Small molecule FSH receptor modifiers

Abstract

This specification discloses small molecule follicular-stimulating hormone (FSH) receptor modifiers, methods for producing them, and therapeutic methods using them.

Description

[Technical Field]

[0001] This disclosure is in the field of pharmaceutical compounds and compositions and therapeutic methods using them. In particular, this disclosure is in the field of follicular-stimulating hormone (FSH) receptor modifiers and their uses. [Background technology]

[0002] Gonadotropins play crucial roles in several physiological processes, including metabolism, thermoregulation, and reproduction. Gonadotropins act on specific gonadal cell types to initiate differentiation of ovarian and testicular cells, as well as steroid production. The gonadotropin FSH (follicular-stimulating hormone) is released from the anterior pituitary gland under the influence of gonadotropin-releasing hormone and estrogen. FSH is a heterodimeric glycoprotein hormone (28-38 kDa) that shares structural similarities with luteinizing hormone (LH), human chorionic gonadotropin (hCG), and thyroid-stimulating hormone (TSH). All FSH proteins are composed of a common α-subunit non-covalently bound to different β-subunits that confer receptor binding specificity. See, for example, Ulloa-Aguirre, A., et al., Front Endocrinol (Lausanne), 2018, 9:707. FSH, LH, and TSH are produced in the pituitary gland, while hCG is primarily produced by the placenta. Cell receptors for FSH (FSHR) are expressed on testicular Sertoli cells and ovarian granulosa cells. See, for example, Anderson, RC, et al., Endocr Rev, 2018, 39(6):911-937.

[0003] In women, FSH plays a crucial role in stimulating follicular development and maturation. Binding of FSH to FSHR stimulates aromatase induction in the ovary, which catalyzes the conversion of androstenedione to estradiol, initiating an increase in the levels of the intracellular secondary messenger adenosine 3',5'-monophosphate (cAMP), enabling follicular growth. See, for example, Donadeu, F.F. and M. Ascoli, Endocrinology, 2005, 146(9):3907-16.

[0004] FSHR activation also stimulates the expression of LH receptors on granulosa cells, enabling them to respond to the pre-ovulatory LH surge. In males, FSH is expressed on Sertoli cells in the testes and plays a crucial role in stimulating spermatogenesis. Before puberty, FSH is involved in the proliferation of Sertoli cells, and in adulthood, FSH can stimulate spermatogonia proliferation and support spermatogenesis up to the round spermatocyte stage.

[0005] FSH receptors are Class A members of the G-coupled protein (GPCR) class of receptors, belonging to the glycoprotein hormone receptor subfamily, which also includes luteinizing hormone / chorionic gonadotropin receptor (LHCGR) and thyroid-stimulating hormone receptor (TSHR). See, for example, Ulloa-Aguirre, cited above. Hydrophobic plots of the amino acid sequences of these receptors reveal three common domains: a hydrophilic amino-terminal region considered to be an extracellular amino-terminal domain; seven hydrophobic segments of transmembrane length considered to be a transmembrane domain; and a carboxy-terminal region containing potential phosphorylation sites (serine, threonine, and tyrosine residues) considered to be an intracellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein-coupled receptors such as β-2-adrenergic receptors, rhodopsin receptors, and substance K receptors by the large size of the hydrophilic amino-terminal domain involved in hormone binding.

[0006] In the United States, 2.4 million couples experience infertility each year, making them potential candidates for treatment. FSH is a parenterally administered protein product used by specialists for ovulation induction and controlled ovarian stimulation, either extracted from urine or produced by recombinant DNA technology. Ovulation induction aims to induce ovulation of a single follicle, while controlled ovarian stimulation aims to aspirate multiple oocytes for use in various in vitro assisted reproductive technologies, such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). See, for example, ESHRE guideline: Ovarian Stimulation for IVF / ICSI, (October 2019). FSH is also clinically used to treat male hypogonadism and male infertility, such as several types of spermatogenesis defects. See, for example, Behre, HM, Front Endocrinol (Lausanne), 2019, 10:322.

[0007] FSHR is a highly specific target in the follicular development process in women and is expressed almost exclusively in the ovaries. However, the use of FSH is limited by its high cost, lack of oral administration, and the need for extensive monitoring by specialists. Therefore, the identification of non-peptide small molecule alternatives to FSH that can potentially be developed for oral administration is desirable.

[0008] FSH and small molecule FSH receptor modifying agents can be used to treat diseases, disorders, and conditions such as female infertility, male infertility, hypogonadism, and defective spermatogenesis. Small molecule FSH agonists are disclosed, for example, in WO 2002 / 09706 pamphlet, WO 2009 / 098283 pamphlet, WO 2010 / 136438 pamphlet, US Patent No. 6,653,338, US Patent No. 8,431,564, WO 2011 / 012600 pamphlet, WO 2014 / 209978 pamphlet, and WO 2015 / 196759 pamphlet. One small molecule FSH receptor modifying agent, MK-8389, was evaluated in clinical trials but did not reach approval. See, for example, Gerrits, M.G.F. et al., Fertility and Sterility Vol. 105, No. 4, April 2016. There is still a need for small molecule FSH receptor modifying agents that selectively activate FSHR.

Summary of the Invention

Means for Solving the Problems

[0009] In one aspect, herein, a compound of formula (A)

Chemical Formula

[0010] In some embodiments, R 1 -NR f R g (In the formula, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (ii)R f R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently).

[0011] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R4b is independently substituted with (selected from C1-C3 alkyl).

[0012] In some embodiments, R 1 is -NR f R g (wherein R f and R g together with the nitrogen to which they are attached optionally contain one additional ring heteroatom selected from oxygen, sulfur and nitrogen to form a 5-member heterocycloalkyl ring, and the ring is substituted with 1-4 R 4 groups (each R 4 group is independently selected from halogen, hydroxy, nitrile, -NR 4a R 4b , -SR 4a , -S(O)2R 4a , and C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, two R 4 groups together with the atoms to which they are attached form a 4-6 member ring; each R 4a and R 4b is independently substituted with (selected from C1-C3 alkyl).

[0013] In some embodiments, R 1 is

Chemical formula

[0014] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0015] In some embodiments, R 1 -NR f R g (In the formula, R f R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently).

[0016] In some embodiments, R 2 is a C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2is a C1-C6 hydroxyalkyl group. In some embodiments, R 2 This is 1 to 4 R 5 Group (each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b R is a phenyl molecule that is optionally substituted with H and C1-C3 alkyl groups independently. In some embodiments, R 2 R is 4-fluorophenyl. In some embodiments, R 2 This consists of 1 to 4 R5 groups (each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b R is a C4-C6 cycloalkyl group that is optionally substituted with H and C1-C3 alkyl groups independently. In some embodiments, R 2 This is a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, where the ring contains 1-4 R 5 Group (each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b R may be optionally substituted independently with H and C1-C3 alkyl groups. In some embodiments, 2 These are 3,3-difluorocyclobutyl, 5-fluoropyridine-2-yl, 2-thiophenyl, 5-thiazolyl, or 1,3,4-thiazolyl.

[0017] In some embodiments, X is CR 20In some embodiments, X is N.

[0018] In another embodiment, the compound of formula (B) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and includes halogens, nitriles, and -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 5-6 member heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 3 is -C(O)NHR 6Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0019] In some embodiments, Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 5-membered heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b Het is independently selected from H and C1-C3 alkyl groups. In some embodiments, Het contains 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR 5a R 5b, 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 6-membered heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups.

[0020] In another embodiment, the compound of formula (C) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0021] In another embodiment, the compound of formula (D) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; Each R 5 These are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0022] In another embodiment, the compound of formula (E) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Alk is a C1-C6 alkyl or -C1-C6 alkenyl; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11, R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0023] In another embodiment, the compound of formula (F) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (i)R fR is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently); R 2 These include C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; and -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0024] In some embodiments, R 1 teeth, [ka] (In the formula, each R 4 R is independently selected from nitriles and C1-C6 alkyl groups optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen groups. In some embodiments, R 1 teeth, [ka] (In the formula, R 4a It is a C1-C6 alkyl group, and R 4b R is selected from nitriles and C1-C6 alkyl groups optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen groups. In some embodiments, R 1 teeth, [ka] (In the formula, R 4b It is a C1-C6 alkyl group, and R 4a(The C1-C6 alkyl group is selected from nitriles and C3-C6 cycloalkyl groups, and is optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl groups, hydroxyl groups, and halogen groups.)

[0025] In some embodiments, R 3 R is a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2). In some embodiments, R 3 R is a 5-6 membered heteroaryl ring, the 5-6 membered heteroaryl ring containing 1-4 ring nitrogen atoms, and the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. In some embodiments, R 3 These are tetrazole, pyrazole, imidazole, oxazole, or pyridine, and R 3 R may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2. In some embodiments, R 3 is -C(O)NHR 6 That is the case.

[0026] In some embodiments, R 6 is, -(CR 7 R 8 ) n C(O)NR d R e In some embodiments, R 7 and R 8 Each of these is independently selected from H and C1-C3 alkyl groups. In some embodiments, R 7 and R 8These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[0027] In some embodiments, R 6 R is a 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with 1-4 substituents independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls). In some embodiments, R 6 is a C1-C6 alkyl group optionally substituted with nitrile or tetrazole. In some embodiments, R 6 R is a phenyl ring, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl ring, saturated or partially unsaturated ring, and heteroaryl ring may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). In some embodiments, R 6 This is either cyclopropane optionally substituted with nitrile or cyclobutene (19yclobutene) optionally substituted with nitrile.

[0028] In some embodiments, R 10 , R 11 , R 12 , and R 13 Each of these is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R11 , R 12 , and R 13 Any two of these, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0029] In another embodiment, the compound of formula (I') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4- to 8-membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); R 2 C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; -(C1~C6 alkyl)-O-(C1~C6 alkyl);-(C1~C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5bSelected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 20 This is selected from H, halogens, nitriles, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 is -C(O)NHR 6 The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and Re Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0030] In another embodiment, the compound of formula (I) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g (In the formula, R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 3 R 4 Group (each R 4 The group independently forms a 4-6 membered heterocycloalkyl ring (selected from C1-C6 alkyl groups, optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyl, and halogens); R 2 The phenyl ring is selected from C1-C6 alkyl rings, C1-C6 haloalkyl rings, phenyl rings, and 5-6 membered heteroaryl rings containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings contain one or two R 5 The base may be replaced by any choice, and each R 5 The group is independently selected from halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys; R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; R 6 teeth, (i)-(CR7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. A solution is provided in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0031] In another embodiment, compounds selected from Table 1, or their stereoisomers, tautomers, or pharmaceutically acceptable salts are provided herein. In another embodiment, compounds selected from Table 2, or their stereoisomers, tautomers, or pharmaceutically acceptable salts are provided herein.

[0032] In another embodiment, salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, cocrystals, intermediates, modifiers, and derivatives of the compounds, stereoisomers, and tautomers described herein.

[0033] In another embodiment, the Specified herein provides a pharmaceutical composition comprising a compound as described herein, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0034] In another embodiment, the Specified provides a method for modulating the follicular-stimulating hormone receptor (FSHR) activity of a subject, comprising administering to a subject requiring such modification a compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a composition disclosed herein.

[0035] In another embodiment, the Specified Publicly Provided is a method for modulating follicular-stimulating hormone receptor (FSHR) activity in a biological sample, comprising contacting the biological sample with a compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a composition disclosed herein.

[0036] In another embodiment, the Specified provides a method for treating a disease or disorder in a subject of interest, comprising administering a therapeutically effective amount of a compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a composition disclosed herein, to the subject. In some embodiments, the disease or disorder is selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngioma, compound pituitary hormone deficiency, reproductively capable eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenoma, cysts, metastatic cancer to the sella turcica (breast in women, lung and prostate in men), invasive lesions, hemoglobinosis, sarcoidosis, histiocytic hyperplasia, lymphoma, lymphohypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders associated with GnRH deficiency.

[0037] In another embodiment, the Specified provides a method for treating fertility disorders in a female or male subject in need, comprising administering a therapeutically effective amount of a compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a composition as disclosed herein, to the subject. The method may be a method for stimulating follicular development, a method for inducing ovulation, a method for controlled ovarian hyperstimulation, a method for controlled ovarian stimulation, a method of assisted reproductive technology (ART) (including in vitro fertilization), a method for treating hypogonadism in males, or a method for treating male infertility, including spermatogenesis defects.

[0038] In another aspect, the Specified Use for Modulating Follicular Stimulating Hormone Receptor (FSHR) Activity in Subjects, or for Use in Subjects Where Use is Necessary, for Diseases or Disorders in Subjects, such as Hypogonadotropic Hypogonadism, Isolated Idiopathic Hypogonadotropic Hypogonadism, Kallmann Syndrome, Idiopathic Hypogonadotropic Hypogonadism, Craniopharyngioma, Compound Pituitary Hormone Deficiency, Reproductively Capable Eunuch Syndrome, Abnormal Beta Subunit of LH, Abnormal Beta Subunit of FSH, Mass Lesions, Pituitary Adenomas, Cysts, Metastatic Carcinoma to the Sella Turcica (Breast in Women, Lung and Prostate in Men), Invasive Lesions, Hemochromocytosis, Sarcoidosis, Histiocytic Proliferation, Lymphoma, Lymphocytic Hypophysitis, Meningitis, Pituitary Stroke, Hyperprolactinemia, A Compounds as disclosed herein, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or compositions as disclosed herein, are provided for use in treating diseases or disorders selected from among disorders associated with hypogonadism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and GnRH deficiency, or for use in treating fertility disorders in subjects where such treatment is required, for example, for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), for treating male hypogonadism, or for treating male infertility including spermatogenesis defects.

[0039] In another embodiment, this specification relates to a disease or disorder in which follicular-stimulating hormone receptor (FSHR) activity is regulated or required in a subject, such as hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngioma, compound pituitary hormone deficiency, reproductively capable eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenoma, cysts, metastatic carcinoma to the sella turcica (breast in women, lung and prostate in men), invasive lesions, hemoglobinosis, sarcoidosis, histiocytic hyperplasia, lymphoma, lymphohypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, and thyroid function The use of compounds as disclosed herein, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or compositions disclosed herein, in the preparation of pharmaceuticals for treating diseases or disorders selected from those associated with hypogonadism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and GnRH deficiency, or for treating fertility disorders in subjects requiring such treatment, for example, for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), for treating male hypogonadism, or for treating male infertility including spermatogenesis defects. [Modes for carrying out the invention]

[0040] definition Unless otherwise defined, the technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this disclosure relates.

[0041] As used herein, singular nouns such as "a," "an," and "the" refer to both singular and plural forms unless explicitly stated otherwise.

[0042] As used herein, the term “about” means that the parameter described is not limited to the exact number described. As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of the term that is not obvious to those skilled in the art from the context in which it is used, “about” means up to plus or minus 10% of the particular term. As used herein, a range should be interpreted as an abbreviation of any value that falls within that range, and each distinct value should be understood to be expressly disclosed herein.

[0043] The phrase "essentially derived from" is to be understood to include additional elements that do not substantially affect those elements specifically enumerated and the basic and novel features of the claimed technology. When "essentially derived from" is used to refer to a composition having only one active agent disclosed herein, the composition may not include any additional active agents not otherwise enumerated. When "essentially derived from" is used to refer to a combination of active agents disclosed herein, the combination may not include any additional active agents not otherwise enumerated.

[0044] As used herein, “pharmaceutically acceptable salt” means a salt of a compound that does not cause significant irritation to the patient to whom it is administered and does not impair the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of the compounds disclosed herein with an acid or a base. Typically, unless otherwise specified, the salts of the present invention are pharmaceutically acceptable salts, but not necessarily. The salts encompassed by the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of the present invention. Salts of the compounds of this disclosure may include acid addition salts. Typical salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bicarbonate, tartrate, borate, bromide, calcium edetate, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride compounds, edetate, edisylate, estrulate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanylate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoic acid, iodide, isethionate, lactate, lactobionate, laurate. Examples include malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, mucinate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalactulose, potassium, salicylate, sodium, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethiodide, trimethylammonium, and valerate. Other pharmaceutically unacceptable salts may be useful in the preparation of the compounds of this disclosure and should be considered to form further embodiments of the art.

[0045] Where a compound disclosed herein has one or more chiral centers, they may exist, be provided, formulated, or used as a racemate or as individual enantiomers. It should be noted that all such stereoisomers and mixtures thereof are within the scope of this disclosure. Therefore, examples of chiral centers without R or S designation mean that the scope of this disclosure includes R isomers, S isomers, racemic mixtures of isomers, and mixtures in which one isomer is more abundant than the other.

[0046] If the processes for preparing the compounds disclosed herein result in a mixture of stereoisomers, such isomers can be separated by conventional techniques such as preparative chiral chromatography. Compounds can be prepared in racemic form, or individual enantiomers can be prepared by stereoselective synthesis or resolution. Compounds can be separated into their component enantiomers by standard techniques such as the formation of diastereomer pairs by salt formation with optically active acids such as (-)-di-p-thuloyl-d-tartaric acid and / or (+)-di-p-thuloyl-l-tartaric acid, followed by fractional recrystallization and regeneration of free bases. Compounds can also be separated by the formation of diastereomer esters or amides, followed by chromatographic separation and removal of chiral auxiliaries.

[0047] As used herein, “aryl” refers to a fully aromatic carbocyclic (all-carbon) ring. An “aryl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When an aryl group is a fused ring system, the rings linked to the remainder of the molecule are fully aromatic. Other rings in the fused ring system may or may not be fully aromatic. Examples of aryl groups include, but are not limited to, the groups of benzene, naphthalene, and azulene. Additional non-limiting examples include: [ka] These are some examples.

[0048] As used herein, “heteroaryl” refers to a ring that is fully aromatic and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some examples, the heteroaryl ring may also contain an oxo group directly attached to the ring carbon, which forms part of the aromatication system. The “heteroaryl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). If the heteroaryl group is a fused ring system, the rings linked to the remainder of the molecule are fully aromatic. The other rings in the fused ring system may or may not be fully aromatic. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, 2-pyridonyl, pyridazine, pyrimidine, pyrazine, and triazine. In some examples, as described herein, the heteroaryl group may be substituted. In other words, a heteroaryl group can contain one or more substituents on an aromatic heterocycle. When a heteroaryl group is substituted, any hydrogen atom can be replaced by a substituent, provided that the valence is satisfied. In some cases, the heteroaryl group may be substituted with a heteroatom; for example, an N-containing heteroaryl group can be an N-substituted heteroaryl group (such as an N-substituted 2-pyridonyl group).

[0049] As used herein, “alkyl” refers to a linear or branched, fully saturated (without double or triple bonds) hydrocarbon group. The alkyl groups of the compounds disclosed may contain 1 to 20 carbon atoms. The alkyl groups as used herein may have 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, 1 to 10 carbon atoms, 1 to 11 carbon atoms, 1 to 12 carbon atoms, 1 to 13 carbon atoms, 1 to 14 carbon atoms, or 1 to 15 carbon atoms. As used herein, C1-C6 alkyl represents an alkyl group having 1 to 6 carbon atoms, C1-C4 alkyl represents an alkyl group having 1 to 4 carbon atoms, and C1-C4 alkyl represents an alkyl group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

[0050] As used herein, "cycloalkyl" refers to a fully saturated (double-bond-free) hydrocarbon ring. The cycloalkyl groups of the compounds disclosed may be in the range of C3-C5, C3-C6, C3-C7, or C3-C8. As used herein, C3-C5 cycloalkyl groups represent cycloalkyl groups containing 3-5 carbon atoms, and C3-C6 cycloalkyl groups represent cycloalkyl groups containing 3-6 carbon atoms.

[0051] As used herein, “heterocycloalkyl” refers to a ring having one or more heteroatoms in its ring system, independently selected from nitrogen, oxygen, and sulfur. The ring may also contain one or more double bonds, provided that the ring is not completely aromatized. A “heterocycloalkyl” ring as defined herein may be a stable 3- to 18-membered ring (including 3- to 5-membered or 3- to 6-membered rings) consisting of a carbon atom and 1 to 5 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0052] As used herein, "alkoxy" refers to an alkyl group as defined above, which is added to the parent molecule via an oxy group, -O-. As used herein, C1-C6 alkoxy refers to an alkoxy group containing 1 to 6 carbon atoms, and C1-C3 alkoxy refers to an alkoxy group containing 1 to 3 carbon atoms. Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0053] As used herein, “haloalkyl” refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogen atoms (e.g., F, Cl, Br, or I). As used herein, “C1-C6 haloalkyl” refers to an alkyl group containing 1 to 6 carbon atoms, in which one or more hydrogen atoms are replaced by halogen atoms.

[0054] As used herein, “haloalkoxy” refers to an alkoxy group as defined herein, in which one or more hydrogen atoms are replaced by halogen atoms (e.g., F, Cl, Br, or I). As used herein, “C1-C3 haloalkoxy” refers to a haloalkoxy group containing one to three carbon atoms.

[0055] As used herein, unless otherwise specified, "independently selected" means that each of the specified bases is independently selected from the subsequent list of species.

[0056] In this specification, unless otherwise specified, where a group is described as being optionally substituted, one or more hydrogen atoms on the group may be independently replaced by substituents, provided that the valence is satisfied.

[0057] In any compound of the present disclosure having one or more chiral centers, where absolute stereochemistry is not explicitly shown, each center may independently be R or S. In addition, in any compound of the present disclosure having one or more double bonds that produce geometric isomers that may be defined as E or Z, each double bond may independently be E or Z.

[0058] It should be understood that the disclosure of compounds in this specification inherently includes the disclosure of their tautomers, where applicable. For example, [ka] The disclosure also applies even if only one of the two structures is disclosed. [ka] This includes disclosure of the above, and vice versa.

[0059] Throughout this disclosure, where compounds are exemplified or named, it should be understood that isotopic-rich analogues of the compounds are also intended and included by this disclosure. For example, a compound may have deuterium incorporated in place of hydrogen, or carbon-13 in place of carbon with a natural isotopic distribution. Isotope enrichment may be at one position on the compound, i.e., only one hydrogen is replaced by deuterium, or at two or more positions, i.e., two or more, all or fewer hydrogens are replaced by deuterium. For example, in some embodiments, 1 to 10 hydrogens are replaced by deuterium. This disclosure also includes compounds in which all analogous atoms are replaced by less common isotopes, e.g., hyperdeuterium compounds in which all hydrogen atoms are replaced by deuterium. Isotopic-rich compounds may be useful, for example, when obtaining NMR spectra or when utilizing isotopic effects in controlling the kinetics of reactions undergoing the compound.

[0060] Throughout this disclosure, when compounds are exemplified or named, it should be understood that their salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, cocrystals, intermediates, modified forms, and derivatives are intended and included in this disclosure.

[0061] The term “pharmaceutical composition” means a mixture of one or more compounds disclosed herein and one or more pharmaceutically acceptable diluents or carriers known in the art, or one or more other pharmaceutically acceptable excipients. Formulating compounds in pharmaceutical compositions can facilitate the administration of compounds to a living organism, for example, the subject to be treated. Certain components of a pharmaceutical composition may depend on or change with the intended route of administration.

[0062] As used herein, the terms “patient” and “subject” refer to vertebrates, including but not limited to mammals (including humans), birds, fish, or reptiles, that are the subject or subject of treatment, observation, or experimentation. “Subject” and “patient” may be used interchangeably. Mammals include, but are not limited to, humans, mice, rodents, rats, monkeys, livestock, dogs, cats, sports animals, and pets. The methods described herein may be useful in human therapy and / or veterinary / animal use. The following discussion is written with reference to adult human patients, but is not limited to this.

[0063] As used herein, the terms “therapeutic dose” and “effective dose” are interchangeable and refer to the amount that provides a specific intended pharmacological effect in a patient requiring treatment. It is emphasized that a therapeutic dose is not always effective in treating a given patient’s condition, even if such a dose is considered therapeutic by those skilled in the art. Exemplary therapeutic doses for adult human patients are provided herein. The therapeutic dose may vary, for example, depending on the characteristics of the patient being treated, the condition being treated, and the severity of the condition.

[0064] compound In one embodiment, the compound of formula (A) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (ii)R f R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently); R 2These include C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; and -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; X is CR 20 or N; R 20 This is selected from H, halogens, nitriles, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NRd R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0065] In another embodiment, the compound of formula (A) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (ii)Rf R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently); R 2 These include C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; and -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; X is CR 20 or N; R 20 This is selected from H, halogens, nitriles, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 is -C(O)NHR 6Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0066] In some embodiments, X is CR 20 In some embodiments, X is N.

[0067] In another embodiment, the compound of formula (I') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4- to 8-membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); R 2 These include C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5bSelected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 20 This is selected from H, halogens, nitriles, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 is -C(O)NHR 6 The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0068] In another embodiment, the compound of formula (I) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NRf R g (In the formula, R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 3 R 4 Group (each R 4 The group independently forms a 4-6 membered heterocycloalkyl ring (selected from C1-C6 alkyl groups, optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyl, and halogens); R 2 The phenyl ring is selected from C1-C6 alkyl rings, C1-C6 haloalkyl rings, phenyl rings, and 5-6 membered heteroaryl rings containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings contain one or two R 5 The base may be replaced by any choice, and each R 5 The group is independently selected from halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys; R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0069] In some embodiments, R1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0070] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0071] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 3 R 4 Group (each R 4 The group is independently substituted with 1 to 4 substituents independently selected from nitriles, hydroxyls, and halogens, which are selected from C1 to C6 alkyl groups.

[0072] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 5-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 -NR f R g (In the formula, Rf and R g Together with the nitrogen to which they are bonded, they form a 5-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 5-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a The C1-C6 alkyl group is substituted with 1 to 4 substituents that are independently selected from C3-C6 cycloalkyl groups, hydroxyl groups, and halogen groups.

[0073] In some embodiments, R 1 -NR f R g (In the formula, R f and R gTogether with the nitrogen to which they are bonded, they form a 5-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 3 R 4 Group (each R 4 The group is independently substituted with 1 to 4 substituents independently selected from nitriles, hydroxyls, and halogens, which are selected from C1 to C6 alkyl groups.

[0074] In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a, and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , as well as selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 1 to 4 R 4 Group (each R 4 The group is independently substituted with halogens, hydroxy, nitriles, and C1-C6 alkyl groups which are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen groups. In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 2 to 4 R 4 Base (2 R 4The groups, together with the atoms to which they are bonded, form a 4-6 membered ring, with each remaining R 4 The group, if present, is independently substituted with halogens, hydroxy, nitriles, and C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen groups.

[0075] In some embodiments, R 1 teeth, [ka] (In the formula, R 1 This is 1 to 3 R 4 Group (each R 4 The group is independently substituted with 1 to 4 substituents independently selected from nitriles, hydroxyls, and halogens, which are selected from C1 to C6 alkyl groups.

[0076] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4bR is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , as well as selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1-NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 2 to 4 R 4 Base (2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring, with each remaining R 4 The group, if present, is independently substituted with halogens, hydroxy, nitriles, and C1-C6 alkyl groups (selected from C3-C6 cycloalkyl groups, hydroxy, and halogens, with optional substitutions of 1-4 substituents independently selected from C3-C6 cycloalkyl groups, hydroxy, and halogens). In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The group is independently substituted with halogens, hydroxy, nitriles, and C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0077] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 6-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 3 R 4 Group (each R 4The group is independently substituted with 1 to 4 substituents independently selected from nitriles, hydroxyls, and halogens, which are selected from C1 to C6 alkyl groups.

[0078] In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 7-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents (e.g., 1 to 6 or 1 to 5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b R is independently substituted with (selected from C1-C3 alkyl groups). In some embodiments, R 1 -NR f R g (In the formula, R f and R g Together with the nitrogen to which they are bonded, they form a 7-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, and the ring has 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a, and is selected from C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, two R 4 groups, together with the atoms to which they are attached, form a 4-6 membered ring; each R 4a and R 4b is independently selected from C1-C3 alkyl).

[0079] In some embodiments, R 1 is -NR f R g (wherein R f and R g together with the nitrogen to which they are attached, optionally contain one additional ring heteroatom selected from oxygen, sulfur, and nitrogen and form an 8-membered heterocycloalkyl ring, the ring having 1-4 R 4 groups (each R 4 group is independently selected from halogen, hydroxy, nitrile, -NR 4a R 4b , -SR 4a , -S(O)2R 4a , and C1-C6 alkyl optionally substituted with 1-13 substituents (e.g., 1-6 substituents, or 1-5 substituents) independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally, two R 4 groups, together with the atoms to which they are attached, form a 4-6 membered ring; each R 4a and R 4b is independently selected from C1-C3 alkyl). In some embodiments, R 1 is -NR f R g (wherein R f and R g together with the nitrogen to which they are attached, optionally contain one additional ring heteroatom selected from oxygen, sulfur, and nitrogen and form an 8-membered heterocycloalkyl ring, the ring having 1-4 R 4 groups (each R 4 group is independently selected from halogen, hydroxy, nitrile, -NR4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0080] In some embodiments, R 1 -NR f R g (In the formula, R f R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently).

[0081] In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0082] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C4 alkyl group. In some embodiments, R 2is a C1-C3 alkyl group. In some embodiments, R 2 These are C1-C6 alkenyls. In some embodiments, R 2 is a C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R 2 teeth, [ka] That is the case.

[0083] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C4 haloalkyl. In some embodiments, R 2 These are C1-C3 haloalkyl groups.

[0084] In some embodiments, R 2 is a C1-C6 hydroxyalkyl group. In some embodiments, R 2 is a C1-C4 hydroxyalkyl group. In some embodiments, R 2 These are C1-C3 hydroxyalkyl groups.

[0085] In some embodiments, R 2 This is 1 to 4 R 5 Group (each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b R is a phenyl molecule that is optionally substituted with H and C1-C3 alkyl groups independently. In some embodiments, R 2 is 1 or 2 R 5 Group (each R 5 The group is a phenyl molecule that is optionally substituted with a halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy group independently.

[0086] In some embodiments, R 2 is phenyl optionally substituted with one or two R 5 groups (each R 5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy). In some embodiments, R 2 is 4-fluorophenyl.

[0087] In some embodiments, R 2 is C4-C6 cycloalkyl optionally substituted with 1 to 4 R 5 groups (each R 5 group is independently selected from halogen, nitrile, -C(O)NR 5a R 5b ; each R 5a and R 5b is independently selected from H and C1-C3 alkyl). In some embodiments, R 2 is C4-C6 cycloalkyl optionally substituted with one or two R 5 groups (each R 5 group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy).

[0088] In some embodiments, R 2 is a 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with 1 to 4 R 5 groups (each R 5 group is independently selected from halogen, nitrile, -C(O)NR 5a R 5b ; each R 5a and R 5b is independently selected from H and C1-C3 alkyl). In some embodiments, R 2This is a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring has 1 or 2 R 5 Group (each R 5 The group may be optionally substituted independently with halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys.

[0089] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] That is the case.

[0090] In some embodiments, R 2 This is a 5-6 membered heteroaryl ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring contains one or two R 5 Group (each R 5 The group may be optionally substituted independently with halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. In some embodiments, R 2 This is a five-membered heteroaryl ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring contains one or two R 5 Group (each R 5 The group may be optionally substituted independently with halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. In some embodiments, R 2 This is a six-membered heteroaryl ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring contains one or two R 5 Group (each R 5The group may be optionally substituted independently with halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. In some embodiments, R 2 It is 2-thiophene.

[0091] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] That is the case.

[0092] In another embodiment, the compound of formula (B) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and includes halogens, nitriles, and -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 5-6 member heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; Rd and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0093] In another embodiment, the compound of formula (II') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and includes halogens, nitriles, and -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 5-6 member heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 3 is -C(O)NHR 6 The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0094] In another embodiment, the compound of formula (II) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 3 R 4 Group (each R 4 The group is independently substituted with C1-C6 alkyl groups (selected from C1-C6 alkyl groups, which are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens); Het contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and one or two R independently selected from halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. 5 It is a 5-6 member heteroaryl ring that has been optionally substituted with a base; R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12, and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0095] In some embodiments, Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 5-membered heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b Het is independently selected from H and C1-C3 alkyl groups. In some embodiments, Het contains 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and 1-4 R groups independently selected from halogens, nitriles, C1-C3 alkyl groups, C1-C3 haloalkyl groups, and C1-C3 alkoxy groups. 5 It is a 5-membered heteroaryl ring that has been optionally substituted with a base.

[0096] In some embodiments, Het contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and one or two R independently selected from halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. 5 It is a 5-membered heteroaryl ring optionally substituted with a base. In some embodiments, Het is [ka] In some embodiments, Het is 2-thiophene. [ka] In some embodiments, Het is [ka] In some embodiments, Het is [ka] In some embodiments, Het is [ka] That is the case.

[0097] In some embodiments, Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR 5a R 5b , 1 to 4 R independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy 5 A 6-membered heteroaryl ring that is optionally substituted with a base; each R 5a and R 5b Het is independently selected from H and C1-C3 alkyl groups. In some embodiments, Het contains 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and 1-4 R groups independently selected from halogens, nitriles, C1-C3 alkyl groups, C1-C3 haloalkyl groups, and C1-C3 alkoxy groups. 5 It is a 6-membered heteroaryl ring that has been optionally substituted with a base.

[0098] In some embodiments, Het contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and one or two R independently selected from halogens, nitriles, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkoxys. 5 It is a 6-membered heteroaryl ring optionally substituted with a base. In some embodiments, Het is [ka] That is the case.

[0099] In another embodiment, the compound of formula (C) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0100] In another embodiment, the compound of formula (IIa') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0101] In another embodiment, the compound of formula (IIa) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 3 R 4 Group (each R 4The group is independently substituted with C1-C6 alkyl groups (selected from C1-C6 alkyl groups, which are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens); R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0102] In another embodiment, the compound of formula (D) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b, -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; Each R 5 These are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0103] In another embodiment, the compound of formula (III') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; Each R 5 These are, independently, halogens, nitriles, and -C(O)NR5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0104] In another embodiment, the compound of formula (III) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 3 R 4 Group (each R 4The group is independently substituted with C1-C6 alkyl groups (selected from C1-C6 alkyl groups, which are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens); R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; m is 0, 1, or 2; Each R 5 These are independently selected from halogens; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0105] In another embodiment, the compound of formula (E) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b, -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Alk is a C1-C6 alkyl or -C1-C6 alkenyl; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0106] In some embodiments, Alk is a C1-C6 alkyl group. In some embodiments, Alk is a C1-C6 alkenyl group. In some embodiments, Alk is [ka] That is the case.

[0107] In another embodiment, the compound of formula (IV') is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups); R 3 is -C(O)NHR 6 The phenyl ring is selected from a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and oxygen, sulfur, and nitrogen, and the phenyl and 5-6 membered heteroaryl rings may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Alk is a C1-C6 alkyl group; R 6 teeth, (i)-(CR 7R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10, R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0108] In another embodiment, the compound of formula (IV) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 teeth, [ka] And R 1 This is 1 to 3 R 4 Group (each R 4 The group is independently substituted with C1-C6 alkyl groups (selected from C1-C6 alkyl groups, which are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens); R 3 is -C(O)NHR 6 Furthermore, a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups; Alk is a C1-C6 alkyl group; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R8 Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0109] In another embodiment, the compound of formula (F) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (i)R f R is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently); R 2These include C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; and -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; R 3 is -C(O)NHR 6 Selected from -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, a 5-6 member heterocycloalkyl ring, and a 5-6 member heteroaryl ring, wherein the 5-6 member heterocycloalkyl ring and the 5-6 member heteroaryl ring contain 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, 5-6 member heterocycloalkyl ring, and 5-6 member heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 6 teeth, (i)-(CR 7 R 8 ) n C(O)NR d R e (In the formula, n is either 1 or 2; R 7 and R 8Each of them is independently selected from H and C1-C3 alkyl groups, or R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R d and R e Each of these is independently selected from H and C1-C3 alkyl groups. (ii) A 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls); and (iii) Phenyl, 3-6 member saturated or partially unsaturated ring, or 5-6 member heteroaryl ring (saturated or partially unsaturated rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; heteroaryl rings optionally contain one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; phenyl, saturated or partially unsaturated rings, and heteroaryl rings may optionally be substituted with one or two substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl groups optionally substituted with 1-7 independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). Selected from; R 10 , R 11 , R 12 , and R 13 Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0110] In another embodiment, the compound of formula (A) is used herein. [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R 1 -NR f R g And, (i)R f and R g It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1 to 13 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b These independently form a 4-8 membered heterocycloalkyl ring substituted with (selected from C1-C3 alkyl groups); or (ii)R fR is a C1-C6 alkyl group; g This is 1 to 4 R 4c group (wherein each R 4c The group is a C1-C6 alkyl group substituted with a halogen, hydroxyl, or nitrile (selected independently); R 2 These include C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; and -(C1-C6 alkyl)-O-(C1-C6 alkyl);-(C1-C6 alkyl)-NR, which are optionally substituted with 1 to 13 halogens. 5a R 5b Selected from phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, phenyl, C4-C6 cycloalkyl, and 5-6 membered heteroaryl rings contain 1-4 R 5 The base may be replaced by any choice, and each R 5 The groups are, independently, halogens, nitriles, and -C(O)NR 5a R 5b Selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; each R 5a and R 5b These are independently selected from H and C1-C3 alkyl groups; X is CR 20 or N; R 20 This is selected from H, halogens, nitriles, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 This is a 5-6 membered heteroaryl ring, which contains 1-4 ring nitrogen atoms, and the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R 10 , R 11 , R 12 , and R 13Each of them is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 10 , R 11 , R 12 , and R 13 Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R 11 and R 12 Together, they form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; A model is disclosed in which 0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.

[0111] As stated above, for each of equations (A), (B), (C), (D), (E), and (F), R 1 teeth, [ka] It may be or be expressed as such, R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0112] As stated above, for each of equations (I'), (II'), (IIa'), (III'), and (IV'), R 1 teeth, [ka] It may be or be expressed as such, R 1 This is 1 to 4 R 4 Group (each R 4 The groups are, independently, halogen, hydroxyl, nitrile, and -NR. 4a R 4b , -SR 4a -S(O)2R 4a , and selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from C3-C6 cycloalkyl, hydroxyl, and halogen; optionally, 2 R 4 The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R 4a and R 4b It is independently substituted with (selected from C1-C3 alkyl groups).

[0113] As described above, for each of equations (I), (II), (IIa), (III), and (IV), R 1 teeth, [ka] It may be or be expressed as such, R 1 This is 1 to 3 R 4 Group (each R 4 The group is independently substituted with a C1-C6 alkyl group (selected from C1-C6 alkyl groups, which are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens).

[0114] In some embodiments, R 1 This is two R 4 It can be a pyrrolidinyl ring (as shown above) that can be substituted with R groups. For example, a pyrrolidinyl ring may have at least two R groups on an atom adjacent to the nitrogen atom. 4 It may be substituted with a group. For example, the pyrrolidinyl group has two R groups in the geminal substitution pattern. 4 It may contain a group (for example, each R 4The group can be added to the same atom on the pyrrolidinyl ring.

[0115] Therefore, in some embodiments of formulas (A), (B), (C), (D), (E), and (F), R 1 teeth, [ka] It can also be expressed as two R 4 The group is added to a carbon atom adjacent to the nitrogen atom. In some embodiments of any of formulas (I'), (II'), (IIa'), (III'), and (IV'), R 1 teeth, [ka] It can also be expressed as two R 4 The group is added to a carbon atom adjacent to the nitrogen atom. In some embodiments of any of formulas (I), (II), (IIa), (III), and (IV), R 1 teeth, [ka] It can also be expressed as two R 4 The group is added to the carbon atom adjacent to the nitrogen atom. 4 At least one of the groups may be a C1-C6 alkyl group. 4 At least one of the groups can be selected from C1-C6 alkyl groups that are optionally substituted with 1-4 substituents independently selected from nitriles, hydroxyls, and halogens.

[0116] Just as an example, R 1 teeth, [ka] It may also be expressed as R 4a R is a C1-C6 alkyl group (such as methyl); 4bThe C1-C6 alkyl group is selected from nitriles and C1-C6 alkyl groups optionally substituted with 1-4 substituents independently selected from hydroxyl and halogen groups. Preferred R 4b Typical examples of groups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3.

[0117] Just as an example, R 1 teeth, [ka] It may also be expressed as R 4b R is a C1-C6 alkyl group (such as methyl); 4a The C1-C6 alkyl group is selected from nitriles and C1-C6 alkyl groups optionally substituted with 1-4 substituents independently selected from hydroxyl and halogen groups. Preferred R 4a Typical examples of groups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3.

[0118] In some embodiments, R 1 teeth, [ka] It may also be expressed as R 4a and R 4b This is defined above.

[0119] In some embodiments of any one or more of the formulas (A), (B), (C), (D), (E), (F), (I'), (II'), (IIa'), (III'), (IV'), (I), (II), (IIa), (III), and (IV), R 3R is a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2). In some embodiments, R 3 These are tetrazole, pyrazole, imidazole, oxazole, or pyridine, and R 3 This may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2.

[0120] In some embodiments of any one or more of formulas (I), (II), (IIa), (III), and (IV), R 3 R is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups). In some embodiments, R 3 These are pyrazoles, imidazoles, oxazoles, pyridonyl (e.g., 2-pyridonyl), or pyridines, and R 3 The ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl groups. If the heteroaryl ring contains a ring nitrogen atom, the substituents may be directly bonded to the nitrogen atom. As just one example, R 3 This can be an N-(C1~C3 alkyl)pyridonyl group.

[0121] In some embodiments of any one or more of the formulas (A), (B), (C), (D), (E), (F), (I'), (II'), (IIa'), (III'), (IV'), (I), (II), (IIa), (III), and (IV), R 3is a 5-6 membered heteroaryl ring containing 1-4 ring nitrogen atoms (the 5-6 membered heteroaryl ring may be optionally substituted with 1-3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2). In some embodiments, R 3 This is a tetrazolyl ring optionally substituted with a C1-C3 alkyl group, for example, a methyl-substituted tetrazolyl ring.

[0122] As described above, in some embodiments of formulas (A), (B), (C), (D), (E), and (F), R 3 is -C(O)NHR 6 In some embodiments of any one or more of the formulas (I'), (II'), (IIa'), (III'), and (IV'), R 3 is -C(O)NHR 6 In some embodiments of any one or more of formulas (I), (II), (IIa), (III), and (IV), R 3 is -C(O)NHR 6 That is the case.

[0123] In some embodiments, R 6 is, -(CR 7 R 8 ) n C(O)NR d R e That is the case.

[0124] In some embodiments, n is 1. In some embodiments, n is 2.

[0125] In some embodiments, R 7 and R 8 Each of these is independently selected from H and C1-C3 alkyl groups. In some embodiments, R 7 and R 8 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[0126] In some embodiments, R d and R e Both are C1-C3 alkyl groups. In some embodiments, R d and R e Both are methyl.

[0127] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] That is the case.

[0128] In some embodiments, R 6 R is a 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with 1-4 substituents independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls). In some embodiments, R 6 R is a 5 or 6-membered heteroaryl ring containing a C1-C6 alkyl or a ring heteroatom independently selected from oxygen and nitrogen, optionally substituted with a nitrile (the ring may be optionally substituted with a 1-4 substituent independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls). In some embodiments, R 6 is a C1-C6 alkyl group optionally substituted with a nitrile. In some embodiments, R 6R is a 5 or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen (the ring may be optionally substituted with 1 to 4 substituents independently selected from halogens, C1-C3 alkyls, C1-C3 haloalkyls, and hydroxyls). In some embodiments, R 6 The substituents are pyrazolyl, oxazolyl, imidazolyl, pyridinyl, or 2-pyridonyl, each of which may be optionally substituted with 1 to 4 substituents independently selected from halogens, C1-C3 alkyls, and C1-C3 haloalkyls. If the heteroaryl ring contains a cyclic nitrogen atom, the substituents may be directly bonded to the nitrogen atom.

[0129] In some embodiments, R 6 R is a C1-C6 alkyl group optionally substituted with nitrile or tetrazole. As just one example, 6 This can be a C1-C3 alkyl group (such as a C3 alkyl group) optionally substituted with nitrile or tetrazole.

[0130] In some embodiments, R 6 is a phenyl ring, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl ring, saturated or partially unsaturated ring, and heteroaryl ring may optionally be substituted with one or two substituents independently selected from halogens, hydroxyl groups, nitrile groups, C1-C3 alkyl groups optionally substituted with one or more independently selected halogens, and C1-C3 alkoxy groups optionally substituted with 1-7 independently selected halogens). In some embodiments, R 6is a phenyl ring, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl ring, saturated or partially unsaturated ring, and heteroaryl ring may optionally be substituted with one or two substituents independently selected from halogens, hydroxyls, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens). In some embodiments, R 6 is a phenyl molecule optionally substituted with one or two substituents optionally selected from halogens, hydroxyls, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens. In some embodiments, R 6 is a 3-6 member saturated or partially unsaturated ring optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may optionally be substituted with one or two substituents independently selected from halogens, hydroxyls, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens. In some embodiments, R 6 is cyclopropane optionally substituted with nitrile or cyclobutane optionally substituted with nitrile. In some embodiments, R 6R is a 5-6 membered heteroaryl ring, the ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with one or two substituents independently selected from halogens, hydroxy, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens. Typical examples include, but are not limited to, pyridonyl (e.g., 2-pyridonyl), which can be optionally substituted with one or two substituents independently selected from halogens, hydroxy, nitriles, and C1-C3 alkyl groups optionally substituted with one or more independently selected halogens. In some examples, R 6 This may be a 2-pyridonyl molecule optionally substituted with a C1-C3 alkyl group (e.g., methyl), and further optionally, the 2-pyridonyl molecule may be substituted with a nitrogen atom by a C1-C3 alkyl group (e.g., methyl).

[0131] In some embodiments of any one or more of formulas (A), (B), (C), (D), (E), and (F), R 10 , R 11 , R 12 , and R 13 Each of these is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R 11 , R 12 , and R 13 Each of them is hydrogen. In some embodiments, R 10 , R 11 , R 12 , and R 13 Two of these, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R 11 , R 12 , and R 13 Two of these, together with the carbon atoms to which they are bonded, form a cyclopropyl ring, while the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0132] In some embodiments of any one or more of the formulas (I'), (II'), (IIa'), (III'), and (IV'), R 10 , R 11 , R 12 , and R 13 Each of these is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R 11 , R 12 , and R 13 Each of them is hydrogen. In some embodiments, R 10 , R 11 , R 12 , and R 13 Two of these, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R 11 , R 12 , and R 13 Two of these, together with the carbon atoms to which they are bonded, form a cyclopropyl ring, while the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0133] In some embodiments of any one or more of formulas (I), (II), (IIa), (III), and (IV), R 10 , R 11 , R 12 , and R 13 Each of these is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 10 , R 11 , R 12 , and R 13 Each of them is hydrogen. In some embodiments, R 10 , R 11 , R 12 , and R 13These two, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, while the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0134] In some embodiments of formula (A), R 11 and R 12 These together form a double bond, R 10 and R 13 R is independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments of formula (I'), R 11 and R 12 These together form a double bond, R 10 and R 13 These are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0135] The compounds of this disclosure have been and can be synthesized using the general synthetic procedures described in the reaction schemes below. The implementation of each individual illustrated step is within the scope of the art of those skilled in the art derived from this disclosure, and those skilled in the art will also know how to modify the synthetic procedures in the schemes below to synthesize the entire range of compounds disclosed herein. The synthetic procedures for individual compounds are provided in the Examples section below.

[0136] In another embodiment, compounds selected from Table 1, or their stereoisomers, tautomers, or pharmaceutically acceptable salts are disclosed herein.

[0137] [Table 1]

[0138] [Table 2]

[0139] [Table 3]

[0140] Table 4

[0141] Table 5

[0142] Table 6

[0143] Table 7

[0144] Table 8

[0145] Table 9

[0146] Table 10

[0147] Table 11

[0148] Table 12

[0149] Table 13

[0150] [Table 14]

[0151] [Table 15]

[0152] [Table 16]

[0153] In another embodiment, compounds selected from Table 2, or their stereoisomers, tautomers, or pharmaceutically acceptable salts are disclosed herein.

[0154] [Table 17]

[0155] [Table 18]

[0156] [Table 19]

[0157] [Table 20]

[0158] [Table 21]

[0159] [Table 22]

[0160] [Table 23]

[0161] [Table 24]

[0162] [Table 25]

[0163] [Table 26]

[0164] [Table 27]

[0165] compound activity As described above, the compounds disclosed herein have activity as FSHR modifiers. This activity can be evaluated by any suitable FSHR interaction assay, such as the cAMP accumulation assay as shown in the Examples, and other assays outlined below and shown in the Examples. The compounds disclosed herein have EC values ​​of less than 1000 nM, 500 nM or less, 100 nM or less, 10 nM or less, or 1 nM or less. 50 The value may be shown, EC 50 This is the effective concentration of the compound at which 50% of the maximum response obtained by FSH is observed.

[0166] The glycoprotein hormone receptors, FSHR, TSHR, and LHR / LHCGR, primarily activate the Gαs class of intracellular G proteins, leading to cAMP accumulation. The homogeneous time-resolved fluorescence (HTRF) assay shown in the examples is based on competition between intrinsic cAMP produced by cells and cAMP labeled with dye d2 (red acceptor) for binding to a cryptotate-labeled antibody (europium donor). The specific energy transfer signal is inversely proportional to the concentration of cAMP in the standard or sample. See, for example, Nataraja, SG, et al., Frontiers in Endocrinology. 2015, 6:142.

[0167] Another assay uses the immortalized rat steroid-producing granulosa cell line GFSHR-17, which stably expresses the FSH receptor and responds to FSH stimulation with human FSH. See, for example, Keren-Tal, I., et al., Molecular and Cellular Endocrinology, 1993, 95:R1-R10. This engineered cell line lacks the aromatase found in primary granulosa cells, which is required for the conversion of androgen precursors to estrogen. However, it exhibits a robust progesterone response that can serve as a surrogate for verifying the activity of FSHR agonists. It can be used in cell-based assays to evaluate the ability of compounds to activate FSHR in GFSHR-17 cells by measuring the progesterone released into the supernatant, for example, by using the progesterone HTRF kit from Cisbio. Ratio-metric HTRF readout information has been established for evaluating the agonist activity of compounds and is described in the examples below.

[0168] The activity of the compounds described herein as FSHR agonists can be investigated using a modified version of the classic FSH bioassay (Steelman-Pohley) based on increased ovarian weight in immature female rats. See Steelman, S.L. and F.M.Pohley, Endocrinology, 1953, 53(6):604-16. Activation of FSHR in females has been well demonstrated to stimulate follicular granulosa cells to increase and induce the expression of aromatase and luteinizing hormone receptors. See, for example, Donadeu, F.F. and M.Ascoli, Endocrinology, 2005, 146(9):3907-16. Appropriate granulosa cell proliferation and gene expression are essential for inducing steroid synthesis and secretion, which allows follicles to respond to the pre-ovulatory luteinizing hormone surge, thereby inducing ovulation of oocytes contained within the follicles into the fallopian tubes, into which they can be fertilized. Therefore, it is reasonable to measure the increase in ovarian weight in response to granulosa cell proliferation, the number of ovulated oocytes in response to follicular maturation, and uterine weight in response to estradiol synthesis and secretion.

[0169] In some embodiments, the compounds disclosed herein selectively activate FSHR compared to TSHR, for example. This selective activity is demonstrated in the assay (EC) shown in the examples. 50 It can be evaluated by any suitable FSHR / TSHR assay that compares efficacy in individual receptor-specific cAMP accumulation (e.g., evaluating selectivity based on ratios).

[0170] In some embodiments, the compounds disclosed herein selectively activate FSHR compared to, for example, luteinizing hormone. This selective activity is demonstrated in the assay (EC) shown in the examples. 50 It can be evaluated by any suitable FSHR / LHR assay that compares efficacy in individual receptor-specific cAMP accumulation (e.g., evaluating selectivity based on ratios).

[0171] In some embodiments, the compounds disclosed herein exhibit at least five times greater selectivity for FSHR than for TSHR. This includes at least five, six, seven, eight, nine, ten, one, two, three, four, five, six, seven, eight, nine, six, nine, six, six, seven, eight, nine, six The compounds disclosed herein may exhibit selectivity for follicular-stimulating hormone receptors approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 times greater than that for thyroid-stimulating hormone receptors.

[0172] In some embodiments, the compounds disclosed herein exhibit at least five times greater selectivity for FSHR than for luteinizing hormone receptor. This includes at least five, six, seven, eight, nine, ten, one, two, three, four, five, six, seven, eight, nine, follicle-stimulating hormone receptor than for luteinizing hormone receptor. The compounds disclosed herein may exhibit selectivity for follicular-stimulating hormone receptors approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 times greater than that for luteinizing hormone receptors.

[0173] Compound synthesis In another embodiment, a method for producing any one of the compounds disclosed herein is provided. The compounds of this disclosure could be synthesized using the general synthetic procedures described in the following schemes A to D. The performance of each individual illustrated step is within the scope of the art of those skilled in the art derived by this disclosure, and those skilled in the art also know how to modify the synthetic procedures of the following schemes to synthesize the entire range of compounds disclosed herein. 1 , R 2 , R 3 , R 6 , R 10 , R 11 , R 12 , R 13 , R f , and R g The definitions relating to are provided in the formulas described herein. The synthesis procedures for individual compounds are disclosed in the Examples section below.

[0174] Scheme A [ka]

[0175] As shown in Scheme A, compound A-1 (which can be synthesized as described in Method 1 below) was converted to oxalylamide A-2. Cyclization of intermediate compound A-2 yielded intermediate compound A-3. Subsequent saponification to intermediate compound A-4 was followed by amine HNR f R g Intermediate compound A-5 was obtained by coupling with [another compound]. Intermediate compound A-6 was obtained by metal-mediated coupling of intermediate compound A-5, and intermediate compound A-7 was obtained after ester hydrolysis. Amine H2NR 6 Compound A-8 (as disclosed herein) was obtained by coupling with compound A-7.

[0176] Scheme B [ka]

[0177] Scheme B shows the metal-mediated conversion of compound B-1 to a boronic acid ester, followed by R 3 Compound B-3 (as disclosed herein) was obtained by reacting with X (X = Cl, Br, I, or OTf) via another metal-mediated transformation.

[0178] Scheme C [ka]

[0179] Scheme C is R 3 - This demonstrates the metal-mediated conversion of compound B-1 to compound B-3 (as disclosed herein) by a boronic acid ester.

[0180] Scheme D [ka]

[0181] Scheme D involves compound D-1 and amine HNR to reach compound B-3 (the compound as disclosed herein). f R g This exhibits amide coupling with [the specified component].

[0182] Pharmaceutical composition In another embodiment, the Specified herein discloses pharmaceutical compositions comprising, essentially comprising, or consisting of, the compounds described herein and one or more pharmaceutically acceptable excipients.

[0183] In another embodiment, the Specified herein discloses pharmaceutical compositions comprising, essentially comprising, or consisting of a compound of formula (I), (II), (IIa), (III), or (IV) as described herein, and one or more pharmaceutically acceptable excipients.

[0184] The compounds may be formulated for administration by any preferred route of administration, such as oral, topical (including transdermal), rectal, vaginal, mucosal, or intestinal administration; intramuscular, subcutaneous, or intravenous injection; and parenteral delivery, including inhalation, intrathecal, direct intraperitoneal, or intranasal delivery.

[0185] Pharmaceutical compositions as disclosed herein may include one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents, disintegrants, sweeteners, lubricants (e.g., magnesium stearate), flavorings, emulsifiers, suspending agents, stabilizers, isotonic agents, etc. Pharmaceutical compositions as disclosed herein may be formulated into oral dosage forms such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or into topical (including transdermal) or transmucosal dosage forms such as liquids, suspensions, emulsions, gels (e.g., ointments); or into parenteral dosage forms such as liquids, suspensions, emulsions, and lyophilized powders. The dosage forms may be formulated in various forms, for example, into single-dose or multi-dose dosage forms.

[0186] Examples of excipients include, but are not limited to, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO3), cremofor, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), lubricants, such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, and combinations thereof.

[0187] The amount of any individual excipient in a composition will vary depending on the role of the excipient, the dose requirements of the active agent, and the specific needs of the composition. However, generally, the excipient will be present in the composition in amounts ranging from about 1% to about 99% by weight, for example, about 5% to about 98% by weight, including about 15% to about 95% by weight. Generally, the amount of excipient present in the compositions of this disclosure is selected from: about 1% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or 95% by weight.

[0188] A pharmaceutical composition as disclosed herein may contain one of the compounds disclosed herein as the sole active agent, or may be formulated in combination with other active agents.

[0189] The techniques for formulation and administration of the compounds disclosed herein can be found in "Remington: The Science and Practice of Pharmacy," Academic Press, London, United Kingdom, 23rd edition, 2020.

[0190] Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of the compound as disclosed herein in a reasonable volume or mass of the composition, which may be administered according to any effective dosing schedule, such as once daily. While the exact dosage may be determined for each drug (each compound), some generalizations regarding dosage can be made for most compounds. For example, a daily dosing regimen for an adult human patient may be 0.001 mg to 1000 mg, e.g., 0.01 mg to 500 mg, e.g., 1 to 200 mg of the compound or a pharmaceutically acceptable salt thereof, calculated as free base or free acid.

[0191] Treatment methods In another embodiment, this specification discloses a method for modulating follicular-stimulating hormone receptor (FSHR) activity in a subject, comprising, essentially, or consisting of administering a compound or pharmaceutical composition as disclosed herein to the subject as required. In an alternative embodiment, this specification discloses a method for modulating follicular-stimulating hormone receptor activity in a biological sample, comprising contacting the biological sample with a compound or pharmaceutical composition as disclosed herein.

[0192] In another embodiment, this specification discloses a method for treating a disease or disorder in a subject of interest, comprising, essentially, or consisting of, administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as disclosed herein. The disease or disorder is hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngioma, compound pituitary hormone deficiency, reproductively capable eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, tumor lesions, pituitary adenoma, cysts, metastatic cancer to the sella turcica (breast in women, lung and prostate in men). This may include any of the following conditions requiring regulation of FSHR activity: prostatic hyperplasia, infiltrative lesions, hemoglobinosis, sarcoidosis, histiocytosis, lymphoma, lymphohypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and one or more disorders associated with GnRH deficiency.

[0193] In another embodiment, the Specified Publication provides a method for treating fertility disorders in a male or female subject in need, comprising, essentially, or consisting of administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as disclosed herein. Such a method may be for stimulating follicular development, for inducing ovulation, for controlled ovarian hyperstimulation, for controlled ovarian stimulation, for assisted reproductive technology (ART) (including in vitro fertilization), for treating hypogonadism in males, or for treating male infertility, including spermatogenesis defects.

[0194] In another aspect, compounds for use in modulating follicular-stimulating hormone receptor (FSHR) activity in a subject are disclosed herein.

[0195] In another aspect, compounds for use in treating diseases or disorders in the subjects where required are disclosed herein. Diseases or disorders include hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngioma, compound pituitary hormone deficiency, reproductively capable eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, tumor lesions, pituitary adenoma, cysts, metastatic cancer to the sella turcica (breast in women, lung and anterior in men). This may include any of the following conditions requiring regulation of FSHR activity: prostatic hyperplasia, infiltrative lesions, hemoglobinosis, sarcoidosis, histiocytosis, lymphoma, lymphohypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and one or more disorders associated with GnRH deficiency.

[0196] In another embodiment, compounds for use in treating fertility disorders in women or men in need, such as for stimulating follicular development, inducing ovulation, for controlled ovarian hyperstimulation, for controlled ovarian stimulation, for assisted reproductive technology (ART) (including in vitro fertilization), for treating male hypogonadism, or for treating male infertility, including spermatogenesis defects.

[0197] In other embodiments, the use of compounds disclosed herein in the preparation of pharmaceuticals for modulating follicular-stimulating hormone receptor (FSHR) activity in subjects for the treatment of diseases or disorders in subjects in need, such as one or more of those listed above, or for the treatment of follicular development, for the treatment of ovulation induction, for controlled ovarian hyperstimulation, for controlled ovarian stimulation, for the treatment of fertility disorders in female or male subjects in need, such as for assisted reproductive technology (ART) (including in vitro fertilization), or for the treatment of male infertility, including male hypogonadism or spermatogenesis defects.

[0198] According to either of these methods or uses, the compound or composition may be administered by any preferred route of administration as described above, and may be administered in a therapeutically effective dose as described above. Also, as described above, administration may be by any effective schedule of administration, such as once daily, 1 to 4 times daily, once a week, 1 to 4 times a week, once a month, or 1 to 4 times a month. The exact dose may be determined for each drug (each compound), but a daily dose regimen for adult human patients may be 0.001 mg to 1000 mg, for example, 0.01 mg to 500 mg, for example, 1 to 200 mg of the compound or a pharmaceutically acceptable salt thereof, calculated as, for example, free base or free acid.

[0199] The generally described Art may be further understood by referring to the following examples, which are provided as illustrations and are not intended to limit the Art. [Examples]

[0200] The analytical LCMS conditions were as follows:

[0201] Analysis method 1 (M1): Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 1.2 minutes, followed by a 100% B gradient over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.01 minutes with a 3 μL injection volume at a flow rate of 1.2 mL / min and held for 0.39 minutes. UV spectra were recorded at 215 nm using an SPD-M20A PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-solution and PsiPort software.

[0202] Analysis method 2 (M2) Analytical uHPLC-MS was performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH® C18 column (2.1 mm x 50 mm, 1.7 μm; temperature 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 1.1 minutes, followed by a 100% B gradient over 0.25 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes with an injection volume of 1 μL at a flow rate of 0.9 mL / min and held for 0.1 minutes. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectral range of 200–400 nm. Mass spectra were obtained using Waters SQD (MSQ1) or Waters ACQUITY QDA (MSQ2, MSQ4). The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0203] Analysis method 3 (M3): Analytical uHPLC-MS was performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH® C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40°C) and a gradient of 5–100% B (A = 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile) over 0.75 minutes, followed by a 100% B gradient over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes with a flow rate of 1 mL / min and an injection volume of 1 μL, held for 0.1 minutes. UV spectra were recorded at 215 nm in a Waters ACQUITY PDA with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0204] Analysis method 4 (M4): Analytical uHPLC-MS was performed on a Waters ACQUITY uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 5.3 minutes, followed by a 100% B gradient for 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes with an injection volume of 1 μL at a flow rate of 0.6 mL / min and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector with a spectral range of 200–400 nm, and ELC data were collected using a Waters ACQUITY ELS detector (if installed). Mass spectra were obtained using Waters SQD (MSQ1) or Waters ACQUITY QDA (MSQ2, MSQ4). The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0205] Analysis method 5 (M5): Analytical uHPLC-MS was performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH® C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) and a gradient of 5–100% B (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = acetonitrile) over 5.3 minutes, followed by a 100% B gradient over 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes with an injection volume of 1 μL at a flow rate of 0.6 mL / min and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector (MS16) or Waters SQD2 (MSQ5). The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0206] Analysis method 6 (M6): Analytical uPLC-MS was performed on a Waters ACQUITY uPLC system using a Phenomenex Kinetex-Core-Shell C8 column (50 x 2.1 mm, 5 μm column; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 1.83 minutes, followed by a 100% B gradient for 0.42 minutes. A second gradient of 100–5% B was then applied over 0.42 minutes with a 3 μL injection volume at a flow rate of 1.2 mL / min and held for 0.54 minutes. UV spectra were recorded at 215 nm using an SPD-M20A PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0207] Analysis method 7 (M7): Analytical HPLC-MS was performed on a Waters LCMS system using a Waters uPLC CORTEX C8 column (2.1 mm x 100 mm, 1.6 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 5.3 minutes, followed by a 100% B gradient for 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes with an injection volume of 1 μL at a flow rate of 0.6 mL / min and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector with a spectral range of 200–400 nm, and ELC data were collected using a Waters ACQUITY ELS detector (if installed). Mass spectra were obtained using Waters SQD or Waters ACQUITY QDa. The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0208] Analysis method 8 (M8): Analytical HPLC-MS was performed on a Waters LC-MS system using a Waters uPLC CORTEX C8 column (2.1 mm x 50 mm, 1.6 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in water; B = 0.01% formic acid in acetonitrile) over 1.1 minutes, followed by a 100% B gradient over 0.3 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes with an injection volume of 1 μL at a flow rate of 0.9 mL / min and held for 0.28 minutes. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector with a spectral range of 200–400 nm, and ELC data were collected using a Waters ACQUITY ELS detector (if installed). Mass spectra were obtained using Waters SQD or Waters ACQUITY QDa. The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0209] Analysis method 9 (M9): Analytical HPLC-MS was performed on a Waters LC-MS system using a Waters CSH C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) and a gradient of 5–100% B (A = 5 mM ammonium acetate, buffered to pH 7; B = acetonitrile) over 5.3 minutes, followed by a 100% B gradient over 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes with an injection volume of 1 μL at a flow rate of 0.6 mL / min and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector with a spectral range of 200–400 nm, and ELC data were collected using a Waters ACQUITY ELS detector (if installed). Mass spectra were obtained using Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0210] Analysis method 10 (M10): Analytical (M14) uHPLC-MS was performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEH® C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40°C) and a gradient of 1–100% B (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = acetonitrile) over 1.1 minutes, followed by a 100% B gradient over 0.25 minutes. A second gradient of 100–1% B was then applied over 0.05 minutes with an injection volume of 1 μL at a flow rate of 1.0 mL / min and held for 0.4 minutes. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector (MS16) or Waters SQD2 (MSQ5). The data were integrated and reported using Waters MassLynx and OpenLynx software.

[0211] Analysis Method 11 (M11): Device: Shimadzu LC-20AD&MS 2020; KARARA: Kinetex C18 2.6μm, 2.1*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.0 mL / min

[0212] Table 28 Analysis: 220nm & 254nm; MS mode: positive; MS range: 100-1000

[0213] Analysis Method 12 (M12) Device: Shimadzu LC-20AD&MS 2020; KARARA: Kinetex C18 2.6μm, 2.1*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.5 mL / min

[0214] Table 29 Analysis: 220nm & 254nm; MS mode: positive; MS range: 100-1000

[0215] Analysis Method 13 (M13) Device: Shimadzu LC-20AD&MS 2020; KARARA: HALO C18 5.0μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.0 mL / min (0.01~3.0 min) 1.2 mL / min (3.01~3.5 min)

[0216] Table 30 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0217] Analysis Method 14 (M14): Device: Shimadzu LC-20AD&MS 2020; KARARA: HALO C18 2.7μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.5 mL / min

[0218] Table 31 Analysis: 220nm & 254nm; MS mode: positive; MS range: 100-1000

[0219] Analytical Method 15 (M15) Device: Shimadzu LC-20AD XR&MS 2020; KARARA: HALO C18 5μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 2.0 mL / min (0.00~0.9 min)

[0220] Table 32 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0221] Analysis Method 16 (M16): Device: Shimadzu LC-20AD&MS 2020; Column: Xbridge-C18 2.1*30mm 5μm; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) acetonitrile Flow rate: 1.5mL / min

[0222] [Table 33] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0223] Analysis method 17 (M17) Equipment: Waters Arc™ Column: HALO 2.7μm C18 90A 30x3.0mm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 1.0mL / min (0.01~4.00min)

[0224] [Table 34] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1200

[0225] Analysis method 18 (M18): Equipment: Shimadzu LC-30AD&MS 2020; Column: InfinityLab Poroshell 120 SB-C18 2.7μm 3.0*30mm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 1.5mL / min (0.01~1.50min)

[0226] [Table 35] Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0227] Analysis Method 19 (M19): Device: Shimadzu LC-30AD&MS 2020; KARARA: InfinityLab Poroshell 120 SB-C18 2.7μm 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.5 mL / min (0.01~1.50 min)

[0228] Table 36 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0229] Analysis Method 20 (M20): Device: Shimadzu LC-20AD&MS 2020; KARARA: Kinetex EVO C18 30*2.1mm, 5μm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1 mL / min (0.01~3.00 min) ~ 1.2 mL / min (3.01~3.50 min)

[0230] Table 37 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0231] Analysis Method 21 (M21) Device: Shimadzu LC-20AD XR&MS 2020; カラム: HALO C18 3.0*30mm, 5μm; カラム temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.5 mL / min (0.00~1.30 min)

[0232] Table 38 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0233] Analysis Method 22 (M22): Device: Shimadzu LC-20AD XR&MS 2020; KARARA: HALO C18 5μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.50 mL / min

[0234] Table 39 Analysis: 220nm & 254nm; MS mode: positive; MS range: 50-500

[0235] Analysis Method 23 (M23): Device: Shimadzu LC-20AD XR&MS 2020; KARARA: HALO C18 5μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 2.0 mL / min (0.00~0.9 min)

[0236] Table 40 Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0237] Analysis method 24 (M24): Equipment: Agilent 1260&6125B: Column: Xbridge C18 2.1*50mm, 5μm; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) acetonitrile Flow rate: 0.8mL / min

[0238] [Table 41] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0239] Analysis method 25 (M25): Equipment: Shimadzu 20AB&MS 2020; Column: Xbridge C18 2.1*50mm, 5μm; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mMOL / L NH4HCO3 Mobile phase B (MPB) 100%ACN Flow rate: 1.0mL / min

[0240] [Table 42] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0241] Analysis method 26 (M26) Equipment: Shimadzu LC-20AB&MS 2020; Column: Xbridge-C18 2.1*50mm 5um; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) acetonitrile Flow rate: 1.0 mL / min (0.01~3.01 min, 1.2 mL / min (3.02~3.50 min)

[0242] Table 43 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0243] Analysis Method 27 (M27): Apparatus: Shimadzu 20AB&MS 2020; カラム:Xbridge C18 2.1*50mm, 5μm; カラムTemperature: 40℃ Mobile phase A(MPA)H2O+10mmol / L NH4HCO3 Moving phase B (MPB) 100% ACN Flow rate: 1.0 mL / min

[0244] Table 44 Analysis: 220nm & 254nm; MS mode: negative; MS range: 100-2000

[0245] Analysis Method 28 (M28) Device: Agilent 1260 & 6125B カラム:Luna-C18(2)2.0*50mm, 5μm; カラムTemperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.0 mL / min

[0246] Table 45 Analysis: 220nm & 254nm; MS mode: positive; MS range: 100-2000

[0247] Analysis Method 29 (M29): Device: Shimadzu LC-20AD XR&MS 2020; KARARA: HALO C18 5μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.50 mL / min

[0248] Table 46 Analysis: 220nm & 254nm; MS mode: positive; MS range: 50-1500

[0249] Analysis Method 30 (M30): Device: Shimadzu LC-20AD XR&MS 2020; KARARA: HALO C18 5μm, 3.0*30mm; KARARA temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 2.0 mL / min (0.00~0.9 min)

[0250] Table 47 Analysis: 220nm & 254nm; MS mode: Yang; MS range: 50-2000

[0251] Analysis Method 31 (M31): Device: Shimadzu LC-20AD XR&MS 2020; カラム: HALO C18 3.0*30mm, 5μm; カラム temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Shifting phase B (MPB)ACN + 0.02% (v / v)TFA Flow rate: 1.5 mL / min (0.00~1.30 min)

[0252] Table 48 Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0253] Analysis method 32 (M32): Equipment: Shimadzu LC-20AD XR&MS 2020; Column: HALO C18 5μm, 3.0*30mm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 2.0mL / min (0.00~0.9min)

[0254] [Table 49] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0255] Analysis method 33 (M33): Equipment: Shimadzu LC-20AD XR&MS 2020; Column: HALO C18 5μm, 3.0*30mm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 2.0mL / min (0.00~0.9min)

[0256] [Table 50] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0257] Analysis method 34 (M34): Equipment: Agilent 1260&6125B: Column: Luna-C18(2) 2.0*50mm, 5μm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 1.0mL / min

[0258] [Table 51] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0259] Analysis method 35 (M35): Equipment: Agilent 1200 & 6110A; Column: Luna-C18(2) 2.0*50mm, 5μm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 1.0mL / min

[0260] [Table 52] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0261] Analysis method 36 (M36): Equipment: Agilent 1200 & 6130; Column: Xbridge-C18 2.1*50mm 5μm; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) acetonitrile Flow rate: 0.8mL / min

[0262] [Table 53] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0263] Analysis method 37 (M37): Equipment: Agilent 1200 & 6110A; Column: Luna-C18(2) 2.0*50mm, 5μm; Column temperature: 40℃ Mobile phase A(MPA)H2O+0.04%(v / v)TFA Mobile phase B (MPB)ACN+0.02%(v / v)TFA Flow rate: 1.0mL / min

[0264] [Table 54] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0265] Analysis method 38 (M38): Equipment: Shimadzu LC-20AD&MS 2020; Column: Gemini C18 2.0*50mm, 5μm; Column temperature: 40℃ Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) acetonitrile Flow rate: 1.0mL / min

[0266] [Table 55] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 50-2000

[0267] Analysis method 39 (M39): Equipment: Agilent 1200 HPLC; MSD: 1956A Single Quadrupole MSD Column: Luna C18, 2.0*50mm, 5μm; Column temperature: 40℃ 0.04% TFA in mobile phase A(MPA)H2O 0.02% TFA in mobile phase B (MPB) ACN Flow rate: 1.0mL / min

[0268] [Table 56] Detection: 220nm & 254nm; MS Mode: Positive; MS Range: 100-1000

[0269] Analysis method 40 (M40): All analyses were performed using an Agilent G1956A LC / MSD quadrupole connected to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostat-controlled column compartment, and diode array detector. The mass spectrometer (MS) was operated in cation mode with an atmospheric pressure electrospray ionization (API-ES) source. The capillary voltage was set to 3000V, the fragmenter voltage to 70V, and the quadrupole temperature was maintained at 100°C. Dry gas flow and temperature values ​​were 12.0 L / min and 350°C, respectively. Nitrogen was used as the nebulizer gas at a pressure of 35 psig. Data acquisition was performed using Agilent Chemstation software.

[0270] Analysis was performed on a YMC-packed ODS-AQ C18 column (50 mm long x 4.6 mm ID; 3 μm particle size) at 35°C and a flow rate of 2.6 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile at 4.8 min; the resulting composition was retained for 1.0 min; and then from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile at 0.2 min. The injection volume was 2 μL. The acquisition range was set to 190–400 nm with respect to the UV-PDA detector and 100–1400 m / z with respect to the MS detector.

[0271] Analysis method 41 (M41): All analyses were performed using an Agilent G6224A TOF-LC / MS quadrupole connected to an Agilent 1290 Infinity series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostat-controlled column compartment, and diode array detector. The TOF-mass spectrometer (TOF-MS) was operated in cation mode with a dual atmospheric pressure electrospray ionization (dual-ESI) source. The capillary voltage was set to 3000V, the fragmenter voltage to 70V, and the quadrupole temperature was maintained at 100°C. Dry gas flow rate and temperature values ​​were 12.0 L / min and 350°C, respectively. Nitrogen was used as the nebulizer gas at a pressure of 35 psig. Data acquisition was performed using MassHunter software.

[0272] Analysis was performed on a YMC Pack ODS-AQ C18 column (50 mm long x 4.6 mm ID; 3 μm particle size) at 35°C and a flow rate of 2.6 mL / min. Gradient elution was performed using an ISET 2V1.0 Emulated Agilent pump G1312A V1.0 from 94.51% (water + 0.1% formic acid) / 5.49% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.8 mins; the resulting composition was retained for 1.0 min; from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile in 0.2 mins. The injection volume was 4 μL. The acquisition range was set to 190–400 nm with respect to the UV-PDA detector and 100–1000 m / z with respect to the TOF-MS detector.

[0273] Analysis method 42 (M42): Analytical HPLC-MS was performed on an Agilent 1260 Infinity (Quat. pump) DAD LC / MS G6120B system using a Thermo Scientific Accucore C18 (50 x 4.6 mm, 2.6 μm; temperature: 35°C) and a gradient of 90% A to 10% A over 1.5 min, retained for 0.9 min, and 95% A over 0.1 min (A: 0.1% HCOOH in H2O; B: CH3CN) with a flow rate of 3 mL / min and a 3 μL injection volume. UV spectra were recorded at 254 nm using a 1260 Infinity II diode array detector with a spectral range of 200–400 nm. Mass spectra were obtained using the LC / MS G6120B system. Data were integrated and reported using ACD Labs software.

[0274] Analysis method 43 (M43): Analytical HPLC-MS was performed on an Agilent 1290 Infinity II HPLC DAD LC / MSD G6125C ISET emulating an Agilent G4220A system, using a 3 μL injection volume at a flow rate of 0.9 mL / min. The 1290 Infinity II diode array detector was used, with a spectral range of 200–400 nm, at 254 nm. Mass spectra were obtained using the LC / MSD G6125C detector. Data were integrated and reported using ACD Labs software. The spectroscopy range was 254 nm, with a spectral range of 200–400 nm.

[0275] Analysis method 44 (M44): Analytical HPLC-MS was performed on an Agilent 1290 Infinity II HPLC DAD LC / MSD iQ G6160A using a Phenomenex Kinetex C18 (50 x 2.1 mm, 1.7 μm; temperature: 60°C) and a gradient from 90% A to 10% A over 1.6 min, retained for 0.4 min, and then to 90% A over 0.2 min. A 3 μL injection volume was used with a flow rate of 1.2 mL / min over 2.2 min (A: 0.1% HCOOH in H2O; B: CH3CN). UV spectra were recorded at 254 nm using a 1290 Infinity II diode array detector with a spectral range of 200–400 nm. Mass spectra were obtained using the LC / MSD iQ G6160A detector. Data were integrated and reported using ACD Labs software.

[0276] Analysis method a: Equipment: Shimadzu LC-20AD&MS 2020 Column: HALO C18 5.0μm, 3.0*30mm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.0mL / min (0.01~3.0min) 1.2mL / min (3.01~3.5min)

[0277] [Table 57]

[0278] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0279] Analysis method b. Equipment: Agilent 1260&6125B Column: Luna-C18(2) 2.0*50mm, 5μm Column temperature: 40 °C Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.0 mL / min

[0280]

Table 58

[0281] Detection: 220 nm MS mode: positive MS range: 100 - 1000

[0282] Analysis method c. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Halo C18 3.0*30 mm, 5 μm Column temperature: 40 °C Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.5 mL / min (0.00 - 1.30 min)

[0283]

Table 59

[0284] Analysis method d. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Halo C18 3.0*30 mm, 5 μm Column temperature: 40 °C[[ID=6S]] Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.5 mL / min (0.00 - 1.30 min)

[0285] [Table 60]

[0286] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0287] Analysis method e. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: HALO C18 5μm, 3.0*30mm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 2.0mL / min (0.00~0.9min)

[0288] [Table 61]

[0289] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0290] Analysis method f. Equipment: Agilent 1260&6125B Column: Xbridge C18 2.1*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 0.8mL / min

[0291] [Table 62]

[0292] Detection: 220nm & 254nm MS Mode: Sun MS range: 100-1000

[0293] Analysis method g. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: HALO C18 5μm, 3.0*30mm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 2.0mL / min (0.00~0.9min)

[0294] [Table 63]

[0295] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0296] Analysis method h. Equipment: Shimadzu LC-20AB&MS 2020 Column: Xtimate C18 2.1*50mm 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1.0mL / min (0.01~3.01min, 1.2mL / min (3.02~3.50min)

[0297] [Table 64]

[0298] Detection: 220 254nm MS Mode: Sun MS range: 50-2000

[0299] Analysis method i. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Halo C18 3.0*30mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.5mL / min (0.00~1.30min)

[0300] [Table 65]

[0301] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0302] Analysis methodj. Equipment: Agilent 1260&6125B Column: Luna-C18(2) 2.0*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.0mL / min

[0303] [Table 66]

[0304] Detection: 220nm & 254nm MS Mode: Sun MS range: 100-1000

[0305] Analysis methodk. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Tiank C18 50*2.1mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1mL / min (0.00~4.5min)

[0306] [Table 67]

[0307] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0308] Analysis method l. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: HALO C18 5μm, 3.0*30mm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 2.0mL / min (0.00~0.9min)

[0309] [Table 68]

[0310] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0311] Analysis method m. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Halo C18 3.0*30mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 2.0mL / min (0.00~0.90min)

[0312] [Table 69]

[0313] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0314] Analysis method n. Equipment: Shimadzu LC-20AD XR&MS 2020 Column: Titank C18, 3.0*30mm 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1.5mL / min (0.00~0.90min)

[0315] [Table 70]

[0316] Detection: 220nm 254nm MS Mode: Yang & Yin MS range: 50-2000

[0317] Analysis method o. Equipment: Shimadzu LC-20ADXR&MS 2020 Column: Xtimate C18 2.1*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1.0mL / min

[0318] [Table 71]

[0319] Detection: 220nm 254nm MS Mode: Sun MS range: 50-2000

[0320] Analysis method p. Equipment: Agilent 1260&6125B Column: Luna-C18(2) 2.0*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.0mL / min

[0321] [Table 72]

[0322] Detection: 220nm MS Mode: Sun MS range: 100-1000

[0323] Analysis methodq. Equipment: Agilent 1260&6125B Column: Luna-C18(2) 2.0*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1.0mL / min

[0324] [Table 73]

[0325] Detection: 220nm & 254nm MS Mode: Sun MS range: 100-1000

[0326] Analysis method r. Equipment: Agilent 1200&6120B Column: Xbridge C18 2.1*50mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 0.8mL / min

[0327] [Table 74]

[0328] Detection: 220nm & 254nm MS Mode: Sun MS range: 100-1000

[0329] Analysis method s. Equipment: Agilent 1200 & 6130 Column: Xbridge-C18 2.1*50mm 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 0.8mL / min

[0330] [Table 75]

[0331] Detection: 220nm 254nm MS Mode: Sun MS range: 100-1000

[0332] Analysis method t. Equipment: Shimadzu LC-20AD&MS 2020 Column: Xtimate C18 2.1*50mm 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1.0mL / min

[0333] [Table 76]

[0334] Detection: ELSD 220nm 254nm MS Mode: Sun MS range: 50-2000

[0335] Analysis method u. Equipment: Shimadzu LC-30AD&MS 2020 Column: Halo C18 3.0*30mm, 5μm Column temperature: 40℃ Mobile phase A (MPA) H2O + 0.04% (v / v) TFA Mobile phase B (MPB) ACN + 0.02% (v / v) TFA Flow rate: 1mL / min (0.01~3.00min), 1.2mL / min (3.01~3.50min)

[0336] [Table 77]

[0337] Detection: ELSD 220nm 254nm MS Mode: Sun MS range: 50-2000

[0338] The purification method was as follows:

[0339] Purification method 1 (P1): Purification LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μm; temperature: rt) and a gradient of 10–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 14.44 minutes, followed by a gradient of 95% B for 2.11 minutes. Next, a second gradient of 95%–10% B was applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0340] Purification method 2 (P2): Purification LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μm; temperature: rt) and a gradient of 30–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 11.00 minutes, followed by a gradient of 95% B for 2.10 minutes. Next, a second gradient of 95%–30% B was applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0341] Purification method 3 (P3): Purification LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 100 mm, 10 μm; temperature: rt) and a gradient of 10–95% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 14.44 minutes, followed by a gradient of 95% B for 2.11 minutes. Next, a second gradient of 95%–10% B was applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0342] Purification method 4 (P4): Purification LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μm; temperature: rt) and a gradient of 30–95% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 11.00 minutes, followed by a gradient of 95% B for 2.10 minutes. Next, a second gradient of 95%–30% B was applied over 0.21 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0343] Purification method 5 (P5): Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.04% HCl); B: ACN; Column: Phenomenex Luna C18 100mm*30mm*3μm; Column temperature: ambient, variable gradient; Flow rate: 25mL / min; Monitor wavelengths: 220nm & 254nm

[0344] Purification method 6 (P6): Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: Water (NH4HCO3); B: ACN; Column: Phenomenex C18 80*40mm*3μm; Column temperature: ambient, variable gradient; Flow rate: 25mL / min; Monitor wavelengths: 220nm & 254nm

[0345] Purification method 7 (P7): Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: Water (NH4HCO3); B: ACN; Column: Waters Xbridge Prep OBD C18 150*40mm*10μm; Column temperature: ambient, variable gradient; Flow rate: 25mL / min; Monitor wavelengths: 220nm & 254nm

[0346] Purification method 8 (P8): Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: Water (NH4HCO3); B: ACN; Column: Waters Xbridge BEH C18 100*30mm*10μm; Column temperature: ambient, variable gradient; Flow rate: 25mL / min; Monitor wavelengths: 220nm & 254nm

[0347] Purification method 9 (P9): Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: Water (NH4HCO3); B: ACN; Column: Waters Xbridge BEH C18 250*70mm*10μm; Column temperature: ambient, variable gradient; Flow rate: 25mL / min; Monitor wavelengths: 220nm & 254nm

[0348] Purification method 10 (P10): Device: Orienda; Mobile phase: A: Water + HCl; B: ACN Column: 4kg Agela C18 column; Flow rate: 500mL / min;

[0349] Purification method 11 (P11): Equipment: Waters SFC350 Preparative SFC: Mobile phase: CO2 (A) and EtOH (B) (0.1% NH3H2O); B% = 55% homogeneous concentration elution mode Column: DAIEL CHIRALPAK AD (250mm x 50mm, 10μm); Column temperature: ambient, variable gradient; Flow rate: 200g / min; Monitor wavelength: 220nm

[0350] Purification method 12 (P12): Equipment: Waters SFC350 Preparative SFC: Mobile phase: CO2 with A and EtOH with B; B% = 20% uniform concentration elution mode Column: DAISEL CHIRALPAK OJ (250mm x 50mm, 10μm); Column temperature: ambient, variable gradient; Flow rate: 200g / min; Monitor wavelength: 220nm

[0351] Purification method 13 (P13): The raw material was purified using a Jasco system consisting of a CO2 preparative pump (PU-4387), a preparative pump for organic solvents (PU-4087 with a 6-channel selector), a preparative SFC autosampler (AS-4358), a column oven with a 4-valve selector (CO-4065), a PDA detector (MD-4015), a back pressure regulator (BP-4340), two open-bed collectors (Gilson-223), and a Julabo recirculation condenser (FL 1201). Data acquisition was performed using ChromNAV 2.04.00 software with a Phnomenex Lux amylose-1 column (250x30mm, 5μm, 5μM; temperature: 35℃) with BPR set at a flow rate of 30 mL / min and 120 Bar. Uniform concentration mode elution was performed in stack injection mode for 20 minutes at 60% B (A=CO2; B=0.1% diethylamine in 2-propanol). The acquisition frequency was set to 220 nm for the PDA detector.

[0352] Purification method 14 (P14): The raw material was purified using a Jasco system consisting of a CO2 preparative pump (PU-4387), a preparative pump for organic solvents (PU-4087 with a 6-channel selector), a preparative SFC autosampler (AS-4358), a column oven with a 4-valve selector (CO-4065), a PDA detector (MD-4015), a back pressure regulator (BP-4340), two open-bed collectors (Gilson-223), and a Julabo recirculation condenser (FL 1201). Data acquisition was performed using ChromNAV 2.03.05 software with a Phnomenex Lux amylose-1 column (250x30mm, 5μm, 5μM; temperature: 35℃) with BPR set at a flow rate of 30 mL / min and 120 Bar. Uniform concentration mode elution was performed in stack injection mode for 20 minutes at 55% B (A=CO2; B=0.1% diethylamine in 2-propanol). The acquisition frequency was set to 220 nm for the PDA detector.

[0353] Purification method 15: Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Waters Xbridge Prep OBD C18 150*40mm*10μm; Column temperature: Ambient; Gradient: 30% to 60% over 8.0 minutes; Flow rate: 25mL / min; Monitor wavelengths: 220 & 254 nm

[0354] Purification method 16: Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Phenomenex Gemini-NX 150*30mm*5μm; Column temperature: Ambient; Gradient: 30% to 70% over 20.0 minutes; Flow rate: 25mL / min; Monitor wavelengths: 220 & 254 nm

[0355] Purification method 17: Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.2% FA)-ACN; B: ACN; Column: Phenomenex Luna C18 100*30mm*3μm; Mobile phase; Column temperature: Ambient; Gradient: 25% to 55% over 8.0 minutes; Flow rate: 25mL / min; Monitor wavelengths: 220 & 254 nm

[0356] Purification method 18: Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Agela DuraShell C18 250*70mm*10μm; Column temperature: Ambient; Gradient: 80% to 95% over 20.0 minutes; Flow rate: 25mL / min; Monitor wavelengths: 220 & 254 nm

[0357] Purification method 19: Equipment: Gilson 281 semi-preparative HPLC system; Mobile phase: A:H2O(0.05% NH3H2O+10mM NH4HCO3);B:ACN; Column: Welch Xtimate C18 250*100mm*10μm; Column temperature: Ambient; Gradient: 40% to 70% over 24.0 minutes; Flow rate: 25mL / min; Monitor wavelengths: 220 & 254 nm

[0358] SFC purification method A: Equipment: Auno-600; Mobile phase: A for heptane and B for EtOH (0.1% NH3H2O); B% = 20% homogeneous concentration elution mode; Column: DAIEL CHIRALPAK IG (250mm x 50mm, 10μm); Column temperature: 25℃ Flow rate: 130mL / min Monitor wavelength: 200nm

[0359] NMR conditions Unless otherwise specified, 1¹H NMR spectra were recorded at 500 MHz or 400 MHz using either a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 400 MHz spectrometer, respectively. Chemical shift δ is cited in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to indicate multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (triplet of doublet), dq (quadruplet of doublet), hep (septuplet), m (multiplet), pent (quintet), td (doublet of triplet), qd (doublet of quadruplet), app. (Apparent) and br (broad). The coupling constant, J, is quoted down to the nearest 0.1 Hz.

[0360] [Table 78]

[0361] [Table 79]

[0362] [Table 80]

[0363] [Table 81]

[0364] [Table 82]

[0365] The compound was named with the help of OpenEye Scientific software (Lexichem TK).

[0366] Synthesis method 1 Scheme for Method 1 [ka]

[0367] Process 1, method 1 2-chloro-2-oxoethyl acetate (12.0 mL, 105.0 mmol, CAS 4755-77-5) was added to a solution of 7-bromo-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (20.00 g, 69.9 mmol) in anhydrous THF (300 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain 7-bromo-2-(2-ethoxy-2-oxoacetyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-1-carboxylic acid as a yellow solid, which was used directly in the next step assuming a quantitative yield. RT(M2) = 0.75 min, [M+H] + (ESI + 386.1 / 388.1.

[0368] Process 2, method 1 Penta-1-yne (8.6 mL, 87.4 mmol, CAS 627-19-0) was added to a stirred solution of 7-bromo-2-(2-ethoxy-2-oxoacetyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-1-carboxylic acid (26.99 g, 69.9 mmol) in acetic anhydride (207 mL). The reaction mixture was placed in a heat block preheated to 140 °C and stirred for 45 minutes. The reaction mixture was cooled and concentrated under vacuum. The resulting residue was dissolved in DCM (200 mL) and stirred with saturated aqueous solution of NaHCO3 (100 mL). The organic layer was separated, dried over MgSO4, and concentrated under vacuum. Heptane (200 mL) and diethyl ether (50 mL) were added, and the resulting mixture was heated at 85 °C for 30 minutes. A solid was obtained by thermal filtration. This solid was dried and ground using a mortar and pestle to obtain 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (13.90 g, yield 48%) as a brown solid. The filtrate was left at room temperature overnight to form orange crystals, which were isolated by filtration to obtain the more desirable product as an orange solid (3.13 g, yield 11%). RT(M2) = 1.31 min, [M+H] + (ESI + )392.3 / 394.3; 1 H NMR(500MHz,DMSO)δ 7.68(s,1H),7.16(s,1H),6.78(s,1H),4.48(t,J=6.6Hz,2H),4.21(q,J=7.1Hz,2H),3.88(s,3H),2.99( t,J=6.5Hz,2H),2.63(t,J=7.6Hz,2H),1.66-1.57(m,2H),1.27(t,J=7.1Hz,3H),0.97(t,J=7.3Hz,3H).

[0369] The following analogues were prepared by similar methods.

[0370] [Table 83]

[0371] [Table 84]

[0372] [Table 85]

[0373] Synthesis method 2 Scheme for Method 2 [ka]

[0374] Process 1, method 2 Potassium hydroxide (7.93 g, 139.0 mmol) was added at 80°C to a stirred solution of 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (prepared according to a method similar to Method 1 (Steps 1 and 2)) using 2-ethinylthiophene (15.00 g, 34.7 mmol) in ethanol (300 mL) and water (100 mL). After 1 hour, the reaction mixture was cooled to room temperature and concentrated under vacuum. The aqueous residue was concentrated to 1 M aq. The solution was acidified to pH 1 using HCl, and the suspended solid in the aqueous layer was recovered by filtration to obtain 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (purity 83%, 14.70 g, yield 87%) as a light brown solid. RT(M2) = 1.03 min, [M+H] + (ESI + )402.9 / 404.9.

[0375] Process 2, method 2 DIPEA (30 mL, 173.0 mmol, CAS 7087-68-5), HATU (14.11 g, 37.1 mmol, CAS 148893-10-1), and (2R)-2-methylpyrrolidine-2-carboxamide hydrochloride (4.89 g, 29.7 mmol, CAS 1262381-66-7) were added at room temperature to a stirred solution of 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (10.00 g, 24.7 mmol) in DCM (400 mL). The reaction mixture was stirred overnight and then diluted with DCM and water. The layers were separated, the organic matter was passed through a phase separator, and then concentrated under vacuum to obtain the crude product as brown oil. The crude product was purified by FCC (elution with 0-100% ethyl acetate in silica and heptane, followed by 0-20% MeOH in ethyl acetate). The fraction containing the product was concentrated under vacuum to obtain (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carboxamide (10.27 g, yield 77%) as a pale brown foam. RT(M2) = 1.00 min, [M+H] + (ESI + )514.2 / 516.2; 1 1H NMR (400MHz, DMSO) δ 8.16(s,1H),7.57(dd,J=5.2,1.2Hz,1H),7.45(s,1H),7.18-7.10(m,2H),7. 07(dd,J=3.4,1.2Hz,1H),6.82(s,1H),6.66(s,1H),4.24-4.20(m,1H),3.96- 3.91(m,1H),3.86(s,3H),3.81-3.74(m,1H),3.69-3.57(m,1H),3.20-3.09( m,1H),3.05-2.97(m,1H),2.10-2.02(m,1H),1.89-1.84(m,3H),1.53(s,3H).

[0376] The following analogues were prepared by similar methods.

[0377] [Table 86]

[0378] [Table 87]

[0379] [Table 88]

[0380] [Table 89]

[0381] [Table 90]

[0382] [Table 91]

[0383] Synthesis method 3 Scheme for Method 3 [ka]

[0384] Process 1, method 3 (1S)-2,2,2-trifluoro-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (447 mg, 2.0 mmol, synthesized by Method 16) was added to a stirred solution of di(imidazole-1-yl)methanone (412 mg, 2.5 mmol, CAS 530-62-1) and 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-carboxylic acid (690 mg, 1.7 mmol) in anhydrous DMF (10 mL), and left overnight at room temperature. Next, the reaction mixture was heated to 50°C and stirred for 8 hours, then retreated with (1S)-2,2,2-trifluoro-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (447 mg, 2.0 mmol), and stirred for a further 72 hours at room temperature. The reaction mixture was concentrated under vacuum and partitioned between DCM and water. The layers were separated, the organic matter was passed through a phase separator, and concentrated under vacuum to obtain the crude product as a yellow oil, which was purified by FCC (eluted with 0-100% ethyl + (ESI + )569.1 / 571.1; 1 H NMR(400MHz,DMSO)δ 7.56(dd,J=5.2,1.2Hz,1H),7.43(s,1H),7.16-7.09(m,2H),7.06(dd,J=3 .5,1.2Hz,1H),6.66(d,J=7.2Hz,1H),6.50(s,1H),4.99(p,J=8.4Hz,1H),4 .31-4.10(m,2H),3.88-3.84(m,4H),3.70-3.59(m,1H),3.02(t,J=6.5Hz, 2H),2.43-2.28(m,1H),1.85-1.74(m,2H),1.74-1.63(m,1H),1.60(s,3H).

[0385] Synthesis method 4 Scheme for Method 4 [ka]

[0386] Process 1, method 4 (1R)-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (492 mg, 3.0 mmol, synthesized by Method 15) was added to a stirred solution of di(imidazole-1-yl)methanone (602 mg, 3.7 mmol, CAS 530-62-1) and 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (1.00 g, 2.5 mmol) in anhydrous DMF (14 mL). The reaction mixture was heated at 90°C for 2.5 hours. DIPEA (1.1 mL, 6.2 mmol, CAS 7087-68-5) was added, and the mixture was stirred overnight at 90°C. The reaction mixture was concentrated under vacuum and dissolved in DCM and water. The layers were separated, the organic matter was passed through a phase separator, and concentrated under vacuum to obtain oil, which was purified by FCC (eluting with 0-100% ethyl + 515.3 / 517.3. 1H NMR(500MHz,DMSO)δ 7.55(dd,J=5.2,1.1Hz,1H),7.43(s,1H),7.14-7.10(m,2H),7.06(dd,J=3.5,1.2Hz,1H),6.53(s,1 H),4.96(d,J=4.9Hz,1H),4.44(p,J=6.3Hz,1H),4.31(dt,J=13.0,6.5Hz,1H),4.11-4.05(m,1H),3. 85(s,3H),3.81(ddd,J=10.0,6.6,3.5Hz,1H),3.67-3.59(m,1H),3.01(t,J=6.5Hz,2H),2.07(ddd, J=12.6,10.2,7.7Hz,1H),1.81-1.71(m,2H),1.57-1.51(m,1H),1.50(s,3H),1.00(d,J=6.3Hz,3H).

[0387] The following analogues were prepared by similar methods.

[0388] [Table 92]

[0389] Synthesis method 5 Scheme for Method 5 [ka]

[0390] Process 1, method 5 1.1 mL, 1.1 mmol of 1 M aqueous lithium hydroxide was added to a stirred suspension of ethyl 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (200 mg, 0.5 mmol, synthesized by Method 1) in ethanol (4.7 mL). The mixture was heated at 80°C for 3 hours to form a solution. After cooling to room temperature, the mixture was concentrated under vacuum to obtain the product 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate lithium hydroxide (226 mg, quantitative) as a grayish-white powder. RT(M2) = 1.03 min, (ESI+)(M+H)+ 364.1 / 366.1; 1 H NMR(400MHz,DMSO-d6)δ 7.54(s,1H),7.06(s,1H),6.30(s,1H),4.62(t,J=6.3Hz,2H),3.84(s,3H),2.84( t,J=6.3Hz,2H),2.60-2.53(m,2H),1.59(h,J=7.3Hz,2H),0.97(t,J=7.3Hz,3H).

[0391] Process 2, method 5 DIPEA (1.4 mL, 8.0 mmol, CAS 7087-68-5) was added to a stirred suspension of lithium hydroxide 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (1.04 g, 2.6 mmol) and (1R)-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (580 mg, 1.3 mmol, synthesized by Method 15) in DMA (25 mL). The mixture was stirred at 20°C for 5 minutes to form a turbid solution. 2-chloro-1-methylpyridinium iodide (1.50 g, 5.9 mmol, CAS 14338-32-0) was added, and the reaction mixture was stirred at 20°C for 17 hours. The reaction mixture was diluted with water (150 mL), sonicated, and allowed to stand for 10 minutes. The solid was recovered by filtration and washed with water (3 x 30 mL). Next, the solid was dissolved in siRNA (200 mL), and the organic mixture was filtered through hydrophobic filter paper. The organic filtrate was concentrated under vacuum to obtain the crude product (913 mg) as a yellowish-brown powder. The crude product was purified by FCC (eluting with 10-100% siRNA in silica and heptane) to obtain (9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone (507 mg, yield 38%) as a pale yellowish-brown powder. RT(M2) = 1.02 min, (ESI+)(M+H) + 475.2 / 477.2; 1H NMR(400MHz,DMSO)δ 7.62(s,1H),7.12(s,1H),6.38(s,1H),5.01(d,J=4.7Hz,1H),4.47-4.35(m,1H),4.25 (dt,J=13.0,6.5Hz,1H),4.05(dt,J=12.6,6.2Hz,1H),3.86(s,3H),3.77(dt,J=10.4, 5.2Hz,1H),3.66-3.52(m,1H),2.93(t,J=6.5Hz,2H),2.66-2.57(m,2H),2.05(dt,J=1 2.8,8.8Hz,1H),1.86-1.68(m,2H),1.67-1.44(m,3H),1.49(s,3H),1.02-0.92(m,6H).

[0392] Synthesis Method 6 Method 6のためのスキーム

change

[0393] Project 1, Method 6 (N-(triethylammonium sulfonyl)carbamate methyl) (2.35 g, 9.9 mmol, CAS 29684-56-8) (Burgess reagent) was added at 0°C to a mixture of (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carboxamide (2.54 g, 4.9 mmol, synthesized by Method 2) in THF (20 mL) and DCM (20 mL). The reaction mixture was heated to 20°C and stirred for 1 hour. The reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine (saturated solution of NaCl in deionized water) (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (eluted with 0-100% Â in silica and heptane), and the fraction containing the product was concentrated under vacuum to obtain (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl (92%) (2.10 g, yield 79%) as a pale yellow solid. RT(M₂) = 1.09 min, (ESI+)(M+H) + 496.0 / 497.9; 1 1H NMR (500MHz, DMSO) δ 7.58(dd,J=5.2,1.2Hz,1H),7.43(s,1H),7.16-7.11(m,2H),7.08(dd,J=3.5,1 .2Hz,1H),6.72(s,1H),4.46-4.37(m,1H),4.33-4.20(m,1H),3.91-3.85(m,4H) ,3.84-3.77(m,1H),3.05(t,J=6.5Hz,2H),2.47(dd,J=9.0,3.7Hz,1H),2.12(dd d,J=12.8,10.1,6.0Hz,1H),2.02-1.99(m,1H),1.95-1.85(m,1H),1.74(s,3H).

[0394] The following analogues were prepared by similar methods.

[0395] [Table 93]

[0396] [Table 94]

[0397] [Table 95]

[0398] [Table 96]

[0399] Synthesis method 7 Scheme for Method 7 [ka]

[0400] Process 1, method 7 In a pressure-relieving vial, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (338 mg, 1.3 mmol, CAS 73183-34-3), (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (600 mg, 1.2 mmol, synthesized by Method 6), and potassium acetate (300 mg, 3.0 mmol, CAS 127-08-2) were dissolved in anhydrous 1,4-dioxane (13 mL) and degassed with nitrogen. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (99 mg, 121 μmol, CAS 95464-05-4) was added, and the reaction mixture was stirred overnight at 90°C. The reaction mixture was concentrated and partitioned between DCM and water. The layers were separated, and the organic matter was passed through a phase separator cartridge and concentrated under vacuum. The crude material was then purified by FCC (eluting with 0-100% ethyl ethyl in silica and heptane). The fractions containing the product were collected, combined, and the solvent was removed under vacuum to obtain (2R)-1-[8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil (425 mg, yield 57%) as a light brown solid. RT(M2) = 1.1 min [M+H] + (ESI + )544.3; 1H NMR(500MHz,DMSO)δ 7.67(s,1H),7.50(dd,J=5.1,1.2Hz,1H),7.09-7.03(m,2H),6.94(s,1H),6.72(s,1H ),4.40(dt,J=13.3,6.5Hz,1H),4.26(dt,J=13.1,6.2Hz,1H),3.89(td,J=8.8,7.3,3. 8Hz,1H),3.84-3.78(m,1H),3.76(s,3H),3.06(t,J=6.5Hz,2H),2.48-2.44(m,1H),2. 17-2.08(m,1H),1.99(s,1H),1.93(dd,J=15.5,6.8Hz,1H),1.74(s,3H),1.17(s,12H)

[0401] Project 2, Method 7 A solution of (2R)-1-[8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (100 mg, 184 μmol), 2-bromo-1,3-oxazole (34 mg, 221 μmol, CAS 125533-82-6), and discesium carbonate (240 mg, 736 μmol, CAS 534-17-8) in 1,4-dioxane (2.4 mL) and water (0.6 mL) was degassed under nitrogen for 5 minutes. Next, XPhos Pd G2 (29 mg, 18 μmol, CAS 1310584-14-5) was added, and the mixture was degassed under nitrogen for 5 minutes. The reaction mixture was stirred overnight at 80°C. The reaction product was cooled to room temperature, treated with water (5 mL), and extracted with  (3 x 5 mL). The organic phases were combined, passed through a phase separator, and concentrated under vacuum. The compound was purified by acidic preparative HPLC (Method P2), followed by basic preparative HPLC (Method P4) to obtain a white solid. The white solid was further purified by chiral preparative extraction (Chiralpak AD-H, mobile phase ethanol 9 mL / min) and lyophilized to obtain (2R)-1-[8-methoxy-9-oxazole-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (compound 7-1) (24 mg, yield 27%) as a white solid. RT(M4) = 3.62 min, (ESI + )(M+H) + 485.2; 1 H NMR(400MHz,DMSO)δ 8.09(s,1H),7.96(s,1H),7.51(dd,J=3.9,2.5Hz,1H),7.28-7.20(m,2H),7.12-7.05(m,2H),6.73(s,1H),4.50-4.39(m,1H),4.35-4.23( m,1H),3.93-3.86(m,4H),3.86-3.77(m,1H),3.13(t,J=6.4Hz,2H),2.47-2.42(m,1H),2.19-2.08(m,1H),2.05-1.85(m,2H),1.74(s,3H).

[0402] The following analogues were prepared by similar methods.

[0403] [Table 97]

[0404] [Table 98]

[0405] [Table 99]

[0406] [Table 100]

[0407] [Table 101]

[0408] [Table 102]

[0409] [Table 103]

[0410] Synthesis method 8 Scheme for Method 8 [ka]

[0411] Process 1, method 8 A solution of (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (600 mg, 1.2 mmol, synthesized by Method 6), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (334 mg, 1.6 mmol, CAS 1020174-04-2), and discesium carbonate (1.58 g, 4.8 mmol, CAS 534-17-8) in 1,4-dioxane (15 mL) and water (6 mL) was degassed with nitrogen. XPhos Pd G2 (190 mg, 121 μmol, CAS 1310584-14-5) was added, and the reaction mixture was heated to 80°C for 2 hours. The mixture was cooled to room temperature, poured into water (50 mL), and extracted with DCM (3 x 50 mL). The organic phases were combined, passed through a phase separator, and concentrated under vacuum. The compound was purified by FCC (0-100% EtOAC in heptane) to obtain a brown solid, which was further purified by reversed-phase FCC (10-100% MeCN in water). The fraction containing the product was concentrated in vacuum, freeze-dried, and dried in a vacuum oven over the weekend to obtain (2R)-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (compound 8-1) (349 mg, yield 57%) as a white solid. RT(M4) = 3.82 min [M+H] + (ESI + )498.3; 1H NMR(400MHz,DMSO)δ 8.09(s,1H),7.60(d,J=2.1Hz,1H),7.50(dd,J=3.8,2.6Hz,1H),7.12-7.09(m,2H ),7.06(s,1H),6.72(s,1H),6.52(d,J=2.2Hz,1H),4.51-4.37(m,1H),4.34-4.20( m,1H),3.94-3.88(m,1H),3.87(s,3H),3.85-3.78(m,1H),3.76(s,3H),3.06(t,J= 6.4Hz,2H),2.48-2.42(m,1H),2.20-2.08(m,1H),2.05-1.87(m,2H),1.74(s,3H).

[0412] The following analogues were prepared by similar methods.

[0413] [Table 104]

[0414] [Table 105]

[0415] [Table 106]

[0416] [Table 107]

[0417] Synthesis method 9 Scheme for Method 9 [ka]

[0418] Process 1, method 9 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (234 mg, 922 μmol, CAS 73183-34-3), [9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone (540 mg, 838 μmol, synthesized by Method 4), and potassium acetate (208 mg, 2.1 mmol, CAS 127-08-2) were dissolved in anhydrous 1,4-dioxane (8 mL), and the mixture was degassed with N2. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (68 mg, 84 μmol, CAS 95464-05-4) was added, and the reaction mixture was stirred overnight at 90°C. The reaction mixture was cooled, concentrated under vacuum, and partitioned between DCM and water. The organic layer was separated, dried by passing it through a phase separator cartridge, and concentrated under vacuum to obtain the crude product. The crude product was purified by FCC (eluted with 0-100% ethyl ethyl phosphate in silica and heptane). The fractions containing the product were combined and concentrated in vacuum to obtain [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-yl]-[8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone (230 mg, yield 44%) as a brown solid. RT(M5) = 1.02 min [M+H] + (ESI) + 563.5; 1H NMR(500MHz,DMSO)δ 7.67(s,1H),7.49-7.46(m,1H),7.07-7.01(m,2H),6.91(s,1H),6.52(s,1H),4.98(d ,J=4.8Hz,1H),4.47-4.40(m,1H),4.34-4.27(m,1H),4.11-4.04(m,1H),3.85-3.79( m,1H),3.75(s,3H),3.67-3.60(m,1H),3.02(t,J=6.5Hz,2H),2.10-2.02(m,1H),1.8 0-1.69(m,2H),1.56-1.51(m,1H),1.51(s,3H),1.17(s,12H),1.00(d,J=6.4Hz,3H).

[0419] Step 2, method 9 A solution of [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-yl]-[8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone (110 mg, 176 μmol), 2-bromoimidazole-1-carboxylate tert-butyl (52 mg, 211 μmol, CAS 1207457-15-5), and discesium carbonate (229 mg, 704 μmol, CAS 534-17-8) in 1,4-dioxane (2 mL) and water (680 μL) was degassed with N2. XPhos Pd G2 (28 mg, 18 μmol, CAS 1310584-14-5) was added, and the reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was diluted with water and extracted with DCM (3 x 10 mL). The combined organic extracts were concentrated under vacuum and purified by acidic preparative HPLC (P3). The fraction containing the product was concentrated under vacuum to obtain [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-yl]-[9-(1H-imidazole-2-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone (compound 9-1) (13 mg, yield 14%) as a white solid. RT(M4) = 2.1 min [M+H] +(ESI + )503.3; 1 H NMR(500MHz,DMSO)δ 11.68(s,1H),8.36(s,1H),7.48-7.43(m,1H),7.13(s,1H),7.11-7.04(m,3H),6.89( s,1H),6.54(s,1H),4.99(s,1H),4.49-4.41(m,1H),4.37-4.29(m,1H),4.13-4.04(m, 1H),3.97(s,3H),3.87-3.79(m,1H),3.69-3.62(m,1H),3.05(t,J=6.4Hz,2H),2.12-2 .03(m,1H),1.83-1.70(m,2H),1.58-1.53(m,1H),1.52(s,3H),1.02(d,J=6.3Hz,3H).

[0420] The following analogues were prepared by similar methods.

[0421] [Table 108]

[0422] Synthesis method 10 Scheme for Method 10 [ka]

[0423] Process 1, method 10 In a 20 mL pressure tube, a stirred solution of (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (300 mg, 604 μmol, synthesized by Method 6), phenyl formate (340 μL, 3.0 mmol, CAS 1864-94-4), and triethylamine (420 μL, 3.0 mmol, CAS 121-44-8) in anhydrous DMF (5 mL) was degassed under nitrogen for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 60 μmol, CAS 72287-26-4) was added, the solution was degassed under nitrogen for 5 minutes, and the mixture was heated to 100 °C for 4 hours. The reaction mixture was cooled to room temperature, CO was slowly released, and then purged with nitrogen. The mixture was concentrated under vacuum, diluted with water (5 mL), and extracted with dichloromethane (3 x 5 mL). The combined organic extract was concentrated under vacuum to obtain a residue, which was purified by FCC (eluted with 0-100% Â in silica and heptane) to obtain 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (280 mg, yield 78%) as a brown solid. RT(M2) = 1.05 min, (ESI + )(M+H) + 538.2; 1 H NMR(500MHz,DMSO-d6)δ 7.99(s,1H),7.54-7.50(m,1H),7.46-7.41(m,2H),7.30-7.23(m,2H),7. 13-7.03(m,4H),6.75(s,1H),4.50-4.43(m,1H),4.35-4.28(m,1H),3.92 -3.85(m,4H),3.86-3.77(m,1H),3.17(t,J=6.7Hz,2H),2.17-2.09(m,1H ),2.03-1.99(m,1H),1.95-1.85(m,1H),1.75(s,3H),1.67-1.53(m,1H).

[0424] Step 2, method 10 2M lithium hydroxide hydrate aq. (1.4 mL, 2.8 mmol) was added at room temperature to a stirred solution of 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (90% purity, 280 mg, 469 μmol) in THF (3 mL), and the reaction mixture was stirred overnight. The reaction mixture was concentrated under vacuum, acidified to pH 1 with 1M aq HCl, and extracted with ELISA (3 x 10 mL). The organic compounds were combined, passed through a phase separator cartridge, and concentrated under vacuum to obtain 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (purity 80%, 270 mg, yield 100%) as a brown solid. RT(M2) = 0.83 min, (ESI + )(M+H) + 462.2.

[0425] Step 3, method 10 HATU (111 mg, 293 μmol, CAS 148893-10-1) and 1-aminocyclobutane carbonitride hydrochloride (1:1) (31 mg, 234 μmol, CAS 845821-84-3) were added at room temperature to a stirred solution of 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (90 mg, 195 μmol) and DIPEA (140 μL, 780 μmol, CAS 7087-68-5) in DCM (4 mL) and anhydrous DMF (400 μL). The reaction mixture was stirred overnight. The reaction mixture was poured into water (3 mL) and extracted with DCM (3 x 3 mL). The organic phases were combined, passed through a phase separator, and concentrated under vacuum. The crude product was purified by acidic preparative HPLC (Method P2), and the fraction containing the product was freeze-dried to obtain N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide (compound 10-1) (36 mg, yield 34%) as a white solid. RT(M4) = 3.76 min, (ESI+)(M+H) + 540.3; 1 H NMR(500MHz,DMSO-d6)δ 8.73(s,1H),7.79(s,1H),7.53(dd,J=5.0,1.4Hz,1H),7.19(s,1H),7.13-7.07(m,2H),6. 73(s,1H),4.43(dt,J=13.2,6.6Hz,1H),4.28(dt,J=12.9,6.2Hz,1H),3.92(s,3H),3.91- 3.76(m,2H),3.12(t,J=6.6Hz,2H),2.71-2.58(m,2H),2.54-2.52(m,1H),2.34(ddd,J=12 .9,9.4,7.7Hz,2H),2.14(ddd,J=12.7,10.1,5.9Hz,1H),2.08-1.86(m,4H),1.75(s,3H).

[0426] The following analogues were prepared by similar methods.

[0427] Table 109

[0428] Table 110

[0429] Table 111

[0430] Table 112

[0431] Table 113

[0432] Table 114

[0433] Table 115

[0434] Table 116

[0435] Table 117

[0436] Table 118

[0437] Table 119

[0438] Synthesis method 11 Scheme for Method 11 [ka]

[0439] Process 1, method 11 In a 40 mL pressure tube, a solution of (2S)-1-[9-bromo-8-methoxy-1-(thiophen-2-yl)-5H,6H-pyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-ethyl-2-methylpyrrolidine (94% purity, 390 mg, 671 μmol, synthesized by Method 2) in anhydrous DMF (5 mL) was degassed with nitrogen for 5 minutes. Phenyl formate (340 μL, 3.1 mmol, CAS 1864-94-4), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 62 μmol, CAS 72287-26-4) and triethylamine (430 μL, 3.1 mmol, 121-44-8) were added, and the reaction mixture was heated to 100 °C for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, and CO was released under vacuum. The pressure tube was evacuated, refilled three times with N2, and the reaction mixture was concentrated under vacuum. The resulting residue was partitioned between DCM (20 mL) and water (30 mL) and extracted with DCM (2 x 20 mL). The organic matter was combined, and the solvent was removed under vacuum to obtain the crude product as a brown oil. This was purified by FCC (eluted with 0-100% ethyl in silica and heptane) to obtain 3-[(2S)-2-ethyl-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (86% purity, 206 mg, 62% yield) as a brown oil. RT(M2) = 1.21 min, (ESI+)(M+H) + 541.3; 1H NMR(500MHz,DMSO-d6)δ 7.99(s,1H),7.50(dd,J=5.1,1.2Hz,1H),7.46-7.40(m,2H),7.29-7.25(m,1H),7.23(s,1H), 7.10(dd,J=3.5,1.2Hz,1H),7.08-7.04(m,3H),6.56(s,1H),4.40-4.30(m,1H),4.23-4.11(m, 1H),3.89(s,3H),3.80-3.73(m,1H),3.70-3.59(m,1H),3.13(t,J=6.5Hz,2H),2.15-2.05(m, 1H),1.97-1.91(m,1H),1.85-1.71(m,3H),1.68-1.56(m,1H),1.46(s,3H),0.89-0.73(m,3H).

[0440] Project 2, Method 11 N,N-dimethylglycinamide (25 mg, 246 μmol, CAS 1857-19-8) and discesium carbonate (112 mg, 345 μmol, CAS 534-17-8) were added to a stirred solution of 3-[(2S)-2-ethyl-2-methyl-cyclopentanecarbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (86% purity, 103 mg, 164 μmol) in anhydrous DMF (2 mL). The mixture was heated to 70°C and stirred for 5 hours and 30 minutes, then cooled to room temperature and left stirred at room temperature over the weekend. The reaction mixture was heated to 70°C and stirred for 51 hours. The reaction mixture was concentrated under vacuum, and DCM (20 mL) and water (20 mL) were added to separate the layers. The aqueous layer was washed with DCM (2 x 20 mL). The organic compounds were combined, passed through a phase separator, and concentrated under vacuum to obtain the crude product as a brown oil. The crude product was purified by acidic preparative HPLC (Method P2), and the fraction containing the product was freeze-dried to obtain N-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2S)-2-ethyl-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide (compound 11-1) (29 mg, yield 32%) as a grayish-white solid. RT(M4) = 3.83 min, (ESI+)(M+H) + 549.3; 1H NMR(500MHz,DMSO-d6)δ 8.63(t,J=4.4Hz,1H),8.19(s,1H),7.47(dd,J=5.1,1.2Hz,1H),7.18(s,1H),7.06(dd,J=5.1,3.5Hz, 1H),7.04(dd,J=3.5,1.2Hz,1H),6.52(s,1H),4.39-4.28(m,1H),4.18-4.07(m,3H),3.97(s,3H),3.81 -3.73(m,1H),3.71-3.60(m,1H),3.08(t,J=6.4Hz,2H),2.95(s,3H),2.87(s,3H),2.16-2.06(m,1H),2 .01-1.90(m,1H),1.78(dp,J=13.6,7.1Hz,3H),1.66-1.59(m,1H),1.46(s,3H),0.82(t,J=7.4Hz,3H).

[0441] Synthesis Method 12 Method 12のためのスキーム

change

[0442] Project 1, Method 12 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.59 g, 7.6 mmol, CAS 1020174-04-2), cesium carbonate (6.63 g, 20.4 mmol, CAS 534-17-8), and XPhos Pd G2 (400 mg, 509 μmol, CAS 1310584-14-5) were added to a solution of 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (2.20 g, 5.1 mmol, synthesized by Method 1) in 1,4-dioxane (60 mL) and water (30 mL). The reaction mixture was degassed with nitrogen and heated to 80°C for 2 hours. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with DCM (3 x 20 mL). The organic phases were combined, passed through a phase separator, and concentrated under vacuum. The resulting residue was purified by FCC (eluted with 0-100% ethyl ethyl silica gel in heptane). The fraction containing the product was concentrated under vacuum to obtain 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (2.11 g, yield 94%) as a brown solid. RT(M2) = 1.08 [M + H] + (ESI + )434.3

[0443] Step 2, method 12 To a solution of potassium hydroxide (1.11 g, 19.5 mmol) in water (15 mL), 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (2.11 g, 4.9 mmol) in ethanol (45 mL) was added. The resulting suspension was heated to 80°C to form a solution and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under vacuum, and acidified to pH 1 with 1 M aq. HCl. The acidic aqueous phase was extracted using DCM (3 x 20 mL). The organic matter was combined and passed through a phase separator cartridge. Some of the product precipitated on the cartridge. The filtrate was collected together with the concentrated organic matter to obtain 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (1.71 g, yield 82%) as a brown solid. RT(M2) = 0.83[M+H] + (ESI + )406.2; 1 H NMR(400MHz,DMSO)δ 12.43(s,1H),8.09(s,1H),7.60(d,J=2.1Hz,1H),7.50(dd,J=3.8,2.6Hz,1H),7.12-7.08(m,2H),7.07(s,1H) ),6.87(s,1H),6.52(d,J=2.2Hz,1H),4.55(t,J=6.5Hz,2H),3.87(s,3H),3.76(s,3H),3.08(t,J=6.5Hz,2H).

[0444] The following analogues were prepared by similar methods.

[0445] [Table 120]

[0446] Synthesis method 13 Scheme for Method 13 [ka]

[0447] Process 1, method 13 DIPEA (1.3 mL, 7.3 mmol, CAS 1205744-09-7), HATU (1.03 g, 2.7 mmol, CAS 148893-10-1), and (1R)-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (360 mg, 2.2 mmol, synthesized by Method 15) were added at room temperature to a stirred solution of 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (735 mg, 1.8 mmol, synthesized by Method 12) in DCM (20 mL). After 24 hours, the reaction mixture was retreated with (1R)-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (360 mg, 2.2 mmol) and DIPEA (1.3 mL, 7.3 mmol), and stirred for a further 2 days. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), the organic phase was passed through a phase separator, and then concentrated under vacuum to obtain the crude product as brown oil. Next, the crude product was purified by FCC (eluted with 30-100% ethyl acetate in silica and heptane). The fractions containing the product were collected, combined, and the solvent was removed under vacuum to obtain brown oil, which was further purified by acidic preparative HPLC (Method P2). The fractions containing the product were collected, combined, and the solvent was removed under vacuum to obtain [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-yl]-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone (compound 13-1) (415 mg, yield 44%) as a white solid. RT(M4) = 3.69 min [M+H] + (ESI + )517.3; 1H NMR(500MHz,DMSO)δ 8.08(s,1H),7.60(d,J=2.1Hz,1H),7.50-7.44(m,1H),7.12-7.06(m,2H),7.03(s,1H),6 .53(s,1H),6.52(d,J=2.2Hz,1H),4.99(d,J=4.8Hz,1H),4.51-4.40(m,1H),4.38-4.26(m ,1H),4.16-4.03(m,1H),3.93-3.79(m,4H),3.76(s,3H),3.69-3.59(m,1H),3.03(t,J=6. 4Hz,2H),2.14-1.99(m,1H),1.87-1.67(m,2H),1.59-1.45(m,4H),1.01(d,J=6.3Hz,3H).

[0448] The following analogues were prepared by similar methods.

[0449] [Table 121]

[0450] [Table 122]

[0451] [Table 123]

[0452] [Table 124]

[0453] Synthesis method 14 Scheme for Method 14 [ka]

[0454] Process 1, method 14 Cbz-Cl (3.1 mL, 21.8 mmol, CAS 501-53-1) was added dropwise at 0°C to a stirred mixture of [(2S)-2-methylpyrrolidine-2-yl]methanol hydrochloride (3.00 g, 19.8 mmol, CAS 1408057-43-1), 2M sodium carbonate (35.0 mL, 69.2 mmol), and DCM (45 mL). The reaction mixture was stirred and warmed overnight to room temperature. The reaction mixture was diluted with DCM and water, and the layers were subsequently separated. The aqueous phase was extracted with further DCM, and the combined organic matter was passed through a phase separator and subsequently concentrated. The material was purified by FCC (eluted with 0-100% ethyl RT(M2)=0.80min[M + H] + (ESI + )250.2

[0455] Step 2, method 14 Oxalyl chloride (3.8 mL, 44.0 mmol, CAS 79-37-8) was dissolved in DCM (92 mL) and cooled to -78°C. DMSO (6.3 mL, 88.5 mmol) was added dropwise, and the reaction mixture was stirred at -78°C for 10 minutes. (2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate benzyl (3.00 g, 12.0 mmol) (as a solution in 5 mL of DCM) was added, and the mixture was stirred at -78°C for 15 minutes. Triethylamine (21.0 mL, 0.150 mol) was added dropwise, and the reaction mixture was stirred at -78°C for 3 hours. The reaction mixture was quenched by adding water (20 mL), warmed to room temperature, diluted with DCM (20 mL), and saturated aqueous solution of NaHCO3 (50 mL) was added. The aqueous phase was extracted into DCM (3 x 50 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting oil was purified by FCC (eluted with 0-60% ethyl + H] + (ESI +)248.1.

[0456] Step 3, method 14 Potassium t-butoxide (1.82 g, 16.2 mmol) was added to a suspension of methyl(triphenyl)phosphonium bromide (5.78 g, 16.2 mmol, CAS 1779-49-3) in diethyl ether (130 mL), and the reaction mixture was stirred at room temperature under N2 for 2 hours. Next, a solution of (2S)-2-formyl-2-methyl-pyrrolidine-1-carboxylate benzyl (2.00 g, 8.1 mmol) in diethyl ether (20 mL) was added dropwise. The reaction mixture was then stirred for 2 hours, diluted with heptane (50 mL), and filtered. The filtered material was washed with diethyl ether / heptane (1:2 mixture, 150 mL), and the combined filtrate was concentrated under reduced pressure. The obtained solid was purified by FCC (elution with 0-100% ethyl + H] + (ESI + )246.2.

[0457] Step 4, method 14 To a solution of (2S)-2-methyl-2-vinyl-pyrrolidine-1-carboxylate benzyl (1.64 g, 6.7 mmol) in ethanol (65 mL), add palladium carbon (10%, 683 mg, 640 μmol) and N2 2(g) It was added below. Mixture, H 2(g) The mixture was stirred at room temperature for 4 hours under the specified atmosphere. The reaction mixture was filtered through Celite and washed with MeOH. 4M HCl (3.3 mL, 13.4 mmol) in dioxane was added to the filtrate, and the mixture was stirred at room temperature for 10 minutes, followed by concentration to obtain a yellow semi-solid. The residue was dissolved in DCM and concentrated (x3) to obtain (2S)-2-ethyl-2-methyl-pyrrolidine hydrochloride (958 mg, yield 94%) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 9.11(br s,1H),8.94(br s,1H),3.19(s,2H),2.03-1.86(m,2H),1.76-1.65(m,4H),1.25(br s,3H),0.92(t,J=7.5Hz,3H).

[0458] Synthesis method 15 Scheme for Method 15 [ka]

[0459] Process 1, method 15 Sodium triacetoxyborohydride (2.80 g, 13.2 mmol, CAS 56553-60-7) was added at room temperature to a stirred solution of [(2R)-2-methylpyrrolidine-2-yl]methanol hydrochloride (1.25 g, 8.2 mmol, CAS 1408057-43-1) and benzaldehyde (1.0 mL, 9.9 mmol, CAS 100-52-7) in anhydrous THF (41 mL). The solution was stirred for 24 hours. Saturated aqueous solution of NH4Cl was added (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined and washed with saturated aqueous solution of NH4Cl (2 x 30 mL). The aqueous layers were combined, basicized to pH 10 using saturated aqueous solution of Na2CO3, and extracted with ethyl acetate (3 x 50 mL). The combined organic matter was washed with brine (30 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain [(2R)-1-benzyl-2-methylpyrrolidine-2-yl]methanol (1.37 g, 6.0 mmol, yield 73%) as a pale yellow oil, which was used without further purification. RT(M10) = 0.77 min [M+H] + (ESI + )206.2; 1H NMR(500MHz,DMSO)δ 7.31-7.24(m,4H),7.23-7.16(m,1H),4.37-4.24(m,1H),3.77(d,J=13.4Hz,1H),3.43(d,J=13.4Hz,1H),3.32-3.29(m ,2H),2.70-2.61(m,1H),2.43(q,J=8.1Hz,1H),1.91-1.82(m,1H),1.69-1.54(m,2H),1.51-1.41(m,1H),1.00(s,3H).

[0460] Step 2, method 15 Oxalyl chloride (5.0 mL, 58.3 mmol, CAS 79-37-8) was dissolved in DCM (70 mL) and cooled to -78°C. DMSO (8.5 mL, 0.120 mol) was added dropwise, and the reaction mixture was stirred at -78°C for 30 minutes. [(2R)-1-benzyl-2-methyl-pyrrolidine-2-yl]methanol (3.38 g, 17.0 mmol) (as a solution in 10 mL of DCM) was added, and the reaction mixture was stirred at -78°C for 30 minutes. Triethylamine (27.0 mL, 0.194 mol, CAS 121-44-8) was added dropwise, and the reaction mixture was stirred at -78°C for 15 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was quenched by adding water (5 mL) and warmed to room temperature. DCM (10 mL) and saturated aqueous solution of NaHCO3 (20 mL) were added, the layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The organic matter was combined, dried with MgSO4, and concentrated under vacuum. The resulting oil was purified by FCC (eluted with 0-20% ethyl + (ESI + )204.4; 1H NMR(400MHz,DMSO)δ 9.34(s,1H),7.36-7.27(m,4H),7.23(ddt,J=7.7,5.7,2.4Hz,1H),3.63-3.51(m,2H),2.86(td,J=8.6,4.4Hz,1 H),2.62-2.54(m,1H),2.01(ddd,J=12.5,10.1,6.5Hz,1H),1.90-1.70(m,2H),1.59-1.49(m,1H),1.09(s,3H).

[0461] Step 3, method 15 (2R)-1-benzyl-2-methylpyrrolidine-2-carbaldehyde (10.0 g, 49.2 mmol) was dissolved in anhydrous THF (106 mL) and cooled to 0°C under N2. 3M bromo(methyl)magnesium (25 mL, 73.8 mmol, CAS 75-16-1) in ether was added over 10 minutes, and the reaction mixture was stirred for 30 minutes before being warmed to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ELISA (3 x 20 mL). The combined organic matter was dried in (MgSO4) and concentrated under vacuum. The crude product was purified by FCC (C18 silica, eluted with 0-100% ELISA in heptane) to obtain (1R)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]ethanol (6.9 g, yield 64%) as a colorless oil. 1H NMR(500MHz,DMSO)δ 7.29(d,J=4.5Hz,4H),7.20(h,J=4.1Hz,1H),4.38(d,J=5.3Hz,1H),3.99(d,J=13.5Hz,1H),3.63(p,J=6.2H z,1H),3.23(d,J=13.5Hz,1H),2.70(td,J=8.4,2.6Hz,1H),2.35-2.22(m,1H),1.86(ddd,J=12.8,9.9,5.0H z,1H), 1.67-1.56(m,1H), 1.57-1.43(m,1H), 1.32(ddd,J=12.8,9.0,7.0Hz,1H), 1.12(d,J=6.4Hz,3H), 1.04(s,3H). Trace amounts of the diastereoisomer (1S)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]ethanol (430 mg, yield 4%) were also isolated as a colorless oil. RT(M2) = 0.39 min [M+H] + (ESI + )220.2

[0462] Step 4, method 15 A solution of (1R)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]ethanol (6.90 g, 31.5 mmol) and palladium carbon (10%, 0.70 g, 658 μmol, CAS 7440-05-3) in ethanol (200 mL) was stirred at room temperature under an H2 atmosphere. After 18 hours, the reaction was stopped, filtered through a Celite pad, cooled to 0°C, and 2M HCl (15 mL, 62.9 mmol, CAS 7647-01-0) in ether was added. The resulting solution was stirred at 0°C for 10 minutes and then warmed to room temperature over 30 minutes. The solvent was removed under vacuum. The remaining oil was dissolved in ethanol (200 mL), palladium carbon (10%, 0.70 g, 658 μmol, CAS 7440-05-3) was added, and the reaction mixture was stirred under a hydrogen atmosphere for a further 24 hours. The mixture was filtered through a Celite pad, washed with methanol (50 mL), and 2 M HCl in ether (15 mL, 62.9 mmol, CAS 7647-01-0) was added. The solvent was removed under vacuum, and the DCM was added to the obtained oil. The mixture was concentrated under vacuum to obtain (1R)-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (3.50 g, yield 67%) as a pale pink solid. 1 H NMR(400MHz,DMSO)δ 8.86(s,1H),8.58(s,1H),3.78(q,J=6.4Hz,1H),3.48-3.41(m,1H),3.22-3.08(m,2H),2. 05-1.84(m,2H),1.82-1.72(m,1H),1.69-1.57(m,1H),1.19(s,3H),1.09(d,J=6.4Hz,3H).

[0463] The following analogues were prepared by similar methods.

[0464] [Table 125]

[0465] [Table 126]

[0466] Synthesis method 16 Scheme for Method 16 [ka]

[0467] Process 1, method 16 Trimethyl(trifluoromethyl)silane (2.4 mL, 16.3 mmol, CAS 81290-20-2) in anhydrous THF (50 mL) was added under N2 conditions to a flask containing (2R)-1-benzyl-2-methyl-pyrrolidine-2-carbaldehyde (2.21 g, 10.9 mmol, synthesized by Method 15, Step 2). The reaction mixture was cooled to 0°C and tetrabutylammonium difluorotriphenylsilicate (60 mg, 0.11 mmol, CAS 163931-61-1) was added. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under vacuum and dissolved in DCM (3 mL) and 1 M aq. HCl (8 mL), and vigorously stirred for 5 hours. Saturated aqueous solution of NaHCO3 was added until pH 10 was reached, the layers were separated, and the aqueous layer was extracted with DCM (10 x 25 mL). The combined organic matter was dried with MgSO4, filtered, and concentrated in vacuum to obtain a brown oil, which was purified by FCC (elution with 0-100% ethyl phosphate in silica and heptane, followed by 0-100% MeOH in ethyl phosphate). The fraction containing the product was concentrated in vacuum to obtain (1S)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]-2,2,2-trifluoroethanol (960 mg, yield 32%) as a yellow oil. RT(M2) = 0.44 min [M+H] + (ESI + )274.1; 1H NMR(500MHz,DMSO)δ 7.34-7.26(m,4H),7.25-7.16(m,1H),6.31(s,1H),4.15(d,J=13.4Hz,1H),3.99(q,J=8.5Hz,1H),3.31(d,J=13.4Hz,1H),2.76 -2.68(m,1H),2.30(q,J=8.5Hz,1H),2.19-2.07(m,1H),1.70-1.60(m,1H),1.60-1.53(m,1H),1.53-1.45(m,1H),1.15(s,3H).

[0468] The mixed fraction (containing trace amounts of diastereoisomers) was concentrated to obtain a colorless oil (625 mg), which was purified by FCC (0-100% DCM in silica and heptane) to obtain (1R)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]-2,2,2-trifluoroethanol (287 mg, yield 10%) as a colorless oil. 1 H NMR(500MHz,DMSO)δ 7.35-7.27(m,4H),7.25-7.19(m,1H),5.64(s,1H),4.05(q,J=8.5Hz,1H),3.92(d,J=13.3Hz,1H),3.33-3.28(m,1H),2.72 (td,J=8.2,3.9Hz,1H),2.35(q,J=8.1Hz,1H),2.25-2.13(m,1H),1.73-1.56(m,2H),1.49-1.38(m,1H),1.12-1.10(m,3H).

[0469] Step 2, method 16 A solution of palladium carbon (10%, 234 mg, 220 μmol, CAS 7440-05-3) and (1S)-1-[(2R)-1-benzyl-2-methylpyrrolidine-2-yl]-2,2,2-trifluoroethanol (300 mg, 1.1 mmol) in ethanol (7 mL) was stirred overnight at room temperature under an atmosphere of H2. The reaction mixture was filtered through Celite and washed with DCM (100 mL) and methanol (25 mL). 2M HCl (1.0 mL, 2.0 mmol, CAS 7647-01-0) in diethyl ether was added to the filtrate, and the mixture was allowed to stand for 5 minutes. After concentration under vacuum, (1S)-2,2,2-trifluoro-1-[(2R)-2-methylpyrrolidine-2-yl]ethanol hydrochloride (240 mg, yield 95%) was obtained as a pink solid. 1 H NMR(400MHz,DMSO)δ 9.11(s,2H),7.55(d,J=6.3Hz,1H),4.57-4.34(m,1H),3.28-3.16(m,2H),2.16-1.93(m,3H),1.93-1.74(m,1H),1.29(s,3H).

[0470] The following analogues were prepared by similar methods.

[0471] [Table 127]

[0472] Synthesis method 17 Scheme for Method 17 [ka]

[0473] Process 1, method 17 To a solution of ethyl 9-bromo-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (118 g, 336.94 mmol) in TFA (600 mL), TFAA (353.84 g, 1.68 mol) was added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The mixture was concentrated and the pH was adjusted to 8 by adding H2O (500 mL) and solid Na2CO3. The mixture was extracted with siRNA (300 mL x 4). The organic layer was concentrated under reduced pressure to obtain the crude product, which was triturated with petroleum ether (400 mL) at 20°C for 15 minutes and filtered. The solid was collected and dried under reduced pressure to obtain 9-bromo-8-methoxy-1-(2,2,2-trifluoroacetyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (118 g, 78%) as a brown solid. RT(M11) = 2.20 min [M + H] + (ESI + )446.1 / 448.2.

[0474] Step 2, method 17 To a solution of ethyl 9-bromo-8-methoxy-1-(2,2,2-trifluoroacetyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (90 g, 201.70 mmol) in THF (900 mL), BH3.THF (1 M, 221.87 mL) was added at 0°C. The mixture was stirred at 25°C for 2 hours under an N2 atmosphere. 240 mL of saturated NaHCO3 was added, and the mixture was extracted with ELISA (150 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with petroleum ether (100 mL) at 25°C for 10 minutes and filtered to obtain 9-bromo-8-methoxy-1-(2,2,2-trifluoro-1-hydroxyethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (80 g, 88%) as a brown solid. RT(M14) = 0.98 min [M + H] + (ESI + )448.0 / 450.0.

[0475] Step 3, method 17 To a solution of ethyl 9-bromo-8-methoxy-1-(2,2,2-trifluoro-1-hydroxyethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (105 g, 234.25 mmol) in DCM (1200 mL), BF3.Et2O (166.24 g, 1.17 mol, 144.55 mL) and Et3SiH (136.19 g, 1.17 mol, 187.08 mL) were added. The mixture was stirred at 20°C for 1 hour under an N2 atmosphere. H2O (100 mL) was added to the mixture. The aqueous layer was separated and extracted with DCM (200 mL x 3). The organic layer was concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 20 / 1~1 / 1) to obtain 9-bromo-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (80 g, 79.01%) as a white solid. RT(M25) = 2.89 min [M + H] + (ESI + )432.0 / 434.1.

[0476] The following analogues were prepared by similar methods.

[0477] [Table 128]

[0478] Synthesis method 18 Scheme for Method 18 [ka]

[0479] Process 1, method 18 In a 20 mL pressure tube, a stirred solution of (2R)-1-[9-bromo-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonitrile (400 mg, 0.8 mmol, synthesized by Method 6), phenyl formate (450 μL, 4.0 mmol, CAS 1864-94-4), and triethylamine (560 μL, 4.0 mmol, CAS 121-44-8) in anhydrous DMF (5 mL) was degassed under nitrogen for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59 mg, 81 μmol, CAS 72287-26-4) was added, the solution was degassed under nitrogen for 5 minutes, and the mixture was heated to 100 °C for 4 hours. The reaction mixture was cooled to room temperature, the pressure was released, and the container was purged with nitrogen. The mixture was concentrated under vacuum, diluted with water (20 mL), and extracted with dichloromethane (3 x 20 mL). The combined organic extract was concentrated under vacuum to obtain a residue, which was purified by FCC (eluted with 0-100% ethyl + )(M+H) + 538.4.

[0480] Step 2, method 18 To a solution of 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (290 mg, 0.5 mmol) in THF (7 mL), potassium trimethylsilanolate (350 mg, 2.6 mmol, CAS 10519-96-7) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and treated with water (10 mL). The mixture was acidified to pH 1 with 1 M aq HCl, and the formation of a precipitate was observed. The mixture was extracted with ethyl acetate (3 x 30 mL). The organic compounds were combined, dried (MgSO4), filtered, and the solvent was removed under vacuum to obtain 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (purity 86%, 280 mg, yield 100%) as a yellow solid. RT(M2) = 0.84 min, (ESI + )(M+H) + 462.4.

[0481] Step 3, method 18 HATU (145 mg, 0.4 mmol, CAS 148893-10-1) and 2-amino-2-methylpropanenitrile hydrochloride (1:1) (31 mg, 0.2 mmol, CAS 50846-36-1) were added at room temperature to a stirred solution of 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (88% purity, 100 mg, 0.2 mmol) and DIPEA (130 μL, 0.8 mmol, CAS 7087-68-5) in DCM (1.5 mL) in anhydrous DMF (0.5 mL). The reaction mixture was stirred overnight. The reaction mixture was poured into water (3 mL) and extracted with DCM (3 x 3 mL). The organic phases were combined, passed through a phase separator, and concentrated under vacuum. The crude product was purified by acidic preparative HPLC (Method P2), and the fraction containing the product was freeze-dried to obtain (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-N-(2-cyanopropan-2-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide (compound 18-1) (34 mg, yield 33%) as a white solid. 1 H NMR(400MHz,DMSO)δ 8.44(s,1H),8.00(s,1H),7.24(s,1H),6.70(s,1H),4.43-4.20(m,2H),3.95(s,3H),3.89-3.81(m,1H),3.81-3.66(m,3H),3.05(t,J=6. 5Hz,2H),2.46(d,J=6.0Hz,1H),2.21-2.09(m,1H),2.07-1.96(m,1H),1.95-1.84(m,1H),1.74(s,3H),1.70(s,6H);RT(M4)=3.67min,(ESI + )(M+H) + 528.1.

[0482] The following analogues were prepared by similar methods.

[0483] [Table 129]

[0484] [Table 130]

[0485] Synthesis method 19 Scheme for Method 19 [ka]

[0486] Process 1, method 19 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (19.0 g, 74.7 μmol, CAS 73183-34-3), 9-bromo-1-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (30.2 g, 67.9 mmol), and potassium acetate (20.0 g, 203.4 mmol) were dissolved in anhydrous 1,4-dioxane (530 mL). After aerating the suspension with nitrogen for 5 minutes, the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (2.8 g, 3.4 mmol, CAS 95464-05-4) was added, and the suspension was aerated with nitrogen for 5 minutes. The mixture was stirred under nitrogen and heated at 90°C for 16 hours. The reaction product was cooled to room temperature, filtered, and washed with DCM (2 x 100 mL). The filtrate was concentrated and purified by trituration with DCM to obtain 1-(4-fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (14.8 g, 26.4 mmol, yield 39%) as a grayish-white solid.

[0487] The second collection was precipitated from the filtrate and filtered to obtain 1-(4-fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (7.9 g, 14.5 mmol, yield 21%) as a grayish-white solid. 1 H NMR(400MHz,DMSO)δ 7.43-7.32(m,3H),7.27-7.15(m,2H),6.93(d,J=17.2Hz,2H),4.57-4.49(m,2H),4.25(q,J=7.1Hz,2H),3.7 5(d,J=4.1Hz,3H),3.10(t,J=6.7Hz,2H),1.30(t,J=7.1Hz,3H),1.16(d,J=8.0Hz,12H);RT(M2)=1.24 min,(ESI + )(M+H) + 492.3.

[0488] Step 2, method 19 A solution of 1-(4-fluorophenyl)-8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (14.8 g, 30.0 mmol), 5-bromo-2-methyl-tetrazole (6.4 g, 39.1 mmol, CAS 16681-80-4), and discesium carbonate (39.2 g, 120.2 mmol, CAS 534-17-8) in 1,4-dioxane (380 mL) and water (150 mL) was degassed with nitrogen, and XPhos Pd G2 (4.7 g, 3.0 mmol, CAS 1310584-14-5) was added. The reaction mixture was heated to 80°C for 2 hours. The reaction mixture was cooled to room temperature, and the organic matter was concentrated under vacuum. The remaining aqueous phase was diluted with water (100 mL) and extracted with DCM (2 x 200 mL). The organic matter was dried with (MgSO4) and concentrated. The residue was triturated with DCM to obtain 1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate ethyl (12.8 g, 27.1 mmol, 90% yield) as a grayish-white solid. 1H NMR(400MHz,DMSO)δ 7.70(s,1H),7.48-7.38(m,2H),7.26(s,1H),7.24-7.15(m,2H),6.93(s,1H),4.62-4.54(m,2H),4.33(s, 3H),4.27(q,J=7.1Hz,2H),3.88(s,3H),3.18(t,J=6.5Hz,2H),1.30(t,J=7.1Hz,3H);RT(M2)=1.07min,(ESI + )(M+H) + 448.2.

[0489] Step 3, method 19 To a solution of ethyl 1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (12.8 g, 28.5 mmol) in ethanol (177 mL) and water (44 mL), potassium hydroxide (6.5 g, 114.0 mmol) was added. The resulting suspension was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, partially concentrated (ethanol removed), diluted with water (50 mL), and then acidified to pH 1 with 1 M aq. HCl. Precipitation was observed. The mixture was filtered, and the gray precipitate was dried under vacuum to obtain 1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (10.8 g, 25.7 mmol, 90% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO)δ 12.46(s,1H),7.69(s,1H),7.47-7.37(m,2H),7.25(s,1H),7.24-7.14(m,2H),6.89(s,1H) ),4.62-4.54(m,2H),4.33(s,3H),3.88(s,3H),3.17(t,J=6.5Hz,2H);RT(M2)=0.82min,(ESI + )(M+H) + 420.2.

[0490] The following analogues were prepared by similar methods.

[0491] [Table 131]

[0492] Synthesis method 20 Scheme for Method 20 [ka]

[0493] Process 1, method 20 2.4M LiAlH4 (1.2 mL, 2.80 mmol) was added to a stirred solution of 4,4-difluoro-2-methylpyrrolidine-2-carboxylate methyl hydrochloride (301 mg, 1.4 mmol, CAS 16853-85-3) in anhydrous THF (5 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was quenched with water and extracted with DCM. 4M HCl (2 mL) in dioxane was added to the combined organic matter, and the mixture was dried and concentrated to obtain (4,4-difluoro-2-methylpyrrolidine-2-yl)methanol hydrochloride (260 mg, yield 89%) as a white solid. 1 H NMR(400MHz,DMSO)δ 9.84(s,2H),5.79(s,1H),3.98-3.62(m,3H),3.57-3.46(m,1H),2.65-2.52(m,1H),2.47-2.28(m,1H),1.40(s,3H).

[0494] Process 2, method 20 2-Chloro-1-methylpyridinium iodide (1.6 g, 6.2 mmol) was added to a stirred suspension of 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (1.0 g, 2.5 mmol, synthesized by Method 19), DIPEA (1.3 mL, 7.4 mmol, CAS 7087-68-5), and (4,4-difluoro-2-methylpyrrolidine-2-yl)methanol hydrochloride (694 mg, 3.7 mmol) in DMF (13 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and DCM, and the resulting precipitate was isolated by filtration. The filtrate was purified by FCC (eluted with 0-100% ethyl ethyl phosphate in silica and heptane). The fraction containing the product was concentrated in vacuum to obtain [4,4-difluoro-2-(hydroxymethyl)-2-methylpyrrolidine-1-yl]-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone (426 mg, yield 28%) as a white solid. RT(M2) = 1.01 min, [M+H] + (ESI + )553.3.

[0495] Process 3, method 20 Des-Martin periodinane (491 mg, 1.2 mmol) was added to a stirred solution of [4,4-difluoro-2-(hydroxymethyl)-2-methylpyrrolidine-1-yl]-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone (426 mg, 0.8 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water. The precipitate was filtered, organic matter was separated, dried, and concentrated. The crude product was purified by FCC (eluting with 0-100% ethyl ethyl ethyl in silica and heptane) to obtain 4,4-difluoro-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbaldehyde (321 mg, yield 67%) as a white solid. RT(M2) = 0.98 min, [M+H] + (ESI + ) 551.0.

[0496] Step 4, Method 20 4,4-difluoro-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbaldehyde (321 mg, 0.6 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen. 3M bromo(methyl)magnesium (290 μL, 0.9 mmol) was added over 10 minutes, and the reaction mixture was stirred for 30 minutes, then warmed to room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ELISA (3 x 20 mL). The combined organic matter was dried and concentrated in (MgSO4). The compound was purified by acidic preparative HPLC (Method P2) to obtain the crude product as a white solid.

[0497] This method was repeated on a large scale, and both batches were combined for chiral separation. The yield was based on the combined theoretical yield.

[0498] Chiral separation on Waters Thar SFC [column: Chiralpak AD-H (4.6 x 250 mm, 5 μm) 40℃; homogeneous concentration eluent: 8 70:30 heptane:ethanol; flow rate: 18 mL / min; dilution solvent: MeOH, i-PrOH, acetonitrile; injection volume: 250 μL] yielded [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R or S)-4,4-difluoro-2-methyl-2-[(1R or S)-1-hydroxyethyl]pyrrolidine-1-yl]methanone (compound 20-1) (26 mg, yield 7%) as a white powder. RT(M4) = 3.64 min, (ESI + )(M+H) + 567.2; 1 1H NMR (400MHz, DMSO) δ 7.72(s,1H),7.50-7.41(m,2H),7.23(s,1H),7.22-7.13(m,2H),6.71(s,1H) ),5.03(d,J=5.1Hz,1H),4.55-4.48(m,1H),4.48-4.35(m,2H),4.33(s,3H), 4.32-4.21(m,1H),4.17-4.06(m,1H),3.87(s,3H),3.13(t,J=6.5Hz,2H),2. 74-2.58(m,1H),2.07(t,J=15.5Hz,1H),1.68(s,3H),1.08(d,J=6.3Hz,3H).

[0499] [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S or R)-4,4-difluoro-2-methyl-2-[(1S or R)-1-hydroxyethyl]pyrrolidine-1-yl]methanone (compound 20-1, isomer 2) (28 mg, yield 6%) as a white powder. RT(M4) = 3.64 min, (ESI + )(M+H) + 567.2; 11H NMR (400MHz, DMSO) δ 7.72(s,1H),7.50-7.39(m,2H),7.23(s,1H),7.22-7.13(m,2H),6.71(s,1H) ),5.03(d,J=5.3Hz,1H),4.55-4.48(m,1H),4.48-4.35(m,2H),4.33(s,3H), 4.32-4.21(m,1H),4.17-4.06(m,1H),3.87(s,3H),3.13(t,J=6.5Hz,2H),2. 73-2.58(m,1H),2.07(t,J=15.6Hz,1H),1.68(s,3H),1.08(d,J=6.3Hz,3H).

[0500] Synthesis method 21 Scheme for Method 21 [ka]

[0501] Process 1, method 21 Ditert-butyl dicarbonate (2.2 g, 10.2 mmol, CAS 24424-99-5) was added in small amounts over 5 minutes to a solution of (3R)-3-methylmorpholine-3-carboxylate methyl hydrochloride (1.0 g, 5.1 mmol, CAS 1434126-90-5) and triethylamine (780 μL, 5.6 mmol) in anhydrous methanol (10 mL). The reaction mixture was stirred at room temperature. After 90 hours, 4-dimethylaminopyridine (31 mg, 0.3 mmol, CAS 1122-58-3) was added. After a further 24 hours, the solvent was removed under vacuum. The crude material was dissolved in siRNA (10 mL) and washed with aq. NaHCO3 (3 x 10 mL). The organic layer was passed through a phase separator, and the solvent was removed under vacuum to obtain (3R)-3-methylmorpholine-3,4-dicarboxylic acid O4-tert-butyl O3-methyl (680 mg, yield 49%) as a white solid. RT(M3) = 0.67 min [M+H] + (ESI + )260.2; 1H NMR(500MHz,DMSO)δ 3.86-3.73(m,1H),3.67-3.61(m,3H),3.61-3.55(m,2H),3.55-3.50(m ,1H),3.50-3.43(m,1H),3.20-3.08(m,1H),1.40(s,3H),1.36(s,9H).

[0502] Process 2, method 21 Potassium hydroxide (589 mg, 10.5 mmol, CAS 1310-58-3) was added to a flask containing (3R)-3-methylmorpholine-3,4-dicarboxylic acid O4-tert-butyl O3-methyl (680 mg, 2.6 mmol) in ethanol (10 mL) and water (7 mL). The reaction mixture was stirred at room temperature for 6 days, followed by heating to 80°C. After a further 24 hours, the reaction mixture was concentrated under vacuum. The resulting brown oil was treated with water (10 mL), acidified to pH 1 with 1 M aq. HCl, and extracted with DCM (3 x 10 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to obtain (3R)-4-tert-butoxycarbonyl-3-methylmorpholine-3-carboxylic acid (660 mg, yield 82%) as brown oil. RT(M3) = 0.32 min [M + H] + (ESI + )246.2; 1 H NMR(500MHz,DMSO)δ 12.58(s,1H),5.75(s,2H),3.73(s,1H),3.67-3.56(m,2H),3.49-3.39(m,2H),3.20-3.09(m,1H),1.38(d,J=3.0Hz,12H).

[0503] Step 3, method 21 DIPEA (1.9 mL, 10.8 mmol, CAS 7087-68-5), HATU (1.5 g, 4.0 mmol, CAS 148893-10-1), and ammonia (35% in water, 180 μL, 3.2 mmol, CAS 7664-41-7) were added at room temperature to a stirred solution of (3R)-4-tert-butoxycarbonyl-3-methylmorpholine-3-carboxylic acid (660 mg, 2.7 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (10 ml), extracted with DCM (3 x 10 ml), and the combined organic extracts were passed through a phase separator and concentrated under vacuum to obtain the crude product as a yellow oil. The crude oil was purified by FCC (elution with 0-100% ethyl ammonium compounds in silica and heptane) to obtain (3R)-3-carbamoyl-3-methylmorpholine-4-carboxylate tert-butyl (440 mg, yield 43%) as a pale yellow solid. RT(M3) = 0.45 min [M+H] + (ESI + )245.2; 1 H NMR(500MHz,DMSO)δ 7.13(s,1H),6.91(s,1H),3.82-3.73(m,1H),3.65-3.57(m,2H),3.51-3.4 4(m,1H),3.44-3.38(m,1H),3.16-3.05(m,1H),1.37(s,9H),1.34(s,3H).

[0504] Step 4, method 21 HCl (4M in dioxane, 2.9 mL, 11.5 mmol, CAS 7647-01-0) was added to a stirred solution of (3R)-3-carbamoyl-3-methylmorpholine-4-carboxylate tert-butyl (440 mg, 1.2 mmol) in dioxane (6 mL), and the mixture was stirred at room temperature over the weekend. The reaction mixture was concentrated under vacuum to obtain (3R)-3-methylmorpholine-3-carboxamide hydrochloride (219 mg, 100% yield) as a white solid. 1H NMR(500MHz,DMSO)δ 10.28-8.99(m,2H),8.00(s,1H),7.79(s,1H),4.14(d,J=12.7Hz,1H),3.80-3.71(m,3H),3.20-3.06(m,2H),1.45(s,3H).

[0505] The following analogues were prepared by similar methods.

[0506] [Table 132]

[0507] Synthesis method 22 Scheme for Method 22 [ka]

[0508] Process 1, method 22 2-Chloro-1-methylpyridinium iodide (236 mg, 0.9 mmol, CAS 14338-32-0) was added to a stirred suspension of 8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (150 mg, 0.4 mmol, prepared by Method 22), DIPEA (190 μL, 1.1 mmol, CAS 7087-68-5), and (3R)-3-methylmorpholine-3-carboxamide hydrochloride (100 mg, 0.6 mmol, prepared by Method 22) in DMA (2 mL). The reaction mixture was stirred at room temperature. After 21 hours, the mixture was diluted with water (5 mL) and extracted with siRNA (3 x 5 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum. The crude product was purified by FCC (elution with 0-100% ethyl acetate in silica and heptane, followed by 0-15% MeOH in ethyl acetate) to obtain (3R)-4-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-3-methylmorpholine-3-carboxamide (100 mg, 0.1 mmol, yield 34%) as an orange solid. RT(M2) = 0.80 min [M+H] + (ESI + )532.2; 1 H NMR(500MHz,DMSO)δ 8.08(s,1H),7.60(d,J=2.1Hz,1H),7.48(dd,J=3.7,2.7Hz,1H),7.18(s,1H),7.10(s,1H) ),7.10-7.08(m,1H),7.05(s,1H),6.96(s,1H),6.64(s,1H),6.52(d,J=2.2Hz,1H),4.30 -4.21(m,1H),4.14-4.04(m,1H),3.95-3.89(m,1H),3.86(s,3H),3.83-3.78(m,3H),3.7 6(s,3H),3.64-3.55(m,1H),3.50(d,J=11.4Hz,1H),3.03(t,J=6.5Hz,2H),1.48(s,3H).

[0509] Synthesis method 23 Scheme for Method 23 [ka]

[0510] Process 1, method 23 Chloro(propan-2-yl)magnesium (2M in Et2O, 18 mL, 36.0 mmol, CAS 1068-55-9) was added dropwise to a solution of 1-bromo-4-iodo-2-methoxybenzene (11.3 g, 36.1 mmol, CAS 755027-18-0) in diethyl ether (10 mL) at -15°C. The solution was stirred at -15°C for 1 hour and 45 minutes. Next, copper(1+) iodide (45 mg, 0.2 mmol, CAS 7681-65-4) was added, and the suspension was stirred at -15°C for a further 15 minutes to obtain a turbid greenish-brown suspension.

[0511] Next, this suspension was added in 5 mL increments over 10 minutes at -15°C to a suspension of (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (4.5 g, 18.0 mmol, CAS 454248-53-4) in diethyl ether (50 mL). After stirring at -15°C for 2 hours, the reaction mixture was sonicated and mixed by hand for 15 minutes. Citric acid (10% w / v in water, 50 mL) was slowly added at -15°C, and the reaction mixture was then warmed to room temperature while stirring. After stirring for 90 minutes, the organic matter was collected, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic matter was washed with brine (10 mL) and concentrated under vacuum. The residue was purified by FCC (eluting with 0-100% ethyl ethyl in silica and heptane) to obtain N-[(1R)-2-(4-bromo-3-methoxyphenyl)-1-methyl-ethyl]carbamate tert-butyl (purity 91%, 5.7 g, 15.2 mmol, yield 84%) as a brown solid. RT(M2) = 0.98 min [M+H] + (ESI + )288.2 / 290.2; 1H NMR(400MHz,DMSO)δ 7.43(d,J=8.0Hz,1H),6.92(d,J=1.9Hz,1H),6.77(d,J=8.4Hz,1H),6.71(dd,J=8.0,1.9Hz, 1H),3.83(s,3H),3.72-3.64(m,1H),2.72-2.54(m,2H),1.33(s,9H),1.02(d,J=6.6Hz,3H).

[0512] Process 2, method 23 N-[(1R)-2-(4-bromo-3-methoxyphenyl)-1-methyl-ethyl] tert-butyl carbamate (5.7 g, 16.7 mmol) was dissolved in DCM (50 mL) and treated with trifluoroacetic acid (5.0 mL, 65.3 mmol, CAS 76-05-1). After stirring for 1 hour, the reaction product was retreated with trifluoroacetic acid (5 mL, 65.3 mmol, CAS 76-05-1). After stirring for another 1 hour, volatile substances were removed under reduced pressure. The residue was dissolved in DCM (50 mL) and treated with DIPEA (5.8 mL, 33.3 mmol, CAS 7087-68-5) and 9H-fluoren-9-ylmethyl carbonochloride (4.8 g, 18.3 mmol, CAS 28920-43-6) (exothermic). After stirring overnight, the reaction mixture was washed with ammonium chloride (saturated in H2O, 2 x 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with heptane (200 mL), filtered, and obtained as a yellowish-brown solid 9H-fluoren-9-ylmethyl N-[(1R)-2-(4-bromo-3-methoxyphenyl)-1-methyl-ethyl]carbamate (9.6 g, yield 86%). RT(M2) = 1.11 min [M+H] + (ESI + )466.2 / 468.2

[0513] Step 3, method 23 A suspension of N-[(1R)-2-(4-bromo-3-methoxyphenyl)-1-methyl-ethyl]carbamate 9H-fluoren-9-ylmethyl (9.6 g, 20.6 mmol) and oxoacetic acid hydrate (1:1) (2.8 g, 30.9 mmol, CAS 563-96-2) in acetic acid (100 mL) was treated with sulfuric acid (10 mL) and stirred for 2 hours. Acetic acid (50 mL) and sulfuric acid (5 mL) were added to the suspension. After stirring for 90 minutes, the mixture was sonicated for 2 hours to obtain a red solution. The solution was poured into water (1 L) and the precipitate was collected by filtration. The pink solid was dissolved in toluene (200 mL), dried over Na₂SO₄, filtered, and concentrated to obtain (3R)-7-bromo-2-(9H-fluoren-9-ylmethoxycarbonyl)-6-methoxy-3-methyl-3,4-dihydro-1H-isoquinoline-1-carboxylic acid (8.5 g, yield 69%) as a pink solid. RT(M₂) = 1.30–1.32 mins [M + H] + (ESI + )522.0 / 524.0

[0514] Step 4, method 23 To a solution of (3R)-7-bromo-2-(9H-fluoren-9-ylmethoxycarbonyl)-6-methoxy-3-methyl-3,4-dihydro-1H-isoquinoline-1-carboxylic acid (87% purity, 8.5 g, 14.1 mmol) in DMF (80 mL), piperidine (8.2 mL, 83.2 mmol, CAS 110-89-4) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (100 mL), after which Et2O (100 mL) was added. The precipitate was collected by filtration to obtain (3R)-7-bromo-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (79% purity, 2.8 g, yield 52%) as a pink solid. RT(M2) = 0.46~0.47 min [M+H] + (ESI + )299.9 / 301.9

[0515] The following analogues were prepared by similar methods.

[0516] [Table 133]

[0517] Synthesis method 24 Scheme for Method 24 [ka]

[0518] Process 1, method 24 In a 20 mL pressure tube, a mixture of (9-bromo-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone (250 mg, 0.5 mmol, synthesized by Method 2), phenyl formate (0.3 mL, 2.7 mmol, CAS 1864-94-4), and triethylamine (0.4 mL, 2.7 mmol, CAS 121-44-8) in anhydrous DMF (4 mL) was degassed under nitrogen for 5 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol, CAS 72287-26-4) was added, the solution was degassed with nitrogen for 5 minutes, and the mixture was heated to 100°C for 6 hours.

[0519] The mixture was cooled to room temperature, the pressure was slowly released, and the container was purged with nitrogen. The mixture was concentrated, diluted with water (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic extract was concentrated under vacuum to obtain a residue, which was purified by FCC (eluted with 0-100% ethyl + )(M+H) + 558.2; 1H NMR(400MHz,DMSO-d6)δ 9.08(d,J=0.6Hz,1H),7.92-7.86(m,2H),7.48-7.39(m,2H),7.31-7.23(m,2H),7.07(dd ,J=8.5,1.0Hz,2H),6.64(s,1H),4.96(d,J=4.9Hz,1H),4.50-4.41(m,1H),4.41-4.30(m, 1H),4.21-4.10(m,1H),3.90(s,3H),3.86-3.78(m,1H),3.71-3.60(m,1H),3.14(t,J=6. 4Hz,2H),2.14-2.02(m,1H),1.87-1.69(m,2H),1.60-1.45(m,4H),1.01(d,J=6.3Hz,3H).

[0520] Process 2, method 24 Potassium trimethylsilanolate (182 mg, 1.3 mmol, CAS 10519-96-7) was added to a solution of 3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate phenyl (150 mg, 0.3 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partially concentrated and treated with water (10 mL). The mixture was acidified to pH 1 with aq. 1 M HCl, and the formation of a precipitate was observed. The mixture was extracted with DCM (3 x 10 mL), the combined organic matter was passed through a phase separator, and concentrated under vacuum to obtain 3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (purity 77%, 160 mg, yield 95%) as a yellow solid. RT(M2) = 0.68 min, (ESI + )(M+H) + 482.2.

[0521] Step 3, method 24 HATU (243 mg, 0.6 mmol, CAS 148893-10-1) was added to a stirred suspension of 3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxylic acid (77%, 160 mg, 0.3 mmol), DIPEA (134 μL, 0.8 mmol, CAS 7087-68-5), and 1-aminocyclobutane carbonitride hydrochloride (1:1) (51 mg, 0.5 mmol, CAS 845821-84-3) in DCM (2 mL) and 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extract was passed through a phase separator and concentrated to obtain a brown oil. The brown oil was purified by acidic preparative HPLC (P1) and freeze-dried to obtain N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide (compound 24-1) (56 mg, yield 38%) as a white solid. RT(M4) = 3.09 min, (ESI + )(M+H) + 560.2. 1 H NMR(500MHz,DMSO-d6)δ 9.09(s,1H),8.70(s,1H),7.86(s,1H),7.72(s,1H),7.18(s,1H),6.62(s,1H),4.96(d,J=4 .8Hz,1H),4.49-4.40(m,1H),4.38-4.28(m,1H),4.16-4.06(m,1H),3.92(s,3H),3.85-3.7 7(m,1H),3.69-3.59(m,1H),3.09(t,J=6.4Hz,2H),2.67-2.58(m,2H),2.39-2.30(m,2H),2 .14-1.91(m,3H),1.85-1.70(m,2H),1.58-1.52(m,1H),1.51(s,3H),1.01(d,J=6.3Hz,3H).

[0522] The following analogues were prepared by similar methods.

[0523] [Table 134]

[0524] Synthesis method 25 Scheme for Method 25 [ka]

[0525] Process 1, method 25 To a stirred suspension of methyl 2-ethyl-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]pyrrolidine-2-carboxylate (468 mg, 0.9 mmol, synthesized by Method 13) in ethanol (8 mL) and water (3 mL), potassium hydroxide (193 mg, 3.4 mmol CAS 1310-58-3) was added, and the reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The aqueous residue was acidified to pH 1 using 1 M aq. HCl and extracted with DCM (3 x 20 mL). The organic matter was passed through a phase separator, dried, and concentrated to obtain 2-ethyl-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]pyrrolidine-2-carboxylic acid (465 mg, yield 84%) as a grayish-white solid. RT(M2) = 0.93 min [M+H] + (ESI + ) 531.2.

[0526] Step 2, method 25 Ethyl carbonochloride (110 μL, 1.1 mmol, CAS 541-41-3) was added dropwise to a stirred solution of ...

Claims

1. Compound of formula (A) 【Chemistry 1】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ -NR ｆ R ｇ And, (i) R ｆ and R ｇ together with the nitrogen to which they are attached optionally contain one additional ring heteroatom selected from oxygen, sulfur and nitrogen, and one to four R ４ groups (each R ４ group is independently halogen, hydroxy, nitrile, -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 13 substituents independently selected from cycloalkyl, hydroxyl, and halogen groups. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Forms a 4- to 8-membered heterocycloalkyl ring substituted with (selected from alkyl); or (ii) R ｆ C １ ~C ６ It is alkyl; R ｇ This includes 1 to 4 R ４ｃ group (wherein each R ４ｃ The group is substituted with C (independently selected from halogen, hydroxyl, and nitrile). １ ~C ６ It is alkyl; R ２ C １ ~C ６ Alkyl; C １ ~C ６ Alkenyl; C １ ~C ６ Haloalkyl; C １ ~C ６ Hydroxyalkyl; -(C １ ~C ３ Alkyl)-SO ２ CH ３ ; Replaced by 1 to 13 halogens as arbitrarily selected - (C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl); -(C １ ~C ６ Alkyl)-NR ５ａ R ５ｂ ; phenyl; C ４ ~C ６ Cycloalkyl; and selected from 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C ４ ~C ６ The cycloalkyl and the 5-6 membered heteroaryl rings have 1-4 R ５ The base may be replaced by any choice, and each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ Selected from alkyl groups; X is CR ２０ or N; R ２０ H, halogen, nitrile, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ each independently is selected from H and C １ to C ３ alkyl, or R ７ and R ８ together with the carbon to which they are attached, optionally contain a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １１ and R １２ Together, they form a double bond, R １０ and R １３ H and C are independent of each other. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

2. X is CR ２０ The compound according to claim 1, its stereoisomer, tautomer, or pharmaceutically acceptable salt.

3. A compound according to claim 1 or 2, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof, wherein X is N.

4. R １ However, -NR ｆ R ｇ (In the formula, (i) R ｆ and R ｇ It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Forms a 4- to 8-membered heterocycloalkyl ring substituted with (selected from alkyl); or (ii) R ｆ C １ ~C ６ It is alkyl; R ｇ This includes 1 to 4 R ４ｃ group (wherein each R ４ｃ The group is substituted with C (independently selected from halogen, hydroxyl, and nitrile). １ ~C ６ (It is alkyl.) A compound according to any one of claims 1 to 3, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. R １ However, -NR ｆ R ｇ (In the formula, R ｆ and R ｇ Together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, wherein the ring has 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ A compound according to any one of claims 1 to 4, which is substituted with (selected from alkyl), a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

6. R １ However, -NR ｆ R ｇ (In the formula, R ｆ and R ｇ Together with the nitrogen to which they are bonded, they form a five-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, wherein the ring has 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ A compound according to any one of claims 1 to 4, which is substituted with (selected from alkyl), a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

7. R １ but, 【Chemistry 2】 And R １ However, 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ However, independently, C １ ~C ３ A compound according to any one of claims 1 to 4, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof, substituted with (selected from alkyl groups).

8. R １ However, -NR ｆ R ｇ (In the formula, R ｆ and R ｇ Together with the nitrogen to which they are bonded, they form a six-membered heterocycloalkyl ring optionally containing one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, wherein the ring has 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ A compound according to any one of claims 1 to 4, which is substituted with (selected from alkyl), a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

9. R １ However, -NR ｆ R ｇ (In the formula, R ｆ C １ ~C ６ It is alkyl; R ｇ This includes 1 to 4 R ４ｃ group (wherein each R ４ｃ The group is substituted with C (independently selected from halogen, hydroxyl, and nitrile). １ ~C ６ A compound according to any one of claims 1 to 4, which is alkyl, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. R ２ However, C １ ~C ６ Alkyl or C １ ~C ６ A compound according to any one of claims 1 to 9, which is an alkenyl, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. R ２ However, C １ ~C ６ A compound according to any one of claims 1 to 9, which is a haloalkyl compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. R ２ However, C １ ~C ６ A compound according to any one of claims 1 to 9, which is a hydroxyalkyl compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

13. R ２ However, 1 to 4 R ５ Group (each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ A compound according to any one of claims 1 to 9, wherein the compound is a phenyl optionally substituted with an alkyl group (selected from alkyl groups), a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

14. R ２ The compound according to any one of claims 1 to 9, wherein the compound is 4-fluorophenyl, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

15. R ２ However, 1 to 4 R ５ Group (each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ C (selected from alkyl) is optionally substituted. ４ ~C ６ A compound according to any one of claims 1 to 9, which is a cycloalkyl compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. R ２ However, it is a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring contains 1-4 R ５ Group (each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ A compound according to any one of claims 1 to 9, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof, which may be optionally substituted with an alkyl group.

17. R ２ The compound according to any one of claims 1 to 9, wherein the compound is 3,3-difluorocyclobutyl, 5-fluoropyridine-2-yl, 2-thiophenyl, 5-thiazolyl, or 1,3,4-thiazolyl, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

18. Compound of formula (B) 【Transformation 3】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ teeth, 【Chemistry 4】 And R １ This includes 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Substituted with (selected from alkyl); Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and includes halogens, nitriles, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ One to four R selected independently of the alkoxy ５ A 5-6 member heteroaryl ring optionally substituted with a base; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ Selected from alkyl groups; R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

19. Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ One to four R selected independently of the alkoxy ５ A five-membered heteroaryl ring that is optionally substituted with a base; each R ５ａ and R ５ｂ However, independently, H and C １ ~C ３ A compound according to claim 18, selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

20. Het contains 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and halogens, nitriles, -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ One to four R selected independently of the alkoxy ５ A six-membered heteroaryl ring that is optionally substituted with a base; each R ５ａ and R ５ｂ However, independently, H and C １ ~C ３ A compound according to claim 18, selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

21. Compound of formula (C) 【Transformation 5】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ teeth, 【Transformation 6】 And R １ This includes 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Substituted with (selected from alkyl); R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

22. Compound of formula (D) 【Transformation 7】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ teeth, 【Transformation 8】 And R １ This includes 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Substituted with (selected from alkyl); R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; m is 0, 1, 2, 3, or 4; Each R ５ These are, independently, halogens, nitriles, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ Selected from alkyl groups; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

23. Compound of formula (E) 【Chemistry 9】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ teeth, 【Chemistry 10】 And R １ This includes 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Substituted with (selected from alkyl); R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; Alk is C １ ~C ６ Alkyl or -C １ ~C ６ It is an alkenil; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

24. Compound of formula (F) 【Chemistry 11】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ -NR ｆ R ｇ And, (i) R ｆ and R ｇ It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 4 R ４ Group (each R ４ The groups are, independently, halogen, hydroxyl, nitrile, and -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ Selected from alkyl groups; optionally, two R groups ４ The groups, together with the atoms to which they are bonded, form a 4-6 membered ring; each R ４ａ and R ４ｂ Independently, C １ ~C ３ Forms a 4- to 8-membered heterocycloalkyl ring substituted with (selected from alkyl); or (i) R ｆ C １ ~C ６ It is alkyl; R ｇ This includes 1 to 4 R ４ｃ group (wherein each R ４ｃ The group is substituted with C (independently selected from halogen, hydroxyl, and nitrile). １ ~C ６ It is alkyl; R ２ C １ ~C ６ Alkyl; C １ ~C ６ Alkenyl; C １ ~C ６ Haloalkyl; C １ ~C ６ Hydroxyalkyl; -(C １ ~C ３ Alkyl)-SO ２ CH ３ ; Replaced by 1 to 13 halogens as arbitrarily selected - (C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl); -(C １ ~C ６ Alkyl)-NR ５ａ R ５ｂ ; phenyl; C ４ ~C ６ Cycloalkyl; and selected from 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C ４ ~C ６ The cycloalkyl and the 5-6 membered heteroaryl rings have 1-4 R ５ The base may be replaced by any choice, and each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ Selected from alkyl groups; R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ Selected from cycloalkyl, phenyl, a 5-6 membered heterocycloalkyl ring, and a 5-6 membered heteroaryl ring, wherein the 5-6 membered heterocycloalkyl ring and the 5-6 membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the phenyl, the 5-6 membered heterocycloalkyl ring, and the 5-6 membered heteroaryl ring contain hydroxy, nitrile, and C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １１ and R １２ Together, they form a double bond, R １０ and R １３ H and C are independent of each other. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

25. R １ but, 【Chemistry 12】 (In the formula, each R ４ These are independently nitrile and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ A compound according to any one of claims 1 to 4, 6, 7, and 10 to 24, which is selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

26. R １ but, 【Chemistry 13】 (In the formula, R ４ｂ C １ ~C ６ It is alkyl, R ４ａ is nitrile and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ A compound according to any one of claims 1 to 4, 6, 7, and 10 to 24, which is selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

27. R １ but, 【Chemistry 14】 (In the formula, R ４ａ C １ ~C ６ It is alkyl, R ４ｂ is nitrile and C ３ ~C ６ C is optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxyl, and halogen. １ ~C ６ A compound according to any one of claims 1 to 4, 6, 7, and 10 to 24, which is selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

28. R ３ However, a 5-6 membered heteroaryl ring containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the 5-6 membered heteroaryl ring is hydroxy, nitrile, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ A compound according to any one of claims 1 to 27, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which may be optionally substituted with one to three substituents independently selected from the compound.

29. R ３ However, it is a 5-6 membered heteroaryl ring, and the 5-6 membered heteroaryl ring contains 1-4 ring nitrogen atoms, and the 5-6 membered heteroaryl ring contains hydroxy, nitrile, and C atoms. １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ A compound according to any one of claims 1 to 27, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which may be optionally substituted with one to three substituents independently selected from the compound.

30. R ３ However, R is a tetrazole, pyrazole, imidazole, oxazole, or pyridine. ３ However, hydroxy, nitrile, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from; optionally, R ３ However, C １ ~C ３ A compound according to any one of claims 1 to 27, which is a tetrazole optionally substituted with an alkyl group, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

31. R ３ However, -C(O)NHR ６ A compound according to any one of claims 1 to 27, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

32. R ６ However, - (CR ７ R ８ ) ｎ C(O)NR ｄ R ｅ The compound according to claim 31, its stereoisomers, tautomers, or pharmaceutically acceptable salts.

33. R ７ and R ８ Each of them independently, H and C １ ~C ３ A compound according to claim 32, selected from alkyl groups, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

34. R ７ and R ８ The compound according to claim 32, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein, together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen.

35. R ６ However, C is optionally substituted with nitrile. １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ The compound according to claim 31, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl.

36. R ６ However, C is optionally substituted with nitrile or tetrazole. １ ~C ６ A compound according to claim 31, which is alkyl, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

37. R ６ However, phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ The compound according to claim 31, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which may be optionally substituted with one or two substituents independently selected from the alkoxy.

38. R ６ The compound according to claim 31, wherein the compound is optionally substituted with a nitrile, or optionally substituted with a nitrile, or is an optionally substituted cyclopropane, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

39. R １０ , R １１ , R １２ , and R １３ Each of these independently is H, C １ ~C ６ Alkyl and C １ ~C ６ A compound according to any one of claims 1 to 38, selected from haloalkyls, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

40. R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C １ ~C ６ Alkyl and C １ ~C ６ A compound according to any one of claims 1 to 38, selected from haloalkyls, a stereoisomer thereof, a tautomer, or a pharmaceutically acceptable salt thereof.

41. Compound of formula (I') 【Chemistry 15】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ is -NR ｆ R ｇ where R ｆ and R ｇ optionally contain, together with the nitrogen to which they are attached, one additional ring heteroatom selected from oxygen, sulfur and nitrogen, and 1 to 4 R ４ groups (each R ４ group is independently selected from halogen, hydroxy, nitrile, -NR ４ａ R ４ｂ , -SR ４ａ , -S(O) ２ R ４ａ , and C ３ to C ６ alkyl optionally substituted with 1 to 4 substituents independently selected from cycloalkyl, hydroxy, and halogen, and R １ to C ６ alkyl; optionally, two R ４ groups together with the atoms to which they are attached form a 4- to 6-membered ring; each R ４ａ and R ４ｂ independently form a 4- to 8-membered heterocycloalkyl ring substituted with C １ to C ３ alkyl). R ２ C １ ~C ６ Alkyl; C １ ~C ６ Haloalkyl; C １ ~C ６ Hydroxyalkyl; -(C １ ~C ３ Alkyl)-SO ２ CH ３ ; -(C) substituted with 1 to 13 halogens by arbitrary selection. １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl); -(C １ ~C ６ Alkyl)-NR ５ａ R ５ｂ ; phenyl; C ４ ~C ６ Cycloalkyl; and selected from 5-6 membered heteroaryl rings containing 1-4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C ４ ~C ６ The cycloalkyl and the 5-6 membered heteroaryl rings have 1-4 R ５ The base may be replaced by any choice, and each R ５ The groups are, independently, halogen, nitrile, and -C(O)NR ５ａ R ５ｂ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxys; each R ５ａ and R ５ｂ H and C are independent of each other. １ ~C ３ Selected from alkyl groups; R ２０ H, halogen, nitrile, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; R ３ is -C(O)NHR ６ , -SO ２ - (C １ ~C ３ Alkyl), -SO ２ - (C ３ ~C ６ A 5-6 membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from cycloalkyl, phenyl, oxygen, sulfur, and nitrogen, wherein the phenyl and the 5-6 membered heteroaryl ring are hydroxy, nitrile, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and -C(O)NH ２ It may be optionally substituted with 1 to 3 substituents independently selected from the above; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ each independently is selected from H and C １ to C ３ alkyl, or R ７ and R ８ together with the carbon to which they are attached optionally contain a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing alkyl or 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring contains, optionally, one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with oxo, halogen, hydroxy, nitrile, or 1-7 independently selected halogens). １ ~C ３ C is optionally substituted with alkyl and 1 to 7 independently selected halogens. １ ~C ３ (The alkoxy may be optionally substituted with one or two substituents selected independently of it.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １１ and R １２ Together, they form a double bond, R １０ and R １３ H and C are independent of each other. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

42. Compound of formula (I) 【Chemistry 16】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (In the formula, R １ -NR ｆ R ｇ (In the formula, R ｆ and R ｇ It optionally contains one additional ring heteroatom selected from oxygen, sulfur, and nitrogen, along with the nitrogen to which they are bonded, and 1 to 3 R ４ Group (each R ４ The group is independently a C molecule that is optionally substituted with 1 to 4 substituents independently selected from nitriles, hydroxyls, and halogens. １ ~C ６ Forms a 4- to 6-membered heterocycloalkyl ring substituted with (selected from alkyl groups); R ２ C １ ~C ６ Alkyl; C １ ~C ６ Selected from haloalkyl; phenyl; and a 5-6 membered heteroaryl ring containing one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5-6 membered heteroaryl ring contain one or two R ５ The base may be replaced by any choice, and each R ５ The groups are, independently, halogen, nitrile, and C. １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ Selected from alkoxy; R ３ is -C(O)NHR ６ Furthermore, selected from a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5-6 membered heteroaryl ring is composed of hydroxy, nitrile, and C １ ~C ３ It may be optionally substituted with 1 to 3 substituents independently selected from the alkyl group; R ６ teeth, (i) - (CR) ７ R ８ ) ｎ C(O)NR ｄ R ｅ (in the formula, n is either 1 or 2; R ７ and R ８ Each of them independently consists of H and C １ ~C ３ Selected from alkyl groups, or R ７ and R ８ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered saturated or partially unsaturated ring containing, optionally, a ring heteroatom selected from oxygen, sulfur, and nitrogen; R ｄ and R ｅ Each of them independently consists of H and C １ ~C ３ (Selected from alkyl groups); (ii) C optionally substituted with nitrile １ ~C ６ A 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from alkyl, oxygen, and nitrogen (the ring is a halogen, C １ ~C ３ Alkyl, C １ ~C ３ (May be optionally substituted with 1 to 4 substituents independently selected from haloalkyl and hydroxyl); and (iii) Phenyl, a 3-6 member saturated or partially unsaturated ring, or a 5-6 member heteroaryl ring (the saturated or partially unsaturated ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; the heteroaryl ring optionally contains one or two ring heteroatoms independently selected from oxygen, sulfur, and nitrogen; and the phenyl, saturated or partially unsaturated ring, and heteroaryl ring are optionally substituted with halogens, hydroxyl, nitriles, and one or more independently selected halogens). １ ~C ３ (The alkyl group may be optionally substituted with one or two substituents independently selected from the alkyl group.) Selected from; R １０ , R １１ , R １２ , and R １３ Each of these is independently H, C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls; or R １０ , R １１ , R １２ , and R １３ Any two of them, together with the carbon atom to which they are bonded, form a 3- to 6-membered ring, while the remaining two independently form H and C １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls, (0 to 10 hydrogen atoms bonded to one or more carbon atoms are replaced by deuterium atoms.)

43. [8-Methoxy-9-(1-methylpyrazole-3-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidine-1-yl]methanone; (1-(5-fluoropyridine-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (3S)-4-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-3-methylmorpholine-3-carbonyl; (2R)-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; (R)-1-(1-(1-hydroxy-2-methylpropane-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonil; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-N-(1-cyanocyclobutyl)-8-methoxy-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-1-(1-(5-fluoropyridine-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonil; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile; (2R)-1-[8-methoxy-9-oxazole-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]-6-methyl-1H-pyridine-2-one; (2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-oxazole-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone; 3-[3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]pyridine-2-carbonitrile; 3-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]pyridine-2-carbonil; [8-Methoxy-9-(2-methyltetrazole-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrroridine-1-yl]methanone; (2R)-1-[9-(1H-imidazole-2-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; (2R)-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; (2R)-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; (2R)-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazole-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrroridine-1-yl]methanone; [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazole-5-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrroridine-1-yl]methanone; (2R)-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl)-5-(trifluoromethyl)picolinonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonil; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(1,3,4-thiadiazole-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophene-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile; (R)-1-(1-(5-fluoropyrrolidine-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophene-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; 5-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl)nicotinamide; 3-((R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-yl)picolinonitrile; ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrroridine-1-yl)methanone; ((1aR,9bR)-8-methoxy-7-(2-methyl-2H-tetrazole-5-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H-cyclopropa[c]pyrrolo[2,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrroridine-1-yl)methanone; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]methanone; [8-Methoxy-9-(2-methyltetrazole-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrroridine-1-yl]methanone; (2R)-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil; (2R)-1-[8-methoxy-9-(1H-pyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil; (2R)-1-[1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazole-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; (2R)-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]-1-methylpyridine-2-one; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(1H-pyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; 6-[8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]-1H-pyridine-2-one; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]-1-methylpyridine-2-one; 3-[3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-yl]pyridine-2-carbonil; [(5R)-8-methoxy-5-methyl-9-(1-methylpyrazole-3-yl)-1-thiazole-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-yl]methanone; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonyl; (R)-1-(8-methoxy-6-methyl-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; ((R)-8-methoxy-5-methyl-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; ((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1-yl)((S)-8-methoxy-5-methyl-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)methanone ((1aR,9bR)-8-methoxy-7-(1-methyl-1H-pyrazole-3-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H-cyclopropa[c]pyrrolo[2,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(1,3,4-thiadiazole-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[9-(1H-imidazole-2-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; (2R)-1-[9-(1H-imidazole-2-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonyl; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-N-(2-oxo-1H-pyridine-3-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-N-(1-methyl-2-oxo-3-pyridyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridine-3-yl)-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3-pyridyl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2R)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-(2,2-dimethylpyrrolidine-1-carbonyl)-8-methoxy-N-(1H-tetrazole-5-ylmethyl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3-pyridyl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridine-3-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-1-(4-fluorophenyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-1-(4-fluorophenyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclopropyl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclopropyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 8-Methoxy-N-(1-methyl-2-oxo-3-pyridyl)-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(3-cyanooxetane-3-yl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(3-cyanooxetane-3-yl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrroridine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-[(3R)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-[(3S)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-(3-cyanooxetane-3-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclopropyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-(3-cyanooxetane-3-yl)-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-(3-cyanooxetane-3-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2-dihydropyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-8-methoxy-3-((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(1,3,4-thiadiazole-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-N-(1-cyanocyclobutyl)-8-methoxy-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1-carbonyl)-8-methoxy-6-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-((R)-2-cyano-2-methylpyrrolidine-1-carbonyl)-N-(1-cyanocyclobutyl)-8-methoxy-6-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-N-(1-cyanocyclobutyl)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (S)-N-(1-cyanocyclobutyl)-3-((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1-carbonyl)-8-methoxy-5-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; (4S)-N-(1-cyanocyclobutyl)-7-methoxy-4-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(thiophen-2-yl)-3a,5-dihydro-4H-cyclopenta[a]naphthalene-8-carboxamide; (S)-3-((R)-2-cyano-2-methylpyrrolidine-1-carbonyl)-N-(1-cyanocyclobutyl)-8-methoxy-5-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-N-(1-cyanocyclobutyl)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (1aR,9bR)-N-(1-cyanocyclobutyl)-8-methoxy-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H-cyclopropa[c]pyrrolo[2,1-a]isoquinoline-7-carboxamide; N-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2S)-2-ethyl-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; [8-Methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-yl]methanone; [(2R)-2-[(1S)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-propyl-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazole-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazole-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-[(1S)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazole-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazole-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-[(1S)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone; [(2S)-2-[(1S)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrroridine-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-[1-hydroxypropyl]-2-methylpyrrolidine-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2S)-2-[(1S)-1-hydroxyethyl]-2-methylpyrrolidine-1-yl]methanone; 2-Cyclopropyl(hydroxy)methyl)-2-methylpyrrolidine-1-yl)(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)methanone; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-N-(2-cyanopropan-2-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3-pyridyl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3-pyridyl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-[(3R or S)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methylpyrrolidine-1-carbonyl]-N-[(3S or R)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl]-[(2R or S)-4,4-difluoro-2-methyl-2-[(1R or S)-1-hydroxyethyl]pyrrolidine-1-yl]methanone; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methylpyrrolidine-1-carbonyl]-8-methoxy-1-thiazole-5-yl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidine-1-carbonyl]-1-thiazole-5-yl-5,6-dihydropyrrololo[2,1-a]isoquinoline-9-carboxamide; 2-ethyl-1-[8-methoxy-9-(1-methylpyrazole-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]pyrrolidine-2-carbonil; rel-(2R,3S)-3-hydroxy-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil; rel-(2R,3S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-3-hydroxy-2-methylpyrroridine-2-carbonil; 2-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-azabicyclo[4.2.0]octane-1-carbonil; (1S,5S)-2-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-5-methyl-2-azabicyclo[3.2.0]heptan-1-carbonitrile; (2R,4S)-4-hydroxy-1-[8-methoxy-9-(2-methyltetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methylpyrrolidine-2-carbonil; and (2R,4S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-4-hydroxy-2-methylpyrroridine-2-carbonil; (2R,4S)-4-hydroxy-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophene-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophene-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1-hydroxypropyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrrolidine-1-yl)methanone; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophene-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide; (2R,4S)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carbonil; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (8-Methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2-dihydropyridine-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-9-carboxamide; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrrolidine-1-yl)(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrololo[2,1-a]isoquinoline-3-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2-dihydropyridine-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-1-isobutyl-8-methoxy-N-(2-oxo-1,2-dihydropyridine-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-1-isobutyl-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-9-carboxamide; (1-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; {(S)-2-[(S)-3,3,3-trifluoro-1-hydroxypropyl]-2-methyl-1-pyrrolidinyl}{11-methoxy-12-(2-methyl-2H-tetraazo-l-5-yl)-3-(2-thienyl)-6-azatricyclo[7.4.0.02,6]trideca-1(13),2,4,9,11-pentaen-5-yl}methanone; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2-methylpropane-1-en-1-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonyl; (S)-3-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4-carbonyl; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4-carbonyl; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-propyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4-carbonyl; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazole-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonil; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonil; (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline-9-yl)picolinonitrile; (R)-3-(3-(2-cyano-2-methylazetidine-1-carbonyl)-1-(4-fluorophenyl)-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline-9-yl)picolinonitrile; (R)-1-(9-(4,4-dimethyl-4,5-dihydroxazole-2-yl)-8-methoxy-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carbonyl)-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-((R)-3-((2R,4S)-2-cyano-4-hydroxy-2-methylpyrrolidine-1-carbonyl)-8-methoxy-5-methyl-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-yl)picolinonitrile; (8-Methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2-methylpropane-1-en-1-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrroridine-1-yl)methanone; (2R,4S)-4-hydroxy-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazole-5-yl)-1-(2-methylpropane-1-1-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(2,2-difluoropropyl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H-tetrazole-5-yl)-1-(1,3,4-thiadiazole-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(5-fluoropyridine-2-yl)-8-methoxy-N-methyl-9-(2-methyl-2H-1,2,3-triazole-4-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxamide; ((R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2-methylpropane-1-en-1-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonyl; (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrrolidine-1-yl)methanone; (R)-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonil; (1-Isobutyl-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrrolidine-1-yl)methanone; (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1-hydroxypropyl)pyrrolidine-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-yl)((S)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)methanone; (2R,4S)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-4-hydroxy-2-methylpyrrolidine-2-carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazole-5-yl)-1-(2-methylallyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonyl; A compound selected from the group consisting of stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

45. A method for regulating follicular-stimulating hormone receptor (FSHR) activity in a subject, comprising administering to the subject in question a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 44.

46. A method for regulating follicular-stimulating hormone receptor (FSHR) activity in a biological sample, comprising contacting the biological sample with a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 44.

47. A method for treating a disease or disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 44, wherein the disease or disorder is optionally a fertility disorder.

48. A compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 44, for use in modulating follicular-stimulating hormone receptor (FSHR) activity in a subject requiring such modification.

49. A compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 44, for use in treating a disease or disorder (optionally, said disease or disorder being a fertility disorder) in a subject requiring treatment.

50. Use of a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the composition according to claim 44, in the preparation of a pharmaceutical for regulating follicular-stimulating hormone receptor (FSHR) activity in a subject.

51. Use of a compound according to any one of claims 1 to 43, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the composition according to claim 44, in the preparation of a medicament for treating a disease or disorder (optionally, said disease or disorder being a fertility disorder) in a subject requiring treatment.

52. The aforementioned diseases or disorders include hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngioma, compound pituitary hormone deficiency, reproductively capable eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenoma, cysts, metastatic cancer to the sella turcica (breast in women, lung and prostate in men), and invasive lesions. The method according to claim 47, the compound for use according to claim 49, or the use according to claim 51, selected from hemoglobinosis, sarcoidosis, histiocytosis, lymphoma, lymphohypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, sella turcica, pituitary infarction, Sheehan's syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders associated with GnRH deficiency.

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