Spirochromane compound

Abstract

The present invention addresses the problem of providing a novel compound having an IL-17 modulator action.　The present invention relates to a spirochromane compound represented by formula (I) or a pharmacologically acceptable salt thereof. The compound of the present invention or a pharmacologically acceptable salt thereof has an IL-17 modulator action and is useful as a therapeutic agent for diseases in which IL-17 is involved (such as psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, axial spondyloarthritis, hidradenitis suppurativa, polymyalgia rheumatica and tendinopathy).

Description

Spirochroman compounds

[0001] The present invention relates to a spirochroman compound useful as a pharmaceutical. More specifically, the present invention relates to a spirochroman compound or a pharmacologically acceptable salt thereof that has an IL-17 modulatory activity and is useful as a therapeutic agent for diseases associated with IL-17.

[0002] Psoriasis is a chronic inflammatory skin disease caused by a complex interaction of genetic, environmental, and immune factors. Psoriasis is classified into five disease types: plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, pustular psoriasis, and psoriatic arthritis. Psoriasis is characterized by multiple, scaly, infiltrative erythema covering the entire body, significantly impairing patients' quality of life (QOL). Histologically, psoriasis manifests as epidermal cell proliferation and hyperkeratosis, along with inflammatory cell infiltration and vascular proliferation. Proinflammatory cytokines are thought to be deeply involved in the pathogenesis of psoriasis. Excessive cytokine production due to activated inflammatory and immune responses leads to reduced epidermal cell turnover, hyperproliferation, and abnormal keratinization. IL-17A, secreted by Th17 cells, is known to play a central role in the pathogenesis and exacerbation of psoriasis. IL-17A, a member of the IL-17 family of molecules, forms homodimers or heterodimers with other IL-17 family molecules and transmits signals through binding to the IL-17 receptor (IL-17RA / IL-17RC complex). IL-17A contributes to homeostasis by inducing the production of inflammatory mediators from various cells, including epithelial cells, and by promoting neutrophil migration, thereby contributing to infection defense, tissue repair, and inflammation induction. However, excessive activation of Th17 cells and increased IL-17A production can lead to immune abnormalities. Increased Th17 cell activity and increased IL-17A production have been observed in the blood and skin lesions of psoriasis patients. IL-17A, in cooperation with other inflammatory cytokines, activates epidermal cells and induces the secretion of antimicrobial peptides, inflammatory cytokines, and chemokines, which are thought to contribute to the chronic skin inflammation of psoriasis.

[0003] Given this relationship between IL-17A and psoriasis, many biologics that target IL-17 or the IL-17 receptor and inhibit IL-17 signaling have been developed and marketed for the treatment of moderate to severe psoriasis, demonstrating excellent clinical efficacy. However, no small molecule compounds with IL-17 modulatory activity have been marketed to date. Therefore, there is a need for orally available small molecule compounds (e.g., inhibitors) with IL-17 modulatory activity that are useful for the treatment of IL-17-mediated diseases.

[0004] Spirocyclic compounds having IL-17 modulatory activity are described in Patent Documents 1 to 5 and Non-Patent Document 1. However, the spirochroman compound of the present invention is not described in any of these documents.

[0005] International Publication No. 2018 / 229079 International Publication No. 2020 / 011731 U.S. Patent Application Publication No. 2023 / 0159465 U.S. Patent Application Publication No. 2023 / 227437 International Publication No. 2023 / 202664

[0006] Expert Opinion on Therapeutic Patents, 32:11, 1161-1173

[0007] An objective of the present invention is to provide novel compounds that have IL-17 modulatory activity.

[0008] The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof:

[0009] That is, the present invention relates to the following [1] to

[23] , etc. [1] A compound represented by formula (I): wherein A is a group selected from the group consisting of the following (a) to (s): (a) C 1-6 Alkyl (b) HaloC 1-6 Alkyl (c) Hydroxy C 1-6 Alkyl (d) C 1-6 Alkoxy (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Mono C 1-6 Alkylamino (g) diC 1-6Alkylamino (h) Amino C 1-6 (i) alkyl C optionally having any group selected from the substituent group C 3-6 Cycloalkyl C 1-6 (j) alkyl C optionally having any group selected from the substituent group C 3-6 CycloalkylhaloC 1-6 (k) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl C 1-6 (l) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl Halo C 1-6 (m) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group C 1-6 (n) 5- or 6-membered heteroaryl halo C optionally having any group selected from the substituent group C 1-6 (o) alkyl C optionally having any group selected from the substituent group C 6-10 (p) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C (q) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C (r) C which may have any group selected from the substituent group C 3-8 cycloalkyl, and (s) 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 are each independently 6 or N; R 1a , and R 1b are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, C 1-6 alkoxy or hydroxy; R 1a , and R 1b Let's get together and C 3-8 Z may form a cycloalkyl; Z is a group selected from the group consisting of (a) to (d) below: (a) CR 2 R 3 R 4(b) C, which may have any group selected from the substituent group D 3-10 (c) 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group D, and (d) C optionally having any group selected from the substituent group D. 6-10 Aryl; R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-8 C optionally having any group selected from cycloalkoxy or substituent group D 3-6 Ring B is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 10-membered heterocycloalkyl; R 5 is a halogen atom, hydroxy, C 1-6 Alkyl, C 1-6 Alkylcarbonyl, HydroxyC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, Cyano, HaloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 cycloalkyl, C optionally having any group selected from the substituent group E 3-6 Cycloalkyl C 1-6 Alkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (when q is 2 or 3, these R 5 may be the same or different); R 6 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy (R 6If there are two or more R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (p): (a) a hydrogen atom (b) a haloC 1-6 Alkyl (c) C 1-6 Alkyl (d) Cyano C 1-6 Alkyl (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Hydroxy C 1-6 Alkyl (g)-CO-R 9 (h)-SO2-R 9 (i) C optionally having any group selected from the substituent group F 3-6 Cycloalkyl C 1-6 (j) 3- to 6-membered heterocycloalkyl C optionally having any group selected from the substituent group F 1-6 (k) C optionally having any group selected from the substituent group F 3-6 (l) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F (m) C optionally having any group selected from the substituent group F 6-10 Aryl C 1-6 (n) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group F 1-6 (o) alkyl C optionally having any group selected from the substituent group F 6-10 (p) 5- or 6-membered heteroaryl optionally having any group selected from the substituent group F; R 8 is a halogen atom, C 1-6 Alkyl or C 1-6 Alkoxy (when r is 2 or 3, these R 8 may be the same or different), or R 8 There are two or more R on the same carbon atom 8 If there are two R 8 Let's get together and C 3-6 may form a cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 9 is C 1-6Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, NR 10 R 11 , C 6-10 Aryl, 5- or 6-membered heteroaryl, 3- to 10-membered heterocycloalkyl or C 3-8 cycloalkyl; R 10 , and R 11 are each independently a hydrogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-6 alkyl; the substituent group C is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, cyano, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-6 The substituent group D is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and haloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 m and n are each independently an integer of 1 to 3; and q and r are each independently an integer of 0 to 3. [2] A compound represented by formula (I): wherein A is a group selected from the group consisting of the following (a) to (s): (a) C 1-6 Alkyl (b) HaloC 1-6 Alkyl (c) Hydroxy C 1-6 Alkyl (d) C 1-6 Alkoxy (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Mono C 1-6 Alkylamino (g) diC 1-6 Alkylamino (h) Amino C 1-6 (i) alkyl C optionally having any group selected from the substituent group C 3-6 Cycloalkyl C 1-6 (j) alkyl C optionally having any group selected from the substituent group C 3-6 CycloalkylhaloC 1-6 (k) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl C 1-6 (l) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl Halo C 1-6 (m) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group C 1-6 (n) 5- or 6-membered heteroaryl halo C optionally having any group selected from the substituent group C 1-6 (o) alkyl C optionally having any group selected from the substituent group C 6-10 (p) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C (q) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C (r) C which may have any group selected from the substituent group C 3-8 cycloalkyl, and (s) 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 are each independently 6 or N; R 1a , and R 1bare each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, C 1-6 alkoxy or hydroxy; R 1a , and R 1b Let's get together and C 3-8 Z may form a cycloalkyl; Z is a group selected from the group consisting of (a) to (d) below: (a) CR 2 R 3 R 4 (b) C, which may have any group selected from the substituent group D 3-10 (c) 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group D, and (d) C optionally having any group selected from the substituent group D. 6-10 Aryl; R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-8 C optionally having any group selected from cycloalkoxy or substituent group D 3-6 Ring B is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 10-membered heterocycloalkyl; R 5 is a halogen atom, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, Cyano, HaloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 cycloalkyl, C optionally having any group selected from the substituent group E 3-6 Cycloalkyl C 1-6Alkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (when q is 2 or 3, these R 5 may be the same or different); R 6 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy (R 6 If there are two or more R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (p): (a) a hydrogen atom (b) a haloC 1-6 Alkyl (c) C 1-6 Alkyl (d) Cyano C 1-6 Alkyl (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Hydroxy C 1-6 Alkyl (g)-CO-R 9 (h)-SO2-R 9 (i) C optionally having any group selected from the substituent group F 3-6 Cycloalkyl C 1-6 (j) 3- to 6-membered heterocycloalkyl C optionally having any group selected from the substituent group F 1-6 (k) C optionally having any group selected from the substituent group F 3-6 (l) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F (m) C optionally having any group selected from the substituent group F 6-10 Aryl C 1-6 (n) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group F 1-6 (o) alkyl C optionally having any group selected from the substituent group F 6-10 (p) 5- or 6-membered heteroaryl optionally having any group selected from the substituent group F; R 8 is a halogen atom, C1-6 Alkyl or C 1-6 Alkoxy (when r is 2 or 3, these R 8 may be the same or different), or R 8 There are two or more R on the same carbon atom 8 If there are two R 8 Let's get together and C 3-6 may form a cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 9 is C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, NR 10 R 11 , C 6-10 Aryl, 5- or 6-membered heteroaryl, 3- to 10-membered heterocycloalkyl or C 3-8 cycloalkyl; R 10 , and R 11 are each independently a hydrogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-6 alkyl; the substituent group C is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, cyano, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-6 The substituent group D is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6Alkoxy and HaloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 m and n are each independently an integer of 1 to 3; q and r are each independently an integer of 0 to 3; or a pharmacologically acceptable salt thereof.

[0010] [3] The compound or pharmacologically acceptable salt thereof according to [1] or [2] above, wherein m and n are not 1 at the same time.

[0011] [4] R 7 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom (b) C 1-6 Alkyl (c) C 1-6 Alkoxy C 1-6 Alkyl (d) -CO-R 9 (e) C optionally having any group selected from the substituent group F 3-6 (f) a 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; the substituent group F is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 alkyl, and cyano; R 9 The compound according to any one of [1] to [3] above, or a pharmacologically acceptable salt thereof, wherein the meaning of [1] above is the same as that of [1] above.

[0012] [5] The compound according to any one of [1] to [4], wherein R 1a , and R 1b is a hydrogen atom; X 1 , X 2 , and X 3 is CR 6 and R 6 is a hydrogen atom or halogen atom (three R 6 may be the same or different) or a pharmacologically acceptable salt thereof.

[0013] [6] The compound according to any one of [1] to [5] above, which is a compound represented by the following formula (II): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n, and r are the same as those in [1] above; Ring C1 is a group represented by the following formula: U is for CR 12 or N; T 1 is CR 12 , C.R. 12 R 13 , O, N, or NR 12 and T 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and T 3 is a bond, O, or CR 12 R 13 and T 4 is CR 12 , C.R. 12 R 13 , O, S, N, or NR 12 and T 5 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (R 12 and R 13When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and haloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof. [7] The compound according to any one of [1] to [6] above, which is a compound represented by the following formula (II): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n, and r are the same as those in [1] above; Ring C1 is a group represented by the following formula: U is for CR 12 or N; T 1 is CR 12 , C.R. 12 R 13 , O, N, or NR 12 and T 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and T 3 is a bond, O, or CR 12 R 13 and T 4 is CR 12 , C.R. 12 R 13 , O, S, N, or NR 12 and T 5 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 cycloalkyl, or a 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group E (R 12 and R 13 When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof.

[0014] [8] The compound according to any one of [1] to [7] above, which is a compound represented by the following formula (III): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n, and r are the same as those in [1] above; Ring C2 is a group represented by the following formula: Y 1 is CR 12 , C.R. 12 R 13 , N, or NR 12 and Y 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and Y 3 is CR 12 , C.R. 12 R 13, O, N, or NR 12 and Y 4 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (R 12 and R 13 When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof. [9] The compound according to any one of [1] to [8] above, which is a compound represented by the following formula (III): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n, and r are the same as those in [1] above; Ring C2 is a group represented by the following formula: Y 1 is CR 12 , C.R.12 R 13 , N, or NR 12 and Y 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and Y 3 is CR 12 , C.R. 12 R 13 , O, N, or NR 12 and Y 4 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 cycloalkyl, or a 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group E (R 12 and R 13 When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof.

[0015]

[10] The compound according to any one of the above [1] to [9], wherein ring C2 is a group represented by the following formula (1), (2), (3), or (4): Y 1 , and Y 3 are each independently 12 or N; R 12 , and R 13

[11] A compound according to any one of [1] to

[10] above, wherein ring C2 is a group represented by the following formula (1), (2), or (3): Y 1 , and Y 3 are each independently 12 or N; R 12 , and R 13 The compound has the same meaning as the above [9] or a pharmacologically acceptable salt thereof.

[0016]

[12] The compound according to any one of the above [1] to

[11] , wherein A is a group selected from the group consisting of the following (a) to (e): (a) C optionally having any group selected from the substituent group C 6-10 (b) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C; (c) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C; (d) C which may have any group selected from the substituent group C; 3-8 (e) a 3- to 8-membered heterocycloalkyl optionally having any group selected from substituent group C, or a pharmacologically acceptable salt thereof.

[0017]

[13] The compound according to any one of the above [1] to

[12] , wherein Z is a group represented by the following formula (a), (b), (c), or (d): or a pharmacologically acceptable salt thereof.

[0018]

[14] The compound according to any one of the above [1] to

[13] , wherein A is a group selected from the group consisting of the following (a) to (e): (a) C optionally having any group selected from the substituent group C 6-10(b) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C; (c) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C; (d) C which may have any group selected from the substituent group C; 3-8 (e) a 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 is CR 6 and R 1a , and R 1b is a hydrogen atom; Z is a group represented by the following formula (a), (b), (c), or (d): Ring B is a 3- to 10-membered heterocycloalkyl; R 5 is C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkyl, substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (when q is 2, two R 5 may be the same or different); R 6 is a hydrogen atom or a halogen atom (three R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom (b) C 1-6 Alkyl (c) C 1-6 Alkoxy C 1-6 Alkyl (d) -CO-R 9 (e) C optionally having any group selected from the substituent group F 3-6 (f) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; R 9 is C 6-10 Aryl C1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 m and n are 2; q is 0, 1 or 2; and r is 0, or a pharmacologically acceptable salt thereof.

[15] The compound according to any one of the above [1] to

[14] , wherein A is a group selected from the group consisting of the following (a) to (e): (a) C optionally having any group selected from the substituent group C 6-10 (b) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C; (c) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C; (d) C which may have any group selected from the substituent group C; 3-8 (e) a 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 is CR 6 and R 1a , and R 1b is a hydrogen atom; Z is a group represented by the following formula (a), (b), (c), or (d): Ring B is a 3- to 10-membered heterocycloalkyl; R 5 is C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 alkyl, or 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group E (when q is 2, two R 5 may be the same or different); R 6 is a hydrogen atom or a halogen atom (three R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom (b) C 1-6 Alkyl (c) C 1-6 Alkoxy C 1-6 Alkyl (d) -CO-R 9 (e) C optionally having any group selected from the substituent group F 3-6 (f) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; R 9 is C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC1-6 m and n are 2; q is 0, 1 or 2; and r is 0, or a pharmacologically acceptable salt thereof.

[0019]

[16] The compound according to any one of [1] to

[15] , wherein R 7 is a group selected from the group consisting of the following (a) to (e): (a) a hydrogen atom (b) C 1-6 Alkoxy C 1-6 Alkyl (c) -CO-R 9 (d) C optionally having any group selected from the substituent group F 3-6 (e) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; R 9 is C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; the substituent group F is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 A compound of the group consisting of alkyl, and cyano, or a pharmacologically acceptable salt thereof.

[0020]

[17] The compound according to any one of [1] to

[16] , wherein R 7 is a group selected from the group consisting of the following (a) and (b): (a) C optionally having any group selected from the substituent group F 3-6 (b) a 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; the substituent group F is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 A compound of the group consisting of alkyl, and cyano, or a pharmacologically acceptable salt thereof.

[0021]

[18] A compound selected from the group consisting of the following compounds: and

[0022] or a pharmacologically acceptable salt thereof.

[0023]

[19] A compound selected from the group consisting of the following compounds: and

[0024] or a pharmacologically acceptable salt thereof.

[0025]

[20] A compound selected from the group consisting of the following compounds: and

[0026] or a pharmacologically acceptable salt thereof.

[0027]

[21] A pharmaceutical composition comprising the compound according to any one of [1] to

[20] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[0028]

[22] The pharmaceutical composition according to

[21] above, which is a pharmaceutical composition for treating a disease in which IL-17 is involved.

[0029]

[23] The pharmaceutical composition according to

[22] above, wherein the disease associated with IL-17 is psoriasis, axial spondyloarthritis, ankylosing spondylitis, or juvenile idiopathic arthritis.

[0030] In one embodiment, the present invention relates to a method for treating a disease associated with IL-17, comprising administering to a patient a required amount of the pharmaceutical composition according to

[21] above.

[0031] In one embodiment, the present invention relates to use of the compound according to any one of [1] to

[20] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a disease in which IL-17 is involved.

[0032] The compounds of the present invention have excellent IL-17 modulatory activity, and therefore, the compounds of the present invention or pharmacologically acceptable salts thereof are useful as therapeutic agents for diseases involving IL-17.

[0033] Hereinafter, embodiments of the present invention will be described in more detail. In the present invention, each term has the following meaning unless otherwise specified. 1-6 The term "alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0034] "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 halogen atoms of the same or different types. 1-6 Examples of the haloC include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. 1-6 "Alkoxy" means a C substituted with 1 to 5 identical or different halogen atoms. 1-6 It means alkoxy, and examples thereof include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,1-trifluoroisopropoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, and the like.

[0035] "Hydroxy C 1-6 "Alkyl" refers to a C alkyl group substituted with 1 to 3 hydroxy groups. 1-6 It means alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1-methyl-1-hydroxyethyl, etc.

[0036] "C 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, tert-butoxy, isopropoxy, and the like.

[0037] "C 1-6 Alkoxy C 1-6 "Alkyl" means a group having one or two C1-6 Alkoxy-substituted C 1-6 It means alkyl, for example, methoxymethyl, methoxyethyl, methoxypropyl, 1-methyl-1-methoxyethyl.

[0038] "C 1-6 "Alkylcarbonyl" means one C 1-6 It means a carbonyl substituted with an alkyl, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, or tert-butylcarbonyl.

[0039] "Mono C 1-6 "Alkylamino" means one C 1-6 It means an amino substituted with alkyl, such as methylamino, ethylamino, and propylamino.

[0040] "The C 1-6 "Alkylamino" means a group consisting of two identical or different C 1-6 It means amino substituted with alkyl, for example, dimethylamino, ethylmethylamino, ethylpropylamino, etc.

[0041] "Amino C 1-6 "Alkyl" refers to a C alkyl group substituted with one or two amino groups. 1-6 It means alkyl, for example, aminomethyl, aminoethyl, aminopropyl, etc.

[0042] "Cyano C 1-6 "Alkyl" refers to a C substituted with one cyano. 1-6 It means alkyl, for example, cyanomethyl, cyanoethyl, etc.

[0043] "C 3-10 "Cycloalkyl" means a 3- to 10-membered monocyclic or bicyclic hydrocarbon group. 3-8 "Cycloalkyl" means a 3- to 8-membered monocyclic or bicyclic hydrocarbon group. 3-6"Cycloalkyl" means a 3- to 6-membered monocyclic or bicyclic hydrocarbon group. The monocyclic or bicyclic hydrocarbon group may be a saturated or partially unsaturated hydrocarbon group. The bicyclic hydrocarbon group may contain a spiro ring, a fused ring, or a bridged ring. Examples of monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused rings include bicyclo[4.4.0]decanyl, etc. Examples of bridged rings include bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. Examples of spiro rings include spiro[4.5]decanyl, etc.

[0044] "C 3-8 "Cycloalkoxy" refers to an alkoxy having a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms. Examples include cyclopropoxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0045] "C 3-8 Cycloalkyl C 1-6 "Alkyl" means one C 3-8 Cycloalkyl-substituted C 1-6 It means alkyl. 3-6 Cycloalkyl C 1-6 "Alkyl" means one C 3-6 Cycloalkyl-substituted C 1-6 Examples of the alkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, and 2-cyclopropylethyl. 3-6 CycloalkylhaloC 1-6 "Alkyl" means one C 3-6 Cycloalkyl-substituted haloC 1-6 Examples thereof include cyclopropyldifluoromethyl, cyclobutyldifluoromethyl, cyclopentyldifluoromethyl, and cyclohexyldifluoromethyl.

[0046] "3- to 10-membered heterocycloalkyl" refers to a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, and a carbon atom in the ring may be substituted with an oxo group. "3- to 8-membered heterocycloalkyl" refers to a 3- to 8-membered monocyclic or bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, and a carbon atom in the ring may be substituted with an oxo group. "3- to 6-membered heterocycloalkyl" refers to a 3- to 6-membered monocyclic or bicyclic heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, and a carbon atom in the ring may be substituted with an oxo group. The monocyclic or bicyclic heterocyclic group may be saturated or partially unsaturated. The bicyclic heterocyclic group may include spiro rings, fused rings, and bridged rings. Examples of monocyclic heterocyclic groups include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, etc. Monocyclic heterocyclic groups also include those in which hydrogen atoms are replaced by bonds, such as morpholin-3-one, thiomorpholin-3-one, piperidin-4-one, piperidin-3-one, piperazine-2,6-dione, morpholin-2-one, piperazin-2-one, piperazine-2,3-dione, and piperazine-2,5-dione. Examples of fused rings include octahydroindolyl and decahydroquinolyl. Fused rings also include those in which hydrogen atoms in non-aromatic ring moieties are replaced by bonds, such as dihydrobenzopyran and oxindole. Examples of spiro rings include 6-oxaspiro[4.5]decanyl. Spiro rings also include those in which a hydrogen atom is replaced by a bond, such as 6-azaspiro[2.5]octan-7-one. Examples of bridged rings include 5-oxabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, and 2-oxa-6-azabicyclo[3.2.2]nonyl.Bridged rings also include those in which a hydrogen atom is replaced by a bond, such as 2-oxa-5-azabicyclo[2.2.1]heptan-6-one.

[0047] 3- to 10-membered heterocycloalkyl C 1-6 "Alkyl" refers to a C substituted with one 3- to 10-membered heterocycloalkyl. 1-6 "3- to 8-membered heterocycloalkyl C 1-6 "Alkyl" refers to a C substituted with one 3- to 8-membered heterocycloalkyl. 1-6 Examples include 3-morpholinoethyl, 2-(azepan-1-yl)ethyl, etc. "3- to 6-membered heterocycloalkyl C 1-6 "Alkyl" refers to a C substituted with one 3- to 6-membered heterocycloalkyl. 1-6 It means alkyl, for example, (oxetan-3-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, etc.

[0048] "C 6-10 "Aryl" means phenyl or naphthyl.

[0049] "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, including isomerized groups with a hydroxyl group on the carbon atom adjacent to the nitrogen atom. Examples include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,5-oxadiazolyl. "5- or 6-membered heteroaryl" also includes groups in which a hydrogen atom is replaced by a bond, such as 1H-pyridin-2-one and 1H-pyrimidin-2-one. "9- or 10-membered heteroaryl" refers to a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, including isomerized groups with a hydroxyl group on the carbon atom adjacent to the nitrogen atom. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, purinyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl.

[0050] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl. For example, benzyl. 6-10 Aryl C 1-6 "Alkoxy" means one C 6-10 Aryl-substituted C 1-6 It means alkoxy. For example, benzyloxy. 6-10 Aryl Halo C 1-6 "Alkyl" means one C 6-10 Aryl-substituted haloC 1-6 "5- or 6-membered heteroaryl C" refers to an alkyl group. For example, difluoro(phenyl)methyl is mentioned. 1-6 "Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 1-6"5- or 6-membered heteroaryl haloC" refers to an alkyl group. For example, pyridylmethyl is mentioned. 1-6 "Alkyl" refers to a haloC substituted with one 5- or 6-membered heteroaryl. 1-6 It means alkyl, for example, difluoro(pyridyl)methyl.

[0051] "C which may have any group selected from the substituent group C 3-6 Cycloalkyl C 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 4 identical or different groups selected from the substituent group C. 3-6 Cycloalkyl C 1-6 It means alkyl. Unsubstituted C 3-6 Cycloalkyl C 1-6 Alkyl or C having one or two of the above groups 3-6 Cycloalkyl C 1-6 Alkyl is preferred. "C" which may have any group selected from the substituent group C 3-6 CycloalkylhaloC 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 4 identical or different groups selected from the substituent group C. 3-6 CycloalkylhaloC 1-6 It means alkyl. Unsubstituted C 3-6 CycloalkylhaloC 1-6 Alkyl or C having one or two of the above groups 3-6 CycloalkylhaloC 1-6 Alkyl is preferred. "C" which may have any group selected from the substituent group C 6-10 Aryl C 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 3 identical or different groups selected from the substituent group C. 6-10 Aryl C 1-6 It means alkyl. Unsubstituted C 6-10 Aryl C 1-6 Alkyl or C having one or two of the above groups 6-10 Aryl C 1-6 Alkyl is preferred. "C" which may have any group selected from the substituent group C 6-10 Aryl Halo C 1-6The term "alkyl" refers to a C alkyl group which may have 1 to 3 identical or different groups selected from the substituent group C. 6-10 Aryl Halo C 1-6 It means alkyl. Unsubstituted C 6-10 Aryl Halo C 1-6 Alkyl or C having one or two of the above groups 6-10 Aryl Halo C 1-6 Alkyl is preferred. 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group C 1-6 "Alkyl" refers to a 5- or 6-membered heteroaryl C which may have 1 to 3 identical or different groups selected from the substituent group C 1-6 alkyl. Unsubstituted 5- or 6-membered heteroaryl C 1-6 Alkyl, or 5- or 6-membered heteroaryl having one or two of the above groups C 1-6 Alkyl is preferred. "5- or 6-membered heteroaryl halo C optionally having any group selected from the substituent group C" 1-6 The term "alkyl" refers to a 5- or 6-membered heteroaryl halo group C which may have 1 to 3 identical or different groups selected from the substituent group C. 1-6 alkyl. Unsubstituted 5- or 6-membered heteroaryl haloC 1-6 alkyl, or 5- or 6-membered heteroaryl haloC having one or two of the above groups 1-6 Alkyl is preferred. "C" which may have any group selected from the substituent group C 6-10 "Aryl" refers to a C aryl group which may have 1 to 3 identical or different groups selected from the substituent group C 6-10 It means aryl. Unsubstituted C 6-10 Aryl or C having one or two of the above groups 6-10Aryl is preferred. "5- or 6-membered heteroaryl which may have any group selected from substituent group C" means a 5- or 6-membered heteroaryl which may have 1 to 3 identical or different groups selected from substituent group C. An unsubstituted 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl having 1 or 2 of the above groups is preferred. "9- or 10-membered heteroaryl which may have any group selected from substituent group C" means a 9- or 10-membered heteroaryl which may have 1 to 3 identical or different groups selected from substituent group C. An unsubstituted 9- or 10-membered heteroaryl or a 9- or 10-membered heteroaryl having 1 or 2 of the above groups is preferred. "C which may have any group selected from substituent group C" means a 9- or 10-membered heteroaryl which may have 1 to 3 identical or different groups selected from substituent group C. An unsubstituted 9- or 10-membered heteroaryl or a 9- or 10-membered heteroaryl having 1 or 2 of the above groups is preferred. 3-8 The term "cycloalkyl" refers to a C cycloalkyl group which may have 1 to 4 identical or different groups selected from the C substituent group. 3-8 It means cycloalkyl. Unsubstituted C 3-8 cycloalkyl or C having one or two of the above groups 3-8 Cycloalkyl is preferred. "3- to 8-membered heterocycloalkyl which may have any group selected from Substituent group C" means a 3- to 8-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from Substituent group C. Unsubstituted 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl having 1 or 2 of the above groups is preferred.

[0052] "C optionally having any group selected from the substituent group D 3-10 The term "cycloalkyl" refers to a C group which may have 1 to 4 identical or different groups selected from the substituent group D. 3-10 It means cycloalkyl. Unsubstituted C 3-10 cycloalkyl or C having one or two of the above groups 3-10 Cycloalkyl is preferred. C may have any group selected from the substituent group D. 3-6 The term "cycloalkyl" refers to a C group which may have 1 to 4 identical or different groups selected from the substituent group D. 3-6 It means cycloalkyl. Unsubstituted C 3-6cycloalkyl or C having one or two of the above groups 3-6 Cycloalkyl is preferred. "3- to 10-membered heterocycloalkyl which may have any group selected from substituent group D" means 3- to 10-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from substituent group D. Unsubstituted 3- to 10-membered heterocycloalkyl or 3- to 10-membered heterocycloalkyl having 1 or 2 of the above groups is preferred. "C which may have any group selected from substituent group D" means 3- to 10-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from substituent group D. 6-10 "Aryl" refers to C which may have 1 to 3 identical or different groups selected from the substituent group D. 6-10 It means aryl. Unsubstituted C 6-10 Aryl or C having one or two of the above groups 6-10 Aryl is preferred.

[0053] "C optionally having any group selected from the substituent group E" 3-6 Cycloalkyl C 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 4 identical or different groups selected from the substituent group E. 3-6 Cycloalkyl C 1-6 It means alkyl. Unsubstituted C 3-6 Cycloalkyl C 1-6 Alkyl or C having one or two of the above groups 3-6 Cycloalkyl C 1-6 Alkyl is preferred. "3- to 10-membered heterocycloalkyl C optionally having any group selected from the substituent group E" 1-6 "Alkyl" refers to a 3- to 10-membered heterocycloalkyl C which may have 1 to 4 identical or different groups selected from the substituent group E. 1-6 Unsubstituted 3- to 10-membered heterocycloalkylC 1-6 Alkyl, or 3- to 10-membered heterocycloalkyl C having 1 or 2 of the above groups 1-6 Alkyl is preferred. C may have any group selected from the substituent group E. 3-6 The term "cycloalkyl" refers to a C group which may have 1 to 4 identical or different groups selected from the substituent group E. 3-6It means cycloalkyl. Unsubstituted C 3-6 cycloalkyl or C having one or two of the above groups 3-6 Cycloalkyl is preferred. "3- to 10-membered heterocycloalkyl which may have any group selected from Substituent Group E" means a 3- to 10-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from Substituent Group E. Unsubstituted 3- to 10-membered heterocycloalkyl or a 3- to 10-membered heterocycloalkyl having 1 or 2 of the above groups is preferred.

[0054] "C optionally having any group selected from the substituent group F" 3-6 Cycloalkyl C 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 4 identical or different groups selected from the substituent group F. 3-6 Cycloalkyl C 1-6 It means alkyl. Unsubstituted C 3-6 Cycloalkyl C 1-6 Alkyl or C having one or two of the above groups 3-6 Cycloalkyl C 1-6 Alkyl is preferred. "3- to 6-membered heterocycloalkyl C optionally having any group selected from the substituent group F" 1-6 "Alkyl" refers to a 3- to 6-membered heterocycloalkyl C which may have 1 to 4 identical or different groups selected from the substituent group F. 1-6 Unsubstituted 3- to 6-membered heterocycloalkylC 1-6 Alkyl, or 3- to 6-membered heterocycloalkyl C having one or two of the above groups 1-6 Alkyl is preferred. C may have any group selected from the substituent group F. 3-6 The term "cycloalkyl" refers to a C cycloalkyl group which may have 1 to 4 identical or different groups selected from the substituent group F. 3-6 It means cycloalkyl. Unsubstituted C 3-6 cycloalkyl or C having one or two of the above groups 3-6Cycloalkyl is preferred. "3- to 6-membered heterocycloalkyl which may have any group selected from substituent group F" means 3- to 6-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from substituent group F. Unsubstituted 3- to 6-membered heterocycloalkyl or 3- to 6-membered heterocycloalkyl having 1 or 2 of the above groups is preferred. "C which may have any group selected from substituent group F" means 3- to 6-membered heterocycloalkyl which may have 1 to 4 identical or different groups selected from substituent group F. 6-10 Aryl C 1-6 The term "alkyl" refers to a C alkyl group which may have 1 to 3 identical or different groups selected from the substituent group F. 6-10 Aryl C 1-6 It means alkyl. Unsubstituted C 6-10 Aryl C 1-6 Alkyl or C having one or two of the above groups 6-10 Aryl C 1-6 Alkyl is preferred. 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group F 1-6 The term "alkyl" refers to a 5- or 6-membered heteroaryl C which may have 1 to 3 identical or different groups selected from the substituent group F. 1-6 alkyl. Unsubstituted 5- or 6-membered heteroaryl C 1-6 Alkyl, or 5- or 6-membered heteroaryl having one or two of the above groups C 1-6 Alkyl is preferred. C may have any group selected from the substituent group F. 6-10 "Aryl" refers to a C aryl group which may have 1 to 3 identical or different groups selected from the substituent group F. 6-10 It means aryl. Unsubstituted C 6-10 Aryl or C having one or two of the above groups 6-10 Aryl is preferred. The term "5- or 6-membered heteroaryl which may have any group selected from Substituent Group F" means a 5- or 6-membered heteroaryl which may have 1 to 3 identical or different groups selected from Substituent Group F. Unsubstituted 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl having 1 or 2 of the above groups is preferred.

[0055] The phrase "may have any group" includes unsubstituted.

[0056] "Leaving group" refers to any group that leaves a molecule during a fragmentation process such as substitution, elimination, and addition-elimination reactions. Examples of leaving groups include sulfonates containing nitrogen (e.g., diazonium salts), alkyl sulfonates (e.g., mesylate), fluoroalkyl sulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), aryl sulfonates (e.g., tosylate, brosylate, closylate, and nosylate), halides, carboxylate, phenolate, alkoxy, and the like.

[0057] The following abbreviations used in the text, figures, and tables have the following meanings: DIPEA: N,N-Diisopropylethylamine DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene DCM: Dichloromethane DEA: Diethylamine DMAP: 4-Dimethylaminopyridine DMF: N,N-Dimethylformamide DPPA: Diphenylphosphoryl azide HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: Lithium diisopropylamide LHMDS: Lithium bis(trimethylsilyl)amide Martin Sulfurane: Bis[α,α-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur mCPBA: 3-Chloroperbenzoic acid (approx. 30% water content) MeCN: Acetonitrile MTBE: Methyl tert-butyl ether NaBH(OAc)3: Sodium triacetoxyborohydride NMP: N-Methylpyrrolidone TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMAD: N,N,N',N'-Tetramethylazodicarboxamide TBAF: Tetrabutylammonium fluoride (approx. 1 mol / L in THF) 2-MeTHF: 2-Methyltetrahydrofuran WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Xphos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) XantPhos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) 10% Pd / C: 10% Palladium on carbon (approx. 55% water-wet) 20% Pd(OH)2 / C: 20% palladium hydroxide carbon (approximately 50% water-wet) DAICEL: Daicel Corporation YMC: YMC CO., LTD.Amino silica gel: Aminopropylated silica gel Chiral preparative column chromatography: High-performance liquid chromatography using a preparative chiral column ODS: Octadecylsilylated silica gel Method A: Column chromatography using an aminopropylated silica gel column connected to the bottom of a silica gel column Method B: Column chromatography using an aminopropylated silica gel column connected to the bottom of a silica gel column Method C: Elution solvent (20 mM ammonium bicarbonate aqueous solution adjusted to pH 9.0 with 40% MeCN / DEA), column (CHIRAL ART Cellulose-SC (YMC)) Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical property values ​​IC. 50 : 50% inhibitory concentration 1 H-NMR: Proton nuclear magnetic resonance spectrum DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 CDCl3: Chloroform-d1 CD3OD: Methanol-d4 MS: Mass spectrometry (The values ​​in the table were measured by electrospray ionization or electrospray ionization-atmospheric pressure chemical ionization multi-ionization method.) CXCL1: CXC motif chemokine ligand 1 FBS: Fetal bovine serum HT-29 cells: Human colon cancer cell line

[0058] When one or more asymmetric carbon atoms are present in the compound of formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0059] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention encompasses both of the cis-trans isomers.

[0060] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0061] The compound of the present invention represented by formula (I) also includes N-oxides in which the nitrogen atom of the spiro ring is oxidized, as represented by the following formula: When the N-oxide has cis-trans isomers, both of the cis-trans isomers are also included.

[0062] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0063] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0064] Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0065] Examples of salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0066] Unless otherwise specified, a suffix to a chemical name or structural formula referring to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply refers to the salt form.

[0067] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, any crystalline form is included. The pharmacologically acceptable salt of the compound represented by formula (I) also includes a cocrystal or a cocrystal salt with a suitable coformer. A cocrystal or a cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). A cocrystal or a cocrystal salt can be prepared according to known cocrystallization methods. The compound represented by formula (I) or a pharmacologically acceptable salt thereof also includes a hydrate or solvate with a pharmaceutically acceptable solvent such as water or ethanol.

[0068] In the compound represented by formula (I), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0069] A compound represented by formula (I) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below, using commercially available building blocks containing isotopes. For example, a compound represented by formula (I) in which some hydrogen atoms are replaced with deuterium atoms can also be produced by the above-mentioned method and methods described in the literature (see, for example, Journal of Organic Synthetic Chemistry, Vol. 65, No. 12, pp. 1179-1190, 2007). In addition, for example, a compound represented by formula (I) in which some carbon atoms are replaced with 13 Compounds substituted at C can also be prepared using the above method and methods described in the literature (see, for example, RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0070] The compounds of the present invention can be produced, for example, by the methods shown in Schemes 1 to 7 or methods analogous thereto, or by methods described in the literature or methods analogous thereto.

[0071] The compounds of the present invention can be produced by the methods shown below, but the following production methods are examples of general production methods and are not intended to limit the production methods.

[0072] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0073] In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.

[0074] In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually −78° C. to reflux temperature unless otherwise specified.

[0075] In the reaction of each step, the pressure varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

[0076] A microwave reactor such as Biotage's Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0077] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, MTBE, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.; Amides: DMF, N,N-dimethylacetamide, NMP, etc.; Halogenated hydrocarbons: DCM, dichloroethane, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, TFA, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0078] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base used include the bases described in the Reference Examples or Examples corresponding to each step, or the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, DBU, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, LDA, LHMDS, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; organomagnesiums: isopropylmagnesium chloride, etc.; organolithiums: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0079] When an acid or acidic catalyst is used in the reaction of each step, the reaction is carried out using an acid or acidic catalyst suitable for the reaction. Specific examples of the acid or acidic catalyst used include the acid or acidic catalysts described in the Reference Examples and Examples corresponding to each step, or the following acid or acidic catalysts: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, TFA, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0080] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents. Carbodiimides: WSC, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0081] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, as well as the following reducing agents: metal hydrides: lithium aluminum hydride, lithium borohydride, NaBH, NaBH(OAc), sodium cyanoborohydride, diisobutylaluminum hydride, etc.; boranes: BH-THF complex, 2-picoline borane complex, decaborane, etc.

[0082] When a carbonyl group-introducing reagent is used in the reaction of each step, the reaction is carried out using a carbonyl group-introducing reagent suitable for the reaction. Specific examples of the carbonyl group-introducing reagent to be used include the carbonyl group-introducing reagents described in the Reference Examples or Examples corresponding to each step, or the following carbonyl group-introducing reagents: phosgene, diphosgene, triphosgene, etc.; chloroformates: 4-nitrophenyl chloroformate, etc.; imidazoles: carbonyldiimidazole, etc.

[0083] In each step, when a protecting group is required depending on the type of functional group, the protective group may be introduced and removed in a suitable combination according to a conventional method. Regarding the type of protective group, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis," edited by Peter GM Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

[0084] When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0085] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, platinum(IV) oxide, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0086] When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent to be used include the above-mentioned examples.

[0087] When a metal reduction reaction is carried out in each step, the reaction can be carried out in the presence of a metal or the like. Examples of the metal or the like that can be used include iron powder, zinc powder, tin chloride, titanium trichloride, etc. If necessary, an acid may be used in the reaction.

[0088] When an amidation reaction is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base to be used include those mentioned above. When a carbodiimide is used as the condensing agent, the reaction may be carried out by adding an additive such as 1-hydroxybenzotriazole or DMAP, as necessary. The reaction can also be carried out using an acyl halide or an acid anhydride in the presence or absence of a base.

[0089] When a reductive amination reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, platinum(IV) oxide, Raney nickel, etc.

[0090] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

[0091] When a Negishi coupling reaction is performed in each step, the reaction can be carried out in the presence of zinc, a palladium catalyst, and a ligand. Examples of palladium catalysts that can be used include palladium(II) acetate and tris(dibenzylideneacetone)palladium(0). Examples of ligands include Xphos, XantPhos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and tris(2-methylphenyl)phosphine. If necessary, the reaction can be carried out with the addition of additives such as iodine or 1,2-dibromoethane.

[0092] When a Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. The palladium catalyst used is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). 、 tetrakis(triphenylphosphine)palladium(0), etc. Examples of the base to be used include the examples mentioned above.

[0093] When a Curtius rearrangement reaction is carried out in each step, the reaction can be carried out in the presence of an azide source, such as sodium azide or DPPA.

[0094] In each step, when a carbamate reaction or a urea reaction is carried out, the reaction can be carried out using a carbonyl group-introducing reagent in the presence or absence of a base. Examples of the carbonyl group-introducing reagent and base to be used include those mentioned above.

[0095] In each step, unless otherwise specified, the symbols in the formulae have the same meanings as in [1] above. Ring B1 is a 5- or 6-membered heteroaryl, a 9- or 10-membered heteroaryl, or a 3- to 10-membered heterocycloalkyl. P, P 1 , P 2 , P 3 , and P 4 is a protecting group. V is a bond, an oxygen atom, a nitrogen atom, or a carbon atom. W 1 is Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkyl, -SO2-R 9 , or -CO-R 9 W 2 is a hydrogen atom, halo C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl. 3 is a hydrogen atom or C 1-6 It is an alkyl. 4 is a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, R b may have C 3-6 Cycloalkyl, or R b X is a leaving group. R a is the same as the substituent group F. b is the same as the substituent group E. 7a means the structure shown in Scheme 2. R 5a means the structure shown in Scheme 5-2. g and h are each independently an integer of 1 to 3. j and k are each independently an integer of 1 to 4.

[0096] Compound (Ia) included in the compound represented by formula (I) can be produced, for example, according to Process 1-1 and 1-2 described in Scheme 1.

[0097] Process 1-1 The compound (1-2) can also be produced by a reduction reaction of the compound (1-1).

[0098] Process 1-2 Compound (Ia) can also be produced by the Mitsunobu reaction of compound (1-2) with compound (1-A).

[0099] As an alternative to Process 1-2, compound (Ia) can also be prepared by converting the hydroxy group of compound (1-2) into a leaving group, followed by nucleophilic substitution reaction with compound (1-A).

[0100] Compound (1-1a), which is included in the compound represented by compound (1-1), can be produced, for example, according to the methods of Processes 2-1 to 2-6 described in Scheme 2.

[0101] Process 2-1 Compound (2-2) can also be produced by coupling reaction of compound (2-1) with compound (2-A) in the presence of a metal catalyst.

[0102] Process 2-2 Compound (2-3) can also be produced by deprotection reaction of compound (2-2).

[0103] Process 2-3 Compound (1-1a) can also be produced by the reductive amination reaction of compound (2-3) with compound (2-B) or compound (2-E). Compound (1-1a) can also be produced by reacting compound (2-3) with compound (2-C) or compound (2-D).

[0104] Process 2-4 Compound (2-4) can also be produced by deprotection reaction of compound (2-1).

[0105] Process 2-5 Compound (2-5) can also be produced by the reductive amination reaction of compound (2-4) with compound (2-B) or compound (2-E). Compound (2-5) can also be produced by reacting compound (2-4) with compound (2-C) or compound (2-D).

[0106] Process 2-6 The compound (1-1a) can also be produced by subjecting the compound (2-5) to a coupling reaction with the compound (2-A) in the presence of a metal catalyst.

[0107] Compound (2-1) can be produced, for example, according to Process 3-1 described in Scheme 3.

[0108] Process 3-1 The compound (2-1) can also be produced by reacting the compound (3-1) with the compound (3-A).

[0109] Compound (2-A) can be produced, for example, according to Processes 4-1 to 4-3 described in Scheme 4.

[0110] Process 4-1 The compound (4-2) can also be produced by amidation reaction of the compound (4-1) with ammonium carbonate or ammonium chloride.

[0111] Process 4-2 Compound (4-3) can also be produced by deprotection of compound (4-2).

[0112] Process 4-3 Compound (2-A) can also be produced by an amidation reaction of compound (4-3) and compound (4-A).

[0113] Among the compounds represented by formula (I), compound (Ib-1) can be produced, for example, according to Processes 5-1 to 5-13 described in Scheme 5-1.

[0114] Process 5-1 Compound (5-1) can also be produced by reductive amination of compound (2-1) with compound (5-E), followed by acid treatment.

[0115] Process 5-2 Compound (5-2) can also be produced by reductive amination of compound (5-1) and compound (5-A).

[0116] Process 5-3 The compound (5-3) can also be produced by reacting the compound (5-1) with the compound (5-B).

[0117] Process 5-4 Compound (5-3) is obtained by removing the protecting group P of compound (5-2). 2 It can also be produced by the deprotection reaction of the following.

[0118] Process 5-5 The compound (5-4) can also be produced by reacting the compound (5-3) with the compound (5-C).

[0119] Process 5-6 Compound (5-5) is prepared by coupling compound (5-4) with compound (5-F) in the presence of a metal catalyst, followed by the addition of a protecting group P 4 It can also be produced by the deprotection reaction of the following.

[0120] Process 5-7 The compound (5-6) can also be produced by an amidation reaction of the compound (5-5) with the compound (4-1).

[0121] Process 5-8 Compound (5-7) is prepared by removing the protecting group P of compound (5-6) by a deprotection reaction, followed by a reductive amination reaction with compound (2-B) or compound (2-E), followed by the removal of the protecting group P. 1 Compound (5-7) can also be produced by removing the protecting group P of compound (5-6) by a deprotection reaction, reacting the compound with compound (2-C) or compound (2-D), and then removing the protecting group P. 1 can also be produced by removing by a deprotection reaction.

[0122] Process 5-9 Compound (Ib-1) can also be produced by an amidation reaction of compound (5-7) and compound (5-D).

[0123] Process 5-10 Compound (5-8) can also be produced by reductive amination of compound (2-2) with compound (5-E), followed by acid treatment.

[0124] Process 5-11 The compound (5-9) can also be produced by reacting the compound (5-8) with the compound (5-B).

[0125] Process 5-12 The compound (5-10) can also be produced by reacting the compound (5-9) with the compound (5-C).

[0126] Process 5-13 Compound (Ib-1) can also be produced by removing the protecting group P from compound (5-10) by a deprotection reaction, followed by a reductive amination reaction with compound (2-B) or compound (2-E). Compound (Ib-1) can also be produced by removing the protecting group P from compound (5-10) by a deprotection reaction, followed by a reaction with compound (2-C) or compound (2-D).

[0127] Among the compounds represented by formula (I), compound (Ib-2) can be produced, for example, according to the methods of Processes 5-14 to 5-22 described in Scheme 5-2.

[0128]

[0129] Process 5-14 Compound (5-11) can also be produced by aldol reaction of compound (5-4) with compound (5-H) or compound (5-I).

[0130] Process 5-15 Compound (5-12) can also be produced by dehydration of compound (5-11).

[0131] Process 5-16 The compound (5-13) can also be produced by the reduction reaction of the compound (5-12).

[0132] Process 5-17 The compound (5-13) can also be produced by reacting the compound (5-3) with the compound (5-G).

[0133] Process 5-18 Compound (5-14) can also be produced by coupling reaction of compound (5-13) with compound (2-A) in the presence of a metal catalyst.

[0134] Process 5-19 Compound (Ib-2) can also be produced by removing the protecting group P from compound (5-14) by a deprotection reaction, followed by a reductive amination reaction with compound (2-B) or compound (2-E). Compound (Ib-2) can also be produced by removing the protecting group P from compound (5-14) by a deprotection reaction, followed by a reaction with compound (2-C) or compound (2-D).

[0135] Process 5-20 The compound (5-14) can also be produced by reacting the compound (5-9) with the compound (5-G).

[0136] Process 5-21 Compound (5-15) can also be produced by aldol reaction of compound (Ib-1) with compound (5-H) or compound (5-I).

[0137] Process 5-22 Compound (5-16) can also be produced by dehydration of compound (5-15).

[0138] Process 5-23 Compound (Ib-2) can also be produced by the reduction reaction of compound (5-16).

[0139] Among the compounds represented by formula (I), compound (Ic) can be produced, for example, according to Processes 6-1 to 6-5 described in Scheme 6.

[0140] Process 6-1 The compound (6-1) can also be produced by reacting the compound (5-8) with the compound (6-A).

[0141] Process 6-2 Compound (6-2) is prepared by reacting compound (6-1) with compound (5-C) and then removing the protecting group P 3 can also be produced by removing by a deprotection reaction.

[0142] Process 6-3 Compound (6-3) can also be produced by reductive amination reaction of compound (6-2) with compound (5-H) or compound (5-I).

[0143] Process 6-4 Compound (6-4) can also be produced by deprotection reaction of compound (6-3).

[0144] Process 6-5 Compound (Ic) can also be produced by the reductive amination reaction of compound (6-4) with compound (2-B) or compound (2-E). Compound (Ic) can also be produced by reacting compound (6-4) with compound (2-C) or compound (2-D).

[0145] Among the compounds represented by formula (I), compound (Id) can be produced, for example, according to Processes 7-1 to 7-7 described in Scheme 7.

[0146]

[0147] Process 7-1 Compound (7-1) can also be produced by converting the ketone of compound (2-2) into an enol triflate.

[0148] Process 7-2 The compound (7-2) can also be produced by subjecting the compound (7-1) to a coupling reaction with the compound (7-A) in the presence of a metal catalyst.

[0149] Process 7-3 Compound (7-3) can also be produced by coupling reaction of compound (7-2) with compound (7-B) in the presence of a metal catalyst.

[0150] Process 7-4 Compound (7-4) can also be produced by removing the protecting group P of compound (7-3) by a deprotection reaction, followed by reducing the double bond.

[0151] Process 7-5 Compound (Id) can also be produced by the reductive amination reaction of compound (7-4) with compound (2-B) or compound (2-E). Compound (Id) can also be produced by reacting compound (7-4) with compound (2-C) or compound (2-D).

[0152] Process 7-6 Compound (7-5) can also be produced by the Mitsunobu reaction of compound (1-2) with compound (7-C). Alternatively, compound (7-5) can be produced by converting the hydroxy group of compound (1-2) to a leaving group, followed by a nucleophilic substitution reaction with compound (7-C).

[0153] Process 7-7 Compound (Id) can also be produced by reduction of compound (7-5).

[0154] The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The scheme can be modified in various ways that can be easily understood by those skilled in the art.

[0155] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0156] The compounds of the present invention have excellent IL-17 modulatory activity and can therefore be used as therapeutic agents for various diseases in which IL-17 is involved. In the present invention, diseases in which IL-17 is involved include, for example, psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, axial spondyloarthritis, hidradenitis suppurativa, polymyalgia rheumatica, tendinopathy, palmoplantar pustulosis, systemic sclerosis, Sjögren's syndrome, lichen planus, lupus nephritis, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver disease, gout, osteoarthritis, SLE, multiple sclerosis, rheumatoid arthritis, pityriasis rubra pilaris, rubella pustules, pyoderma gangrenosum, hidradenitis abscess, discoid lupus erythematosus, papulopustular rosacea, atopic dermatitis, ichthyosis, bullous pemphigoid, chronic wounds, and cancer. Preferably, it can be used as a therapeutic agent for psoriasis, axial spondyloarthritis, ankylosing spondylitis, and juvenile idiopathic arthritis, more preferably for psoriasis.

[0157] Psoriasis includes plaque psoriasis, guttate psoriasis, psoriatic arthritis, pustular psoriasis, and erythrodermic psoriasis.

[0158] In the present invention, "treatment" includes the meaning of "prevention."

[0159] In the present invention, the term "modulator" refers to any agent or molecule, including small molecule compounds, that binds to and regulates the activity of IL-17, for example, any agent or molecule that inhibits a signal involving IL-17.

[0160] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the method of use, such as powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and enemas, and may be administered orally or parenterally.

[0161] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0162] The pharmaceutical composition of the present invention is prepared using a compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. The pharmaceutical composition of the present invention can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, using methods known in pharmaceutical sciences depending on the dosage form.

[0163] When the pharmaceutical composition of the present invention is used for treatment, the dose of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. The daily dose may be administered in one, two, three, or four divided doses.

[0164] For oral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 2000 mg / day. In one embodiment, the oral dosage can be set in the range of 1 to 500 mg / day, preferably in the range of 10 to 200 mg / day.

[0165] For parenteral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 1000 mg / day. In one embodiment, the parenteral dosage can be set in the range of 0.5 to 200 mg / day, preferably in the range of 1 to 20 mg / day. Preferably, the pharmaceutical composition of the present invention is administered orally.

[0166] In one embodiment, the pharmaceutical composition of the present invention can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is considered to be effective. Examples include steroid drugs, active vitamin D3 drugs, cyclosporine, retinoids, methotrexate, PDE4 inhibitors, JAK inhibitors, anti-TNFα antibodies, anti-p40 antibodies, anti-p19 antibodies, etc. Known drugs can be selected as the steroid drugs, active vitamin D3 drugs, PDE4 inhibitors, JAK inhibitors, anti-TNFα antibodies, anti-p40 antibodies, and anti-p19 antibodies.

[0167] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced depending on the dosage of the other drug used in combination.

[0168] The compound represented by formula (I) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a prodrug-constituting group using a prodrug-converting reagent such as a corresponding halide, followed by purification. Examples of the prodrug-constituting group include those described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0169] The present invention will be further illustrated in the following examples.

[0170] The present invention is not limited to these contents, and may be modified within the scope of the present invention. The names of compounds described in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

[0171] Reference Example A-1 (S)-2-Amino-3,3-dicyclopropylpropanamide Hydrochloride To a mixture of tert-butyl (S)-(1-amino-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (24.5 g) and ethyl acetate (98 mL) was added hydrogen chloride (4 mol / L in ethyl acetate) (91 mL) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. n-Heptane (200 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The precipitate was collected by filtration, and the resulting solid was dried to give the title compound (18.3 g).

[0172] Reference Example A-2 7-amino-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl hydrochloride. A mixture of Reference Example D-4 (3.1 g), methanol (7.5 mL), and hydrogen chloride (4 mol / L in 1,4-dioxane) (7.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (2.8 g). The chemical structure of Reference Example A is shown in the following table.

[0173]

[0174] Reference Example B-1 (S)-N-(1-amino-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide To a mixture of 1-ethyl-1H-pyrazole-5-carboxylic acid (2.1 g), 4-methylmorpholine (1.3 g), and THF (10 mL) was added a mixture of isobutyl chloroformate (1.6 g) and THF (10 mL) in an ice-salt bath. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture in an ice-salt bath was added a mixture of Reference Example A-1 (2.0 g) and THF (5 mL), followed by a mixture of 4-methylmorpholine (1.3 g) and THF (5 mL). The reaction mixture was stirred at the same temperature for 0.5 hours. Water (20 mL) and ethanol (10 mL) were added to the reaction mixture. The mixture was stirred at room temperature for 15 hours. The precipitate was collected by filtration, and the resulting solid was dried to obtain the title compound (1.1 g).

[0175] Reference Example B-2 (S)—N-(1-amino-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of 1-methyl-1H-pyrazole-5-carboxylic acid (0.25 g), 4-methylmorpholine (0.26 g), and THF (4 mL) was added a mixture of isobutyl chloroformate (0.35 g) and THF (1 mL) at 0° C. The reaction mixture was stirred at the same temperature for 10 minutes. A mixture of Reference Example A-1 (0.40 g) and THF (1 mL) was added to the reaction mixture in an ice-salt bath, followed by the addition of a mixture of 4-methylmorpholine (0.26 g) and THF (1 mL). The reaction mixture was stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The precipitate was collected by filtration, and the resulting solid was dried to give the title compound (0.19 g).

[0176] Reference Example B-3 (S)—N-(1-Amino-3,3-dicyclopropyl-1-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (0.93 g), 4-methylmorpholine (0.74 g), and THF (16.5 mL) was added dropwise isobutyl chloroformate (1.0 g) at 0°C under an argon atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added a mixture of Reference Example A-1 (1.4 g), 4-methylmorpholine (0.77 g), and DMF (18.2 mL) at 0°C. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (1.9 g). The chemical structure of Reference Example B is shown in the following table.

[0177]

[0178] Reference Example C-1: Benzyl 7-bromo-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate. Pyrrolidine (4.3 g) was added to a mixture of benzyl 4-oxopiperidine-1-carboxylate (7.0 g), 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethan-1-one (7.0 g), and ethanol (49 mL) at room temperature. The reaction mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain the title compound (10.5 g).

[0179] Reference Example C-2 tert-Butyl 7-bromo-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate A mixture of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethan-1-one (2.0 g), tert-butyl 4-oxopiperidine-1-carboxylate (1.7 g), pyrrolidine (0.61 g), and methanol (12 mL) was stirred at 100 °C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified using Method B (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain the title compound (3.4 g). The chemical structure of Reference Example C is shown in the following table.

[0180]

[0181] Reference Example D-1: (S)-7-(3,3-Dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate. Potassium carbonate (1.9 g), XantPhos (0.77 g), and palladium(II) acetate (0.15 g) were added to a mixture of Reference Example B-1 (1.9 g), Reference Example C-1 (3.0 g), and THF (18 mL) at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated aqueous ammonium chloride were added to the residue. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (3.8 g).

[0182] Reference Example D-2: (S)-7-(3,3-Dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example B-2 (0.77 g), Reference Example C-1 (1.2 g), potassium carbonate (0.77 g), and 2-MeTHF (12.5 mL), XantPhos (0.16 g) and palladium(II) acetate (0.031 g) were added at room temperature under an argon atmosphere. The reaction mixture was refluxed for 3 hours. After cooling to room temperature, water, saturated aqueous ammonium chloride, ethyl acetate, and n-hexane were added. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 19 / 81) to obtain the title compound (1.5 g).

[0183] Reference Example D-3 (S)-7-(3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester The title compound was obtained in the same manner as in Reference Example D-2 using Reference Example B-3 instead of Reference Example B-2.

[0184] Reference Example D-4 Benzyl 7-((tert-butoxycarbonyl)amino)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example F-7 (5.8 g), DCM (25 mL), and 2 mol / L aqueous sodium hydroxide solution (12.8 mL) was added chloroacetyl chloride (2.9 g) under water-cooling. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. To a mixture of the residue and tert-butanol (60 mL), potassium tert-butoxide (1.7 g) was added under water-cooling. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 30 / 70) to give Reference Example D-4Pa (2.9 g) which eluted later and Reference Example D-4Pb (3.2 g) which eluted earlier. Reference Example D-4Pa and Reference Example D-4Pb are diastereomers. A mixture of tert-butyl carbamate (0.84 g), Reference Example D-4Pa (2.9 g), cesium carbonate (4.7 g), XPhos-Pd-G2 (0.57 g), and 1,4-dioxane (40 mL) was stirred at 100 °C for 3 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 55 / 45) to give the title compound (3.1 g). Reference Example D-4Pa Benzyl 7-bromo-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate 1H-NMR(CDCl3) δ ppm:1.49-2.01 (6H, m), 2.92-3.18 (2H, m), 3.19-3.50 (2H, m), 3.82-4.22 (3H, m), 4.35 (1H, d, J=16.8Hz), 4.56 (1H, d, Reference example D-4Pb 7-Bromo-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl 1 H-NMR(CDCl3) δ ppm:1.49-2.00 (6H, m), 2.95-3.16 (2H, m), 3.29-3.50 (2H, m), 3.83-4.23 (3H, m), 4.42 (1H, d, J=16.8Hz), 4.52 (1H, d, J=16.8Hz), 5.14 (2H, s), 5.98-6.12 (1H, m), 6.75 (1H, dd, J=0.8, 8.4Hz), 7.14 (1H, d, J=6.0Hz), 7.29-7.41 (5H, m)

[0185] Reference Example D-5 (S)-7-(3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate tert-butyl ester Reference Example B-2 and Reference Example C-1 were replaced with Reference Example B-3 and Reference Example C-2, respectively, to obtain the title compound in the same manner as in Reference Example D-2. The chemical structure of Reference Example D is shown in the following table.

[0186]

[0187] Reference Example E-1: Benzyl 4-amino-7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamide)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of (R)-2-methylpropane-2-sulfinamide (1.4 g), Reference Example D-1 (3.8 g), and 2-MeTHF (7.6 mL) was added titanium(IV) ethoxide (6.6 g) at room temperature. The reaction mixture was refluxed for 5.5 hours. The reaction mixture was allowed to cool to room temperature, and 2-MeTHF (38 mL) was added. Sodium borohydride (0.66 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 20 hours while warming to room temperature. Saturated brine and ethyl acetate were added to the reaction mixture, and the mixture was stirred vigorously at room temperature for 10 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethanol (70 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (8.7 mL) was added at 0°C. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (40 mL) was added to the reaction mixture at 0°C. Water (80 mL) was added to the mixture at the same temperature, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration. The resulting solid was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (2.0 g). Reference Example E-1 1H-NMR(CDCl3) δ ppm:0.19-0.29 (2H, m), 0.31-0.46 (2H, m), 0.47-0.62 (3H, m), 0.63-0.73 (1H, m), 0.74-0.93 (3H, m), 1.44 (3H, t, J=7.2Hz), 1.53-1.90 (7H, m), 1.98-2.08 (1H, m), 3.03-3.47 (2H, m), 3.80-4.08 (3H, m), 4.51-4.68 (2H, m), 4.77-4.88 (1H, m), 5.14 (2H, s), 6.60 (1H, d, J=2.0Hz), 7.08 (1H, d, J=8.0Hz), 7.20-7.28 (1H, m), 7.29-7.41 (5H, m), 7.50 (1H, d, J=2.0Hz), 7.82 (1H, d, J=8.0Hz), 7.94-8.03 (1H, m)

[0188] Reference Example E-2: Benzyl 4-amino-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamide)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example D-2 (1.4 g), 2-MeTHF (2.8 mL), and (R)-2-methylpropane-2-sulfinamide (0.54 g), titanium(IV) ethoxide (2.5 g) was added at room temperature under an argon atmosphere. The reaction mixture was refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature, and (R)-2-methylpropane-2-sulfinamide (0.13 g) and titanium(IV) ethoxide (0.50 g) were added. The reaction mixture was refluxed for 1 hour. To the reaction mixture was added 2-MeTHF (11 mL) and sodium borohydride (0.50 g) at 0 °C. The reaction mixture was stirred at the same temperature for 16 hours. The reaction mixture was added to a mixture of ethyl acetate and saturated brine at 0 °C and stirred at the same temperature for 0.5 hours. The mixture was filtered through Celite. Water and saturated aqueous ammonium chloride solution were added to the filtrate. The organic layer was separated and concentrated under reduced pressure. To a mixture of the residue and 1,4-dioxane (3 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (5.5 mL) was added under water cooling. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and 2 mol / L aqueous sodium hydroxide solution (15 mL) were added to the residue at 0 °C. The mixture was stirred at the same temperature for 0.5 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (1.0 g). 1H-NMR(CDCl3) δ ppm:0.19-0.28 (2H, m), 0.31-0.46 (2H, m), 0.47-0.63 (3H, m), 0.64-0.74 (1H, m), 0.76-0.92 (3H, m), 1.40-1.91 (7H, m), 1.99-2.07 (1H, m), 3.01-3.49 (2H, m), 3.81-4.08 (3H, m), 4.17 (3H, s), 4.79-4.86 (1H, m), 5.14 (2H, s), 6.60 (1H, d, J=2.0Hz), 7.09 (1H, d, J=8.0Hz), 7.20-7.28 (1H, m), 7.29-7.42 (5H, m), 7.48 (1H, d, J=2.0Hz), 7.82 (1H, d, J=6.8Hz), 7.93-8.01 (1H, m)

[0189] Reference Example E-3: Benzyl 4-amino-7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example D-3 (5.6 g), 2-MeTHF (11 mL), and (R)-2-methylpropane-2-sulfinamide (2.1 g), titanium(IV) ethoxide (9.9 g) was added at room temperature under an argon atmosphere. The reaction mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, and (R)-2-methylpropane-2-sulfinamide (0.53 g) and titanium(IV) ethoxide (2.0 g) were added. The reaction mixture was refluxed for 3 hours. To the reaction mixture was added 2-MeTHF (45 mL) and sodium borohydride (1.5 g) at 0°C. The reaction mixture was stirred at the same temperature for 62 hours. The reaction mixture was added to a mixture of ethyl acetate and saturated brine at 0°C and stirred at the same temperature for 0.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 85 / 15 to 0 / 100) to give benzyl 4-(((R)tert-butylsulfinyl)amino)-7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (Reference Example E-3P) (3.6 g). To a mixture of Reference Example E-3P (1.0 g) and 1,4-dioxane (4 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (2.0 mL) was added. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. DCM and saturated aqueous sodium bicarbonate solution were added to the residue. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain the title compound (0.84 g). Reference Example E-3 1H-NMR(CDCl3) δ ppm:0.20-0.30 (2H, m), 0.31-0.45 (2H, m), 0.49-0.62 (3H, m), 0.63-0.74 (1H, m), 0.75-0.96 (3H, m),1.35-1.91 (7H, m), 1.98-2.08 (1H, m), 2.62 (3H, s), 3.02-3.50 (2H, m), 3.83-4.08 (3H, m), 4.80-4.88 (1H, m), 5.14 (2H, s), 7.21-7.28 (1H, m), 7.29-7.41 (5H, m), 7.78-7.90 (3H, m)

[0190] Reference Example E-4: Benzyl 4-amino-7-bromo-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate. Titanium(IV) ethoxide (25.1 g) was added to a mixture of (R)-2-methylpropane-2-sulfinamide (5.3 g), Reference Example C-1 (9.9 g), and 2-MeTHF (20 mL) at room temperature. The reaction mixture was refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature, and 2-MeTHF (100 mL) and methanol (5.9 mL) were added. Sodium borohydride (2.5 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 15 hours while warming to room temperature. Saturated brine and ethyl acetate were added to the reaction mixture, and the mixture was stirred vigorously at room temperature for 30 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to give benzyl 7-bromo-4-(((R)tert-butylsulfinyl)amino)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (Reference Example E-4P). To a mixture of the obtained compound and methanol (12 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (12 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 1 mol / L aqueous sodium hydroxide solution (50 mL) and ethyl acetate at room temperature. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (9.7 g). Reference Example E-4P1 H-NMR (CDCl) δ ppm: 1.25 (9H, s), 1.48-1.98 (5H, m), 2.02-2.12 (1H, m), 3.00-3.39 (2H, m), 3.44 (1H, d, J=7.2 Hz), 3.85-4.09 (2H, m), 4.47-4.58 (1H, m), 5.14 (2H, s), 7.06 (1H, d, J=6.0 Hz), 7.28-7.41 (5H, m), 7.45-7.52 (1H, m). The chemical structure of Reference Example E is shown in the following table.

[0191]

[0192] Reference Example F-1 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example E-1 (0.20 g) and MeCN (1 mL), 2-(trifluoromethyl)oxirane (0.20 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1.5 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (0.20 g) as a diastereomeric mixture.

[0193] Reference Example F-2 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example E-2 (0.36 g) and MeCN (3.6 mL), 2-(trifluoromethyl)oxirane (0.38 g) was added at room temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature, and MTBE (3 mL) was added. The precipitate was collected by filtration, and the resulting solid was dried to obtain the title compound (0.10 g). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=80 / 20 to 0 / 100) and combined with the solid obtained by filtration to give the title compound (0.38 g) as a diastereomeric mixture.

[0194] Reference Example F-3 7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-((3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester Using Reference Example E-3 instead of Reference Example E-1, the title compound was obtained as a diastereomeric mixture by the same method as in Reference Example F-1.

[0195] Reference Example F-4: Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((2-hydroxybutyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example E-1 (0.15 g) and 2-ethyloxirane (0.49 g), lithium bromide (0.004 g) was added at room temperature. The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (0.069 g) as a diastereomeric mixture.

[0196] Reference Example F-5 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(((S)-2-hydroxy-3-methoxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example E-1 (0.15 g) and MeCN (0.5 mL), (S)-2-(methoxymethyl)oxirane (0.50 g), lithium bromide (0.004 g), and potassium carbonate (0.094 g) were added at room temperature. The reaction mixture was refluxed for 8 hours. The reaction mixture was allowed to cool to room temperature, and water and DCM were added. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=90 / 10 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.068 g).

[0197] Reference Example F-6: Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((2-hydroxyethyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. A mixture of Reference Example E-1 (0.15 g), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.16 g), NaBH(OAc)3 (0.15 g), and THF (1.5 mL) was stirred at room temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 20 / 80) to give benzyl 4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (Reference Example F-6P). To a mixture of the obtained compound and THF (1.5 mL) was added TBAF (0.20 mL) at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure to give the title compound (0.091 g).

[0198] Reference Example F-7 Benzyl 7-bromo-6-fluoro-4-((3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example E-4 (4.6 g) and MeCN (46 mL), 2-(trifluoromethyl)oxirane (6.9 g) was added at room temperature. The reaction mixture was refluxed for 7 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain the title compound (5.8 g) as a diastereomeric mixture.

[0199] Reference Example F-8: 7-((S)-3,3-Dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-(((S)-3,3,3-trifluoro-2-((2-nitrophenyl)sulfonamido)propyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl carboxylate. To a mixture of Reference Example E-3 (0.41 g) and MeCN (4 mL), Reference Example G-2 (0.21 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 17 hours. To the reaction mixture, Reference Example G-2 (0.38 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (0.45 g).

[0200] Reference Example F-9 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(((S)-3,3,3-trifluoro-2-((2-nitrophenyl)sulfonamido)propyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester. To a mixture of Reference Example E-2 (0.18 g), MeCN (2 mL), and THF (0.5 mL) was added Reference Example G-2 (0.11 g) at room temperature. The reaction mixture was stirred at the same temperature for 13 hours. Methanol (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to give the title compound (0.26 g).

[0201] Reference Example F-10 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(((S)-3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example E-1 (0.43 g), MeCN (4 mL), and (S)-2-(trifluoromethyl)oxirane (0.22 g), lithium perchlorate (0.069 g) was added at room temperature. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (0.50 g).

[0202] Reference Example F-11 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(((S)-3,3,3-trifluoro-2-hydroxypropyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example E-2 (2.6 g), MeCN (20 mL), and (S)-2-(trifluoromethyl)oxirane (1.6 g), lithium perchlorate (0.42 g) was added at room temperature. The reaction mixture was stirred at 40°C for 4 hours. To the reaction mixture at the same temperature, (S)-2-(trifluoromethyl)oxirane (0.44 g) was added. The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (2.9 g). The chemical structure of Reference Example F is shown in the following table.

[0203]

[0204]

[0205] Reference Example G-1 (R)-2-nitro-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide A mixture of sodium bicarbonate (2.4 g) and water (40 mL) was stirred at room temperature for 5 minutes. To the reaction mixture was added (R)-3-amino-1,1,1-trifluoropropan-2-ol (3.7 g) and THF (40 mL) at 0°C. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a mixture of 2-nitrobenzenesulfonyl chloride (6.7 g) and DCM (40 mL) dropwise at 0°C. The reaction mixture was stirred at room temperature for 20 hours. 5 mol / L aqueous sodium hydroxide solution (10 mL) and DCM were added to the reaction mixture, and the aqueous layer was separated. 2 mol / L hydrochloric acid (50 mL) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (7.3 g).

[0206] Reference Example G-2 (S)-1-((2-nitrophenyl)sulfonyl)-2-(trifluoromethyl)aziridine To a mixture of Reference Example G-1 (6.4 g), pyridine (4.1 mL), and DCM (25 mL), trifluoromethanesulfonic anhydride (7.2 g) was added dropwise at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with 1 mol / L hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. MTBE (45 mL) was added to the residue, and the mixture was stirred at 60°C for 3 minutes. The mixture was allowed to cool to room temperature, and n-heptane (45 mL) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was stirred at 0°C for 10 minutes. The precipitate was collected by filtration and dried. To a mixture of the obtained solid and MeCN (24 mL) was added cesium carbonate (6.1 g) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (4.6 g). The chemical structure of Reference Example G is shown in the following table.

[0207]

[0208] Example H-1 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl Example H-2 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl Reference Example F-1 (0.20 g), 2 mol / L aqueous sodium hydroxide solution (1.3 mL) and DCM (2 mL) were added at room temperature to a mixture, 2-chloroacetyl chloride (0.15 g). The reaction mixture was stirred at the same temperature for 0.5 hours. Saturated aqueous ammonium chloride and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. To a mixture of the residue, tert-butanol (6 mL), and THF (1 mL) was added potassium tert-butoxide (0.087 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain Example H-1 (0.071 g) which eluted later and Example H-2 (0.080 g) which eluted earlier. Example H-1 and Example H-2 are diastereomers.

[0209] Example H-3 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example F-2 (0.38 g), DCM (5 mL), and 2 mol / L aqueous sodium hydroxide solution (2.5 mL), 2-chloroacetyl chloride (0.29 g) was added under ice cooling. The reaction mixture was stirred at the same temperature for 1 hour. The organic layer was separated and concentrated under reduced pressure. To a mixture of the residue, tert-butanol (7 mL), and THF (3 mL) was added potassium tert-butoxide (0.085 g) at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Potassium tert-butoxide (0.085 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous solution of ammonium chloride, water, and ethyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (0.37 g) as a diastereomeric mixture.

[0210] Example H-4 7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl The title compound was obtained as a diastereomeric mixture in the same manner as in Example H-3, using Reference Example F-3 instead of Reference Example F-2.

[0211] Example H-5 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-4-(2-ethyl-5-oxomorpholino)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester The title compound was obtained as a diastereomeric mixture in the same manner as in Example H-3, using Reference Example F-4 instead of Reference Example F-2.

[0212] Example H-6 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-(methoxymethyl)-5-oxomorpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester The title compound was obtained in the same manner as in Example H-3 using Reference Example F-5 instead of Reference Example F-2.

[0213] Example H-7 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(3-oxomorpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester The title compound was obtained in the same manner as in Example H-3 using Reference Example F-6 instead of Reference Example F-2.

[0214] Example H-8 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-oxopiperidin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of Reference Example D-5 (7.1 g) and methanol (7 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (14 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue (6.9 g). To a mixture of the residue (6.3 g), THF (31.7 mL), and NaBH(OAc) (9.8 g), 3-oxetanone (2.8 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 1 mol / L aqueous sodium hydroxide solution (60 mL), water, and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give (S)-N-(1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-oxospiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Reference Example H-8P1) (5.8 g). To a mixture of Reference Example H-8P1 (0.52 g), 2-MeTHF (1 mL), and (R)-2-methylpropane-2-sulfinamide (0.22 g) was added titanium(IV) ethoxide (1.3 g) at room temperature under an argon atmosphere. The reaction mixture was refluxed for 2 hours. To the reaction mixture, 2-MeTHF (4 mL) and sodium borohydride (0.17 g) were added at 0°C. The reaction mixture was stirred at the same temperature for 66 hours. The reaction mixture was added to a mixture of ethyl acetate and saturated brine at 0°C and stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give N-((2S)-1-((4-(((R)tert-butylsulfinyl)amino)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Reference Example H-8P2) (0.29 g). To a mixture of Reference Example H-8P2 (0.070 g), THF (0.5 mL), and methanol (0.5 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.16 mL) was added. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate at 0°C. The organic layer was separated and concentrated under reduced pressure. A mixture of the residue, DCM (1 mL), 2 mol / L aqueous sodium hydroxide (1.0 mL), and 5-bromopentanoyl chloride (0.21 g) was stirred at room temperature for 0.5 hours. To the reaction mixture was added DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 85 / 15 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give N-((2S)-1-((4-(5-bromopentanamido)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Reference Example H-8P3) (0.070 g). To a mixture of Reference Example H-8P3 (0.035 g), THF (1 mL), and DMF (0.5 mL), sodium hydride (approximately 55% oily) (0.021 g) was added at 0 °C. The reaction mixture was stirred at room temperature for 15 hours. Ethyl acetate, saturated aqueous ammonium chloride solution, water and n-hexane were added to the reaction mixture at 0° C. The organic layer was separated and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=57 / 40 / 3 to 0 / 97 / 3 to 0 / 67 / 33) and then by ODS column chromatography (eluent: water / MeCN=90 / 10 to 10 / 90) to obtain the title compound (0.0051 g).

[0215] Example H-9 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide Reference Example H-8 To a mixture of P2 (0.070 g) and ethyl acetate (1 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.16 mL) was added. The reaction mixture was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 °C. The organic layer was separated and concentrated under reduced pressure. MeCN (1 mL) and Reference Example G-2 (0.046 g) were added to the residue. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(((S)-3,3,3-trifluoro-2-((2-nitrophenyl)sulfonamido)propyl)amino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Reference Example H-9P1) (0.060 g). To a mixture of Reference Example H-9P1 (0.035 g), DCM (0.4 mL), and 2 mol / L aqueous sodium hydroxide solution (0.2 mL) was added 2-chloroacetyl chloride (0.046 g) at room temperature. The reaction mixture was stirred at the same temperature for 62 hours. DCM was added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 50 / 50) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-4-((2-nitrophenyl)sulfonyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Reference Example H-9P2). To the resulting compound were added MeCN (1 mL), TEA (0.082 g), and 4-methoxybenzenethiol (0.11 g). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50 to 47 / 53) and then by ODS column chromatography (eluent: water / MeCN=90 / 10 to 10 / 90) to obtain the title compound (0.0031 g).

[0216] Example H-10 Benzyl 7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example F-8 (1.8 g), DCM (36 mL), and 2 mol / L aqueous sodium hydroxide solution (9.6 mL), 2-chloroacetyl chloride (1.7 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. DCM was added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. To the residue, MeCN (36 mL), TEA (1.2 g), and 4-methoxybenzenethiol (1.6 g) were added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10 to 0 / 100) to obtain the title compound (1.1 g).

[0217] Example H-11 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamide)propanamide)-6-fluoro-4-((2R,6S)-2-methyl-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester Reference Example F-11 (0.15 g) and MeCN (1 mL) were added to a mixture of DIPEA (0.075 g), (S)-2-chloropropanoic acid (0.15 g) and propylphosphonic anhydride (cyclic trimer) (1.7 mol / L in ethyl acetate) (0.17 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at the same temperature for 16 hours. To the reaction mixture was added propylphosphonic anhydride (cyclic trimer) (1.7 mol / L in ethyl acetate) (0.17 mL). The reaction mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added DIPEA (0.075 g) and (S)-2-chloropropanoic acid (0.063 g). The reaction mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added propylphosphonic anhydride (cyclic trimer) (1.7 mol / L in ethyl acetate) (0.17 mL). The reaction mixture was stirred at the same temperature for 16 hours. To the reaction mixture was added ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 79 / 20 / 1 to 0 / 99 / 1 to 0 / 80 / 20) to give benzyl 4-((S)-2-chloro-N-((S)-3,3,3-trifluoro-2-hydroxypropyl)propanamido)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (0.084 g). To a mixture of the resulting compound (0.084 g) and THF (1 mL), sodium hydride (approximately 55% oil) (0.012 g) was added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.075 g).

[0218] Example H-12 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido) propanamide)-6-fluoro-4-((2S,6S)-2-methyl-3-oxo-6-(trifluoromethyl)morpholino) spiro [chroman-2,4'-piperidine] -1'-carboxylic acid benzyl (S)-2-chloropropanoic acid was used instead of (R)-2-chloropropanoic acid, and the title compound was obtained in the same manner as in Example H-11.

[0219] Example H-13 4-((6S)-2-cyclopropyl-3-oxo-6-(trifluoromethyl)morpholino)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester. To a mixture of Reference Example F-11 (0.47 g), TEA (0.094 g), and ethyl acetate (3.3 mL), 2-bromo-2-cyclopropylacetyl chloride (0.16 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, 2-bromo-2-cyclopropylacetyl chloride (0.061 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was filtered. To the filtrate, potassium tert-butoxide (0.11 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Potassium tert-butoxide (0.11 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give the title compound (0.31 g) as a diastereomeric mixture.

[0220] Example H-14 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-(3-oxo-2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of Reference Example D-4Pa (1.5 g) and THF (13 mL) was added LHMDS (1.3 mol / L in THF) (7.7 mL) at -78°C. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a mixture of tetrahydro-4H-pyran-4-one (1.0 g) and THF (2 mL) at the same temperature. The reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was stirred at 0°C for 0.5 hours. To the reaction mixture, saturated aqueous ammonium chloride and DCM were added at 0°C. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain benzyl 7-bromo-6-fluoro-4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate (1.8 g) as a diastereomeric mixture. To a mixture of the obtained compound (1.2 g) and DCM (3 mL), Martin sulfurane (1.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Water and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to give benzyl 7-bromo-6-fluoro-4-(3-oxo-2-(tetrahydro-4H-pyran-4-ylidene)-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate (0.54 g). To a mixture of the resulting compound (0.54 g), methanol (14 mL), and cobalt(II) chloride hexahydrate (0.094 g), NaBH4 (0.064 g) was added at 0 °C. The reaction mixture was stirred at the same temperature for 1 hour. NaBH4 (0.063 g) was added to the reaction mixture at 0 °C.The reaction mixture was stirred at the same temperature for 0.5 hours. NaBH4 (0.065 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours. NaBH4 (0.065 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours. NaBH4 (0.071 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours. NaBH4 (0.050 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain 7-bromo-6-fluoro-4-(3-oxo-2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-benzyl carboxylate (0.40 g) as a diastereomeric mixture. A mixture of the obtained compound (0.40 g), Reference Example B-2 (0.13 g), palladium(II) acetate (0.018 g), XantPhos (0.086 g), potassium carbonate (0.11 g), and THF (10 mL) was stirred under microwave irradiation at 120 °C for 1 hour. The reaction mixture was stirred under microwave irradiation at 120 °C for 0.5 hours. The reaction mixture was stirred under microwave irradiation at 120 °C for 1 hour. The reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give the title compound (0.14 g) as a diastereomeric mixture.

[0221] Example H-15 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-4-((6S)-2-((3,3-difluoroazetidin-1-yl)methyl)-3-oxo-6-(trifluoromethyl)morpholino)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate Using 2,3-dichloropropanoyl chloride instead of 2-bromo-2-cyclopropylacetyl chloride, 4-((6S)-2-(chloromethyl)-3-oxo-6-(trifluoromethyl)morpholino)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-benzyl carboxylate was obtained in the same manner as in Example H-13. To a mixture of the obtained compound (0.080 g), 3,3-difluoroazetidine hydrochloride (0.12 g), and MeCN (0.8 mL) was added sodium iodide (0.014 g) and DBU (0.14 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium bicarbonate, water, and DCM were added. The organic layer was separated and concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give the title compound (0.096 g) as a diastereomeric mixture.

[0222] Example H-16 4-((6S)-2-((3-cyanoazetidin-1-yl)methyl)-3-oxo-6-(trifluoromethyl)morpholino)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamide)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl ester Using azetidine-3-carbonitrile hydrochloride instead of 3,3-difluoroazetidine hydrochloride, the title compound was obtained as a diastereomeric mixture in the same manner as in Example H-15.

[0223] Example H-17 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example F-11 (0.20 g), TEA (0.080 g), and ethyl acetate (1.5 mL), 2-chloro-3-methoxypropanoyl chloride (0.062 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was filtered and washed with ethyl acetate (0.5 mL). Potassium tert-butoxide (0.045 g) was added to the filtrate at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to give the title compound (0.18 g) as a diastereomeric mixture.

[0224] Example H-18 7- ((S)-3,3-dicyclopropyl-2- (1-methyl-1H-pyrazole-5-carboxamido) propanamide) -6-fluoro-4- (2- (oxetan-3-yl) -3-oxo-6- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidine] -1'-carboxylic acid benzyl tetrahydro-4H-pyran-4-one was used in place of 3-oxetanone, and the title compound was obtained as a diastereomeric mixture in the same manner as in Example H-14.

[0225] Example H-19 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example F-10 (0.20 g), TEA (0.079 g), and ethyl acetate (1.5 mL), 2-chloro-3-methoxypropanoyl chloride (0.061 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Potassium tert-butoxide (0.044 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was filtered and washed with ethyl acetate. Potassium tert-butoxide (0.058 g) was added to the filtrate at 50°C. The reaction mixture was stirred at 50°C for 1 hour. After cooling to room temperature, the reaction mixture was added to saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 0 / 100) to give the title compound (0.21 g) as a diastereomeric mixture.

[0226] Example H-20 Benzyl 7-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate To a mixture of Reference Example E-4 (3.7 g) and MeCN (5 mL) was added a mixture of Reference Example G-2 (2.0 g) and MeCN (7 mL) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. To the reaction mixture was added a mixture of Reference Example G-2 (0.62 g) and MeCN (5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give benzyl 7-bromo-6-fluoro-4-(((S)-3,3,3-trifluoro-2-((2-nitrophenyl)sulfonamido)propyl)amino)spiro[chroman-2,4'-piperidine]-1'-carboxylate (6.1 g). To a mixture of the obtained compound (2.1 g), ethyl acetate (15 mL), and TEA (0.86 g), 2-chloroacetyl chloride (0.80 g) was added at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered. To a mixture of the filtrate and TEA (0.86 g), 4-methoxybenzenethiol (1.2 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give benzyl 7-bromo-6-fluoro-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (1.0 g). To a mixture of the resulting compound (0.15 g) and THF (1.5 mL), 4-formyltetrahydropyran (0.14 g) and NaBH(OAc) (0.27 g) were added. The reaction mixture was stirred at the same temperature for 3 hours.To the reaction mixture, saturated aqueous sodium bicarbonate and DCM were added. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give benzyl 7-bromo-6-fluoro-4-((S)-2-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (0.16 g). A mixture of the obtained compound (0.16 g), Reference Example B-1 (0.066 g), palladium(II) acetate (0.010 g), XantPhos (0.052 g), potassium carbonate (0.063 g), and THF (3.0 mL) was stirred at 120 °C for 1 hour under microwave irradiation. Water and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to give the title compound (0.14 g). The chemical structure of Reference Example H is shown in the following table.

[0227] The chemical structure of Example H is shown in the table below.

[0228]

[0229]

[0230]

[0231]

[0232]

[0233] Example I-1 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide A mixture of Example H-1 (0.070 g), 10% Pd / C (0.030 g), and ethanol (0.5 mL) was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.12 g), and THF (1 mL), NaBH(OAc) (0.18 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0 to 0 / 100 / 0 to 0 / 90 / 10) and then by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 20 / 80) to obtain the title compound (0.026 g).

[0234] Example I-2 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide A mixture of Example H-2 (0.080 g), 20% Pd(OH)2 / C (0.030 g), and ethanol (0.5 mL) was stirred under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.14 g), and THF (1 mL), NaBH(OAc)3 (0.21 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate / methanol = 75 / 20 / 5 to 0 / 95 / 5) and then by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 20 / 80) to obtain the title compound (0.032 g).

[0235] Example I-3 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-4 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example H-3 (0.37 To a mixture of 10% Pd / C (0.22 g) and methanol (5.2 mL) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a residue (0.31 g). To a mixture of the residue (0.080 g), THF (1.2 mL), and NaBH(OAc)3 (0.10 g), 3-oxetanone (0.043 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. Ethyl acetate, water, and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 80 / 20) to obtain N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide as a single diastereomer, each of which differs in stereochemistry at the carbon atom to which the trifluoromethyl group is attached. The later-eluted diastereomer was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain Example I-3 (0.013 g).The diastereomer eluted first was purified by ODS column chromatography (elution solvent: water / MeCN=90 / 10 to 10 / 90) to obtain Example I-4 (0.014 g).

[0236] Example I-5 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(2-methoxyacetyl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide Example H-4 (0.020 g), 20% Pd(OH)2 / C (0.010 g), and ethanol (0.5 mL) were stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.016 g), and THF (0.5 mL) was added 2-methoxyacetyl chloride (0.014 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(2-methoxyacetyl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide as a single diastereomer. The obtained compound was purified by ODS column chromatography (eluent: water / MeCN=70 / 30 to 20 / 80) and then by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=90 / 10 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.0024 g).

[0237] Example I-6 N-((2S)-1,1-dicyclopropyl-3-((4-(2-ethyl-5-oxomorpholino)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide A mixture of Example H-5 (0.017 g), 20% Pd(OH)2 / C (0.010 g) and ethanol (0.5 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was stirred under a hydrogen atmosphere at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature and then filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.032 g), and THF (1 mL) was added NaBH(OAc)3 (0.047 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain N- ((2S) -1,1-dicyclopropyl-3- ((4- (2-ethyl-5-oxomorpholino) -6-fluoro-1 '- (oxetan-3-yl) spiro [chroman-2,4'-piperidine] -7-yl) amino) -3-oxopropan-2-yl) -1-ethyl-1H-pyrazole-5-carboxamide as a single diastereomer. The obtained compound was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 20 / 80) to obtain the title compound (0.0075 g).

[0238] Example I-7 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-2-(methoxymethyl)-5-oxomorpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Using Example H-6 instead of Example H-5, the title compound was obtained in the same manner as in Example I-6.

[0239] Example I-8 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(3-oxomorpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide The title compound was obtained in the same manner as in Example I-6 using Example H-7 instead of Example H-5.

[0240] Example I-9 tert-Butyl ((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)carbamate A mixture of Example J-1 (2.5 g), 10% Pd / C (0.13 g), and ethanol (5 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, THF (5 mL), and 3-oxetanone (2.3 g), NaBH(OAc)3 (3.4 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 77 / 20 / 3 to 0 / 97 / 3) to give the title compound (1.4 g).

[0241] Example I-10 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide Using Example J-2 instead of Example H-1, the title compound was obtained in the same manner as in Example I-1.

[0242] Example I-11 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-methyl-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of Example H-10 (0.070 g) and methanol (1 mL), 10% Pd / C (0.041 g) was added at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a residue (0.053 g). To a mixture of the residue (0.025 g), THF (0.5 mL), and NaBH(OAc)3 (0.064 g), formalin (37%) (0.056 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hours. Water, saturated aqueous sodium bicarbonate solution, and ethyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to obtain the title compound (0.010 g).

[0243] Example I-12 N-((2S)-1-((1'-Benzoyl-6-fluoro-4-((S)-4-methyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of Example K-2 (0.045 g) and methanol (1 mL), 10% Pd / C (0.052 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture was added 10% Pd / C (0.021 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a residue (0.030 g). To a mixture of the residue (0.013 g), DCM (0.4 mL), and DIPEA (0.0076 g), benzoyl chloride (0.0041 g) was added at 0° C. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2) and then by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.0032 g).

[0244] Example I-13 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-4-methyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-1'-picolinoylspiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide The title compound was obtained in the same manner as in Example I-12, using picolinoyl chloride hydrochloride instead of benzoyl chloride.

[0245] Example I-14 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-4-isopropyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of Example H-10 (0.078 g), acetone (0.040 g), and methanol (1 mL), decaborane (0.024 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. Amino silica gel (1 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and methanol (2 mL), 10% Pd / C (0.093 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 60 hours. To the reaction mixture, 10% Pd / C (0.021 g) was added at room temperature under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a residue (0.060 g). To a mixture of the residue (0.020 g), THF (0.7 mL), and NaBH(OAc)3 (0.024 g), 3-oxetanone (0.010 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. Ethyl acetate, water, and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0 to 0 / 100 / 0 to 0 / 70 / 30) and then by ODS column chromatography (eluent: water / MeCN=90 / 10 to 10 / 90) to obtain the title compound (0.0071 g).

[0246] Example I-15 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-4-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Reference Example F-9 (0.26 g) was added with DCM (1.5 mL), 2 mol / L aqueous sodium hydroxide solution (1.4 mL) and 2-chloroacetyl chloride (0.16 g) at room temperature. The reaction mixture was stirred under water cooling for 1 hour. To the reaction mixture, THF (1.5 mL), 2 mol / L aqueous sodium hydroxide solution (1.5 mL), and 2-chloroacetyl chloride (0.18 g) were added at the same temperature. The reaction mixture was stirred at the same temperature for 2 hours. DCM was added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. To the residue, MeCN (2 mL), TEA (0.17 g), and 4-methoxybenzenethiol (0.24 g) were added under ice-cooling. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (Example I-15P1) (0.19 g). To a mixture of Example I-15P1 (0.089 g), tetrahydro-4H-pyran-4-one (0.056 g), and methanol (1 mL), decaborane (0.027 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Tetrahydro-4H-pyran-4-one (0.056 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Amino silica gel (1 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to give benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-4-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate. To a mixture of the resulting compound and methanol (1 mL), 10% Pd / C (0.040 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. To the reaction mixture was added 10% Pd / C (0.080 g) at room temperature under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 10 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, THF (1 mL), and NaBH(OAc)3 (0.040 g) was added 3-oxetanone (0.050 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.015 g).

[0247] Example I-16 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((2R,6S)-2-methyl-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of Example H-11 (0.075 g), methanol (1 mL), and acetic acid (0.011 g), 10% Pd / C (0.0075 g) was added at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added 3-oxetanone (0.077 g) and NaBH(OAc)3 (0.038 g) at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 20 / 80) to obtain the title compound (0.026 g).

[0248] Example I-17 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((2S,6S)-2-methyl-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Using Example H-12 instead of Example H-11, the title compound was obtained in the same manner as in Example I-16.

[0249] Example I-18 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-15 To a mixture of P1 (0.050 g) and THF (1.5 mL), 4-formyltetrahydropyran (0.072 g) and NaBH(OAc) (0.13 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (0.056 g). To a mixture of the resulting compound (0.056 g), acetic acid (0.011 g), isopropanol (0.5 mL), and THF (0.5 mL) was added 20% Pd(OH)2 / C (0.022 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 55 °C for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL), 3-oxetanone (0.013 g) and NaBH(OAc)3 (0.037 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture, 3-oxetanone (0.013 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Isopropyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 36.8-56.8% 0.2% NH3 in MeCN / 0.2% NH 3 in H2O) to give the title compound (0.009 g).

[0250] Example I-19 N-((2S)-1,1-dicyclopropyl-3-((4-((S)-4-(cyclopropylmethyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-6-fluoro-1 '-(oxetan-3-yl)spiro [chroman-2,4'-piperidine] -7-yl) amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Using 1-(formyl)cyclopropane instead of 4-formyltetrahydropyran, the title compound was obtained in the same manner as in Example I-18.

[0251] Example I-20 N-((2S)-1,1-dicyclopropyl-3-((4-((6S)-2-cyclopropyl-3-oxo-6-(trifluoromethyl)morpholino)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-21 N-((2S)-1,1-dicyclopropyl-3-((4-((6S)-2-cyclopropyl-3-oxo-6-(trifluoromethyl)morpholino)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example H-13 (0.30 g), acetic acid (0.043 g), and isopropanol (2 mL) were added with 20% Pd(OH)2 / C (0.060 g) at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 1 hour. The reaction mixture was allowed to cool to room temperature, and 20% Pd(OH)2 / C (0.060 g) was added. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. TEA (0.036 g) was added to the filtrate, which was then concentrated under reduced pressure to give a residue (0.27 g). To a mixture of the residue (0.20 g), 3-oxetanone (0.027 g), and THF (1 mL) was added NaBH(OAc)3 (0.083 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 95 / 5) followed by chiral preparative column chromatography (Method C) to give Example I-20 (0.051 g) which eluted first and Example I-21 (0.020 g) which eluted second. Example I-20 and Example I-21 are diastereomers.

[0252] Example I-22 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(3-oxo-2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-23 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(3-oxo-2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example H-14 (0.14 g), acetic acid (0.010 g), isopropanol (2 mL), and THF (2 mL) were added with 20% Pd(OH)2 / C (0.072 g) at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (2 mL) were added 3-oxetanone (0.24 g) and NaBH(OAc)3 (0.12 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water, saturated aqueous ammonium chloride, and isopropyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: DCM / methanol = 100 / 0 to 95 / 5) and then chiral preparative column chromatography (Method C) to obtain Example I-22 (0.011 g) which eluted later and Example I-23 (0.0035 g) which eluted earlier. Example I-22 and Example I-23 are diastereomers.

[0253] Example I-24 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-4-pivaloyl-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-15 Pivaloyl chloride (1.93 g) was added to a mixture of P1 (0.055 g), TEA (0.021 g), and ethyl acetate (0.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to give benzyl 7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-4-((S)-2-oxo-4-pivaloyl-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (0.027 g). To a mixture of the resulting compound (0.027 g), acetic acid (0.0037 g), and isopropanol (0.5 mL) was added 20% Pd(OH)2 / C (0.0054 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 50 °C for 50 minutes. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.022 g), and THF (1 mL) was added NaBH(OAc)3 (0.099 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 20 / 80) to obtain the title compound (0.016 g).

[0254] Example I-25 N-((2S)-1,1-dicyclopropyl-3-((4-((6S)-2-((3,3-difluoroazetidin-1-yl)methyl)-3-oxo-6-(trifluoromethyl)morpholino)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of Example H-15 (0.096 g), acetic acid (0.013 g), and isopropanol (0.5 mL), 20% Pd(OH)2 / C (0.019 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 50°C for 6 hours. The reaction mixture was stirred at room temperature for 15 hours. To the reaction mixture was added 20% Pd(OH)2 / C (0.019 g) at room temperature under an argon atmosphere. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.077 g), and THF (0.9 mL) was added NaBH(OAc)3 (0.25 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride, water, and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 20 / 80) to obtain the title compound (0.020 g).

[0255] Example I-26 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(2-hydroxypropan-2-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-27 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(2-hydroxypropan-2-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of Example I-3 (0.10 g) and THF (1 mL) was added LHMDS (1.0 mol / L in toluene) (0.43 mL) at -78°C. The reaction mixture was stirred at the same temperature for 10 minutes. Acetone (0.025 g) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 10 minutes. A saturated aqueous ammonium chloride solution and DCM were added to the reaction mixture at -78°C. The organic layer was separated and concentrated under reduced pressure to give a residue (0.11 g). The residue (0.037 g) was purified by ODS column chromatography (eluent: 37.8-57.8% 0.2% NH in MeCN / 0.2% NH 3 in H2O) to give Example I-26 (0.0030 g) which eluted first and Example I-27 (0.0095 g) which eluted later. Example I-26 and Example I-27 are diastereomers.

[0256] Example I-28 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(2-methoxypropan-2-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-29 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(2-methoxypropan-2-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of Example I-3 (0.25 g) and THF (5 mL) was added LHMDS (1.0 mol / L in THF) (2.8 mL) at -78°C. The reaction mixture was stirred at the same temperature for 20 minutes. Acetone (0.16 g) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous ammonium chloride solution and DCM were added to the reaction mixture at -78°C. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / DCM = 100 / 0 to 0 / 100) to obtain a diastereomeric mixture (0.27 g) of Examples I-26 and I-27. To a mixture of the obtained compound (0.040 g) and THF (2 mL), iodomethane (0.23 g) and sodium hydride (approximately 55% oily) (0.027 g) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. DCM and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 43.9-63.9% 0.2% NH3 in MeCN / 0.2% NH 3 in H2O) to give Example I-28 (0.00076 g) which eluted first and Example I-29 (0.0049 g) which eluted later. Example I-28 and Example I-29 are diastereomers.

[0257] Example I-30 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-4-(oxetan-3-ylmethyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Using oxetane-3-carbaldehyde instead of 4-formyltetrahydropyran, the title compound was obtained in the same manner as in Example I-18.

[0258] Example I-31 N-((2S)-1-((4-((6S)-2-((3-cyanoazetidin-1-yl)methyl)-3-oxo-6-(trifluoromethyl)morpholino)-6-fluoro-1 '-(oxetan-3-yl)spiro [chroman-2,4'-piperidine] -7-yl) amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Using Example H-16 instead of Example H-15, the title compound was obtained in the same manner as in Example I-25.

[0259] Example I-32 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-33 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide To a mixture of Example I-3 (0.26 g) and THF (5 mL) was added LHMDS (1.0 mol / L in THF) (2.9 mL) at -78°C. The reaction mixture was stirred at the same temperature for 10 minutes. Tetrahydro-4H-pyran-4-one (0.29 g) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture, saturated aqueous ammonium chloride and DCM were added at -78 °C. The organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / DCM = 100 / 0 to 0 / 100) to obtain a mixture of Examples I-32 and I-33 (0.30 g). The mixture (0.050 g) was purified by ODS column chromatography (elution solvent: 33.7-53.7% 0.2% NH3 in MeCN / 0.2% NH3 in H2O) to obtain Example I-32 (0.0023 g), which eluted first, and Example I-33 (0.018 g), which eluted later. Example I-32 and Example I-33 are diastereomers.

[0260] Example I-34 N-((2S)-1,1-dicyclopropyl-3-((4-((S)-4-((1-cyclopropylpiperidin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-15 To a mixture of P1 (0.11 g) and THF (1 mL), 1-(tert-butoxycarbonyl)-4-formylpiperidine (0.12 g) and NaBH(OAc) (0.085 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 5 hours. A saturated aqueous ammonium chloride solution, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give benzyl 4-((S)-4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (0.13 g). To a mixture of the resulting compound (0.13 g) and THF (2.0 mL) was added hydrogen chloride (4 mol / L in 1,4-dioxane) (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 49.1-69.1% 0.2%NH3 in MeCN / 0.2%NH 3 The resulting mixture was purified by HCl (HCl, ... To the reaction mixture, (1-ethoxycyclopropoxy)trimethylsilane (0.034 g), acetic acid (0.012 g), and sodium cyanoborohydride (0.018 g) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. To the reaction mixture, (1-ethoxycyclopropoxy)trimethylsilane (0.067 g), acetic acid (0.021 g), and sodium cyanoborohydride (0.020 g) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and DCM and 1 mol / L aqueous sodium hydroxide solution were added. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 84 / 14 / 2 to 0 / 98 / 2) to give benzyl 4-((S)-4-((1-cyclopropylpiperidin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-7-((S)-3,3-dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate (0.012 g). To a mixture of the resulting compound (0.012 g), acetic acid (0.0021 g), and THF (1.0 mL) was added 20% Pd(OH)2 / C (0.0062 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 50 °C for 2 hours. To the reaction mixture were added 20% Pd(OH)2 / C (0.0079 g), acetic acid (0.0021 g), and THF (0.5 mL) at room temperature.The reaction mixture was stirred under a hydrogen atmosphere at 50°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and TEA (0.0057 g) was added. The reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1.0 mL) was added 3-oxetanone (0.025 g) and NaBH(OAc)3 (0.014 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride, water, and isopropyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 20 / 80) to obtain the title compound (0.0012 g).

[0261] Example I-35 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-36 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example H-17 (0.18 g), acetic acid (0.025 g), and THF (2.0 mL) were added with 20% Pd(OH)2 / C (0.036 g) at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 1 hour. The reaction mixture was allowed to cool to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.15 g), and THF (1.6 mL) was added NaBH(OAc)3 (0.67 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 35.8-55.8% 0.2% NH3 in MeCN / 0.2% NH 3 in HO) to give a diastereomeric mixture of Examples I-35 and I-36 (0.044 g). The resulting mixture was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 85 / 15, column: CHIRALPAK_IB-N5 (DAICEL)) to give Example I-35 (0.0041 g) which eluted later and Example I-36 (0.029 g) which eluted earlier. Example I-35 and Example I-36 are diastereomers.

[0262] Example I-37 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-(oxetan-3-yl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-38 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-(oxetan-3-yl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example H-18 (0.072 g), acetic acid (0.015 g), isopropanol (1 mL), and THF (0.2 mL) were added with 20% Pd(OH)2 / C (0.022 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 55°C for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(oxetan-3-yl)-3-oxo-6-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.066 g). To a mixture of the obtained compound (0.096 g) and THF (1.0 mL) was added 3-oxetanone (0.071 g) and NaBH(OAc) (0.10 g) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate and isopropyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: 35.8-55.8% 0.2%NH in MeCN / 0.2%NH 3 in HO) to give a diastereomeric mixture of Examples I-37 and I-38 (0.052 g). The resulting mixture was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 80 / 20, column: CHIRALPAK_IB-N5 (DAICEL)) to give Example I-37 (0.0097 g) which eluted first and Example I-38 (0.027 g) which eluted later. Example I-37 and Example I-38 are diastereomers.

[0263] Example I-39 N-((2S)-1,1-dicyclopropyl-3-((4-((S)-4-cyclopropyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-15 To a mixture of P1 (0.51 g), acetic acid (0.19 g), isopropanol (1.2 mL), and THF (0.3 mL), 20% Pd(OH)2 / C (0.15 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 55°C for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added 3-oxetanone (0.18 g) and NaBH(OAc)3 (0.54 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate and isopropyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / methanol = 100 / 0 to 80 / 20) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.27 g). A mixture of the obtained compound (0.12 g), bromocyclopropane (0.097 g), palladium(II) acetate (0.0072 g), XantPhos (0.037 g), potassium carbonate (0.044 g), and THF (1.5 mL) was stirred under microwave irradiation at 120° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography (eluent: DCM / methanol = 100 / 0 to 80 / 20) and then by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 20 / 80) to give the title compound (0.012 g).

[0264] Example I-40 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Example I-41 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((6S)-2-(methoxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Example H-19 (0.21 g), acetic acid (0.029 g), and isopropanol (2.0 mL) were added with 20% Pd(OH)2 / C (0.021 g) at room temperature. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 1 hour. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue, 3-oxetanone (0.17 g), and THF (1.9 mL) was added NaBH(OAc)3 (0.77 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride, water, and DCM were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 20 / 80) to obtain a diastereomeric mixture of Examples I-40 and I-41 (0.090 g). The mixture (0.048 g) was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 80 / 20, column: CHIRALPAK_IB-N5 (DAICEL)) to obtain Example I-40 (0.018 g) which eluted first and Example I-41 (0.018 g) which eluted second. Example I-40 and Example I-41 are diastereomers.

[0265] Example I-42 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-43 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide. A mixture of Reference Example C-2 (2.5 g), 1,4-dioxane (2 mL), and hydrogen chloride (4 mol / L in 1,4-dioxane) (27 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue and THF (3 mL), 3-oxetanone (1.2 g) and NaBH(OAc)3 (2.3 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and ethyl acetate was added. The precipitate was collected by filtration, and the resulting solid was dried to give 7-bromo-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-4-one (0.99 g). The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 98 / 2 / 0 to 0 / 100 / 0 to 0 / 50 / 50) and combined with the solid collected by filtration to give 7-bromo-6-fluoro-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-4-one (1.7 g). A mixture of the obtained compound (0.92 g), Reference Example B-2 (0.76 g), potassium carbonate (0.69 g), XantPhos (0.29 g), palladium(II) acetate (0.095 g), and 2-MeTHF (30 mL) was stirred at 75°C for 3 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 93 / 7) to give (S)-N-(1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-oxospiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.64 g). To a mixture of the obtained compound (0.40 g) and methanol (8 mL), NaBH4 (0.060 g) was added at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 98 / 2 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-hydroxy-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.39 g) as a diastereomeric mixture. To a mixture of the obtained compound (0.050 g), 5-(trifluoromethyl)pyridin-2(1H)-one (0.017 g), and toluene (1.2 mL) was added TMAD (0.077 g) and tributylphosphine (0.090 g) at 100 °C. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was allowed to cool to room temperature and purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain a mixture of Example I-42 and Example I-43. The resulting mixture was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 20 / 80) to obtain Example I-42 (0.0076 g) which eluted later and Example I-43 (0.010 g) which eluted earlier. Example I-42 and Example I-43 are diastereomers.

[0266] Example I-44 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(2-oxo-5-(trifluoromethyl)piperidin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-43 (0.0071 g) and methanol (0.5 mL) were mixed at room temperature, and 83% platinum(IV) oxide (0.011 g) was added. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 33.7-53.7% 0.2% NH in MeCN / 0.2% NH 3 in H2O) to give the title compound (0.0040 g) as a single diastereomer.

[0267] Example I-45 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide To a mixture of Example H-20 (0.14 g), acetic acid (0.028 g), isopropanol (1.0 mL), and THF (0.5 mL), 20% Pd(OH)2 / C (0.056 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 55°C for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue (0.13 g). To a mixture of the residue (0.069 g) and THF (2.0 mL) were added 3-oxetanone (0.024 g) and NaBH(OAc)3 (0.070 g) at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate and isopropyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 38.8-58.8% 0.2% NH3 in MeCN / 0.2% NH 3 in H2O) to give the title compound (0.015 g).

[0268] Example I-46 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-4-(4-methoxycyclohexyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-47 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-((S)-4-(4-methoxycyclohexyl)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-15 To a mixture of P1 (0.61 g), acetic acid (0.23 g), isopropanol (4.0 mL), and THF (2.0 mL), 20% Pd(OH)2 / C (0.31 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 55°C for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1.0 mL) were added 3-oxetanone (0.22 g) and NaBH(OAc) (0.32 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and isopropyl acetate were added to the reaction mixture. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to give N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-((S)-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.32 g). To a mixture of the resulting compound (0.10 g) and methanol (1.0 mL), 4-methoxycyclohexanone (0.089 g) and decaborane (0.085 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour.4-Methoxycyclohexanone (0.089 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. 4-Methoxycyclohexanone (0.089 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Amino silica gel (0.1 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 37.8-57.8% 0.2% NH3 in MeCN / 0.2% NH). 3 in H2O) to give Example I-46 (0.023 g) which eluted first and Example I-47 (0.031 g) which eluted later. Example I-46 and Example I-47 are diastereomers.

[0269] Example I-48 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(hydroxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Example I-49 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(hydroxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide A mixture of paraformaldehyde (0.10 g) and THF (2.0 mL) was stirred at 50°C for 10 minutes. The mixture was allowed to stand at room temperature for 3 minutes. The precipitated solid was removed to obtain mixture A. To a mixture of Example I-3 (0.15 g) and THF (3.0 mL) was added LHMDS (1.0 mol / L in THF) (1.0 mL) at -78°C. The reaction mixture was stirred at the same temperature for 20 minutes. Mixture A was added to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Saturated aqueous ammonium chloride and DCM were added to the reaction mixture at -78°C. The mixture was stirred at room temperature for 10 minutes. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: 10 mM aqueous ammonium acetate / MeCN = 90 / 10 to 20 / 80) to give a mixture of Examples I-48 and I-49. The resulting mixture was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 60 / 40, column: CHIRALPAK_IC (DAICEL)) to give Example I-48 (0.0074 g) which eluted first and Example I-49 (0.010 g) which eluted second. Example I-48 and Example I-49 are diastereomers.

[0270] Example I-50 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(hydroxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Example I-51 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-4-(2-(hydroxymethyl)-3-oxo-6-(trifluoromethyl)morpholino)-1'-(oxetan-3-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide A mixture of paraformaldehyde (0.13 g) and THF (3.0 mL) was stirred at 50°C for 10 minutes. The mixture was allowed to stand at room temperature for 3 minutes. The precipitated solid was removed to obtain mixture B. To a mixture of Example I-1 (0.17 g) and THF (5.0 mL) was added LHMDS (1.0 mol / L in THF) (1.1 mL) at -78°C. The reaction mixture was stirred at the same temperature for 20 minutes. Mixture B was added to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. Saturated aqueous ammonium chloride and DCM were added to the reaction mixture at -78°C. The mixture was stirred at room temperature for 10 minutes. The organic layer was separated and concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: 10 mM aqueous ammonium acetate / MeCN = 90 / 10 to 20 / 80) to give a mixture of Examples I-50 and I-51. The resulting mixture was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 50 / 50, column: CHIRALPAK_IC (DAICEL)) to give Example I-50 (0.020 g) which eluted first and Example I-51 (0.015 g) which eluted later. Example I-50 and Example I-51 are diastereomers. The chemical structure of Example I is shown in the table below.

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Example J-1 Benzyl 7-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanamido)-6-fluoro-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-1'-carboxylate A mixture of Reference Example A-2 (0.020 g), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (0.014 g), WSC (0.033 g), and pyridine (0.5 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (0.020 g).

[0282] Example J-2 7- ((S)-3,3-dicyclopropyl-2- (4-methyl-1,2,5-oxadiazole-3-carboxamido) propanamido) -6-fluoro-4- (5-oxo-2- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidine] -1'-carboxylic acid benzyl Using Example J-1 instead of Reference Example D-4, 7- ((S)-2-amino-3,3-dicyclopropylpropanamido) -6-fluoro-4- (5-oxo-2- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidine] -1'-carboxylic acid benzyl hydrochloride (Reference Example J-2P) was obtained in the same manner as in Reference Example A-2. The title compound was obtained in the same manner as in Example J-1, except that Reference Example J-2P and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid were used instead of Reference Example A-2 and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid.

[0283] Reference Example J-3P (2S)-2-amino-3,3-dicyclopropyl-N-(6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)propanamide A mixture of Example I-9 (1.3 g), TFA (5.9 g), and DCM (20 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (10.6 mL), water, and DCM at 0°C. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.1 g).

[0284] Example J-3 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxamide A mixture of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid (0.0093 g), Reference Example J-3P (0.015 g), WSC (0.0094 g), 1-hydroxybenzotriazole monohydrate (0.0075 g), TEA (0.0099 g) and DMF (0.5 mL) was stirred at room temperature for 3 hours. The reaction mixture was purified by ODS column chromatography (eluent: water / MeCN=90 / 10 to 20 / 80) to obtain the title compound (0.014 g).

[0285] Example J-4 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide The title compound was obtained in the same manner as in Example J-3, except that 1-isopropyl-1H-pyrazole-5-carboxylic acid was used instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0286] Example J-5 1-cyclopropyl-N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1H-pyrazole-5-carboxamide The title compound was obtained in the same manner as in Example J-3 using 1-cyclopropyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0287] Example J-6 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1H-pyrazole-5-carboxamide The title compound was obtained in the same manner as in Example J-3, using 1H-pyrazole-5-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0288] Example J-7 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide The title compound was obtained in the same manner as in Example J-3 using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0289] Example J-8 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)pyridazine-4-carboxamide The title compound was obtained in the same manner as in Example J-3, except that pyridazine-4-carboxylic acid was used instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0290] Example J-9 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-3-fluoroisonicotinamide Using 3-fluoroisonicotinic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0291] Example J-10 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-5-(trifluoromethyl)nicotinamide The title compound was obtained in the same manner as in Example J-3 using 5-(trifluoromethyl)nicotinic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0292] Example J-11 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)tetrahydro-2H-pyran-4-carboxamide The title compound was obtained in the same manner as in Example J-3 using tetrahydro-2H-pyran-4-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0293] Example J-12 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-(2-methoxyethyl)-1H-pyrazole-5-carboxamide 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, and the title compound was obtained in the same manner as in Example J-3.

[0294] Example J-13 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxamide 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid was used instead of 1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylic acid, and the title compound was obtained in the same manner as in Example J-3.

[0295] Example J-14 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1 '- (oxetan-3-yl) -4- (5-oxo-2- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidine] -7-yl) amino) -3-oxopropan-2-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-5-carboxamide 1- (3,3-difluoropropyl) -1H-pyrazole-5-carboxylic acid was used instead of 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-5-carboxylic acid, and the title compound was obtained in the same manner as in Example J-3.

[0296] Example J-15 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)cyclopropanecarboxamide The title compound was obtained in the same manner as in Example J-3 using cyclopropanecarboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0297] Example J-16 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide Using 1-(trifluoromethyl)cyclopropane-1-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0298] Example J-17 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-1-fluorocyclopropane-1-carboxamide The title compound was obtained in the same manner as in Example J-3 using 1-fluorocyclopropane-1-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0299] Example J-18 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-3-methylisoxazole-4-carboxamide The title compound was obtained in the same manner as in Example J-3 using 3-methylisoxazole-4-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0300] Example J-19 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4,5-dimethylisoxazole-3-carboxamide The title compound was obtained in the same manner as in Example J-3 using 4,5-dimethylisoxazole-3-carboxylic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid.

[0301] Example J-20 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)isonicotinamide Using isonicotinic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0302] Example J-21 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-2-methylisonicotinamide Using 2-methylisonicotinic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0303] Example J-22 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-2-methoxyisonicotinamide Using 2-methoxyisonicotinic acid instead of 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0304] Example J-23 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-1-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide 1-(3,3-difluoropropyl)-1H-pyrazole-5-carboxylic acid was used instead of 1-(2-hydroxyethyl)-1H-pyrazole-5-carboxylic acid, and the title compound was obtained in the same manner as in Example J-3.

[0305] Example J-24 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)piperidine-1-carboxamide. To a mixture of Reference Example J-3P (0.015 g), THF (0.5 mL), DMF (0.5 mL) and TEA (0.025 g), piperidine-1-carbonyl chloride (0.036 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was purified by ODS column chromatography (elution solvent: water / MeCN=90 / 10-20 / 80) to obtain the title compound (0.0048 g).

[0306] Example J-25 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)-4-methylpiperazine-1-carboxamide Using 4-methylpiperazine-1-carbonyl chloride instead of piperidine-1-carbonyl chloride, the title compound was obtained in the same manner as in Example J-24.

[0307] Example J-26 (2S)-3,3-dicyclopropyl-2- (2-cyclopropylacetamido) -N- (6-fluoro-1 '- (oxetan-3-yl) -4- (5-oxo-2- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidin] -7-yl) propanamide Using 2-cyclopropylacetic acid instead of 1- (3,3-difluoropropyl) -1H-pyrazole-5-carboxylic acid, the title compound was obtained in the same manner as in Example J-3.

[0308] Example J-27 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]-7-yl)amino)-3-oxopropan-2-yl)benzamide Using benzoyl chloride instead of piperidine-1-carbonyl chloride, the title compound was obtained in the same manner as in Example J-24.

[0309] Example J-28 (2S)-3,3-dicyclopropyl-2- (2,2-difluoro-2-phenylacetamido) -N- (6-fluoro-1 '- (oxetan-3-yl) -4- (5-oxo-2- (trifluoromethyl) morpholino) spiro [chroman-2,4'-piperidin] -7-yl) propanamide Using 2,2-difluoro-2-phenylacetic acid instead of 1- (3,3-difluoropropyl) -1H-pyrazole-5-carboxylic acid, the title compound was obtained by the same method as in Example J-3. The chemical structure of Reference Example J is shown in the following table.

[0310] The chemical structure of Example J is shown in the table below.

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] Example K-1 N-((2S)-1,1-dicyclopropyl-3-((6-fluoro-1'-methyl-4-((S)-4-methyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidin]-7-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of Example I-11 (0.010 g), THF (0.2 mL), and NaBH(OAc)3 (0.026 g), paraformaldehyde (0.018 g) and acetic acid (0.037 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, and water, a 1 mol / L aqueous sodium hydroxide solution, and ethyl acetate were added. The organic layer was separated and concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0 to 70 / 30) to obtain the title compound (0.0073 g).

[0318] Example K-2 7-((S)-3,3-dicyclopropyl-2-(4-methyl-1,2,5-oxadiazole-3-carboxamido)propanamido)-6-fluoro-4-((S)-4-methyl-2-oxo-5-(trifluoromethyl)piperazin-1-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate benzyl Example H-10 (0.065 g), formalin (37%) (0.026 g), and methanol (1 mL) were added with decaborane (0.020 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Amino silica gel (1 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 69 / 29 / 2 to 0 / 98 / 2) to give the title compound (0.050 g). The chemical structure of Example K is shown in the following table.

[0319]

[0320] Example L-1 7-((S)-3,3-Dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]1'-oxide. To a mixture of Example I-1 (0.0042 g), DCM (0.5 mL), and 1 mol / L aqueous sodium hydroxide solution (0.25 mL) was added mCPBA (0.0020 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 64 / 16 / 20 to 0 / 80 / 20) to obtain the title compound (0.0036 g).

[0321] Example L-2 7-((S)-3,3-Dicyclopropyl-2-(1-methyl-1H-pyrazole-5-carboxamido)propanamido)-6-fluoro-1'-(oxetan-3-yl)-4-(5-oxo-2-(trifluoromethyl)morpholino)spiro[chroman-2,4'-piperidine]1'-oxide. To a mixture of Example I-3 (0.011 g), DCM (1 mL), and 1 mol / L aqueous sodium hydroxide solution (0.5 mL) was added mCPBA (0.0072 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 64 / 16 / 20 to 0 / 80 / 20) to obtain the title compound (0.0099 g). The chemical structure of Example L is shown in the following table.

[0322]

[0323] Test Example 1: Human IL-17A / A-Induced Response Inhibition Assay Using HT-29 Cells. The inhibitory effect of test compounds on the chemokine CXCL1 secretion response induced by treatment of HT-29 cells with human IL-17A / A was evaluated. Test compounds were dissolved in DMSO (Fujifilm Wako Pure Chemical Industries) and serially diluted 10-fold using a mosquito dispenser (SPT Labtech). This test compound solution (0.1–10,000 nM as final assay concentrations) or DMSO was dispensed into a 384-well assay plate (Corning) at 0.1 μL / well using a mosquito dispenser. Complete medium was prepared by adding 10% FBS (Biological Industries) to McCoy's 5A (modified) medium (Gibco). Recombinant human IL-17A / A (#7955-IL / CF, R&D Systems) to the complete medium at 200 ng / mL. This IL-17A / A solution (100 ng / mL final assay concentration) or complete medium was added to the same assay plate at 20 μL / well. Subsequently, HT-29 cells (#HTB-38, ATCC) were suspended in complete medium at 2,000,000 cells / mL and added to the same assay plate at 20 μL / well (40,000 cells / well) using a Multidrop Combi dispenser (Thermo Fisher Scientific). The assay plate was incubated at 37°C in a CO2 incubator (SANYO) for 24 hours. After incubation, 20 μL of supernatant was collected from each well of the assay plate using an EDR-384SX dispenser (Biotech). The collected supernatant was evaluated for the ratio, an indicator of CXCL1 concentration in the supernatant, using the HUMAN CXCL1 KITS (Cisbio). The ratio was measured using a PHERAstar FSX microplate reader (BMG Labtech). The ratio value was calculated using the following formula: Ratio value = (fluorescence intensity at 665 nm / fluorescence intensity at 620 nm) x 10,000 The ratio value in each well was used to calculate the % of control value using the following formula.% of control value = (ratio value of the well - ratio value of bottom) / (ratio value of top - ratio value of bottom) Top: Wells to which DMSO and IL-17A / A were added Bottom: Wells to which DMSO and complete medium were added The % of control value at each concentration of the test compound was subjected to nonlinear regression analysis using the statistical software Prism version 4.0.3 (GraphPad) to calculate the IC. 50 The IL-17A / A inhibitory activity was calculated using the IL-17A / A IC 50 The results are classified and described in the columns as follows: A: < 100 nM B: 100-1,000 nM C: 1,001-100,000 nM -: Not tested These results demonstrate that the compounds of the present invention have IL-17A / A inhibitory activity.

[0324] Test Example 2: Human IL-17A / F-Induced Response Inhibition Assay Using HT-29 Cells. The inhibitory effect of test compounds on the chemokine CXCL1 secretion response induced by treatment of HT-29 cells with human IL-17A / F was evaluated. Test compounds were dissolved in DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.) and serially diluted at 10- or 3-fold common ratios using a mosquito dispenser (SPT Labtech). This test compound solution (10-10,000 nM as final assay concentrations) or DMSO was dispensed into a 384-well assay plate (Corning) at 0.1 μL / well using a mosquito dispenser. Complete medium was prepared by adding 10% FBS (SERANA) to McCoy's 5A (modified) medium (Gibco). Recombinant human TNFα (#210-TA / CF, R&D Systems) was mixed with complete medium to prepare a TNFα solution at 200 pg / mL (final assay concentration: 100 pg / mL). Furthermore, recombinant human IL-17A / F (#5837-IL / CF, R&D Systems) was mixed with the TNFα solution at 400 ng / mL to prepare an IL-17A / F + TNFα solution (final assay concentrations: TNFα 100 pg / mL, IL-17A / F 200 ng / mL). This IL-17A / F + TNFα solution or TNFα solution was added to the same assay plate at 20 μL / well. Next, HT-29 cells (#HTB-38, ATCC) were suspended in complete medium at 2,000,000 cells / mL and added to the same assay plate at 20 μL / well (40,000 cells / well) using a Multidrop Combi dispenser (Thermo Fisher Scientific). The assay plate was incubated at 37°C in a CO2 incubator (SANYO) for 24 hours. After incubation, 20 μL of supernatant was collected from each well using an EDR-384SX dispenser (Biotech). CXCL1 concentrations in the collected supernatants were measured using the Human CXCL1 / GRO alpha DuoSet ELISA (R&D Systems).Measurements were performed using a microplate reader PHERAstar FSX (BMG Labtech). % of control values ​​were calculated using the following formula: % of control value = (CXCL1 concentration in the well - CXCL1 concentration in the bottom) / (CXCL1 concentration in the top - CXCL1 concentration in the bottom). Top: Wells to which DMSO and IL-17A / F + TNFα solution were added. Bottom: Wells to which DMSO and TNFα solution were added. The % of control values ​​at each concentration of test compound were subjected to nonlinear regression analysis using the statistical software Prism version 4.0.3 (GraphPad) to obtain the IC. 50 The IL-17A / F inhibitory activity was calculated using the IL-17A / F IC value in the table above. 50 The results are classified and recorded in the columns as follows: A: < 500 nM B: 500-5,000 nM C: 5,001-100,000 nM These results demonstrate that the compounds of the present invention have IL-17A / F inhibitory activity.

[0325]

[0326] The compound of the present invention or a pharmacologically acceptable salt thereof has an IL-17 modulatory action and is therefore useful as a therapeutic agent for diseases in which IL-17 is involved.

Claims

1. A compound represented by formula (I): wherein A is a group selected from the group consisting of the following (a) to (s): (a) C 1-6 Alkyl (b) HaloC 1-6 Alkyl (c) Hydroxy C 1-6 Alkyl (d) C 1-6 Alkoxy (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Mono C 1-6 Alkylamino (g) diC 1-6 Alkylamino (h) Amino C 1-6 (i) alkyl C optionally having any group selected from the substituent group C 3-6 Cycloalkyl C 1-6 (j) alkyl C optionally having any group selected from the substituent group C 3-6 CycloalkylhaloC 1-6 (k) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl C 1-6 (l) alkyl C optionally having any group selected from the substituent group C 6-10 Aryl Halo C 1-6 (m) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group C 1-6 (n) 5- or 6-membered heteroaryl halo C optionally having any group selected from the substituent group C 1-6 (o) alkyl C optionally having any group selected from the substituent group C 6-10 (p) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C (q) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C (r) C which may have any group selected from the substituent group C 3-8 cycloalkyl, and (s) 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 are each independently 6 or N; R 1a , and R 1b are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, C 1-6 alkoxy or hydroxy; R 1a , and R 1b Let's get together and C 3-8 Z may form a cycloalkyl; Z is a group selected from the group consisting of (a) to (d) below: (a) CR 2 R 3 R 4 (b) C, which may have any group selected from the substituent group D 3-10 (c) 3- to 10-membered heterocycloalkyl optionally having any group selected from the substituent group D, and (d) C optionally having any group selected from the substituent group D. 6-10 Aryl; R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-8 C optionally having any group selected from cycloalkoxy or substituent group D 3-6 Ring B is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 10-membered heterocycloalkyl; R 5 is a halogen atom, hydroxy, C 1-6 Alkyl, C 1-6 Alkylcarbonyl, HydroxyC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, Cyano, HaloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 cycloalkyl, C optionally having any group selected from the substituent group E 3-6 Cycloalkyl C 1-6 Alkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (when q is 2 or 3, these R 5 may be the same or different); R 6 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy (R 6 If there are two or more R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (p): (a) a hydrogen atom (b) a haloC 1-6 Alkyl (c) C 1-6 Alkyl (d) Cyano C 1-6 Alkyl (e) C 1-6 Alkoxy C 1-6 Alkyl (f) Hydroxy C 1-6 Alkyl (g)-CO-R 9 (h)-SO2-R 9 (i) C optionally having any group selected from the substituent group F 3-6 Cycloalkyl C 1-6 (j) 3- to 6-membered heterocycloalkyl C optionally having any group selected from the substituent group F 1-6 (k) C optionally having any group selected from the substituent group F 3-6 (l) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F (m) C optionally having any group selected from the substituent group F 6-10 Aryl C 1-6 (n) 5- or 6-membered heteroaryl C optionally having any group selected from the substituent group F 1-6 (o) alkyl C optionally having any group selected from the substituent group F 6-10 (p) 5- or 6-membered heteroaryl optionally having any group selected from the substituent group F; R 8 is a halogen atom, C 1-6 Alkyl or C 1-6 Alkoxy (when r is 2 or 3, these R 8 may be the same or different), or R 8 There are two or more R on the same carbon atom 8 If there are two R 8 Let's get together and C 3-6 may form a cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 9 is C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, NR 10 R 11 , C 6-10 Aryl, 5- or 6-membered heteroaryl, 3- to 10-membered heterocycloalkyl or C 3-8 cycloalkyl; R 10 , and R 11 are each independently a hydrogen atom, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-6 alkyl; the substituent group C is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, cyano, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-6 The substituent group D is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and haloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 m and n are each independently an integer of 1 to 3; q and r are each independently an integer of 0 to 3; or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein m and n are not 1 at the same time.

3. R 7 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom (b) C 1-6 Alkyl (c) C 1-6 Alkoxy C 1-6 Alkyl (d) -CO-R 9 (e) C optionally having any group selected from the substituent group F 3-6 (f) a 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; the substituent group F is a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 alkyl, and cyano; R 9 The compound according to claim 2, wherein R is the same as R in claim 1, or a pharmacologically acceptable salt thereof.

4. The compound according to claim 3, wherein R 1a , and R 1b is a hydrogen atom; X 1 , X 2 , and X 3 is CR 6 and R 6 is a hydrogen atom or halogen atom (three R 6 may be the same or different) or a pharmacologically acceptable salt thereof.

5. The compound according to claim 1, which is represented by the following formula (II): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n and r have the same meanings as in claim 1; Ring C1 is a group represented by the following formula: U is for CR 12 or N; T 1 is CR 12 , C.R. 12 R 13 , O, N, or NR 12 and T 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and T 3 is a bond, O, or CR 12 R 13 and T 4 is CR 12 , C.R. 12 R 13 , O, S, N, or NR 12 and T 5 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (R 12 and R 13 When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and haloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof.

6. The compound according to claim 1, which is represented by the following formula (III): [In the formula, A, Z, X 1 , X 2 , X 3 , R 7 , R 8 , m, n and r have the same meanings as in claim 1; ring C2 is a group represented by the following formula: Y 1 is CR 12 , C.R. 12 R 13 , N, or NR 12 and Y 2 is CR 12 , C.R. 12 R 13 , N, or NR 12 and Y 3 is CR 12 , C.R. 12 R 13 , O, N, or NR 12 and Y 4 is CR 12 , C.R. 12 R 13 or O; R 12 , and R 13 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, cyano, haloC 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkoxy and substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (R 12 and R 13 When there are two or more R 12 and R 13 may be the same or different); R 12 If there are two or more R 12 Together, C 3-8 The substituent group E may form a cycloalkyl or a 3- to 8-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof.

7. The compound according to claim 6, wherein ring C2 is a group represented by the following formula (1), (2), (3), or (4): Y 1 , and Y 3 are each independently 12 or N; R 12 , and R 13 A compound having the same meaning as in claim 6 or a pharmacologically acceptable salt thereof.

8. The compound according to claim 1, wherein A is a group selected from the group consisting of the following (a) to (e): (a) C optionally having any group selected from the substituent group C 6-10 (b) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C; (c) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C; (d) C which may have any group selected from the substituent group C; 3-8 (e) a 3- to 8-membered heterocycloalkyl optionally having any group selected from substituent group C, or a pharmacologically acceptable salt thereof.

9. The compound according to claim 1, wherein Z is a group represented by the following formula (a), (b), (c), or (d): or a pharmacologically acceptable salt thereof.

10. The compound according to claim 1, wherein A is a group selected from the group consisting of the following (a) to (e): (a) C optionally having any group selected from the substituent group C 6-10 (b) 5- or 6-membered heteroaryl which may have any group selected from the substituent group C; (c) 9- or 10-membered heteroaryl which may have any group selected from the substituent group C; (d) C which may have any group selected from the substituent group C; 3-8 (e) a 3- to 8-membered heterocycloalkyl optionally having any group selected from the substituent group C; X 1 , X 2 , and X 3 is CR 6 and R 1a , and R 1b is a hydrogen atom; Z is a group represented by the following formula (a), (b), (c), or (d): Ring B is a 3- to 10-membered heterocycloalkyl; R 5 is C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 C optionally having any group selected from alkyl, substituent group E 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl optionally having any group selected from Substituent Group E, or 3- to 10-membered heterocycloalkyl C optionally having any group selected from Substituent Group E 1-6 alkyl (when q is 2, two R 5 may be the same or different); R 6 is a hydrogen atom or a halogen atom (three R 6 may be the same or different); R 7 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom (b) C 1-6 Alkyl (c) C 1-6 Alkoxy C 1-6 Alkyl (d) -CO-R 9 (e) C optionally having any group selected from the substituent group F 3-6 (f) 3- to 6-membered heterocycloalkyl optionally having any group selected from the substituent group F; R 9 is C 6-10 Aryl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylC 1-6 Alkyl and C 3-8 The substituent group E is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 The substituent group F is a group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 m and n are 2; q is 0, 1 or 2; and r is 0, or a pharmacologically acceptable salt thereof.

11. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

12. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof, and pharmaceutical additives.

14. The pharmaceutical composition according to claim 13, which is a pharmaceutical composition for treating a disease in which IL-17 is involved.

15. The pharmaceutical composition according to claim 14, wherein the disease associated with IL-17 is psoriasis, axial spondyloarthritis, ankylosing spondylitis, or juvenile idiopathic arthritis.

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