceutical thereof according to any one of claims 1 to 3. A generally acceptable salt.

5. X １ Equation (A): 【Transformation 6】 It is the basis of, and X ２ａ These are equations (C), (E), and (F): 【Transformation 7】 (In the formula, ＊＊ is, X １ａ (Indicates the attachment point) A compound selected from any one of claims 1 to 4 or a pharmaceutically acceptable compound thereof Salt.

6. X １ teeth, 【Transformation 8】 (In the formula, ＊ (wherein is an atom attached to the phenyl ring in formula (I) or formula (Ia)) A compound selected from any one of claims 1 to 5 or a pharmaceutically acceptable compound thereof Salt.

7. rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrrhizin) Midine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrrhizin) Midine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-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- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium N-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]u Ndecane-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-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-fluorobenzoyl)piperidine-4-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 - (2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl Piperazine-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-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)oxy Piperidine-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- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl Ropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy (C)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid (-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxy) Loxypropan-2-yl)benzamide, N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidium 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-dioxotetrahydropyrimidium n-1(2H)-yl)benzoyl)-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-hydroxypropane-2) - Benzamide (Il), N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-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- (Iyl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl Ropan-2-yl)benzamide, N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Ropyr)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyryl Midine-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperazine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Di-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperazine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Di-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-Dioxote Trahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4 -yl)oxy)-3-hydroxypropyl)piperidine-4-yl)oxy)phenyl )-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methyl (enyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl)methyl Piperidine-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-dioxotetrahydropyrimidium 1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5] Undecane-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2,3-d ] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) Ethyl)piperidine-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 - (2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrim (Zin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-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, rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrrhizin) Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrrhizin) Midine-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)- 3,9-diazaspiro[5.5]undecane-3-yl)methyl)phenyl)-7H-py Rolo[2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2 -Fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)butyl)piperazin-1-yl )methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-5-flu Oro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl) ) Benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]unde Can-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-i (L)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropyl Pan-2-yl)benzamide, 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxyl Cypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3 -d] Pyrimidine-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenz Amido, 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoro -N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxyl Cypropan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3 -d] Pyrimidine-6-yl)benzyl)amino)pentyl)-4-methylbenzamide 、 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-N-(5-( (4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropane-2 -yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl N-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 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-hydroxyl) Cypropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-4-methoxybenzoyl)-2,7-diazaspiro[3.5]nona (H-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl) benzamide, N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydropyrim (Di-1(2H)-yl)-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Xy)piperidine-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Di-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,8-diazaspi Ro[4.5]decane-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-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 Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)amino)butoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-i (L)-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 Hydropyrimidine-1(2H)-yl)benzamide)ethyl)-1-oxa-4,9- Diazaspiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrim (Di-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-1-oxa-4,9 -diazaspiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu Oro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl)butyl )amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-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-Gioqi Sotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, 4-Chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)- N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxy Propan-2-yl)benzamide)-2-methylphenyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-yl)benzyl)amino)pentyl)-N-methylbenzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) (Tyl)piperidine-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-3,9-diazaspi Ro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((3-((2-(4-(3-(2,4-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) Ethyl)amino)propoxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrim (Di-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-H) Droxypropan-2-yl)benzamide, N-(3-(6-(4-(((1r,4r)-4-((1-(3-(2,4-dioxo Tetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-( 2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidium 1(2H)-yl)-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-hydroxyl) Cypropan-2-yl)benzamide, N-(3-(6-(4-((4-(3-(4-chloro-3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)benzamide)propyl)-1-oxa-4,9 -diazaspiro[5.5]undecane-9-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-flu 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 (H-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl) benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyri Midine-1(2H)-yl)-4-methylbenzoyl)piperidine-4-yl)oxy) Piperidine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxyl) Cypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(4-(3-(2,4-dioxotetrahydro Pyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-yl) (Tyl)piperidine-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,7-diazaspi Ro[3.5]nonan-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2- Hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrim Zin-1(2H)-yl)-4-methoxybenzamide)ethyl)-2,8-diazaspi Ro[4.5]decane-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyri Midine-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 Tetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine- 4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-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 (H-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl )-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropane n-2-yl) benzamide, N-(3-(6-(4-((((1r,4r)-4-((1-(3-(2,4-Gioq Sotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine -4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluor Ro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(4-chloro-3-(2,4-dioxotetra Hydropyrimidine-1(2H)-yl)benzamide)propyl)-3,9-diazaspi Ro[5.5]undecane-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-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-dioxotetrahydr Lopyrimidine-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-yl) Oxy)ethyl)piperidine-4-yl)oxy)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4 - (2-hydroxypropan-2-yl)benzamide The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more A pharmaceutical composition containing the above-mentioned pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more A combination of the above therapeutically active drugs.

10. A compound or pharmaceutically acceptable substance as described in any one of claims 1 to 7 for use as a pharmaceutical. A generally acceptable salt.

11. Any of claims 1 to 7 for use in the prevention or treatment of diseases transmitted by BTK Any compound listed in item one, or a pharmaceutically acceptable salt thereof.

12. A compound or pharmaceutically thereof according to any one of claims 1 to 7 for use in the treatment of cancer A generally acceptable salt.

13. The aforementioned cancers include chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and small phosphorus cancer. familial lymphoma (SLL), Waldenström macroglobulinemia, diffuse large cell lung cancer B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, marginal zone lymphoma Parkinson's disease, immunoblastic large cell lymphoma, Richter syndrome, and precursor B lymphoblastic lymphoma Primary and secondary multiple myeloma, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma 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, intravascular large B-cell lymphoma Cellular lymphoma, primary exudative lymphoma, lymphoma granulomatosis, and acute lymphoblastic leukemia Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, hairy cell leukemia, A compound for use according to claim 12, selected from histiocytic and dendritic neoplasms or The pharmaceutically acceptable salt.

14. Autoimmune disorders, inflammatory disorders, allergic diseases, anaphylaxis, allergic asthma and for use in the treatment of airway diseases and transplantation, according to any one of claims 1 to 7 A compound or a pharmaceutically acceptable salt thereof.

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