Small molecule fsh receptor modulators

Abstract

Disclosed herein are small molecule follicle-stimulating hormone (FSH) receptor modulators, methods of making them, and therapeutic methods using them.

Description

SMALL MOLECULE FSH RECEPTOR MODULATORS FIELD

[0001] The present disclosure is in the field of pharmaceutical compounds and compositions and therapeutic methods of their use. In particular, the present disclosure is in the field of follicle- stimulating hormone (FSH) receptor modulators and their use. BACKGROUND

[0002] Gonadotropins serve important functions in several physiological processes including metabolism, temperature regulation, and reproduction. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular cell differentiation and steroidogenesis. The gonadotropin FSH (follicle-stimulating hormone) is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens. FSH is a heterodimeric glycoprotein hormone that shares structural similarities with luteinizing hormone (LH), human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH), all of which are proteins (28-38 kDa) composed of a \hffhg ^-subunit non-\hoZe^gmer [hng] mh Z ]blmbg\m ^-subunit that confers receptor binding specificity. See, e.g, Ulloa-Aguirre, A., et al., Front Endocrinol (Lausanne), 2018, 9:707. FSH, LH, and TSH are produced in the pituitary gland, while hCG is produced primarily by the placenta. The cellular receptor for FSH (FSHR) is expressed on testicular Sertoli cells and ovarian granulosa cells. See, e.g., Anderson, R.C., et al., Endocr Rev, 2018, 39(6):911-937.

[0003] In the female, FSH plays a pivotal role in the stimulation of follicle development and maturation. Binding of FSH to FSHR initiates an increase in the level of the intracellular second messenger adenosine 3', 5'-monophosphate (cAMP), which stimulates aromatase induction that catalyzes the conversion of androstenedione to estradiol within the ovary, enabling follicle growth. See, e.g., Donadeu, F.X. and M. Ascoli, Endocrinology, 2005, 146(9):3907-16.

[0004] FSHR activation also stimulates the expression of LH receptors on granulosa cells, allowing them to respond to the preovulatory LH surge. In the male, FSH is expressed on the Sertoli cells of the testis and plays a key role in stimulating spermatogenesis. Prepubertally, FSH 4886-0959-3510.1is responsible for Sertoli cell proliferation and in adulthood FSH stimulates spermatogonial proliferation and can support spermatogenesis to the round spermatid stage.

[0005] The FSH receptor is a class A member of the G-coupled protein (GPCR) class of receptors, belonging to the subfamily of glycoprotein hormone receptors, which also includes luteinizing hormone / choriogonadotropin receptor (LHCGR) and thyroid stimulating hormone receptor (TSHR). See, e.g, Ulloa-Aguirre, supra. Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic amino-terminal region, considered to be the amino-terminal extracellular domain; seven hydrophobic segments of membrane- spanning length, considered to be the transmembrane domain; and a carboxy-terminal region that contains potential phosphorylation sites (serine, threonine, and tyrosine residues), considered to be the carboxyterminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein-coupled receptors, su\a Zl ma^ ^-2-adrenergic, rhodopsin, and substance K receptors, by the large size of the hydrophilic amino-terminal domain, which is involved in hormone binding.

[0006] Annually in the U.S. there are 2.4 million couples experiencing infertility that are potential candidates for treatment. FSH, either extracted from urine or produced by recombinant DNA technology, is a parenterally-administered protein product used by specialists for ovulation induction and for controlled ovarian stimulation. Whereas ovulation induction is directed at achieving a single follicle to ovulate, controlled ovarian stimulation is directed at aspirating multiple oocytes for use in various in-vitro assisted reproductive technologies, e.g., in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). See, e.g., ESHRE guideline: Ovarian Stimulation for IVF / ICSI, (October 2019). FSH is also used clinically to treat male hypogonadism and male infertility, e.g., some types of failure of spermatogenesis. See, e.g., Behre, H.M., Front Endocrinol (Lausanne), 2019, 10:322.

[0007] FSHR is a highly specific target in the ovarian follicle growth process in the female and is almost exclusively expressed in the ovary. However, the use of FSH is limited by its high cost, lack of oral dosing, and the need for extensive monitoring by specialist physicians. Hence, 4886-0959-3510.1identification of a non-peptidic small molecule substitute for FSH that could potentially be developed for oral administration is desirable.

[0008] FSH and small molecule FSH receptor modulators may be used to treat diseases, disorders, and conditions such as female infertility, male infertility, hypogonadism, and failure of spermatogenesis. Small molecule FSH agonists have been disclosed in, e.g., WO 2002 / 09706, WO 2009 / 098283, WO 2010 / 136438, U.S. Patent No. 6,653,338, US Patent No. 8,431,564, WO 2011 / 012600, WO 2014 / 209978, and WO 2015 / 196759. One small molecule FSH receptor modulator, MK-8389, was evalulated in clinical trials, but did not reach approval. See, e.g., Gerrits, M.G.F. et al., Fertility and Sterility Vol. 105, No. 4, April 2016. There remains a need for small molecule FSH receptor modulators that selectively activate FSHR. SUMMARY

[0009] In one aspect, provided herein is a compound of Formula (A)or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 13 substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the 4886-0959-3510.1atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; or (ii) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)- NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl; X is CR20or N; R20is selected from H, halogen, nitrile, C1-C6alkyl, and C1-C6haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or 4886-0959-3510.1partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0010] In some embodiments, R1is -NRfRg, wherein: (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R44886-0959-3510.1group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; or (ii) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile.

[0011] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

[0012] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

[0013] In some embodiments, R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the 4886-0959-3510.1atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

[0014] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl.

[0015] In some embodiments, R1is -NRfRg, wherein Rfis C1-C6alkyl; and Rgis C1-C6alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile.

[0016] In some embodiments, R2is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R2is C1-C6 haloalkyl. In some embodiments, R2is C1-C6 hydroxyalkyl. In some embodiments, R2is phenyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl. In some embodiments, R2is 4-fluorophenyl. In some embodiments, R2is C4-C6cycloalkyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl. In some embodiments, R2is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1- C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl. In some embodiments, R2is 3,3-difluorocyclobutyl, 5-fluoropyridin-2-yl, 2-thiophenyl, 5-thiazolyl, or 1,3,4-thiadiazolyl. 4886-0959-3510.1

[0017] In some embodiments, X is CR20. In some embodiments, X is N.

[0018] In another aspect, provided herein is a compound of Formula (B)Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: 4886-0959-3510.1(i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0019] In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 4886-0959-3510.11 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl. In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl.

[0020] In another aspect, provided herein is a compound of Formula (C)Formula (C) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl 4886-0959-3510.1ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; 4886-0959-3510.1wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0021] In another aspect, provided herein is a compound of Formula (D)Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; 4886-0959-3510.1each R5is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1- C3 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are 4886-0959-3510.1attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0022] In another aspect, provided herein is a compound of Formula (E)Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Alk is C1-C6alkyl or C1-C6alkenyl; R6is selected from: 4886-0959-3510.1(i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0023] In another aspect, provided herein is a compound of Formula (F) 4886-0959-3510.1or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl; or (i) Rfis C1-C6alkyl; and Rgis C1-C6alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6alkyl; C1-C6alkenyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; 4886-0959-3510.1R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 4886-0959-3510.17 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0024] In some embodiments, R1is , wherein each R4is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen. In some embodiments, R1is , wherein R4ais C1-C6 alkyl and R4bis selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen. In some embodiments, R1is , wherein R4bis C1-C6 alkyl and R4ais selected from nitrile and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0025] In some embodiments, R3is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2. In some embodiments, R3is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains 1 4886-0959-3510.1to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring 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, R3is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3may 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, R3is - C(O)NHR6.

[0026] In some embodiments, R6is |(CR7R8)nC(O)NRdRe. In some embodiments, each of R7and R8is independently selected from H and C1-C3alkyl. In some embodiments, R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[0027] In some embodiments, R6is C1-C6 alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6is C1-C6alkyl optionally substituted with nitrile or tetrazole. In some embodiments, R6is phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6- membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens. In some embodiments, R6is cyclopropane optionally substituted with nitrile or is 19yclobutene optionally substituted with nitrile.

[0028] In some embodiments, each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments, any two of R10, R11, R12, and R13, 4886-0959-3510.1together with the carbon atom(s) to which they are attached, 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 aspect, ikhob]^] a^k^bg bl Z \hfihng] h_ ChkfneZ (F^)ChkfneZ (F^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6- membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R2is selected from C1-C6alkyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)- NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R20is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; 4886-0959-3510.1R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and 4886-0959-3510.1each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0030] In another aspect, provided herein is a compound of Formula (I)Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2is selected from C1-C6 alkyl; C1-C6 haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- 4886-0959-3510.1membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl, 4886-0959-3510.1wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0031] In another aspect, provided herein is a compound selected from Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In another aspect, provided herein is a compound selected from Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0032] In another aspect, provided herein are salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications and derivatives of the compounds, stereoisomers, and tautomers described herein.

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

[0034] In another aspect, provided herein is a method of modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, comprising administering to a subject in need thereof the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein.

[0035] In another aspect, provided herein is a method of modulating follicle-stimulating hormone receptor (FSHR) activity in a biological sample, comprising contacting the biological sample with the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein.

[0036] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the composition disclosed herein. In some embodiments, the disease or disorder is selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal 4886-0959-3510.1beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

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

[0038] In another aspect, provided herein is a compound as disclosed herein or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, for use in modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, or for use in in treating a disease or disorder in a subject in need thereof, such as a disease or disorder selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency, or for use in treating a fertility disorder in a subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled 4886-0959-3510.1ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[0039] In another aspect, provided herein is the use of a compound as disclosed herein, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, in the preparation of a medicament for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, or for treating a disease or disorder in a subject in need thereof, such as a disease or disorder selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency, or for treating a fertility disorder in a subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis. DETAILED DESCRIPTION DEFINITIONS

[0040] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure pertains, unless otherwise defined.

[0041] As used herein, the singular forms "a," "an," and "the" and the like designate both the singular and the plural, unless expressly stated to designate the singular only. 4886-0959-3510.1

[0042] As used herein, the term "about" means that the stated parameter is not limited to the exact number stated. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. As used herein, ranges are to be construed as shorthand for each and every value falling within the range, and each separate value should be understood to be expressly disclosed herein.

[0043] Qa^ iakZl^ }\hglblmbg` ^ll^gmbZeer h_~ pbee [^ ng]^klmhh] mh bg\en]^ mahl^ ^e^f^gml specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. Ta^g }\hglblmbg` ^ll^gmbZeer h_~ bl nl^] mh k^_^k mh compositions with only one active agent disclosed herein, the compositions cannot include any additional active agents that are not otherwise recited. Ta^g }\hglblmbg` ^ll^gmbZeer h_~ bl nl^] mh refer to combinations of active agents disclosed herein, the combinations cannot include any additional active agents that are not otherwise recited.

[0044] >l nl^] a^k^bg, }iaZkfZ\^nmb\Zeer Z\\^imZ[e^ lZem~ k^_^kl mh Z lZem h_ Z \hfihng] maZm does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Typically, but not necessarily unless otherwise stated, the salts of the present invention are pharmaceutically acceptable salts. Salts ^g\hfiZll^] pbmabg ma^ m^kf }iaZkfZ\^nmb\Zeer Z\\^imZ[e^ lZeml~ k^_^k mh ghg-toxic salts of the compounds of this invention. Salts of the compounds of the present disclosure may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, 4886-0959-3510.1phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this disclosure and these should be considered to form a further aspect of the present technology.

[0045] Where compounds disclosed herein have one or more chiral centers, they may exist as, be provided or formulated as, or be used as, a racemate or as individual enantiomers. It should be noted that all such stereoisomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, racemic mixtures of the isomers, and mixtures where one isomer is present in greater abundance than another.

[0046] Where processes for the preparation of compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

[0047] >l nl^] a^k^bg, }Zkre~ k^_^kl mh Z \Zk[h\r\eb\ (Zee \Zk[hg) kbg` maZm is fully aromatized. An }Zkre~ `khni \Zg [^ fZ]^ ni h_ mph hk fhk^ _nl^] kbg`l (kbg`l maZm laZk^ mph Z]cZ\^gm \Zkbon atoms). When an aryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include: 4886-0959-3510.1

[0048] >l nl^] a^k^bg, }a^m^khZkre~ k^_^kl mh Z kbg` maZm is fully aromatized and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. In some examples, a heteroaryl ring may comprise an oxo group directly appended to a ring carbon, the oxo group forming part of the aromatized system. A }a^m^khZkre~ `khni \Zg [^ fZ]^ ni h_ mph or more fused rings (rings that share two adjacent carbon atoms). When a heteroaryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, 2-pyridonyl, pyridazine, pyrimidine, pyrazine and triazine. As described herein, in some examples, the heteroaryl group may be substituted. In other words, the heteroaryl group may comprise one or more substituents on the heteroaromatic ring. When a heteroaryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s) provided that valencies are satisfied. In some cases, the heteroaryl group may be substituted at the heteroatom, e.g., a N-containing heteroaryl group may be an N-substituted heteroaryl group (such as a N-substituted 2-pyridonyl group).

[0049] >l nl^] a^k^bg, }Zedre~ k^_^kl mh Z lmkZb`am hk [kZg\a^] \aZbg _neer lZmnkZm^] (gh ]hn[e^ or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 20 carbon atoms. An alkyl group 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, a C1-C6alkyl represents an alkyl group having 1 to 6 carbon atoms, a C1-C4alkyl represents an alkyl group having 1 to 4 carbon atoms and a C1-C4alkyl represents an alkyl group having 1 to 3 carbon atoms, etc. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. 4886-0959-3510.1

[0050] >l nl^] a^k^bg, }\r\ehZedre~ k^_^kl mh Z \hfie^m^er lZmnkZm^] (gh ]hn[e^ [hg]l) hydrocarbon ring. Cycloalkyl groups of the presently disclosed compounds may range from C3 to C5, C3 to C6, C3 to C7, or C3 to C8. As used herein, a C3-C5 cycloalkyl represents a cycloalkyl group containing 3 to 5 carbon atoms and a C3-C6 cycloalkyl represents a cycloalkyl group containing 3 to 6 carbon atoms.

[0051] As nl^] a^k^bg, }a^m^kh\r\ehZedre~ k^_^kl to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that the ring is not fully aromatized. A }a^m^kh\r\ehZedre~ ring as defined herein can be a stable 3- to 18-membered ring (which includes a 3- to 5-membered or 3- to 6-membered ring) that consists of carbon atoms and from one to five ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0052] >l nl^] a^k^bg, }Zedhqr~ k^_^kl mh an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a C1-C6 alkoxy represents an alkoxy group containing 1 to 6 carbon atoms and a C1-C3 alkoxy represents an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

[0053] >l nl^] a^k^bg, }aZehZedre~ k^_^kl mh Zg Zedre `khni, Zl ]^fined above, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). >l nl^] a^k^bg, }@1-C6aZehZedre~ k^ik^l^gml Zg Zedre `khni \hgmZbgbg` 1 mh 6 \Zk[hg Zmhfl, bg which one or more hydrogens thereon has been replaced with a halogen atom.

[0054] >l nl^] a^k^bg, }aZehZedhqr~ k^_^kl mh Zg Zedhqr `khni, Zl ]^_bg^] a^k^bg, bg pab\a hg^ or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). >l nl^] a^k^bg, }@1-C3 haloaldhqr~ k^ik^l^gml Z aZehalkoxy group containing 1 to 3 carbon atoms.

[0055] >l nl^] a^k^bg, nge^ll hma^kpbl^ lmZm^], }bg]^i^g]^gmer l^e^\m^]~ indicates that each one of a designated group is selected independently from a subsequent list of species. 4886-0959-3510.1

[0056] As used herein, and unless otherwise stated, where a group is described as being optionally substituted, one or more hydrogen atoms on the group may each independently be replaced with a substituent, provided valencies are satisfied.

[0057] It is to be understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S. In addition, it is to be understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z.

[0058] It is to be understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of:(wherein Rxis H) also includes the disclosure of:and vice versa, even if only one of the two structures is disclosed.

[0059] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that isotopically enriched analogs of the compound are also contemplated and encompassed by the disclosure. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon-13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location, i.e., two or more or all or a plurality less than all hydrogens are replaced by deuterium. For example, in some embodiments, 1 to 10 hydrogens are replaced by deuterium. The present disclosure also encompasses compounds where all similar atoms are replaced by a less common isotope, for example, a perdeutero compound where all hydrogen atoms are replaced by deuterium. The isotopically enriched compounds may be useful, 4886-0959-3510.1for example, when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound is undergoing.

[0060] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications, and derivatives thereof are contemplated and encompassed by the disclosure.

[0061] Qa^ m^kf }iaZkfZ\^nmb\Ze \hfihlbmbhg~ k^_^kl mh Z fbqmnk^ h_ hg^ hk fhk^ \hfihng]l disclosed herein with another pharmaceutically acceptable excipient, such as one or more pharmaceutically acceptable diluents or carriers or one or more other pharmaceutically acceptable excipients known in the art. Formulating a compound in a pharmaceutical composition may facilitate administration of the compound to an organism, e.g., the subject to be treated. The specific components of a pharmaceutical composition may depend on and vary with the intended route of administration.

[0062] >l nl^] a^k^bg, ma^ m^kfl }iZmb^gm~ Zg] }ln[c^\m~ k^_^k mh Z vertebrate, such as but not limited to a mammal (including a human), bird, fish, or reptile, that has been or will be the object of treatment, observation, hk ^qi^kbf^gm. }Pn[c^\m~ Zg] }iZmb^gm~ fZr [^ nl^] bgm^k\aZg`^Z[er. Mammals include, but are not limited to, humans, mice, rodents, rats, simians, farm animals, dogs, cats, sport animals, and pets. The methods described herein may be useful in human therapy and / or veterinary / animal husbandry applications. Without being limiting, the discussion that follows is written with reference to adult human patients.

[0063] >l nl^] a^k^bg, ma^ m^kfl }ma^kZi^nmb\Zeer ^__^\mbo^ Zfhngm~ Zg] }^__^\mbo^ Zfhngm~ are used interchangeably and refer to an amount that provides the specific intended pharmacological effect in a patient in need of treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein in a given patient, even though such amount is deemed to be a therapeutically effective amount by those of skill in the art. Exemplary therapeutically effective amounts are provided herein with reference to adult human patients. The therapeutically effective amount may vary depending upon 4886-0959-3510.1characteristics of the patient being treated, the condition being treated, and the severity of the condition, for example. COMPOUNDS

[0064] In one aspect, disclosed herein is a compound of Formula (A)Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; or (ii) Rfis C1-C6alkyl; and Rgis C1-C6alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6alkyl; C1-C6alkenyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)-NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, 4886-0959-3510.1wherein the phenyl, C4-C6cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl; X is CR20or N; R20is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and 4886-0959-3510.1(iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0065] In another aspect, disclosed herein is a compound of Formula (A)or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from 4886-0959-3510.1oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; or (ii) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6alkyl; C1-C6alkenyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)-NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; X is CR20or N; R20is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein 4886-0959-3510.1n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0066] In some embodiments, X is CR20. In some embodiments, X is N. 4886-0959-3510.1

[0067] In another Zli^\m, ]bl\ehl^] a^k^bg bl Z \hfihng] h_ ChkfneZ (F^)ChkfneZ (F^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R2is selected from C1-C6alkyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)- SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1- C6alkyl)-NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R20is selected from H, halogen, nitrile, C1-C6alkyl, and C1-C6haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from 4886-0959-3510.1oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected 4886-0959-3510.1from H, C1-C6alkyl, and C1-C6haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0068] In another aspect, disclosed herein is a compound of Formula (I)Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2is selected from C1-C6alkyl; C1-C6haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6is selected from: 4886-0959-3510.1(i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0069] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 4886-0959-3510.1additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl.

[0070] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl.

[0071] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0072] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 13 substituents (e.g. 1 to 6, or 1 to 5 substituents) independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are 4886-0959-3510.1attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5- membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen.

[0073] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0074] In some embodiments, R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl. In some embodiments, R14886-0959-3510.1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl. In some embodiments, R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; ; and each R4aand R4bis independently selected from C1-C3alkyl. In some embodiments, R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen. In some embodiments, R1is , wherein R1is substituted with 2 to 4 R4groups, wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring and each remaining R4group, if present, is independently selected from halogen, hydroxy, nitrile, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0075] In some embodiments, R1is , wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0076] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, 4886-0959-3510.1hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6- membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; and each R4aand R4bis independently selected from C1-C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 2 to 4 R4groups, wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring and each remaining R4group, if present, is independently selected from halogen, hydroxy, nitrile, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group 4886-0959-3510.1is independently selected from halogen, hydroxy, nitrile, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

[0077] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0078] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 7-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 7-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl.

[0079] In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, 4886-0959-3510.1hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl 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 wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3 alkyl. In some embodiments, R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

[0080] In some embodiments, R1is -NRfRg, wherein Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile.4886-0959-3510.1.

[0082] In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is C1-C4alkyl. In some embodiments, R2is C1-C3 alkyl. In some embodiments, R2is C1-C6 alkenyl. In some embodiments, R2is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R2is, ,

[0083] In some embodiments, R2is C1-C6 haloalkyl. In some embodiments, R2is C1-C4 haloalkyl. In some embodiments, R2is C1-C3 haloalkyl.

[0084] In some embodiments, R2is C1-C6 hydroxyalkyl. In some embodiments, R2is C1-C4 hydroxyalkyl. In some embodiments, R2is C1-C3 hydroxyalkyl. 4886-0959-3510.1

[0085] In some embodiments, R2is phenyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1- C3 alkyl. In some embodiments, R2is phenyl optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3alkoxy.

[0086] In some embodiments, R2is phenyl optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy. In some embodiments, R2is 4-fluorophenyl.

[0087] In some embodiments, R2is C4-C6cycloalkyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1- C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl. In some embodiments, R2is C4-C6 cycloalkyl optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0088] In some embodiments, R2is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl. In some embodiments, R2is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. 4886-0959-3510.1

[0090] In some embodiments, R2is a 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy. In some embodiments, R2is a 5- membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, R2is a 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy. In some embodiments, R2is 2- thiophene.4886-0959-3510.1

[0092] In another aspect, disclosed herein is a compound of Formula (B)Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the 4886-0959-3510.1phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; 4886-0959-3510.1wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0093] In another aspect, disclosed herein is a \hfihng] h_ ChkfneZ (FF^)ChkfneZ (FF^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: 4886-0959-3510.1(i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0094] In another aspect, disclosed herein is a compound of Formula (II) 4886-0959-3510.1Formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is , wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; Het is a 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 or 2 R5groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3alkyl; 4886-0959-3510.1(ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0095] In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl. In some embodiments, Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy.

[0096] In some embodiments, Het is a 5-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 4886-0959-3510.11 or 2 R5groups independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy. In some embodiments, Het is, , . In some embodiments, Het is 2-thiophene. In some embodiments, Het is. In some embodiments, Het is. .

[0097] In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl. In some embodiments, Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3alkoxy.

[0098] In some embodiments, Het is a 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 or 2 R5groups independently selected from halogen, nitrile, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy. In some embodiments, Het is.

[0099] In another aspect, disclosed herein is a compound of Formula (C) Formula (C)4886-0959-3510.1or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and 4886-0959-3510.1nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0100] In another aspect, disclosed herein is a \hfihng] h_ ChkfneZ (FFZ^)ChkfneZ (FFZ^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein 4886-0959-3510.1R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the 4886-0959-3510.1heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0101] In another aspect, disclosed herein is a compound of Formula (IIa)Formula (IIa) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is , wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- 4886-0959-3510.1membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; 4886-0959-3510.1wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0102] In another aspect, disclosed herein is a compound of Formula (D)Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; 4886-0959-3510.1each R5is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1- C3 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are 4886-0959-3510.1attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0103] In another aspect, disclosed herein is a compound of Formula (FFF^)ChkfneZ (FFF^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 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; 4886-0959-3510.1each R5is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1- C3 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are 4886-0959-3510.1attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0104] In another aspect, disclosed herein is a compound of Formula (III)Formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3alkyl; m is 0, 1, or 2; each R5is independently selected from halogen; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; 4886-0959-3510.1each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0105] In another aspect, disclosed herein is a compound of Formula (E) 4886-0959-3510.1Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; Alk is C1-C6 alkyl or C1-C6 alkenyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or 4886-0959-3510.1partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0106] In some embodiments, Alk is C1-C6alkyl. In some embodiments, Alk is C1-C6alkenyl. In some embodiments, Alk

[0107] In another aspect, disclosed herein is a compound of Formula (FS^) 4886-0959-3510.1ChkfneZ (FS^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; Alk is C1-C6alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; 4886-0959-3510.1each of Rdand Reis independently selected from H and C1-C3alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0108] In another aspect, disclosed herein is a compound of Formula (IV)Formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein 4886-0959-3510.1R1is , wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl; Alk is C1-C6 alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently 4886-0959-3510.1selected from halogen, hydroxy, nitrile, and C1-C3alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0109] In another aspect, disclosed herein is a compound of Formula (F)Formula (F) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; or (i) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; 4886-0959-3510.1R2is selected from C1-C6alkyl; C1-C6alkenyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and 4886-0959-3510.1(iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0110] In another aspect, disclosed herein is a compound of Formula (A)Formula (A) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from 4886-0959-3510.1oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 13 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; or (ii) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6alkyl; C1-C6alkenyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)-NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; X is CR20or N; R20is selected from H, halogen, nitrile, C1-C6 alkyl, and C1-C6 haloalkyl; and R3is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains 1 to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; 4886-0959-3510.1wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

[0111] As stated above, for each of Formulas (A), (B), (C), (D), (E), and (F), R1is or may be represented as , wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3 alkyl.

[0112] >l lmZm^] Z[ho^, _hk ^Z\a h_ ChkfneZl (F^), (FF^), (FFZ^), (FFF^) Zg] (FS^), O1is or may be represented as, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl.

[0113] As stated above, for each of Formulas (I), (II), (IIa), (III) and (IV), R1is or may be represented as, wherein R1is substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0114] In some embodiments, R1may be a pyrrolidinyl ring (as shown above) that may be substituted with two R4groups. By way of example, the pyrrolidinyl ring may be substituted with at least two R4groups on an atom adjacent the nitrogen atom. For example, the pyrrolidinyl group may comprise two R4groups in a geminal substitution pattern (e.g., each R4group may be appended to the same atom on the pyrrolidinyl ring). 4886-0959-3510.1

[0115] As such, in some embodiments of any of Formulas (A), (B), (C), (D), (E), and (F), R1may be representedwhich two R4groups are appended to a carbon atom adjacent the nitrogen atom. In some embodiments of Zgr h_ ChkfneZl (F^), (FF^), (FFZ^), (FFF^), Zg] (FS^), O1may be represented as , in which two R4groups are appended to a carbon atom adjacent the nitrogen atom. In some embodiments of any of Formulas (I), (II), (IIa), (III) and (IV), R1may be represented as , in which two R4groups are appended to a carbon atom adjacent the nitrogen atom. At least one of the R4groups may be C1-C6alkyl. At least one of the R4groups may be selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen.

[0116] By way of example only, R1may be represented as ,wherein R4ais C1-C6alkyl (such as methyl); and R4bis selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen. Representative examples of suitable R4bgroups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3.

[0117] By way of example only, R1may be represented as,wherein R4bis C1-C6 alkyl (such as methyl); and R4ais selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen. Representative examples of suitable R4agroups include, but are not limited to, nitrile, methyl, ethyl, CH2OH, CH(OH)CH3, and CH(OH)CF3. 4886-0959-3510.1

[0118] In some embodiments, R1may be represented as , wherein R4aand R4bare as defined above.

[0119] Fg lhf^ ^f[h]bf^gml h_ Zgr hg^ hk fhk^ h_ ChkfneZl (>), (?), (@), (A), (B), (C), (F^), (FF^), (FFZ^), (FFF^), (FS^), (F), (FF), (FFZ), (FFF) Zg] (FS), R3is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6-membered heteroaryl ring 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, R3is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2.

[0120] In some embodiments of any one or more of Formulas (I), (II), (IIa), (III) and (IV), R3is a 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3 alkyl. In some embodiments, R3is pyrazole, imidazole, oxazole, pyridonyl (e.g., 2-pyridonyl), or pyridine, wherein R3may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3alkyl. Where the heteroaryl ring comprises a ring nitrogen atom, the substituent may be bonded directly to the nitrogen atom. By way of example only, R3may be a N-(C1-C3alkyl) pyridonyl group.

[0121] In some embodiments of any one or more of Formulas (A), (B), (C), (D), (E), (F), (F^), (FF^), (FFZ^), (FFF^), (FS^), (F), (FF), (FFZ), (FFF) Zg] (FS), O3is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring nitrogens, wherein the 5- to 6-membered heteroaryl ring 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, R3is a tetrazolyl, optionally substituted with C1-C3alkyl, e.g. a methyl-substituted tetrazolyl ring. 4886-0959-3510.1

[0122] As stated above, in some embodiments of Formulas (A), (B), (C), (D), (E), and (F), R3is -C(O)NHR6. Fg lhf^ ^f[h]bf^gml h_ Zgr hg^ hk fhk^ h_ ChkfneZl (F^), (FF^), (FFZ^), (FFF^) Zg] (FS^), O3is -C(O)NHR6. In some embodiments of any one or more of Formulas (I), (II), (IIa), (III) and (IV), R3is -C(O)NHR6.

[0123] In some embodiments, R6is |(CR7R8)nC(O)NRdRe.

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

[0125] In some embodiments, each of R7and R8is independently selected from H and C1-C3 alkyl. In some embodiments, R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

[0126] In some embodiments, Rdand Reare both C1-C3alkyl. In some embodiments, Rdand Reare both methyl.4886-0959-3510.1

[0128] In some embodiments, R6is C1-C6 alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy. In some embodiments, R6is C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. In some embodiments, R6is C1-C6 alkyl optionally substituted with nitrile. In some embodiments, R6is a 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy. In some embodiments, R6is pyrazolyl, oxazolyl, imidazolyl, pyridinyl, or 2-pyridonyl, each of which may be optionally substituted with 1 to 4 4886-0959-3510.1substituents independently selected from halogen, C1-C3alkyl, and C1-C3haloalkyl. Where the heteroaryl ring comprises a ring nitrogen atom, the substituent may be bonded directly to the nitrogen atom.

[0129] In some embodiments, R6is C1-C6 alkyl optionally substituted with nitrile or tetrazole. By way of example only, R6may be a C1-C3 alkyl (such as a C3 alkyl) optionally substituted with nitrile or tetrazole.

[0130] In some embodiments, R6is phenyl, a 3- to 6-membered saturated or partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with one or more independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens. In some embodiments, R6is phenyl, a 3- to 6-membered saturated or partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens. In some embodiments, R6is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1- C3alkyl optionally substituted with one or more independently selected halogens. In some embodiments, R6is a 3- to 6-membered saturated or partially unsaturated ring optionally containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently 4886-0959-3510.1selected halogens. In some embodiments, R6is cyclopropane optionally substituted with nitrile or is cyclobutane optionally substituted with nitrile. In some embodiments, R6is a 5- to 6-membered heteroaryl ring, wherein the ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens. Representative examples include but are not limited to, pyridonyl (e.g., 2-pyridonyl) which may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3alkyl optionally substituted with one or more independently selected halogens. In some examples, R6may be 2-pyridonyl optionally substituted with a C1-C3 alkyl (e.g., methyl), further optionally wherein the 2-pyridonyl is substituted at the nitrogen atom with a C1-C3 alkyl (e.g., methyl)

[0131] In some embodiments of any one or more of Formulas (A), (B), (C), (D), (E), and (F), each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a cyclopropyl ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0132] In some embodiments h_ Zgr hg^ hk fhk^ h_ ChkfneZl (F^), (FF^), (FFZ^), (FFF^) Zg] (FS^), each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a cyclopropyl ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. 4886-0959-3510.1

[0133] In some embodiments of any one or more of Formulas (I), (II), (IIa), (III) and (IV), each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each of R10, R11, R12, and R13is hydrogen. In some embodiments, two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6- membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0134] In some embodiments of Formula (A), R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments h_ ChkfneZ (F^), O11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl.

[0135] The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in reaction schemes below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. The synthetic procedure for individual compounds is provided in the Examples section, below.

[0136] In another aspect, disclosed herein is a compound selected from Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0137] Table 1 Compd No. Name 4-1 [8-methoxy-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinolin- 3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl]methanone 4-2 (1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 4886-0959-3510.14-3 (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-dihydropyridin-3-yl)-1-(2,2,2-triflu oroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 6-1 (3S)-4-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-3-methyl-morpholine-3-carbonitrile 6-2 (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 6-3 (R)-1-(1-(1-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 6-4 (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 6-5 (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-6(R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-7 (R)-1-(1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 6-8 (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-1 (2R)-1-[8-methoxy-9-oxazol-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-2 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-9-yl]-6-methyl-1H-pyridin-2-one 7-3 (2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-oxazol-2-yl-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 7-4 3-[3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl]pyridine-2-carbonitrile 7-5 3-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl- 5,6-dihydropyrrolo[2,1-a]isoquinolin-9-yl]pyridine-2-carbonitrile 4886-0959-3510.17-6 [8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin- 3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone 7-7 (2R)-1-[9-(1H-imidazol-2-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-8 (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-9 (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-10 [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(2-methyltetrazol- 5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 7-11 (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-12 [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1- yl]methanone 7-13 [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-1-thiazol-5-yl-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy- ethyl]pyrrolidin-1-yl]methanone 7-14 (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 7-15 (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl)-5-(trifluoromethyl)picolinonitrile 7-16 (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-17 (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 7-18 (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 4886-0959-3510.17-19 (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 7-20 (R)-1-(1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 7-21 (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 7-22 ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 7-23 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-dihydropyrrolo[2,1- a]isoquinolin-9-yl)nicotinamide 7-24 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-dihy dropyrrolo[2,1- a]isoquinolin-9-yl)picolinonitrile 7-25 ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydrop yrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 7-26 ((1aR,9bR)-8-methoxy-7-(2-methyl-2H-tetrazol-5-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H- cyclopropa[c]pyrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 7-27 [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(2-methyltetrazol- 5-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 7-28 [8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin- 3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone 8-1 (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-2 (2R)-1-[8-methoxy-9-(1H-pyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 4886-0959-3510.18-3 (2R)-1-[1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-4 (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 8-5 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl- 5,6-dihydropyrrolo[2,1-a]isoquinolin-9-yl]-1-methyl-pyridin-2-one 8-6 [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1H-pyrazol-3-yl)- 1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 8-7 6-[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]isoquinolin-9-yl]-1H-pyridin-2-one 8-8 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-9-yl]-1-methyl-pyridin-2-one 8-9 3-[3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2,1-a]isoquinolin-9-yl]pyridine-2-carbonitrile 8-10 [(5R)-8-methoxy-5-methyl-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy- ethyl]pyrrolidin-1-yl]methanone 8-11 (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylazetidine-2-carbonitrile 8-12 (R)-1-((S*)-8-methoxy-6-methyl-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile 8-13 ((R)-8-methoxy-5-methyl-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrr olo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin- 1-yl)methanone 8-14 ((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidin-1-yl)((S)-8-methoxy-5-methyl-9-(1- methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)methanone 8-15 ((1aR,9bR)-8-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H- cyclopropa[c]pyrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 4886-0959-3510.18-16 (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone 9-1 [(2R)-2-[(1R) -1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[9-(1H-imidazol-2-yl)-8- methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 9-2 (2R)-1-[9-(1H-imidazol-2-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 10-1 N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-2 N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4- fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-3 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-N-(2- oxo-1H-pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-4 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-N-(1- methyl-2-oxo-3-pyridyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-5 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)- 1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-6 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3- pyridyl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-7 N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1- carbonyl]-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-8 N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]- 8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-9 N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy- 1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-10 N-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2R)-2-(hydroxymethyl)-2-methyl-pyrrolidine-1- carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-11 3-(2,2-dimethylpyrrolidine-1-carbonyl)-8-methoxy-N-(1H-tetrazol-5-ylmethyl)-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 4886-0959-3510.110-12 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(1-methyl-2-oxo-3- pyridyl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-13 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)- 1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-14 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 10-15 N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]- 8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-16 N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1- carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-17 N-(1-cyanocyclobutyl)-1-(4-fluorophenyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl- pyrrolidine-1-carbonyl]-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-18 N-(1-cyano-1-methyl-ethyl)-1-(4-fluorophenyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl- pyrrolidine-1-carbonyl]-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-19 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-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-20 N-(1-cyanocyclopropyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1- carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-21 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 10-22 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 10-23 N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]- 8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-24 N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4- fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 4886-0959-3510.110-25 N-(3-cyanooxetan-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 10-26 N-(3-cyanooxetan-3-yl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1- carbonyl]-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-27 N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy- 1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-28 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-[(3R*)-3-cyanotetrahydrofuran-3-yl]- 8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-29 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-[(3S*)-3-cyanotetrahydrofuran-3-yl]- 8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-30 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-3-yl)-8-methoxy-1- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-31 N-(1-cyanocyclopropyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-32 N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1- propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-33 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-3-yl)-8-methoxy-1- propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-34 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-3-yl)-8-methoxy-1- (2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-35 N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1- thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 10-36 (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-37 (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2-dihydropyridin-3- yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 4886-0959-3510.110-38 N-(1-cyanocyclobutyl)-8-methoxy-3-((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxy ethyl) pyrrolidine-1-carbonyl)-1-(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-39 (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 10-40 (S*)-N-(1-cyanocyclobutyl)-3-((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1- carbonyl)-8-methoxy-6-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-41 (S*)-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 10-42 (R)-N-(1-cyanocyclobutyl)-3-((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1- carbonyl)-8-methoxy-5-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-43 (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 10-44 (S)-N-(1-cyanocyclobutyl)-3-((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidine-1- carbonyl)-8-methoxy-5-methyl-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 10-45 (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 10-46 (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 10-47 (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 10-48 (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 4886-0959-3510.111-1 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 13-1 [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol- 3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 13-2 [8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin- 3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone 13-3 [(2R)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol- 3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 13-4 [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1- yl]methanone 13-5 [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2R)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone 13-6 [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone 13-7 [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone 13-8 [(2S)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol- 3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone 13-9 [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1- yl]methanone 13-10 [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-[(1S*)-1-hydroxypropyl]-2-methyl-pyrrolidin-1-yl]methanone 13-11 [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2S)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone 13-12 (R*)-2-(R*)-cyclopropyl(hydroxy)methyl)-2-methylpyrrolidin-1-yl)(1-(4-fluorophenyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)methanone 4886-0959-3510.118-1 (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 18-2 N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1- (2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 18-3 3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(1- methyl-2-oxo-3-pyridyl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 18-4 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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 18-5 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)- 1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 18-6 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-[(3R*)-3-cyanotetrahydrofuran-3-yl]- 8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 18-7 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-[(3S*)-3-cyanotetrahydrofuran-3-yl]- 8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 20-1 [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl]-[(2R or S)-4,4-difluoro-2-methyl-2-[(1R or S)-1- hydroxyethyl]pyrrolidin-1-yl]methanone 24-1 N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]- 8-methoxy-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide 24-2 N-(1-cyanocyclobutyl)-8-methoxy-3-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy- ethyl]pyrrolidine-1-carbonyl]-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 25-1 (2R*-2-ethyl-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]pyrrolidine-2-carbonitrile 26-1 rel-(2R,3S)-3-hydroxy-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 26-2 rel-(2R,3S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-3-hydroxy-2-methyl-pyrrolidine-2- carbonitrile 4886-0959-3510.132-1 (1S*,6R*)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-azabicyclo[4.2.0]octane-1-carbonitrile 32-2 (1S,5S)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-5-methyl-2-azabicyclo[3.2.0]heptane-1-carbonitrile 33-1 (2R,4S)-4-hydroxy-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6-dihydropyrro- lo[2,1-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carbonitrile 34-1 (2R,4S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2- carbonitrile

[0138] In another aspect, disclosed herein is a compound selected from Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 4886-0959-3510.1

[0139] Table 2 Example Name (2R,4S)-4-hydroxy-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen- 1 2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine- 2-carbonitrile (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- 2 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- 3 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- 4 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 5 2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3- carboxamide (2R,4S)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5- 6 yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile 4886-0959-3510.1(R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- 7 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- 8 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- 9 dihydroimidazo[5,1a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl) methanone (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- 10 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- 11 dihydroimidazo[5,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(1-methyl-2- 12 oxo-1,2-dihydropyridin-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1- a]isoquinoline-9-carboxamide 4886-0959-3510.1(R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2- 13 dihydropyridin-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1- a]isoquinoline-9-carboxamide (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- 14 a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrrolidin-1-yl)(1-(4- 15 fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)methanone (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 16 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 17 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo- 18 1,2-dihydropyridin-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide 4886-0959-3510.1(R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2- 19 dihydropyridin-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydroimidazo[5,1- 20 a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydroimidazo[5,1- 21 a]isoquinolin-3-yl) ((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-1-isobutyl-8-methoxy-N-(2- 22 oxo-1,2-dihydropyridin-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- 23 methyl-2-oxo-1,2-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline- 9-carboxamide (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- 24 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone 4886-0959-3510.1(R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo- 25 1,2-dihydropyridin-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-pyrazol-3-yl)-5,6- 26 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 27 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8- 28 methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-9-carboxamide (1-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 29 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone {(S)-2-[(S)-3,3,3-trifluoro-1-hydroxypropyl]-2-methyl-1-pyrrolidinyl}{11- 30 methoxy-12-(2-methyl-2H-tetraazol-5-yl)-3-(2-thienyl)-6- azatricyclo[7.4.0.0^,êYmkb]^\Z-1(13),2,4,9,11-pentaen-5-yl}methanone 4886-0959-3510.1(R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- 31 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)- 32 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile (S)-3-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 33 dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6- 34 dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6- 35 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-5,6- 36 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 4886-0959-3510.1(R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)- 37 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- 38 dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-5,6- 39 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-5,6- 40 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 41 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 42 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8- 43 methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)picolinonitrile 4886-0959-3510.1(R)-3-(3-(2-cyano-2-methylazetidine-1-carbonyl)-1-(4-fluorophenyl)-8- 44 methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)picolinonitrile (R)-1-(9-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-8-methoxy-1-(thiophen-2-yl)- 45 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (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-dihydropyridin- 46 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- 47 methoxy-5-methyl-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-9-yl)picolinonitrile (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)-5,6- 48 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (2R,4S)-4-hydroxy-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 49 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile 4886-0959-3510.1(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 50 2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(2,2-diflu oropropyl)-8-methoxy- 51 N-methyl-9-(2-methyl-2H-tetrazol-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- 52 2H-tetrazol-5-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(5-fluoropyridin-2-yl)-8-methoxy- 53 N-methyl-9-(2-methyl-2H-1,2,3-triazol-4-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide ((R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)- 54 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 55 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone 4886-0959-3510.1(R)-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 56 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 57 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile (1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1- 58 a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 59 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 60 dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone (2R,4S)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- 61 dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile 4886-0959-3510.1(R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylallyl)-5,6- 62 dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile ACTIVITY OF THE COMPOUNDS

[0140] As noted above, the compounds disclosed herein have activity as FSHR modulators. This activity may be assessed by any suitable FSHR interaction assay, such as a cAMP accumulation assay as illustrated in the examples, and the other assays outlined below and illustrated in the examples. The compounds disclosed herein may show EC50 values of less than 1000 nM, less than or equal to 500 nM, less than or equal to 100 nm, less than or equal to 10 nM, or less than or equal to 1 nM, wherein the EC50is the effective concentration of a compound at which 50% of the maximum response of that that would be obtained with FSH is observed.

[0141] Glycoprotein hormone receptors, FSHR, TSHR and LHR / LHCGR predominantly Z\mboZm^ D^l \eZll h_ bgmkZ\^eeneZk D ikoteins, resulting in cAMP accumulation. The Homogeneous Time Resolved Fluorescence (HTRF) assay illustrated in the examples is based on competition between native cAMP produced by cells and cAMP labeled with the dye d2 (red acceptor) for binding to a cryptate labeled antibody (Europium donor). The specific energy transfer signal is inversely proportional to the concentration of cAMP in the standard or sample. See, e.g., Nataraja, S.G., et al., Frontiers in Endocrinology.2015, 6:142.

[0142] Another assay uses the immortalized rat steroidogenic granulosa cell line, GFSHR-17, which stably expresses the FSH Receptor and is responsive to FSH stimulation with human FSH. See, e.g., Keren-Tal, I., et al., Molecular and Cellular Endocrinology, 1993, 95:Rl-Rl0. This engineered cell line lacks the aromatase found in primary granulosa cells required for conversion of androgen precursors to estrogens. However it shows a robust progesterone response which can serve as a surrogate to verify the activity of FSHR agonists. It can be used in a cell-based assay to evaluate the ability of compounds to activate FSHR in GFSHR-17 cells by measuring progesterone released into the supernatant, such as by using a progesterone HTRF kit from Cisbio. A ratiometric 4886-0959-3510.1HTRF read-out has been established to assess agonist activity of compounds and is described in the examples below.

[0143] The activity of the compounds described herein as agonists of the FSHR can be investigated using a modification of the classic FSH bioassay (Steelman-Pohley) which is based on the increase in ovarian weight in immature female rats. See Steelman, S.L. and F.M. Pohley, Endocrinology, 1953, 53(6):604-16. It is well-documented that activation of the FSHR in females stimulates granulosa cells of the ovarian follicles to proliferate and induce the expression of aromatase and luteinizing hormone receptor. See, e.g., Donadeu, F.X. and M. Ascoli, Endocrinology, 2005, 146(9):3907-16. Proper granulosa cell expansion and gene expression is essential to induce steroid synthesis and secretion to allow the follicle to respond to the preovulatory luteinizing hormone surge, which triggers ovulation of the oocytes contained within follicles into the oviduct where they can be fertilized. Therefore, it is reasonable to measure ovarian weight gain as a function of granulosa cell expansion, the number of ovulated oocytes as a function of follicle maturation, and uterine weight as a function of estradiol synthesis and secretion.

[0144] In some embodiments, a compound as disclosed herein selectively activates FSHR as compared to, for example, TSHR. This selective activity may be assessed by any suitable FSHR / TSHR assay comparing the potency in cAMP accumulation specific to the individual receptors, such as an assay illustrated in the examples (assessing selectivity based on EC50ratios).

[0145] In some embodiments, a compound as disclosed herein selectively activates FSHR as compared to, for example, luteinizing hormone receptor. This selective activity may be assessed by any suitable FSHR / LHR assay comparing the potency in cAMP accumulation specific to the individual receptors, such as an assay illustrated in the examples(assessing selectivity based on EC50 ratios).

[0146] In some embodiments, a compound as disclosed herein exhibits at least 5-fold greater selectivity for FSHR than for TSHR. This includes at least 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-fold, or more, greater selectivity for follicle-stimulating hormone receptor than for thyroid-stimulating hormone 4886-0959-3510.1receptor. A compound as disclosed herein may exhibit about 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-fold greater selectivity for follicle-stimulating hormone receptor than for thyroid-stimulating hormone receptor.

[0147] In some embodiments, a compound as disclosed herein exhibits at least 5-fold greater selectivity for FSHR than for luteinizing hormone receptor. This includes at least 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-fold, or more, greater selectivity for follicle-stimulating hormone receptor than for luteinizing hormone receptor. A compound as disclosed herein may exhibit about 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-fold greater selectivity for follicle-stimulating hormone receptor than for luteinizing hormone receptor. SYNTHESIS OF THE COMPOUNDS

[0148] In another aspect there is provided a method of manufacture of any one of the compounds disclosed herein. The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in Schemes A-D below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. Definitions for R1, R2, R3, R6,R10, R11R12, R13, Rf, and 4886-0959-3510.1Rgare as provided in the formulas described herein. The synthetic procedure for individual compounds is disclosed in the Examples section below.

[0149] Scheme A

[0150] As shown in Scheme A, compound A-1 (which may be synthesized as described in Method 1 below) was converted to oxalyl amide A-2. Cyclization of intermediate compound A-2 provided intermediate compound A-3. Subsequent saponification to intermediate compound A-4 followed by coupling with amine HNRfRgresulted in intermediate compound A-5. Metal-mediated coupling of intermediate compound A-5 led to intermediate compound A-6, which after ester hydrolysis provided intermediate compound A-7. Coupling of compound A-7 with amine H2NR6afforded compound A-8 (compounds as disclosed herein). 4886-0959-3510.1

[0151] Scheme B

[0152] Scheme B illustrates metal-mediated conversion of compound B-1 to a boronate ester which is then reacted with R3X (X = Cl, Br, I, or OTf) to compound B-3 (a compound as disclosed herein) through another metal-mediated conversion.

[0153] Scheme C

[0154] Scheme C illustrates metal-mediated conversion of compound B-1 with an R3-boronate ester to compound B-3 (a compound as disclosed herein).

[0155] Scheme D4886-0959-3510.1

[0156] Scheme D illustrates amide coupling of compound D-1 with amine HNRfRgto arrive at compound B-3 (a compound as disclosed herein). PHARMACEUTICAL COMPOSITIONS

[0157] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound as described herein, and one or more pharmaceutically acceptable excipients.

[0158] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound of Formulas (I), (II), (IIa), (III), or (IV) as described herein, and one or more pharmaceutically acceptable excipients.

[0159] The compounds may be formulated for administration by any suitable route of administration, such as for example, oral, topical (including transdermal), rectal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including by intramuscular, subcutaneous, or intravenous injection, as well as inhalation, intrathecal, direct intraperitoneal, or intranasal delivery.

[0160] Pharmaceutical compositions as disclosed herein may comprise, as one or more pharmaceutically acceptable excipients, a pharmaceutically acceptable carrier, diluent, disintegrant, sweetening agent, glidant (such as magnesium stearate), flavoring agent, emulsifying agent, suspending agent, stabilizer, isotonic agent, etc. Pharmaceutical compositions as disclosed herein may be formulated into an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a topical (including transdermal) or transmucosal dosage form such as liquids, suspensions, emulsions, gels (ointments or the like), or a parenteral dosage form such as liquids, suspensions, emulsions, and freeze-dried powders. Said dosage forms may be formulated in various forms, e.g., a dosage form for single administration or for multiple administrations.

[0161] Exemplary excipients include, without limitation, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or 4886-0959-3510.1magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0162] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent, and particular needs of the composition. Generally, however, the excipient will be present in the composition in an amount of from about 1% to about 99% by weight, such as from about 5% to about 98% by weight, including from about 15 to about 95% by weight of the composition. In general, the amount of excipient present in a composition of the disclosure is selected from the following: about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.

[0163] A pharmaceutical composition as disclosed herein may include a compound disclosed herein as the only active agent, or may be formulated with other active agents.

[0164] Techniques for formulation and administration of the compounds disclosed herein may be _hng] bg }O^fbg`mhg: The Science and Practice of Pharmacy,~ Academic Press, London, United Kingdom, 23rd edition, 2020.

[0165] Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of a compound as disclosed herein in a reasonable volume or mass of the composition, which may be administered by any effective dosing schedule, such as once a day. Although the exact dosage may be determined on a drug-by-drug (compound-by- compound) basis, for most compounds, some generalizations regarding the dosage can be made. For example, the daily dosage regimen for an adult human patient may be between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example from 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid. METHODS OF TREATMENT

[0166] In another aspect, disclosed herein are methods of modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical 4886-0959-3510.1composition as disclosed herein. In an alternative aspect, disclosed herein are methods of modulating follicle-stimulating hormone receptor activity in a biological sample, comprising contacting the biological sample with a compound or pharmaceutical composition as disclosed herein.

[0167] In another aspect, disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein. The disease or disorder may be any for which modulation of FSHR activity is desired, such as one or more of hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

[0168] In another aspect, disclosed herein are methods for treating a fertility disorder in a male or female subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein. Such a method may be for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[0169] In another aspect, disclosed herein are compounds for use in modulating follicle- stimulating hormone receptor (FSHR) activity in a subject.

[0170] In another aspect, disclosed herein are compounds for use in treating a disease or disorder in a subject in need thereof. The disease or disorder may be any for which modulation of 4886-0959-3510.1FSHR activity is desired, such as one or more of hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

[0171] In another aspect, disclosed herein are compounds for use in treating a fertility disorder in a female or male subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[0172] In other aspects, disclosed herein are uses of the compounds disclosed herein in the preparation of medicaments for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject, for treating a disease or disorder in a subject in need thereof, such as any one or more listed above, or for treating a fertility disorder in a female or male subject in need thereof, such as for stimulating follicular development, ovulation induction, controlled ovarian hyperstimulation, controlled ovarian stimulation, assisted reproductive technology (ART) (including in vitro fertilization), treating male hypogonadism, or treating male infertility, including failure of spermatogenesis.

[0173] In accordance with any of these methods or uses, the compound or composition may be administered by any suitable route of administration as discussed above, and may be administered in a therapeutically effective amount as discussed above. As also discussed above, the administration may be by any effective dosing schedule, such as once a day, 1 to 4 times per day, once a week, 1 to 4 times per week, once a month, 1 to 4 times month, etc. Although the exact dosage may be determined on a drug-by-drug (compound-by-compound) basis, the daily dosage 4886-0959-3510.1regimen for an adult human patient may be, for example, between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

[0174] The present technology, thus generally described, may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology. EXAMPLES

[0175] Analytical LCMS conditions were as follows:

[0176] Analytical Method 1 (M1):

[0177] Analytical HPLC-MS were 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 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min and held for 0.39 min with an injection volume of 3 µL at a flow rate of 1.2 mL / min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0178] Analytical Method 2 (M2)

[0179] Analytical uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEHTMC18 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 min, then 100% B for 0.25 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 µL at a flow rate of 0.9 mL / min. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters SQD (MSQ1) or Waters ACQUITY QDA (MSQ2, MSQ4). Data were integrated and reported using Waters MassLynx and OpenLynx software. 4886-0959-3510.1

[0180] Analytical Method 3 (M3):

[0181] Analytical uHPLC-MS were performed on a Waters ACQUITY uPLC system using Waters uPLC® BEHTMC18 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 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 µL at a flow rate of 1 mL / min. UV spectra were recorded 215 nm Waters ACQUITY PDA spectrum 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.

[0182] Analytical Method 4 (M4):

[0183] Analytical uHPLC-MS were 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) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 µL at flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD (MSQ1) or Waters ACQUITY QDA (MSQ2, MSQ4). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0184] Analytical Method 5 (M5):

[0185] Analytical uPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEHTMC18 column (2.1 mm x 100 mm, 1.7 µm column; temperature: 40°C) and a gradient of 5-100% B (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min pbma Zg bgc^\mbhg ohenf^ h_ 1 ^I Zg] Zm _ehp kZm^ h_ 0.6 fI / fbg. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector Spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector 4886-0959-3510.1(MS16) or a Waters SQD2 (MSQ5). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0186] Analytical Method 6 (M6):

[0187] Analytical uPLC-MS were performed on a Waters ACQUITY uPLC system using a Phenomenex Kinetex Core-Shell C8 column (50 x 2.1mm, 5µm 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) over 1.83 min, then 100% B for 0.42 min. A second gradient of 100-5% B was then applied over 0.42 min and held for 0.54 min with an injection volume of 3 ^L and at flow rate of 1.2 mL / min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0188] Analytical Method 7 (M7):

[0189] Analytical HPLC-MS were performed on a Waters LCMS systems 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) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1µL at a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0190] Analytical Method 8 (M8):

[0191] Analytical HPLC-MS were performed on a Waters LCMS systems 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 min, then 100% B for 0.3 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 0.28 min with an injection volume of 1µL at a flow rate of 0.9 mL / min. UV spectra were recorded 4886-0959-3510.1at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0192] Analytical Method 9 (M9):

[0193] Analytical HPLC-MS were performed on a Waters LCMS systems 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 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 µL at a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector spectrum range: 200-400 nm, ELS data was collected using a Waters ACQUITY ELS detector (where fitted). Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0194] Analytical Method 10 (M10):

[0195] Analytical (M14) uHPLC-MS were performed on a Waters ACQUITY uPLC system using a Waters uPLC® BEHTMC18 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 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min with an injection volume of 1 µL at a flow rate of 1.0 mL / min. UV spectra were recorded at 215 nm on a Waters ACQUITY PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector (MS16) or a Waters SQD2 (MSQ5). Data were integrated and reported using Waters MassLynx and OpenLynx software. 4886-0959-3510.1

[0196] Analytical Method 11 (M11): Instrument: Shimadzu LC-20AD&MS 2020; Column: Kinetex C182.6 ^m, 2.1*30mm; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.01 3.00 3.50 3.51 4.30 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0197] Analytical Method 12 (M12): Instrument: Shimadzu LC-20AD&MS 2020; Column: Kinetex C182.6 ^m, 2.1*30mm; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.01 0.70 1.15 1.16 1.50 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0198] Analytical Method 13 (M13): Instrument: Shimadzu LC-20AD&MS 2020; Column: HALO C185.0 ^m, 3.0*30mm; Column temperature: 40oC 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 (0.01-3.0 min(1.2 mL / min'3.01-3.5 min( 4886-0959-3510.1Gradient Ratio: Time (min) 0.01 2.5 3.0 3.01 3.5 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0199] Analytical Method 14 (M14): Instrument: Shimadzu LC-20AD&MS 2020; Column: HALO C182.7 ^m, 3.0*30mm; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.01 0.70 1.15 1.16 1.50 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0200] Analytical Method 15 (M15): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185 ^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04% (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9 min) Gradient Ratio: Time (min) 0.00 0.50 0.90 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0201] Analytical Method 16 (M16): Instrument: Shimadzu LC-20AD&MS 2020; Column: Xbridge-C182.1*30mm 5^m; Column temperature: 40oC 4886-0959-3510.1Mobile phase A (MPA) H2O+10mM NH4HCO3Mobile phase B (MPB) Acetonitrile Flow rate: 1.5 mL / min Gradient Ratio: Time(min) 0.01 0.70 1.16 1.50 MPA (%) 95 5 5 95 MPB (%) 5 95 95 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0202] Analytical Method 17 (M17): Instrument: Waters Arc&Qda; Column: HALO 2.7 ^f @1890> 30^3.0mm; Column temperature: 40oC 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 (0.01-4.00 min) Gradient Ratio: Time(min) 0.01 3.00 3.50 3.51 4 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1200

[0203] Analytical Method 18 (M18): Instrument: Shimadzu LC-30AD&MS 2020; Column: InfinityLab Poroshell 120 SB-C182.7 ^m 3.0*30mm; Column temperature: 40oC 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 (0.01-1.50 min) Gradient Ratio: Time(min) 0.01 0.70 1.16 1.50 MPA (%) 95 5 5 95 4886-0959-3510.1MPB (%) 5 95 95 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0204] Analytical Method 19 (M19): Instrument: Shimadzu LC-30AD&MS 2020; Column: InfinityLab Poroshell 120 SB-C182.7 ^m 3.0*30mm; Column temperature: 40oC 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 (0.01-1.50 min) Gradient Ratio: Time(min) 0.01 0.70 1.16 1.50 MPA (%) 95 5 5 95 MPB (%) 5 95 95 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0205] Analytical Method 20 (M20): Instrument: Shimadzu LC-20AD&MS 2020; Column: Kinetex EVO C1830*2.1mm, 5 ^m; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA Mobile 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) Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 MPA (%) 95 5 5 95 MPB (%) 5 95 95 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0206] Analytical Method 21 (M21): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C183.0*30mm, 5^m; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA 4886-0959-3510.1Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 1.5 mL / min (0.00-1.30 min) Gradient Ratio: Time(min) 0.01 0.8 1.30 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0207] Analytical Method 22 (M22): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 1.50 mL / min Gradient Ratio: Time(min) 0 0.70 1.30 MPA (%) 95 5 5 MPB (%) 5 95 95 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-500

[0208] Analytical Method 23 (M23): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04% (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9 min) Gradient Ratio: Time (min) 0.00 0.50 0.90 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 4886-0959-3510.1

[0209] Analytical Method 24 (M24): Instrument: Agilent 1260 & 6125B; Column: Xbridge C182.1*50mm,5 ^m; Column temperature: 40oC Mobile phase A (MPA) H2O+10mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 0.8 mL / min Gradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0210] Analytical Method 25 (M25): Instrument: Shimadzu 20AB&MS 2020; Column: Xbridge C182.1*50mm, 5^m; Column temperature: 40oC Mobile phase A (MPA) H2O+10 mMOL / L NH4HCO3Mobile phase B (MPB) 100%ACN Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 3.00 3.50 3.51 4.30 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0211] Analytical Method 26 (M26): Instrument: Shimadzu LC-20AB&MS 2020; Column: Xbridge-C182.1*50mm 5um; Column temperature: 40oC Mobile phase A (MPA) H2O+10 mM NH4HCO3Mobile phase B (MPB) Acetonitrile Flow rate: 1.0 mL / min (0.01-3.01 min,1.2 mL / min (3.02-3.50 min) 4886-0959-3510.1Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0212] Analytical Method 27 (M27): Instrument: Shimadzu 20AB&MS 2020; Column: Xbridge C182.1*50mm, 5^m; Column temperature: 40oC Mobile phase A (MPA) H2O+10 mMOL / L NH4HCO3Mobile phase B (MPB) 100%ACN Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 3.00 3.50 3.51 4.30 4.30 MPA (%) 95 5 5 95 95 95 MPB (%) 5 95 95 5 5 5 Detection: 220 nm & 254 nm; MS Mode: Negative; MS Range: 100-2000

[0213] Analytical Method 28 (M28): Instrument: Agilent 1260 & 6125B; Column: Luna-C18 (2) 2.0*50mm, 5^m; Column temperature: 40oC 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 Gradient Ratio: Time (min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000 4886-0959-3510.1

[0214] Analytical Method 29 (M29): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 1.50 mL / min Gradient Ratio: Time(min) 0 0.70 1.30 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-1500

[0215] Analytical Method 30 (M30): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9 min) Gradient Ratio: Time(min) 0 0.5 0.90 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0216] Analytical Method 31 (M31): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C183.0*30mm, 5^m; Column temperature: 40oC 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) 4886-0959-3510.1Gradient Ratio: Time(min) 0.01 0.8 1.30 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0217] Analytical Method 32 (M32): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 %(v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9 min) Gradient Ratio: Time(min) 0 0.5 0.90 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000

[0218] Analytical Method 33 (M33): Instrument: Shimadzu LC-20AD XR&MS 2020; Column: HALO C185^m, 3.0*30mm; Column temperature: 40oC Mobile phase A (MPA) H2O+0.04 % (v / v) TFA Mobile phase B (MPB) ACN+0.02 % (v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9 min) Gradient Ratio: Time(min) 0 0.5 0.90 MPA (%) 90 0 0 MPB (%) 10 100 100 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 4886-0959-3510.1

[0219] Analytical Method 34 (M34): Instrument: Agilent 1260 & 6125B; Column: Luna-C18 (2) 2.0*50mm,5 ^m; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm&254nm; MS Mode: Positive; MS Range: 100-1000

[0220] Analytical Method 35 (M35): Instrument: Agilent 1200 & 6110A; Column: Luna-C18 (2) 2.0*50mm, 5^m; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0221] Analytical Method 36 (M36): Instrument: Agilent 1200 & 6130; Column: Xbridge-C182.1*50mm 5^m; Column temperature: 40oC Mobile phase A (MPA) H2O+10 mM NH4HCO3Mobile phase B (MPB) Acetonitrile Flow rate: 0.8 mL / min 4886-0959-3510.1Gradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0222] Analytical Method 37 (M37): Instrument: Agilent 1200 & 6110A; Column: Luna-C18 (2) 2.0*50mm,5^m; Column temperature: 40oC 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0223] Analytical Method 38 (M38): Instrument: Shimadzu LC-20AD&MS 2020; Column: Gemini C182.0*50mm, 5 ^m; Column temperature: 40oC Mobile phase A (MPA) H2O+10 mM NH4HCO3 Mobile phase B (MPB) Acetonitrile Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.50 MPA (%) 95 5 5 95 95 MPB (%) 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 50-2000 4886-0959-3510.1

[0224] Analytical Method 39 (M39): Instrument: Agilent 1200 HPLC MSD: 1956A single quadrupole MSD Column: IngZ @18, 2.0*50ff, 5^f; @henfg m^fi^kZmnk^: 40oC Mobile phase A (MPA) 0.04%TFA in H2O Mobile phase B (MPB) 0.02%TFA in ACN Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 0.40 3.00 4.00 4.01 4.50 MPA (%) 95 95 5 5 95 95 MPB (%) 5 5 95 95 5 5 Detection: 220 nm & 254 nm; MS Mode: Positive; MS Range: 100-1000

[0225] Analytical Method 40 (M40):

[0226] All the analysis were performed using an Agilent G1956A LC / MSD quadrupole coupled to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionization (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L / min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software.

[0227] Analysis were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 ff F.A.; 3 ^f iZkmb\e^ lbs^) Zm 35 w@, pbma Z _ehp kZm^ h_ 2.6 fI / fbg. > `kZ]b^gm ^enmbhg pZl performed from 95% (Water + 0.1% Formic acid) / 5% Acetonitrile to 5% (Water + 0.1% Formic acid) / 95% Acetonitrile in 4.8 min; the resulting composition was held 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 fbg. Qa^ bgc^\mbhg ohenf^ pZl 2 ^I. >\jnblbmbhg kZg`^l p^k^ l^m mh 190-400 nm for the UV-PDA detector and 100-1400 m / z for the MS detector. 4886-0959-3510.1

[0228] Analytical Method 41 (M41):

[0229] All the analysis were performed using an Agilent G6224A TOF-LC / MS quadrupole coupled to an Agilent 1290 Infinity series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The TOF-mass spectrometer (TOF-MS) was operated with an atmospheric pressure dual- electro-spray ionization (Dual-ESI) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L / min and 350 °C, respectively. Nitrogen was used as the nebuliser gas, at a pressure of 35 psig. Data acquisition was performed with MassHunter software.

[0230] Analysis were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 ff F.A..; 3 ^f iZkmb\e^ lbs^) Zm 35 w@, pbma Z _ehp kZm^ h_ 2.6 fI / fbg. > `kZ]b^gm ^enmbhg pZl performed using 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 min; the resulting composition was held 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 min. The injection volume pZl 4 ^I. >\jnblbmbhg kZg`^l p^k^ l^m mh 190-400 nm for the UV-PDA detector and 100-1000 m / z for the TOF-MS detector.

[0231] Analytical Method 42 (M42):

[0232] Analytical HPLC-MS were performed on Agilent 1260 Infinity (Quat. Pump) DAD LC / MS G6120B system using a Thermo Scientific Accucore C18 (50 q 4.6 ff, 2.6 ^f; temperature: 35 °C) and a gradient From 90% A to 10% A in 1.5 min, held for 0.9 min, to 95% A in 0.1 min (A: 0.1% HCOOH in H2O; B: CH3CN) with an injection volume of 3 µL at a flow rate of 3 mL / min. UV spectra were recorded at 254 nm using a 1260 Infinity II Diode Array Detector HS spectrum range: 200-400 nm. Mass spectra were obtained using a LC / MS G6120B system. Data were integrated and reported using ACD Labs software. 4886-0959-3510.1

[0233] Analytical Method 43 (M43):

[0234] Analytical HPLC-MS were performed on Agilent 1290 Infinity II HPLC DAD LC / MSD G6125C ISET emulating Agilent G4220A system using a Phenomenex Kinetex C18 (50 x 2.1 mm, 1.7 ^m; temperature: 60 °C) and a gradient of from 90% A to 10% A in 2.4 min, held for 0.4 min, to 90% A in 0.2 min (A: 0.1% HCOOH in H2O; B: CH3CN) with an injection volume of 3 µL at a flow rate of 0.9 mL / min.254 nm using 1290 Infinity II Diode Array Detector spectrum range: 200-400 nm. Mass spectra were obtained using a LC / MSD G6125C detector. Data were integrated and reported using ACD Labs software.

[0235] Analytical Method 44 (M44):

[0236] Analytical HPLC-MS were performed on Agilent 1290 Infinity II HPLC DAD LC / MSD iQ G6160A using a Phenomenex Kinetex C18 (50 x 2.1 mm, 1.7 ^m; Temperature: 60 ºC) and a gradient from 90% A to 10% A in 1.6 min, held for 0.4 min, to 90% A in 0.2 min. (A: 0.1% HCOOH in H2O; B: CH3CN) over 2.2 min with an injection volume of 3 µL at a flow rate of 1.2 mL / min. UV spectra were recorded at 254 nm using 1290 Infinity II Diode Array Detector spectrum range: 200-400 nm. Mass spectra were obtained using a LC / MSD iQ G6160A detector. Data were integrated and reported using ACD Labs software.

[0237] Analytical Method a: Instrument: Shimadzu LC-20AD&MS 2020 Column: E>IL @185.0^f,3.0*30ff Column temperature: 40ë 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( Gradient Ratio: Time(min) 0.01 2.5 3.0 3.01 3.5 MPA(%) 95 5 5 95 95 MPB(%) 5 95 95 5 5 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0238] Analytical Method b. Instrument: Agilent 1260 & 6125B Column: Luna-@18(2) 2.0*50ff,5^f Column temperature: 40ë 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 Detection: 220 nm MS Mode: Positive MS Range: 100-1000

[0239] Analytical Method c. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: EZeh @183.0*30ff, 5^f Column temperature: 40ë 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 (0.00-1.30min) Gradient Ratio: Time(min) 0.01 0.8 1.30 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0240] Analytical Method d. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: EZeh @183.0*30ff, 5^f Column temperature: 40ë 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 (0.00-1.30min) Gradient Ratio: Time(min) 0.01 0.8 1.30 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive MS Range: 50-2000

[0241] Analytical Method e. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: E>IL @185^f, 3.0*30ff Column temperature: 40ë Mobile phase A(MPA) H2O+0.04 %(v / v) TFA Mobile phase B(MPB) ACN+0.02 %(v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9min) Gradient Ratio: Time(min) 0 0.5 0.90 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0242] Analytical Method f. Instrument: Agilent 1260 & 6125B Column: U[kb]`^ @182.1*50ff,5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3 Mobile phase B(MPB) Acetonitrile Flow rate: 0.8 mL / min Gradient Ratio: Time(min) 0.00 0.40 3.40 3.85MPA(%) 95 95 5 5MPB(%) 5 5 95 95Detection: 220 nm &254 nm MS Mode: Positive MS Range: 100-1000

[0243] Analytical Method g. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: E>IL @185^f, 3.0*30ff Column temperature: 40ë Mobile phase A(MPA) H2O+0.04 %(v / v) TFA Mobile phase B(MPB) ACN+0.02 %(v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9min) Gradient Ratio: Time(min) 0 0.5 0.90 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0244] Analytical Method h. Instrument: Shimadzu LC-20AB&MS 2020 Column: UmbfZm^ @182.1*50ff 5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3 Mobile phase B(MPB) Acetonitrile Flow rate: 1.0 mL / min(0.01-3.01min,1.2mL / min(3.02-3.50min) Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5 MPA(%) 95 5 5 95 95 MPB(%) 5 95 95 5 5 Detection: 220254nm MS Mode: Positive MS Range: 50-2000

[0245] Analytical Method i. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: EZeh @183.0*30ff, 5^f Column temperature: 40ë 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 (0.00-1.30min) Gradient Ratio: Time(min) 0.01 0.8 1.30 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0246] Analytical Method j. Instrument: Agilent 1260 & 6125B Column: Luna-@18(2) 2.0*50ff,5^f Column temperature: 40ë 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 Detection: 220 nm&254nm MS Mode: Positive MS Range: 100-1000

[0247] Analytical Method k. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: QbZgd @1850*2.1ff, 5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3Mobile phase B(MPB) Acetonitrile Flow rate: 1 mL / min (0.00-4.5min) Gradient Ratio: Time(min) 0.01 3.5 4.5 MPA(%) 95 5 5 MPB(%) 5 95 95 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0248] Analytical Method l. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: E>IL @185^f, 3.0*30ff Column temperature: 40ë Mobile phase A(MPA) H2O+0.04 %(v / v) TFA Mobile phase B(MPB) ACN+0.02 %(v / v) TFA Flow rate: 2.0 mL / min (0.00-0.9min) Gradient Ratio: Time(min)MPA(%)MPB(%)Detection: 220 nm 254nm MS Mode: Positive MS Range: 50-2000

[0249] Analytical Method m. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: EZeh @183.0*30ff, 5^f Column temperature: 40ë Mobile phase A(MPA) H2O+0.04 %(v / v) TFA Mobile phase B(MPB) ACN+0.02 %(v / v) TFA Flow rate: 2.0 mL / min (0.00-0.90min) Gradient Ratio: Time(min) 0.01 0.5 0.9 MPA(%) 90 0 0 MPB(%) 10 100 100 Detection: 220 nm 254nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0250] Analytical Method n. Instrument: Shimadzu LC-20AD XR&MS 2020 Column: QbmZgd @18, 3.0*30ff 5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3 Mobile phase B(MPB) Acetonitrile Flow rate: 1.5 mL / min (0.00-0.90min) Gradient Ratio: Time(min)0.9Detection: 220 nm 254nm MS Mode: Positive&Negative MS Range: 50-2000

[0251] Analytical Method o. Instrument: Shimadzu LC-20ADXR&MS 2020 Column: UmbfZm^ @182.1*50ff,5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3Mobile phase B(MPB) Acetonitrile Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 2.50 3.00 MPA(%) 95 5 5 MPB(%) 5 95 95 Detection: 220 nm 254 nm MS Mode: Positive 4886-0959-3510.1MS Range: 50-2000

[0252] Analytical Method p. Instrument: Agilent 1260 & 6125B Column: Luna-@18(2) 2.0*50ff,5^f Column temperature: 40ë 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 Detection: 220 nm MS Mode: Positive MS Range: 100-1000

[0253] Analytical Method q. Instrument: Agilent 1260 & 6125B Column: Luna-@18(2) 2.0*50ff,5^f Column temperature: 40ë 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 Gradient Ratio: Time(min) 0.00 0.40 3.00 4.00 4.01 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 Detection: 220 nm&254nm MS Mode: Positive 4886-0959-3510.1MS Range: 100-1000

[0254] Analytical Method r. Instrument: Agilent 1200 & 6120B Column: Xbridge C182.1*50ff,5^f Column temperature: 40ë Mobile phase A(MPA) H2O+10mM NH4HCO3 Mobile phase B(MPB) Acetonitrile Flow rate: 0.8 mL / min Gradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 Detection: 220 nm&254nm MS Mode: Positive MS Range: 100-1000

[0255] Analytical Method s. Instrument: Agilent 1200 & 6130 Column: Xbridge-@182.1*50ff 5^f Column temperature: 40ë Mobile phase H2O+10mM NH4HCO3A(MPA) Mobile phase Acetonitrile B(MPB) Flow rate: 0.8 mL / min Gradient Ratio: Time(min) 0.00 0.40 3.40 3.85 3.86 4.50 MPA(%) 95 95 5 5 95 95 MPB(%) 5 5 95 95 5 5 4886-0959-3510.1Detection: 220 nm 254nm MS Mode: Positive MS Range: 100-1000

[0256] Analytical Method t. Instrument: Shimadzu LC-20AD&MS 2020 Column: Xtimate C182.1*50ff 5^f Column 40ë temperature: Mobile phase H2O+10mM NH4HCO3A(MPA) Mobile phase Acetonitrile B(MPB) Flow rate: 1.0 mL / min Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5 MPA(%) 95 5 5 95 95 MPB(%) 5 95 95 5 5 Detection: ELSD 220 nm 254nm MS Mode: Positive MS Range: 50-2000

[0257] Analytical Method u. Instrument: Shimadzu LC-30AD&MS 2020 Column: EZeh @183.0*30ff, 5^f Column 40ë temperature: Mobile phase H2O+0.04 %(v / v) TFA A(MPA) 4886-0959-3510.1Mobile phase ACN+0.02 %(v / v) TFA B(MPB) Flow rate: 1 mL / min(0.01-3.00min),1.2mL / min(3.01-3.50min) Gradient Ratio: Time(min) 0.01 2.50 3.00 3.01 3.5 MPA(%) 95 5 5 95 95 MPB(%) 5 95 95 5 5 Detection: ELSD 220 nm 254nm MS Mode: Positive MS Range: 50-2000

[0258] Purification methods were as follows:

[0259] Purification Method 1 (P1):

[0260] Purifications LC were performed on a Gilson LC system using a Waters Sunfire C18 \henfg (30 ff q 100 ff, 10 ^J; m^fi^kZmnk^: km) Zg] Z `kZ]b^gm h_ 10-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 14.44 min then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min pbma Zg bgc^\mbhg ohenf^ h_ 1500 ^I at flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0261] Purification Method 2 (P2):

[0262] Purifications LC were performed on a Gilson LC system using a Waters Sunfire C18 \henfg (30 ff q 10 ff, 10 ^J; m^fi^kZmnk^: km) Zg] Z `kZ]b^gm h_ 30-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in acetonitrile) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.2 min pbma Zg bgc^\mbhg ohenf^ h_ 1500 ^I at flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0263] Purification Method 3 (P3):

[0264] Purifications LC were performed on a Gilson LC system using a Waters X-Bridge C18 \henfg (30 ff q 100 ff, 10 ^J; m^fi^kZmnk^: km) Zg] Z `kZ]b^gm h_ 10-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in acetonitrile) over 14.44 min 4886-0959-3510.1then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an bgc^\mbhg ohenf^ h_ 1500 ^I Zm _ehp kZm^ h_ 40 fI / fbg. RS li^\mkZ p^k^ k^\hk]^] Zm 215 gf nlbg` a Gilson detector.

[0265] Purification Method 4 (P4):

[0266] Purifications LC were performed on a Gilson LC system using a Waters X-Bridge C18 column (30 ff q 10 ff, 10 ^J; m^fi^kZmnk^: km) Zg] Z `kZ]b^gm h_ 30-95% B (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in acetonitrile) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min with an bgc^\mbhg ohenf^ h_ 1500 ^I Zm _ehp kZm^ h_ 40 fI / fbg. RS li^\mkZ p^k^ k^\hk]^] Zm 215 gf nlbg` a Gilson detector.

[0267] Purification Method 5 (P5): Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.04% HCl); B: ACN; Column: Phenomenex Luna C18100*30mm*3^m; Column temperature: ambient, variable gradient; Flow rate: 25 mL / min; Monitor wavelength: 220 nm & 254 nm

[0268] Purification Method 6 (P6): Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: water (NH4HCO3); B: ACN; Column: Phenomenex C1880*40mm*3^m; Column temperature: ambient, variable gradient; Flow rate: 25 mL / min; Monitor wavelength: 220 nm & 254 nm

[0269] Purification Method 7 (P7): Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: water (NH4HCO3); B: ACN; Column: Waters Xbridge Prep OBD C18150*40mm*10^m; 4886-0959-3510.1Column temperature: ambient, variable gradient; Flow rate: 25 mL / min; Monitor wavelength: 220 nm & 254 nm

[0270] Purification Method 8 (P8): Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: water (NH4HCO3); B: ACN; Column: Waters Xbridge BEH C18100*30mm*10^m; Column temperature: ambient, variable gradient; Flow rate: 25 mL / min; Monitor wavelength: 220 nm & 254 nm

[0271] Purification Method 9 (P9): Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: water (NH4HCO3); B: ACN; Column: Waters Xbridge BEH C18250*70mm*10^m; Column temperature: ambient, variable gradient; Flow rate: 25 mL / min; Monitor wavelength: 220 nm & 254 nm

[0272] Purification Method 10 (P10): Instrument: Orienda; Mobile phase: A: water+HCl; B: ACN Column: 4kg Agela C18 column; Flow rate: 500 mL / min;

[0273] Purification Method 11 (P11): Instrument: Waters SFC350 preparative SFC; Mobile phase: A for CO2 and B for EtOH (0.1% NH3H2O); B%=55% isocratic elution mode Column: DAICEL CHIRALPAK AD (250mm*50mm,10 ^m); Column temperature: ambient, variable gradient; Flow rate: 200 g / min; 4886-0959-3510.1Monitor wavelength: 220 nm

[0274] Purification Method 12 (P12): Instrument: Waters SFC350 preparative SFC; Mobile phase: A for CO2 and B for EtOH; B%=20% isocratic elution mode Column: DAICEL CHIRALCEL OJ (250mm*50mm,10 ^m); Column temperature: ambient, variable gradient; Flow rate: 200 g / min; Monitor wavelength: 220 nm

[0275] Purification Method 13 (P13):

[0276] The raw material was purified by using a Jasco System consisting of a CO2Preparative Pump (PU-4387), a Preparative Pump for organic solvent (PU-4087 with six channel selector), Preparative SFC Autosampler (AS-4358), column oven with four valve selector (CO-4065), a PDA detector (MD-4015), a Back Pressure Regulator (BP-4340), two open-bed collectors (Gilson- 223) and a Julabo recirculating cooler (FL 1201). Data acquisition was performed with ChromNAV 2.04.00 software, equipped with a Phenomenex Lux Amylose-1 column (250x30mm 5^f, 5 ^J; m^fperature: 35 ºC), with a flow rate of 30 mL / min and BPR set at 120 Bar. An isocratic mode elution was performed 60% B (A= CO2; B= 0.1% diethylamine in 2-propanol) in 20 min on a stacked injection mode. Acquisition frequency was set to 220 nm for the PDA detector.

[0277] Purification Method 14 (P14):

[0278] The raw material was purified by using a Jasco System consisting of a CO2Preparative Pump (PU-4387), a Preparative Pump for organic solvent (PU-4087 with six channel selector), Preparative SFC Autosampler (AS-4358), column oven with four valve selector (CO-4065), a PDA detector (MD-4015), a Back Pressure Regulator (BP-4340), two open-bed collectors (Gilson- 223) and a Julabo recirculating cooler (FL 1201). Data acquisition was performed with ChromNAV 2.03.05 software, equipped with a Phenomenex Lux Amylose-1 column (250x30mm 5^f, 5 ^J; m^fi^kZmnk^: 35 {@), pbma Z _ehp kZm^ h_ 30 mL / min and BPR set at 120 Bar. An isocratic mode elution was performed 55% B (A= CO2; B= 0.1% diethylamine in 2-propanol) in 20 min on a stacked injection mode. Acquisition frequency was set to 220 nm for the PDA detector. 4886-0959-3510.1

[0279] Purification Method 15: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Waters Xbridge Prep OBD C18150*40mm*10^m; Column temperature: ambient; Gradient: 30%-60% B over 8.0 min; Flow rate: 25mL / min; Monitor wavelength: 220&254nm

[0280] Purification Method 16: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Phenomenex Gemini-KU 150*30ff*5^f; Column temperature: ambient; Gradient: 30%-70% B over 20.0 min; Flow rate: 25mL / min; Monitor wavelength: 220&254nm

[0281] Purification Method 17: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.2% FA)-ACN; B: ACN; Column: Phenomenex Luna C18100*30mm*3^m; mobile phase; Column temperature: ambient; Gradient: 25%-55% B over 8.0 min; Flow rate: 25mL / min; 4886-0959-3510.1Monitor wavelength: 220&254nm

[0282] Purification Method 18: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (10mM NH4HCO3); B: ACN; Column: Agela DuraShell C18250*70mm*10^m; Column temperature: ambient; Gradient: 80%-95% B over 20.0 min; Flow rate: 25mL / min; Monitor wavelength: 220&254nm

[0283] Purification Method 19: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: H2O (0.05% NH3H2O+10mM NH4HCO3); B: ACN; Column: Welch Xtimate C18250*100mm*10^m; Column temperature: ambient; Gradient: 40%-70% B over 24.0 min; Flow rate: 25mL / min; Monitor wavelength: 220&254nm

[0284] SFC Purification Method A: Instrument: Auno-600; Mobile phase: A for Heptane and B for EtOH (0.1% NH3H2O); B%=20% isocratic elution mode; Column: DAICEL CHIRALPAK IG (250mm*50mm,10 ^m) Column temperature: 25 ^@ Flow rate: 130mL / min 4886-0959-3510.1Monitor wavelength: 200nm

[0285] NMR Conditions

[0286] Unless otherwise stated,1H NMR spectra were recorded at 500 MHz or 400 MHz on either a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 400 MHz spectrometer respectively. Chemical shifts, ^, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz. 4886-0959-3510.1

[0287] List of Abbreviations AIBN ^,^^-azoisobutyronitrile Ac acyl AcN acetonitrile Ac2O acetic anhydride Ar aromatic aq aqueous Bn benzyl BOC tertbutoxy carbonyl Cbz carboxybenzyl group CDI carbonyldiimidazole CuI copper iodide CV column volumes d doublet DAST diethylaminosulfur trifluoride DCM dichloromethane DCE 1,2-dichloroethane DBA dibenzylideneacetone DIAD diisopropyl azodicarboxylate DIPEA diisopropyl ethylamine DMA N-N-dimethylacetamide DME dimethoxyethane DMF N-N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenyl phosphoryl azide DPPE ethylenebis(diphenylphosphine) dppb 1,3-bis(diphenylphosphino)propane 4886-0959-3510.1dppf 1,1'-bis(diphenylphosphino)ferrocene dtbpf 1,1-bis(di-tert-butylphosphino) ferrocene EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ESI+ Electrospray ionization under positive ion mode Et2O diethyl ether EtOAc or EA ethyl acetate EtOH ethyl alcohol EtONa sodium ethoxide FCC flash column chromatography h hour(s) HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate HFIP hexafluoroisopropanol HOAc acetic acid HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography i-PrOH isopropyl alcohol KOAc potassium acetate KOH potassium hydroxide LAH lithium aluminum hydride LCMS liquid chromatography and mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide M+H ion observed by mass spectrometry created by addition of a hydrogen cation mCPBA 3-chloroperbenzoic acid MeCN acetonitrile MeOH methanol 4886-0959-3510.1Me4tBuXphos 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2^,4^,6^-triisopropyl-1,1^- biphenyl MTBE methyl tert-butyl ether m multiplet min minute(s) mL millilitre mol / M mole / molar mmol millimole N2 nitrogen NBS N-bromo succinimide NH4OAc ammonium acetate NMO 4-methylmorpholine N-oxide NMP 1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance OTf trifluoromethanesulfonate PE petroleum ether PPA polyphosphoric acid q quartet rt room temperature RT retention time s singlet Sat. saturated SFC supercritical fluid chromatography STAB sodium triacetoxy borohydride t triplet TBAF tetrabutyl ammonium fluoride TBAT tetrabutylammonium difluorotriphenylsilicate 4886-0959-3510.1TBDPS tertbutyl diphenyl silyl TBSCl tert-butylchlorodimethylsilane t-BuOH tert-butanol t-BuOK potassium tert-butoxide t-BuOLi lithium tert-butoxide TCFH K,K,K^,K^-tetramethylchloroformamidinium hexafluorophosphate TEA triethylamine TFA 2,2,2-trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TMSN3 azidotrimethylsilane TMSOK potassium trimethylsilanolate µL microliter XPhos Pd G2 chloro(2-dicyclohexylphosphino-2^,4^,6^-triisopropyl-1,1^-biphenyl)[2-(2^- amino-1,1^-biphenyl)]palladium(II) XPhos Pd G3 (2-dicyclohexylphosphino-2^,4^,6^-triisopropyl-1,1^-biphenyl)[2-(2^-amino- 1,1^-biphenyl)]palladium(II) methanesulfonate

[0288] Compounds were named with the aid of OpenEye Scientific software (Lexichem TK).

[0289] Synthetic Method 1

[0290] Scheme for Method 14886-0959-3510.1

[0291] Step 1, Method 1

[0292] Ethyl 2-chloro-2-oxo-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 stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to give 7-bromo-2-(2-ethoxy-2-oxo-acetyl)-6-methoxy-3,4- dihydro-1H-isoquinoline-1-carboxylic acid as a yellow solid which was used directly in the next step assuming quantitative yield. RT (M2) = 0.75 min, [M+H]+(ESI+) 386.1 / 388.1.

[0293] Step 2, Method 1

[0294] Pent-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-oxo-acetyl)-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 into a pre- heated heating block at 140 °C and stirred for 45 min. The reaction mixture was cooled and concentrated in vacuo. The resulting residue was taken up in DCM (200 mL) and stirred with sat. aq. NaHCO3 (100 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Heptane (200 mL) and diethyl ether (50 mL) were added and the resulting mixture heated at 85 ºC for 30 min. A hot filtration was carried out to afford a solid. This solid was dried and ground with a pestle and mortar to give ethyl 9-bromo-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (13.90 g, 48% yield) as a brown solid. The filtrate was left overnight at rt and orange crystals formed which were isolated by filtration to give more desired product (3.13 g, 11% yield) as an orange solid. RT (M2) = 1.31 min, [M+H]+(ESI+) 392.3 / 394.3;1H NMR (500 MHz, DMSO) ^ 7.68 (s, 1H), 7.16 (s, 1H), 6.78 (s, 1H), 4.48 (t, J = 6.6 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.99 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.66 | 1.57 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H). 4886-0959-3510.1

[0295] The following analogs were made by analogous method: Structure Name LCMS ethyl 9-bromo-1-(4-fluorophenyl)- RT (M8) = 1.10 min, 8-methoxy-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 444.1 / 446.1 3-carboxylate ethyl 9-bromo-8-methoxy-1- RT (M3) = 1.10 min, thiazol-5-yl-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 433.1 / 435.1 3-carboxylate ethyl (5R)-9-bromo-8-methoxy-5- RT (M2) = 1.09 min, methyl-1-thiazol-5-yl-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 447.1 / 449.0 3-carboxylate ethyl (5R)-9-bromo-8-methoxy-5- RT (M2) = 1.32 min, methyl-1-(2-thienyl)-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 446.1 / 448.1 3-carboxylate ethyl 9-bromo-8-methoxy-5,6- RT (M11) = 2.04 min, dihydropyrrolo[2,1-a]isoquinoline- [M+H]+(ESI+) 3-carboxylate 350.1 / 352.1 ethyl 1-(1-(benzyloxy)-2- RT (M13) = 2.67 min, methylpropan-2-yl)-9-bromo-8- [M+H]+(ESI+) methoxy-5,6-dihydropyrrolo[2,1- 512.3 / 514.1 a]isoquin-oline-3-carboxylate 4886-0959-3510.1ethyl 9-bromo-8-methoxy-1- RT (M14) = 1.13 min, (1,3,4-thiadiazol-2-yl)-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 434.1 / 436.0 3-carboxylate ethyl 9-bromo-1-(3,3- RT (M22) = 0.97 min, difluorocyclobutyl)-8-methoxy- [M+H]+(ESI+) 5,6-dihydropyrrolo[2,1- 440.1 / 442.1 a]isoquinoline-3-carboxylate ethyl 9-bromo-1-(5-fluoropyridin- RT (M19) = 0.89 min, 2-yl)-8-methoxy-5,6- [M+H]+(ESI+) dihydropyrrolo[2,1-a]isoquinoline- 445.2 / 447.1 3-carboxylate ethyl (R*)- 9-bromo-8-methoxy-6- RT (M25) = 3.13 min, methyl-1-(thiophen-2-yl)-5,6- [M+H]+(ESI+) RT = dihydropyrrolo[2,1-a]isoquinoline- 0.89 min, [M+H]+3-carboxylate (ESI+) 445.2 / 447.1 ethyl (R*)- 9-bromo-8-methoxy-6- SFC Method (11) methyl-1-(thiophen-2-yl)-5,6- First enantiomer dihydropyrrolo[2,1-a]isoquinoline- RT (M25) = 0.89 min, 3-carboxylate [M+H]+(ESI+) 446.0 / 447.9 Second enantiomer RT (M25) = 1.80 min, [M+H]+(ESI+) 417.9 / 419.9 4886-0959-3510.1ethyl (R*)-9-bromo-8-methoxy-5- SFC Method (11) methyl-1-(thiophen-2-yl)-5,6- Second enantiomer dihydropyrrolo[2,1-a]isoquinoline- RT (M15) = 1.08 min, 3-carboxylate [M+H]+(ESI+) 444.8 / 446.1 ethyl-9-bromo-8-methoxy-5- RT (M1) = 2.07 min, methyl-5,6-dihydropyrrolo[2,1- [M+H]+(ESI+) a]isoquinoline-3-carboxylate 364.1 / 366.1 ethyl (1aR,9bR)-7-bromo-8- RT (M22) = 1.02 min, methoxy-5-(thiophen-2-yl)-1a,9b- [M+H]+(ESI+) dihydro-1H-cyclopropa 444.1 / 446.1 [c]pyrrolo[2,1-a]isoquinoline-3- carboxylate * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[0296] Synthetic Method 2

[0297] Scheme for Method 24886-0959-3510.1

[0298] Step 1, Method 2

[0299] Potassium hydroxide (7.93 g, 139.0 mmol) was added to a stirred solution of ethyl 9- bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (prepared in accordance with an analogous method to method 1 (steps 1 and 2) using 2-ethynyl-thiophene) (15.00 g, 34.7 mmol) in ethanol (300 mL) and water (100 mL) at 80 °C. After 1 h, the reaction mixture was cooled to rt and concentrated in vacuo. The aqueous residue was acidified to pH 1 using 1 M aq HCl, and the solid suspended in the aqueous layer was collected by filtration to give 9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (83% purity, 14.70 g, 87% yield) as a pale brown solid. RT (M2) = 1.03 min, [M+H]+(ESI+) 402.9 / 404.9.

[0300] Step 2, Method 2

[0301] 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 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) at rt. The reaction mixture was stirred overnight and then diluted with DCM and water. The layers were separated, the organic passed through a phase separator and then concentrated in vacuo to yield the crude product as a brown oil. The crude was purified by FCC (silica, eluting with 0-100% EtOAc in heptane, then 0-20% MeOH in EtOAc). The product containing fractions were concentrated in vacuo to give (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (10.27 g, 77% yield) as a pale brown foam. RT (M2) = 1.00 min, [M+H]+(ESI+) 514.2 / 516.2;1H NMR (400 MHz, DMSO) ^ 8.16 (s, 1H), 7.57 (dd, J = 5.2, 1.2 Hz, 1H), 7.45 (s, 1H), 7.18 | 7.10 (m, 2H), 7.07 (dd, J = 3.4, 1.2 Hz, 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). 4886-0959-3510.1

[0302] The following analogs were made by analogous method: Structure Name LCMS [9-bromo-8-methoxy-1-(2-thienyl)-5,6- RT (M2) = 1.23 dihydropyrrolo[2,1-a]isoquinolin-3-yl]- min, [M+H]+[(2S)-2-ethyl-2-methyl-pyrrolidin-1- (ESI+) 499.1 / 501.1 yl]methanone [9-bromo-8-methoxy-1-(2-thienyl)-5,6- RT (M2) = 0.95 dihydropyrrolo[2,1-a]isoquinolin-3-yl]- min, [M+H]+[(2R)-2-(hydroxymethyl)-2-methyl- (ESI+) 501.2 / pyrrolidin-1-yl]methanone 503.2 [9-bromo-8-methoxy-1-(2-thienyl)-5,6- RT (M2) = 1.18 dihydropyrrolo[2,1-a]isoquinolin-3-yl]- min, [M+H]+(2,2-dimethylpyrrolidin-1-yl)methanone (ESI+) 485.1 / 487.1 (2R)-1-(9-bromo-8-methoxy-1-propyl- RT (M2) = 0.96 5,6-dihydropyrrolo[2,1-a]isoquinoline- min, [M+H]+3-carbonyl)-2-methyl-pyrrolidine-2- (ESI+) 474.2 / carboxamide 476.2 (2R)-1-[9-bromo-1-(4-fluorophenyl)-8- RT (M2) = 0.98 methoxy-5,6-dihydropyrrolo[2,1- min, [M+H]+a]isoquinoline-3-carbonyl]-2-methyl- (ESI+) 526.0 / 528.0 pyrrolidine-2-carboxamide [9-bromo-1-(4-fluorophenyl)-8- RT (M3) = 0.99 methoxy-5,6-dihydropyrrolo[2,1- min, [M+H]+a]isoquinolin-3-yl]-[(2R)-2-[(1R)-1- (ESI+) 527.3 / 529.3 hydroxyethyl]-2-methyl-pyrrolidin-1- yl]methanone -160- 4886-0959-3510.1(2R)-1-[9-bromo-8-methoxy-1-(2,2,2- RT (M3) = 0.90 trifluoroethyl)-5,6-dihydropyrrolo[2,1- min, [M+H]+ a]isoquinoline-3-carbonyl]-2-methyl- (ESI+) pyrrolidine-2-carboxamide 514.1 / 516.1 [9-bromo-8-methoxy-1-(2,2,2- RT (M3) = 1.09 trifluoroethyl)-5,6-dihydropyrrolo[2,1- min, [M+H]+ a]isoquinolin-3-yl]-[(2R)-2-[(1R)-1- (ESI+) hydroxyethyl]-2-methyl-pyrrolidin-1- 515.3 / 517.3 yl]methanone [(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M2) = 0.91 methyl-pyrrolidin-1-yl]-[8-methoxy-9- min, [M+H]+ (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- (ESI+) 2-yl)-1-thiazol-5-yl-5,6- 516.1 / 518.1 dihydropyrrolo[2,1-a]isoquinolin-3- yl]methanone (9-bromo-8-methoxy-1-thiazol-5-yl-5,6- RT (M2) = 0.99 dihydropyrrolo[2,1-a]isoquinolin-3-yl)- min, [M+H]+ [(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro- (ESI+) 1-hydroxy-ethyl]pyrrolidin-1- 570.0 / 572.0 yl]methanone (2R)-1-(9-bromo-8-methoxy-1-thiazol- RT (M2) = 0.97 5-yl-5,6-dihydropyrrolo[2,1- min, [M+H]+ a]isoquinoline-3-carbonyl)-2-methyl- (ESI+) pyrrolidine-2-carboxamide 515.1 / 517.1 -161- 4886-0959-3510.1[9-bromo-8-methoxy-1-(2-thienyl)-5,6- RT (M2) = 1.14 dihydropyrrolo[2,1-a]isoquinolin-3-yl]- min, [M+H]+ [(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro- (ESI+) 1-hydroxy-ethyl]pyrrolidin-1- 569.1 / 571.1 yl]methanone (R)-1-(9-bromo-8-methoxy-1-(2,2,2- RT (M13) = 1.74 trifluoroethyl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinoline-3-carbonyl)-2- (ESI+) methylazetidine-2-carboxamide 500.3 / 502.0 (R)-1-(1-(2,2-difluoropropyl)-8- RT (M29) = 0.62 methoxy-9-(2-methyl-2H-tetrazol-5-yl)- min [M+H]+ 5,6-dihydropyrrolo[2,1-a]isoquinoline- (ESI+) 514.1 3-carbonyl)-2-methylpyrrolidine-2- carboxamide (R)-1-(1-(2,2-difluoropropyl)-8- RT (M13) = 1.38 methoxy-9-(2-methyl-2H-tetrazol-5-yl)- min [M+H]+ 5,6-dihydropyrrolo[2,1-a]isoquinoline- (ESI+) 500.3 3-carbonyl)-2-methylazetidine-2- carboxamide (9-bromo-8-methoxy-1-(1,3,4- RT (M11) = 1.13 thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((S)-2-methyl-2-((R)- (ESI+) 2,2,2-trifluoro-1- 571.2 / 573.2 hydroxyethyl)pyrrolidin-1-yl)methanone 4886-0959-3510.1(R)-1-(9-bromo-1-(3,3- RT (M13) = 1.86 difluorocyclobutyl)-8-methoxy-5,6- min [M-128.1]+ dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) carbonyl)-2-methylpyrrolidine-2- 394.2 / 396.2 carboxamide (R)-1-(9-bromo-8-methoxy-1-(thiophen-1H NMR (400 2-yl)-5,6-dihydropyrrolo[2,1- MHz, DMSO-d6) ^ a]isoquinoline-3-carbonyl)-2- ppm 7.58 (br, d, J methylazetidine-2-carboxamide = 5.13 Hz, 2 H), 7.41 (s, 1 H), 7.21 (br s, 1 H), 7.10 - 7.16 (m, 2 H), 7.06 (br d, J = 2.75 Hz, 1 H), 6.69 (br s, 1 H), 4.46 - 4.57 (m, 1 H), 4.28 - 4.45 (m, 3 H), 3.86 (s, 3 H), 3.01 (br t, J = 6.38 Hz, 2 H), 2.36 - 2.46 (m, 1 H), 1.97 - 2.09 (m, 1 H), 1.68 (br s, 3 H) (R)-1-(9-bromo-1-(5-fluoropyridin-2- RT (M13) = 1.48 yl)-8-methoxy-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinoline-3-carbonyl)-2- (ESI+) methylpyrrolidine-2-carboxamide 528.2 / 530.2 4886-0959-3510.1(R)-1-(1-(5-fluoropyridin-2-yl)-8- RT (M20) = 1.34 methoxy-9-(2-methyl-2H-tetrazol-5-yl)- min [M+H]+ 5,6-dihydropyrrolo[2,1-a]isoquinoline- (ESI+) 517.2 3-carbonyl)-2-methylazetidine-2- carboxamide ((S*)-9-bromo-8-methoxy-6-methyl-1- RT (M11) = 2.11 (thiophen-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((R)-2-((R)-1- (ESI+) hydroxyethyl)-2-methylpyrrolidin-1- 529.2 / 531.2 yl)methanone (R)-1-((S*)-9-bromo-8-methoxy-6- RT (M11) = 3.21 methyl-1-(thiophen-2-yl)-5,6- min [M+H]+ dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) carbonyl)-2-methylpyrrolidine-2- 528.2 / 530.2 carboxamide ((R)-9-bromo-8-methoxy-5-methyl-1- RT (M11) = 2.12 (thiophen-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((R)-2-methyl-2-((S)- (ESI+) 2,2,2-trifluoro-1- 583.3 / 585.3 hydroxyethyl)pyrrolidin-1-yl)methanone ((S)-9-bromo-8-methoxy-5-methyl-1- RT (M11) = 2.28 (thiophen-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((R)-2-methyl-2-((S)- (ESI+) 2,2,2-trifluoro-1- 583.2 / 585.3 hydroxyethyl)pyrrolidin-1-yl)methanone 4886-0959-3510.1((R)-9-bromo-8-methoxy-5-methyl-1- RT (M11) = 2.12 (thiophen-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((R)-2-((R)-1- (ESI+) hydroxyethyl)-2-methylpyrrolidin-1- 529.1 / 531.1 yl)methanone ((S)-9-bromo-8-methoxy-5-methyl-1- RT (M11) = 2.12 (thiophen-2-yl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl)((R)-2-((R)-1- (ESI+) hydroxyethyl)-2-methylpyrrolidin-1- 529.1 / 531.2 yl)methanone (R)-1-((S)-9-bromo-8-methoxy-5- RT (M27) = 2.47 methyl-1-(thiophen-2-yl)-5,6- min [M+H]+ dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) carbonyl)-2-methylpyrrolidine-2- 528.4 / 530.0 carboxamide ((R)-9-bromo-8-methoxy-5-methyl-1- RT (M30) = 0.62 (2,2,2-trifluoroethyl)-5,6- min [M+H]+ dihydropyrrolo[2,1-a]isoquinolin-3- (ESI+) yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro- 583.2 / 585.1 1-hydroxyethyl)pyrrolidin-1- yl)methanone ((1aR,9bR)-7-bromo-8-methoxy-5- RT (M11) = 0.72 (thiophen-2-yl)-1a,9b-dihydro-1H- min [M+H]+ cyclopropa[c] pyrrolo[2,1-a]isoquinolin- (ESI+) 3-yl)((R)-2-methyl-2-((S)-2,2,2- 581.2 / 583.2 trifluoro-1-hydroxyethyl) pyrrolidin-1- yl)methanone 4886-0959-3510.1* Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[0303] Synthetic Method 3

[0304] Scheme for Method 3

[0305] Step 1, Method 3

[0306] (1S)-2,2,2-trifluoro-1-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (447 mg, 2.0 mmol, synthesized by method 16) was added to a stirred solution of di(imidazol-1- yl)methanone (412 mg, 2.5 mmol, CAS 530-62-1) and 9-bromo-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (690 mg, 1.7 mmol) in anhydrous DMF (10 mL) and left at rt overnight. The reaction was then heated to 50 °C and stirred for 8 h before it was retreated with (1S)-2,2,2-trifluoro-1-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (447 mg, 2.0 mmol) and stirred at rt for a further 72 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The layers were separated, the organic passed through a phase separator and concentrated in vacuo to give the crude product as a yellow oil which was purified by FCC (silica, eluting 0-100% EtOAc in heptane). Product containing fractions were collected, combined and the solvent removed in vacuo to give [9-bromo-8-methoxy-1-(2-thienyl)- 5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy- ethyl]pyrrolidin-1-yl]methanone (80% purity, 1.05 g, 87% yield) as a beige solid. RT (M2) = 1.15 min [M+H]+(ESI+) 569.1 / 571.1;1H NMR (400 MHz, DMSO) ^ 7.56 (dd, J = 5.2, 1.2 Hz, 1H), 7.43 (s, 1H), 7.16 | 7.09 (m, 2H), 7.06 (dd, J = 3.5, 1.2 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 6.50 (s, 1H), 4.99 (p, J = 8.4 Hz, 1H), 4.31 | 4.10 (m, 2H), 3.88-3.84 (m, 4H), 3.70 | 3.59 (m, 1H), 3.02 (t, J = 6.5 Hz, 2H), 2.43 | 2.28 (m, 1H), 1.85 | 1.74 (m, 2H), 1.74 | 1.63 (m, 1H), 1.60 (s, 3H). 4886-0959-3510.1

[0307] Synthetic Method 4

[0308] Scheme for Method 4

[0309] Step 1, Method 4

[0310] (1R)-1-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (492 mg, 3.0 mmol, synthesized by method 15) was added to a stirred solution of di(imidazol-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) and the reaction mixture heated at 90 °C for 2.5 h. DIPEA (1.1 mL, 6.2 mmol, CAS 7087-68-5) was added and the mixture stirred at 90 °C overnight. The reaction mixture was concentrated in vacuo and dissolved in DCM and water. The layers were separated, the organic passed through a phase separator and concentrated in vacuo to give an oil that was purified by FCC (silica, eluting 0-100% EtOAc in heptane). The fractions were concentrated in vacuo to give [9-bromo-8-methoxy-1-(2-thienyl)- 5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin- 1-yl]methanone (72.0% purity) (594 mg, 0.8 mmol, 34% yield) as a pale brown solid. RT (M3) = 0.99 min, (ESI+) (M+H)+515.3 / 517.3.1H NMR (500 MHz, DMSO) ^ 7.55 (dd, J = 5.2, 1.1 Hz, 1H), 7.43 (s, 1H), 7.14 | 7.10 (m, 2H), 7.06 (dd, J = 3.5, 1.2 Hz, 1H), 6.53 (s, 1H), 4.96 (d, J = 4.9 Hz, 1H), 4.44 (p, J = 6.3 Hz, 1H), 4.31 (dt, J = 13.0, 6.5 Hz, 1H), 4.11 | 4.05 (m, 1H), 3.85 (s, 3H), 3.81 (ddd, J = 10.0, 6.6, 3.5 Hz, 1H), 3.67 | 3.59 (m, 1H), 3.01 (t, J = 6.5 Hz, 2H), 2.07 (ddd, J = 12.6, 10.2, 7.7 Hz, 1H), 1.81 | 1.71 (m, 2H), 1.57 | 1.51 (m, 1H), 1.50 (s, 3H), 1.00 (d, J = 6.3 Hz, 3H).

[0311] The following analogs were made by analogous method: 4886-0959-3510.1Structure Name LCMS [(5R)-9-bromo-8-methoxy-5-methyl-1-(2- thienyl)-5,6-dihydropyrrolo[2,1- RT (M2) = 1.25 min, a]isoquinolin-3-yl]-[(2S)-2-methyl-2-[(1R)- (ESI+) (M+H)+2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1- 583.0 / 585.0 yl]methanone [(5R)-9-bromo-8-methoxy-5-methyl-1- thiazol-5-yl-5,6-dihydropyrrolo[2,1- RT (M2) = 1.25 min, a]isoquinolin-3-yl]-[(2R)-2-methyl-2-[(1S)- (ESI+) (M+H)+2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1- 583.0 / 585.0 yl]methanone [8-methoxy-9-(1-methylpyrazol-3-yl)-1- thiazol-5-yl-5,6-dihydropyrrolo[2,1- RT (M4) = 3.46 min, a]isoquinolin-3-yl]-[(2S)-2-methyl-2-[(1R)- (ESI+) (M+H)+572.2 2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1- Compound 4-1 yl]methanone (1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2- methyl-2H-tetrazol-5-yl)-5,6- RT (M36) = 3.99 dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)- min, (ESI+) (M+H)+2-methyl-2-((R)-2,2,2-trifluoro-1- 586.3 Compound 4-2 hydroxyethyl)pyrrolidin-1-yl)methanone (R)-8-methoxy-5-methyl-3-((R)-2-methyl-2- ((S)-2,2,2-trifluoro-1-hydroxyethyl) RT (M34) = 2.77 pyrrolidine-1-carbonyl)-N-(1-methyl-2-oxo- min, (ESI+) (M+H)+1,2-dihydropyridin-3-yl)-1-(2,2,2- 655.3 Compound 4-3 trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-9-carboxamide 4886-0959-3510.1

[0312] Synthetic Method 5

[0313] Scheme for Method 5

[0314] Step 1, Method 5

[0315] 1 M Aqueous lithium hydroxide (1.1 mL, 1.1 mmol) 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) and the mixture heated at 80 °C for 3 h, forming a solution. After cooling to rt the mixture was concentrated in vacuo to afford the product lithium 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate hydroxide (226 mg, quantitative) as an off-white powder. RT (M2) = 1.03 min, (ESI+) (M+H)+364.1 / 366.1;1H NMR (400 MHz, DMSO-d6) ^ 7.54 (s, 1H), 7.06 (s, 1H), 6.30 (s, 1H), 4.62 (t, J = 6.3 Hz, 2H), 3.84 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H), 2.60 | 2.53 (m, 2H), 1.59 (h, J = 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H).

[0316] Step 2, Method 5

[0317] DIPEA (1.4 mL, 8.0 mmol, CAS 7087-68-5) was added to a stirred suspension of lithium 9-bromo-8-methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate hydroxide (1.04 g, 2.6 mmol) and (1R)-1-[(2R)-2-methylpyrrolidin-2-yl]ethanol hydrochloride (580 mg, 1.3 mmol, synthesized by method 15) in DMA (25 mL) and the mixture stirred at 20 °C for 5 min, forming a hazy solution. 2-Chloro-1-methylpyridinium iodide (1.50 g, 5.9 mmol, CAS 14338-32-0) was added and the reaction mixture stirred at 20 °C for 17 h. The reaction mixture was diluted with water (150 mL), sonicated and left to stand for 10 min. The solids were collected by filtration, washing with water (3 x 30 mL). The solids were then dissolved into EtOAc (200 4886-0959-3510.1mL) and the organic mixture filtered through a hydrophobic filter paper. The organic filtrate was concentrated in vacuo to afford the crude product (913 mg) as a tan powder. The crude product was purified by FCC (silica, eluting with 10-100% EtOAc in heptane) to give (9-bromo-8- methoxy-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)-[(2R)-2-[(1R)-1-hydroxyethyl]-2- methyl-pyrrolidin-1-yl]methanone (507 mg, 38% yield) as a pale tan powder. RT (M2) = 1.02 min, (ESI+) (M+H)+475.2 / 477.2;1H NMR (400 MHz, DMSO) ^ 7.62 (s, 1H), 7.12 (s, 1H), 6.38 (s, 1H), 5.01 (d, J = 4.7 Hz, 1H), 4.47 | 4.35 (m, 1H), 4.25 (dt, J = 13.0, 6.5 Hz, 1H), 4.05 (dt, J = 12.6, 6.2 Hz, 1H), 3.86 (s, 3H), 3.77 (dt, J = 10.4, 5.2 Hz, 1H), 3.66 | 3.52 (m, 1H), 2.93 (t, J = 6.5 Hz, 2H), 2.66 | 2.57 (m, 2H), 2.05 (dt, J = 12.8, 8.8 Hz, 1H), 1.86 | 1.68 (m, 2H), 1.67 | 1.44 (m, 3H), 1.49 (s, 3H), 1.02 | 0.92 (m, 6H).

[0318] Synthetic Method 6

[0319] Scheme for Method 6

[0320] Step 1, Method 6

[0321] (Methyl N-(triethylammoniumsulfonyl)carbamate) (2.35 g, 9.9 mmol, CAS 29684-56- 8) (Burgess reagent) was added to a mixture of (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-2-carboxamide (2.54 g, 4.9 mmol, synthesized by method 2) in THF (20 mL) and DCM (20 mL) at 0 °C and the reaction mixture warmed to 20 °C and stirred for 1 h. The reaction mixture was poured into water (20 mL) and the aqueous phase extracted with DCM (3 x 20 mL). The combined organic phases were washed with brine (saturated solution of NaCl in deionized water) (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by FCC (silica, eluting 0-100% EtOAc in heptane) and the product containing fractions concentrated in vacuo to 4886-0959-3510.1give (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (92%) (2.10 g, 79% yield) as a pale yellow solid. RT (M2) = 1.09 min, (ESI+) (M+H)+496.0 / 497.9;1H NMR (500 MHz, DMSO) ^ 7.58 (dd, J = 5.2, 1.2 Hz, 1H), 7.43 (s, 1H), 7.16 | 7.11 (m, 2H), 7.08 (dd, J = 3.5, 1.2 Hz, 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 = 6.5 Hz, 2H), 2.47 (dd, J = 9.0, 3.7 Hz, 1H), 2.12 (ddd, J = 12.8, 10.1, 6.0 Hz, 1H), 2.02 | 1.99 (m, 1H), 1.95 | 1.85 (m, 1H), 1.74 (s, 3H).

[0322] The following analogs were made by analogous method: Structure Name LCMS (2R)-1-[9-bromo-1-(4-fluorophenyl)-8- RT (M2) = 1.11 min, methoxy-5,6-dihydropyrrolo[2,1- (ESI+) (M+H)+a]isoquinoline-3-carbonyl]-2-methyl- 508.0 / 510.0 pyrrolidine-2-carbonitrile (2R)-1-(9-bromo-8-methoxy-1-propyl- RT (M2) = 1.13 min, 5,6-dihydropyrrolo[2,1-a]isoquinoline- (ESI+) (M+H)+3-carbonyl)-2-methyl-pyrrolidine-2- 456.2 / 458.2 carbonitrile (2R)-1-[9-bromo-8-methoxy-1-(2,2,2- RT (M3) = 1.06 min, trifluoroethyl)-5,6-dihydropyrrolo[2,1- (ESI+) (M+H)+ a]isoquinoline-3-carbonyl]-2-methyl- 496.2 / 498.2 pyrrolidine-2-carbonitrile 4886-0959-3510.1(3S)-4-[8-methoxy-9-(1-methylpyrazol- 3-yl)-1-(2-thienyl)-5,6- RT (M5) = 3.78 min, dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) (M+H)+ carbonyl]-3-methyl-morpholine-3- 514.3 Compound 6-1 carbonitrile (2R)-1-[8-methoxy-9-(1- methylpyrazol-3-yl)-1-thiazol-5-yl-5,6- RT (M4) = 3.17 min, dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) (M+H)+ carbonyl]-2-methyl-pyrrolidine-2- 499.3 Compound 6-2 carbonitrile (2R)-1-(9-bromo-8-methoxy-1-thiazol- RT (M2) = 0.93 min, 5-yl-5,6-dihydropyrrolo[2,1- (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2-methyl- 497.1 / 499.1 pyrrolidine-2-carbonitrile (R)-1-(9-bromo-8-methoxy-1-(2,2,2- RT (M11) = 1.99 trifluoroethyl)-5,6-dihydropyrrolo[2,1- min, (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2- 482.2 / 484.1 methylazetidine-2-carbonitrile (R)-1-(9-bromo-1-(3,3- difluorocyclobutyl)-8-methoxy-5,6- RT (M27) = 2.61 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylpyrrolidine-2- 504.0 / 506.0 carbonitrile 4886-0959-3510.1(R)-1-(9-bromo-8-methoxy-1- (thiophen-2-yl)-5,6- RT (M25) = 2.66 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylazetidine-2- 482.0 / 484.0 carbonitrile (R)-1-(9-bromo-1-(5-fluoropyridin-2- RT (M13) = 1.88 yl)-8-methoxy-5,6-dihydropyrrolo[2,1- min, (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2- 509.2 / 511.1 methylpyrrolidine-2-carbonitrile (R*)-1-((S)-9-bromo-8-methoxy-6- methyl-1-(thiophen-2-yl)-5,6- RT (M11) = 2.14 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylpyrrolidine-2- 510.2 / 512.2 carbonitrile (R)-1-((S)-9-bromo-8-methoxy-5- methyl-1-(thiophen-2-yl)-5,6- RT (M12) = 0.733 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylpyrrolidine-2- 510.2 / 512.2 carbonitrile (R)-1-(1-(1-hydroxy-2-methylpropan- 2-yl)-8-methoxy-9-(2-methyl-2H- RT (M36) = 3.08 tetrazol-5-yl)-5,6-dihydropyrrolo[2,1- min, (ESI+) (M- a]isoquinoline-3-carbonyl)-2- OH)+ 472.1 Compound 6-3 methylpyrrolidine-2-carbonitrile 4886-0959-3510.1(R)-1-(1-(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M36) = 2.92 yl)-5,6-dihydropyrrolo[2,1- min, (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2- 496.3 Compound 6-4 methylpyrrolidine-2-carbonitrile (R)-1-(1-(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M24)= 2.84 yl)-5,6-dihydropyrrolo[2,1- min, (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2- 482.2 Compound 6-5 methylazetidine-2-carbonitrile (R)-1-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1-propyl-5,6- RT (M37) = 2.67 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylazetidine-2- 446.2 Compound 6-6 carbonitrile (R)-1-(1-(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M24) = 2.76 yl)-5,6-dihydropyrrolo[2,1- min, (ESI+) (M+H)+ a]isoquinoline-3-carbonyl)-2- 499.1 Compound 6-7 methylazetidine-2-carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy- 9-(2-methyl-2H-tetrazol-5-yl)-5,6- RT (M24) = 3.02 dihydropyrrolo[2,1-a]isoquinoline-3- min, (ESI+) (M+H)+ carbonyl)-2-methylazetidine-2- 498.2 Compound 6-8 carbonitrile 4886-0959-3510.1* Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[0323] Synthetic Method 7

[0324] Scheme for Method 7

[0325] Step 1, Method 7

[0326] In a pressure relief vial, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (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-methyl-pyrrolidine-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. X1,1^-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (99 f`, 121 ^fhe, @>P 95464-05-4) was added and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and partitioned between DCM and water. The layers were separated, the organics passed through a phase separator cartridge and concentrated in vacuo. The crude material was then purified by FCC (silica, eluting with 0-100% EtOAc in heptane). Product containing fractions were collected, combined and the solvent removed in vacuo to give (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-methyl-pyrrolidine-2- carbonitrile (425 mg, 57% yield) as a pale brown solid. RT (M2) = 1.1 min [M+H]+(ESI+) 544.3; 1H NMR (500 MHz, DMSO) ^ 7.67 (s, 1H), 7.50 (dd, J = 5.1, 1.2 Hz, 1H), 7.09 | 7.03 (m, 2H), 6.94 (s, 1H), 6.72 (s, 1H), 4.40 (dt, J = 13.3, 6.5 Hz, 1H), 4.26 (dt, J = 13.1, 6.2 Hz, 1H), 3.89 (td, J = 8.8, 7.3, 3.8 Hz, 1H), 3.84 | 3.78 (m, 1H), 3.76 (s, 3H), 3.06 (t, J = 6.5 Hz, 2H), 2.48 | 2.44 4886-0959-3510.1(m, 1H), 2.17 | 2.08 (m, 1H), 1.99 (s, 1H), 1.93 (dd, J = 15.5, 6.8 Hz, 1H), 1.74 (s, 3H), 1.17 (s, 12H)

[0327] Step 2, Method 7

[0328] 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-methyl-pyrrolidine-2- carbonitrile (100 mg, 184 ^mol), 2-bromo-1,3-oxazole (34 mg, 221 ^mol, CAS 125533-82-6) and dicaesium carbonate (240 mg, 736 ^mol, CAS 534-17-8) in 1,4-dioxane (2.4 mL) and water (0.6 mL) was degassed with nitrogen for 5 min. UMahl M] D2 (29 f`, 18 ^fhe, @>P 1310584-14-5) was then added and the mixture degassed with nitrogen for 5 min. The reaction mixture was stirred at 80 °C overnight. The reaction was allowed to cool to rt, treated with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The compound was purified by acidic prep HPLC (Method P2) and then basic prep HPLC (Method P4) to give a white solid. The white solid was further purified by chiral prep (Chiralpak AD-H, mobile phase ethanol at 9 mL / min) and freeze dried to give (2R)-1-[8- methoxy-9-oxazol-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile (Compound 7-1) (24 mg, 27% yield) as a white solid. RT (M4) = 3.62 min, (ESI+) (M+H)+485.2;1H NMR (400 MHz, DMSO) ^ 8.09 (s, 1H), 7.96 (s, 1H), 7.51 (dd, J = 3.9, 2.5 Hz, 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 = 6.4 Hz, 2H), 2.47 | 2.42 (m, 1H), 2.19 | 2.08 (m, 1H), 2.05 | 1.85 (m, 2H), 1.74 (s, 3H).

[0329] The following analogs were made by analogous method: Structure Name LCMS 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M4) = 3.17 methyl-pyrrolidine-1-carbonyl]-8- min [M+H]+ methoxy-1-(2-thienyl)-5,6- (ESI+) 544.3 dihydropyrrolo[2,1-a]isoquinolin-9- Compound 7-2 yl]-6-methyl-1H-pyridin-2-one 4886-0959-3510.1[(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M4) = 3.54 methyl-pyrrolidin-1-yl]-[8-methoxy-9- min [M+H]+ oxazol-2-yl-1-(2-thienyl)-5,6- (ESI+) 504.3 dihydropyrrolo[2,1-a]isoquinolin-3- Compound 7-3 yl]methanone 3-[3-[(2R)-2-cyano-2-methyl- RT (M4) = 4.02 pyrrolidine-1-carbonyl]-1-(4- min [M+H]+ fluorophenyl)-8-methoxy-5,6- (ESI+) 532.3 dihydropyrrolo[2,1-a]isoquinolin-9- yl]pyridine-2-carbonitrile Compound 7-4 3-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M2) = 0.99 methyl-pyrrolidine-1-carbonyl]-8- min [M+H]+ methoxy-1-propyl-5,6- (ESI+) 499.7 dihydropyrrolo[2,1-a]isoquinolin-9- Compound 7-5 yl]pyridine-2-carbonitrile [8-methoxy-9-(2-methyltetrazol-5-yl)- RT (M4) = 3.80 1-(2-thienyl)-5,6-dihydropyrrolo[2,1- min [M+H]+ a]isoquinolin-3-yl]-[(2R)-2-methyl-2- (ESI+) 573.2 [(1S)-2,2,2-trifluoro-1-hydroxy- Compound 7-6 ethyl]pyrrolidin-1-yl]methanone (2R)-1-[9-(1H-imidazol-2-yl)-8- RT (M4) = 2.05 methoxy-1-(2,2,2-trifluoroethyl)-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) 484.3 carbonyl]-2-methyl-pyrrolidine-2- Compound 7-7 carbonitrile 4886-0959-3510.1(2R)-1-[8-methoxy-9-(2- methyltetrazol-5-yl)-1-(2-thienyl)-5,6- RT (M4) = 3.53 dihydropyrrolo[2,1-a]isoquinoline-3- min [M+H]+carbony+Compound 7-8 l]-2-methyl-pyrrolidine-2- (ESI ) 500.2 carbonitrile (2R)-1-[8-methoxy-9-(2- RT (M4) = 3.61 methyltetrazol-5-yl)-1-propyl-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) 460.1 carbonyl]-2-methyl-pyrrolidine-2- Compound 7-9 carbonitrile [(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M4) = 3.57 methyl-pyrrolidin-1-yl]-[8-methoxy-9- min [M+H]+(2-methyltetrazol-5-yl)-1-(2-thienyl)- (ESI+) 519.1 5,6-dihydropyrrolo[2,1-a]isoquinolin- Compound 7-10 3-yl]methanone (2R)-1-[8-methoxy-9-(2- RT (M4) = 3.52 methyltetrazol-5-yl)-1-(2,2,2- min [M+H]+trifluoroethyl)-5,6-dihydropyrrolo[2,1- (ESI+) 500.1 a]isoquinoline-3-carbonyl]-2-methyl- Compound 7-11 pyrrolidine-2-carbonitrile [(5R)-8-methoxy-5-methyl-9-(2- methyltetrazol-5-yl)-1-(2-thienyl)-5,6- RT (M4) = 4.04 dihydropyrrolo[2,1-a]isoquinolin-3- min [M+H]+Compound 7-12 yl]-[(2S)-2-methyl-2-[(1R)-2,2,2- (ESI+) 587.4 trifluoro-1-hydroxy-ethyl]pyrrolidin- 1-yl]methanone 4886-0959-3510.1[(5R)-8-methoxy-5-methyl-9-(2- RT (M5) = 3.49 methyltetrazol-5-yl)-1-thiazol-5-yl- min [M+H]+5,6-dihydropyrrolo[2,1-a]isoquinolin- (ESI+) 588.3 3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2- Compound 7-13 trifluoro-1-hydroxy-ethyl]pyrrolidin- 1-yl]methanone (2R)-1-[8-methoxy-9-(2- methyltetrazol-5-yl)-1-thiazol-5-yl- RT (M4) = 2.93 5,6-dihydropyrrolo[2,1- min [M+H]+a]isoquinoline-3-carbonyl]-2-methyl- (ESI+) 501.2 Compound 7-14 pyrrolidine-2-carbonitrile (R)-3-(3-(2-cyano-2- methylpyrrolidine-1-carbonyl)-8- RT (M36) = 3.45 methoxy-1-(2,2,2-trifluoroethyl)-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinolin-9- (ESI+) 588.3 Compound 7-15 yl)-5-(trifluoromethyl)picolinonitrile (R)-1-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)- RT (M24) = 2.89 5,6-dihydropyrrolo[2,1- min [M+H]+a]isoquinoline-3-carbonyl)-2- (ESI+) 489.1 Compound 7-16 methylazetidine-2-carbonitrile (8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6- RT (M36) = 2.71 dihydropyrrolo[2,1-a]isoquinolin-3- min [M+H]+yl)((S)-2-methyl-2-((R)-2,2,2- Compound 7-17 (ESI+) 575.3 trifluoro-1-hydroxyethyl)pyrrolidin-1- yl)methanone 4886-0959-3510.1(R)-1-(1-(3,3-difluorocyclobutyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M36) = 3.04 yl)-5,6-dihydropyrrolo[2,1- min [M+H]+a]isoquinoline-3-carbonyl)-2- (ESI+) 508.3 Compound 7-18 methylpyrrolidine-2-carbonitrile (R)-1-(8-methoxy-9-(2-methyl-2H- tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- RT (M24) = 2.96 dihydropyrrolo[2,1-a]isoquinoline-3- min [M+H]+carbonyl)-2-methylazetidine-2- (ESI+) 486.1 Compound 7-19 carbonitrile (R)-1-(1-(5-fluoropyridin-2-yl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M36) = 2.82 yl)-5,6-dihydropyrrolo[2,1- min [M+H]+a]isoquinoline-3-carbonyl)-2- (ESI+) 513.2 Compound 7-20 methylpyrrolidine-2-carbonitrile (R)-1-(1-(4-fluorophenyl)-8-methoxy- 9-(2-methyl-2H-tetrazol-5-yl)-5,6- RT (M24) = 3.10 dihydropyrrolo[2,1-a]isoquinoline-3- min [M+H]+carbonyl)-2-methylpyrrolidine-2- (ESI+) 512.1 Compound 7-21 carbonitrile ((R)-8-methoxy-5-methyl-9-(2- methyl-2H-tetrazol-5-yl)-1-(thiophen- 2-yl)-5,6-dihydropyrrolo[2,1- RT (M35) = 3.07 a]isoquinolin-3-yl)((R)-2-methyl-2- min [M+H]+Compound 7-22 ((S)-2,2,2-trifluoro-1- (ESI+) 587.2 hydroxyethyl)pyrrolidin-1- yl)methanone 4886-0959-3510.15-((R)-8-methoxy-5-methyl-3-((R)-2- methyl-2-((S)-2,2,2-trifluoro-1- RT (M35) = 2.91 hydroxyethyl)pyrrolidine-1-carbonyl)- = min [M+H]+1-(2,2,2-trifluoroethyl)-5,6- Compound 7-23 (ESI+) 625.0 dihydropyrrolo[2,1-a]isoquinolin-9- yl)nicotinamide 3-((R)-8-methoxy-5-methyl-3-((R)-2- methyl-2-((S)-2,2,2-trifluoro-1- RT (M35) = 3.14 hydroxyethyl)pyrrolidine-1-carbonyl)- min [M+H]+1-(2,2,2-trifluoroethyl)-5,6-dihy (ESI+) 607.3 Compound 7-24 dropyrrolo[2,1-a]isoquinolin-9- yl)picolinonitrile ((R)-8-methoxy-5-methyl-9-(2- methyl-2H-tetrazol-5-yl)-1-(2,2,2- trifluoroethyl)-5,6-dihydrop RT (M25) = 2.42 yrrolo[2,1-a]isoquinolin-3-yl)((R)-2- min [M+H]+Compound 7-25 methyl-2-((S)-2,2,2-trifluoro-1- (ESI+) 587.2 hydroxyethyl)pyrrolidin-1- yl)methanone ((1aR,9bR)-8-methoxy-7-(2-methyl- 2H-tetrazol-5-yl)-5-(thiophen-2-yl)- 1a,9b-dihydro-1H- RT (M13) = 3.20 cyclopropa[c]pyrrolo[2,1- Compound 7-26 min [M+H]+a]isoquinolin-3-yl)((R)-2-methyl-2- (ESI+) 585.2 ((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1- yl)methanone 4886-0959-3510.1[(2R)-2-[(1R)-1-hydroxyethyl]-2- methyl-pyrrolidin-1-yl]-[8-methoxy-9- RT (M4) = 2.82 (2-methyltetrazol-5-yl)-1-thiazol-5-yl- min [M+H]+5,6-dihydropyrrolo[2,1-a]isoquinolin- (ESI+) 520.2 Compound 7-27 3-yl]methanone [8-methoxy-9-(2-methyltetrazol-5-yl)- 1-(2-thienyl)-5,6-dihydropyrrolo[2,1- RT (M4) = 3.80 a]isoquinolin-3-yl]-[(2S)-2-methyl-2- min [M+H]+ [(1R)-2,2,2-trifluoro-1-hydroxy- (ESI+) 573.2 Compound 7-28 ethyl]pyrrolidin-1-yl]methanone ethyl 1-(1-(benzyloxy)-2- methylpropan-2-yl)-8-methoxy-9-(2- RT (M34) = 0.65 methyl-2H-tetrazol-5-yl)-5,6- min [M+H]+ dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) 516.4 carboxylate ethyl 1-(2,2-difluoropropyl)-8- methoxy-9-(2-methyl-2H-tetrazol-5- RT (M29) = 1.32 yl)-5,6-dihydropyrrolo[2,1- min [M-Et]+ a]isoquinoline-3-carboxylate (ESI+) 404.2 4886-0959-3510.1

[0330] Synthetic Method 8

[0331] Scheme for Method 8

[0332] Step 1, Method 8

[0333] A solution of (2R)-1-[9-bromo-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl]-2-methyl-pyrrolidine-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), dicaesium carbonate (1.58 g, 4.8 mmol, CAS 534-17-8) in 1,4- ]bhqZg^ (15 fI) Zg] pZm^k (6 fI) pZl ]^`Zll^] pbma gbmkh`^g. UMahl M] D2 (190 f`, 121 ^fhe, CAS 1310584-14-5) was added and the reaction mixture was heated to 80 °C for 2 h. The mixture was allowed to cool to rt, 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 in vacuo. The compound was purified by FCC (0-100% EtOAC in heptane) to give a brown solid which was further purified by reverse phase FCC (10-100% MeCN in water). Product containing fractions were concentrated in vacuo, freeze dried and dried in vacuum oven over the weekend to give (2R)- 1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile (Compound 8-1) (349 mg, 57% yield) as a white solid. RT (M4) = 3.82 min [M+H]+(ESI+) 498.3;1H NMR (400 MHz, DMSO) ^ 8.09 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 3.8, 2.6 Hz, 1H), 7.12 | 7.09 (m, 2H), 7.06 (s, 1H), 6.72 (s, 1H), 6.52 (d, J = 2.2 Hz, 1H), 4.51 | 4.37 (m, 1H), 4.34 | 4.20 (m, 1H), 3.94 | 3.88 (m, 1H), 3.87 (s, 4886-0959-3510.13H), 3.85 | 3.78 (m, 1H), 3.76 (s, 3H), 3.06 (t, J = 6.4 Hz, 2H), 2.48 | 2.42 (m, 1H), 2.20 | 2.08 (m, 1H), 2.05 | 1.87 (m, 2H), 1.74 (s, 3H).

[0334] The following analogs were made by analogous method: Structure Name LCMS (2R)-1-[8-methoxy-9-(1H-pyrazol-3- RT (M4) = 3.57 yl)-1-(2-thienyl)-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) 484.2 carbonyl]-2-methyl-pyrrolidine-2- Compound 8-2 carbonitrile (2R)-1-[1-(4-fluorophenyl)-8- RT (M4) = 3.94 methoxy-9-(1-methylpyrazol-3-yl)- min [M+H]+5,6-dihydropyrrolo[2,1- (ESI+) 510.3 a]isoquinoline-3-carbonyl]-2-methyl- Compound 8-3 pyrrolidine-2-carbonitrile (2R)-1-[8-methoxy-9-(1- RT (M4) = 3.95 methylpyrazol-3-yl)-1-propyl-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinoline-3- (ESI+) 458.3 carbonyl]-2-methyl-pyrrolidine-2- Compound 8-4 carbonitrile 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]- RT (M4) = 3.36 2-methyl-pyrrolidine-1-carbonyl]-8- min [M+H]+methoxy-1-propyl-5,6- (ESI+) 504.4 dihydropyrrolo[2,1-a]isoquinolin-9- Compound 8-5 yl]-1-methyl-pyridin-2-one 4886-0959-3510.1[(2R)-2-[(1R)-1-hydroxyethyl]-2- RT (M4) = 3.5 methyl-pyrrolidin-1-yl]-[8-methoxy- min [M+H]+9-(1H-pyrazol-3-yl)-1-(2-thienyl)- (ESI+) 503.3 5,6-dihydropyrrolo[2,1-a]isoquinolin- Compound 8-6 3-yl]methanone 6-[8-methoxy-3-[(2R)-2-methyl-2- RT (M4) = 3.66 [(1S)-2,2,2-trifluoro-1-hydroxy- min [M+H]+ethyl]pyrrolidine-1-carbonyl]-1-(2- (ESI+) 584.2 thienyl)-5,6-dihydropyrrolo[2,1- Compound 8-7 a]isoquinolin-9-yl]-1H-pyridin-2-one 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]- RT (M4) = 3.28 2-methyl-pyrrolidine-1-carbonyl]-8- min [M+H]+methoxy-1-(2-thienyl)-5,6- (ESI+) 544.3 dihydropyrrolo[2,1-a]isoquinolin-9- Compound 8-8 yl]-1-methyl-pyridin-2-one 3-[3-[(2R)-2-cyano-2-methyl- RT (M4) = pyrrolidine-1-carbonyl]-8-methoxy- 3.71min 1-(2,2,2-trifluoroethyl)-5,6- [M+Na]+(ESI+) dihydropyrrolo[2,1-a]isoquinolin-9- 542.2 Compound 8-9 yl]pyridine-2-carbonitrile [(5R)-8-methoxy-5-methyl-9-(1- methylpyrazol-3-yl)-1-thiazol-5-yl- RT (M4) = 3.62 5,6-dihydropyrrolo[2,1-a]isoquinolin- min [M+H]+3-yl]-[(2R)-2-methyl-2-[(1S)-2,2,2- Compound 8-10 (ESI+) 586.2 trifluoro-1-hydroxy-ethyl]pyrrolidin- 1-yl]methanone 4886-0959-3510.1(R)-1-(8-methoxy-9-(1-methyl-1H- pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- RT (M36) = 3.10 dihydropyrrolo[2,1-a]isoquinoline-3- min [M+H]+carbonyl)-2-methylazetidine-2- (ESI+) 484.2 Compound 8-11 carbonitrile (R)-1-((S*)-8-methoxy-6-methyl-9- (1-methyl-1H-pyrazol-3-yl)-1- RT (M36) = 3.24 (thiophen-2-yl)-5,6- min [M+H]+dihydropyrrolo[2,1-a]isoquinoline-3- Compound 8-12 (ESI+) 512.3 carbonyl)-2-methylpyrrolidine-2- carbonitrile ((R)-8-methoxy-5-methyl-9-(1- methyl-1H-pyrazol-3-yl)-1- (thiophen-2-yl)-5,6- RT (M35) = 3.19 Compound 8-13 dihydropyrrolo[2,1-a]isoquinolin-3- min [M+H]+yl)((R)-2-methyl-2-((S)-2,2,2- (ESI+) 585.2 trifluoro-1-hydroxyethyl)pyrrolidin- 1-yl)methanone ((R)-2-((R)-1-hydroxyethyl)-2- methylpyrrolidin-1-yl)((S)-8- RT (M35) = 2.99 methoxy-5-methyl-9-(1-methyl-1H- min [M+H]+pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- Compound 8-14 (ESI+) 531.2 dihydropyrrolo[2,1-a]isoquinolin-3- yl)methanone 4886-0959-3510.1((1aR,9bR)-8-methoxy-7-(1-methyl- 1H-pyrazol-3-yl)-5-(thiophen-2-yl)- 1a,9b-dihydro-1H- RT (M25) = 2.54 cyclopropa[c]pyrrolo[2,1- Compound 8-15 min [M+H]+a]isoquinolin-3-yl)((R)-2-methyl-2- (ESI+) 583.2 ((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1- yl)methanone (8-methoxy-9-(1-methyl-1H-pyrazol- 3-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6- RT (M36) = 2.84 dihydropyrrolo[2,1-a]isoquinolin-3- min [M+H]+yl)((S)-2-methyl-2-((R)-2,2,2- (ESI+) Compound 8-16 trifluoro-1-hydroxyethyl)pyrrolidin- 573.3 / 574.3 1-yl)methanone * Denotes unknown stereochemistry, isolated from a diastereomeric mixture using SFC chromatography

[0335] Synthetic Method 9

[0336] Scheme for Method 9

[0337] Step 1, Method 9

[0338] 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- ]bhqZ[hkheZg^ (234 f`, 922 ^fhe, @>P 73183-34-3), [9-bromo-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1- 4886-0959-3510.1yl]methanhg^ (540 f`, 838 ^fhe, lrgma^lbsed 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 degassed with N2. X1,1^-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (68 f`, 84 ^fhe, @>P 95464-05-4) was added and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was cooled, concentrated in vacuo and partitioned between DCM and water. The organic layer was separated, dried through a phase separator cartridge and concentrated in vacuo to give the crude product. The crude was purified by FCC (silica, eluting with 0-100% EtOAc in heptane). Product containing fractions were combined and concentrated in vacuo to give [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-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]isoquinolin-3-yl]methanone (230 mg, 44% yield) as a brown solid. RT (M5) = 1.02 min [M+H]+(ESI)+563.5;1H NMR (500 MHz, DMSO) ^ 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 = 4.8 Hz, 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 = 6.5 Hz, 2H), 2.10 | 2.02 (m, 1H), 1.80 | 1.69 (m, 2H), 1.56 | 1.51 (m, 1H), 1.51 (s, 3H), 1.17 (s, 12H), 1.00 (d, J = 6.4 Hz, 3H).

[0339] Step 2, Method 9

[0340] A solution of [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-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]isoquinolin-3-yl]methanone (110 mg, 176 ^mol), tert-butyl 2-bromoimidazole-1-carboxylate (52 mg, 211 ^mol, CAS 1207457-15-5), dicaesium carbonate (229 mg, 704 ^mol, CAS 534-17-8) in 1,4-dioxane (2 mL) and water (680 ^L) was degassed with N2. XPhos M] D2 (28 f`, 18 ^fhe, CAS 1310584-14-5) was added, the reaction heated to 80 °C and stirred overnight. The reaction was cooled to rt and concentrated in vacuo. The resulting residue was diluted with water and extracted with DCM (3 x 10 mL). The combined organic extracts were concentrated in vacuo and purified by acidic prep HPLC (P3). Product containing fractions were concentrated in vacuo and freeze dried to give [(2R)-2-[(1R) -1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[9-(1H-imidazol-2- yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone (Compound 4886-0959-3510.19-1) (13 mg, 14% yield) as a white solid. RT (M4) = 2.1 min [M+H]+(ESI+) 503.3;1H NMR (500 MHz, DMSO) ^ 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 = 6.4 Hz, 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 = 6.3 Hz, 3H).

[0341] The following analog was made by analogous method: Structure Name LCMS (2R)-1-[9-(1H-imidazol-2-yl)-8- methoxy-1-(2-thienyl)-5,6- RT (M4) = 2.15 dihydropyrrolo[2,1-a]isoquinoline-3- min [M+H]+carbonyl]-2-methyl-pyrrolidine-2- (ESI+) 484.3 Compound 9-2 carbonitrile

[0342] Synthetic Method 10

[0343] Scheme for Method 10

[0344] Step 1, Method 10

[0345] 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-methyl-pyrrolidine-2-carbonitrile (300 f`, 604 ^fhe, lrgma^lbzed by method 6), ia^gre _hkfZm^ (340 ^I, 3.0 ffhe, CAS 1864-94- 4886-0959-3510.14) and mkb^mareZfbg^ (420 ^I, 3.0 ffhe, @>P 121-44-8) in anhydrous DMF (5 mL) was degassed with nitrogen for 5 min. X1,1^-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 f`, 60 ^fhe, @>P 72287-26-4) was added, the solution degassed with nitrogen for 5 min and heated to 100 °C for 4 h. The reaction mixture was cooled to rt, the CO released slowly and then purged with nitrogen. The mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic extracts were concentrated in vacuo to afford a residue that was purified by FCC (silica, eluting with 0-100% EtOAc in heptane) to give phenyl 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxylate (280 mg, 78% yield) as a brown solid. RT (M2) = 1.05 min, (ESI+) (M+H)+538.2;1H NMR (500 MHz, DMSO-d6) f 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 = 6.7 Hz, 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).

[0346] Step 2, Method 10

[0347] 2 M lithium hydroxide ...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (A)or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 13 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; or (ii) Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)-NR5aR5b; phenyl; C4-C6cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected -0959-3510.1from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl; X is CR20or N; R20is selected from H, halogen, nitrile, C1-C6alkyl, and C1-C6haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the -0959-3510.1heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

2. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR20.

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

4. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R1is -NRfRg, wherein: (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; or -0959-3510.1(ii) Rfis C1-C6alkyl; and Rgis C1-C6alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile.

5. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

6. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 5-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

7. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, - NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl. -0959-3510.

18. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl.

9. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1is -NRfRg, wherein Rfis C1-C6 alkyl; and Rgis C1-C6 alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile.

10. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is C1-C6 alkyl or C1-C6 alkenyl.

11. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is C1-C6haloalkyl.

12. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is C1-C6hydroxyalkyl.

13. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is phenyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1- C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl.

14. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is 4-fluorophenyl. -0959-3510.

115. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is C4-C6 cycloalkyl optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl.

16. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl.

17. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R2is 3,3-difluorocyclobutyl, 5-fluoropyridin-2-yl, 2- thiophenyl, 5-thiazolyl, or 1,3,4-thiadiazolyl.

18. A compound of Formula (B)Formula (B) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms -0959-3510.1to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; Het is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and -0959-3510.1(iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

19. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 18, wherein Het is a 5-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl.

20. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 18, wherein Het is a 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, optionally substituted with 1 to 4 R5groups independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and each R5aand R5bis independently selected from H and C1-C3 alkyl.

21. A compound of Formula (C) -0959-3510.1Formula (C) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3 alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring , wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or -0959-3510.1partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

22. A compound of Formula (D) -0959-3510.1Formula (D) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1- C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; m is 0, 1, 2, 3, or 4; each R5is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1- C3alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein -0959-3510.1n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, , and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

23. A compound of Formula (E) -0959-3510.1Formula (E) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein R1is substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R3is selected from |C(O)NHR6, -SO2-(C1-C3 alkyl), -SO2-(C3-C6 cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; Alk is C1-C6 alkyl or C1-C6 alkenyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3 alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or -0959-3510.1partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

24. A compound of Formula (F) Formula (F)-0959-3510.1or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein (i) Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6-membered ring; and each R4aand R4bis independently selected from C1- C3alkyl; or (i) Rfis C1-C6alkyl; and Rgis C1-C6alkyl substituted with 1 to 4 R4cgroups, wherein each R4cgroup is independently selected from halogen, hydroxy, and nitrile; R2is selected from C1-C6 alkyl; C1-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; -(C1-C3 alkyl)-SO2CH3; -(C1-C6 alkyl)-O-(C1-C6 alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6 alkyl)-NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, 5- to 6-membered heterocycloalkyl ring, and 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heterocycloalkyl ring and the 5- to 6-membered heteroaryl ring contain 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, the 5- to 6-membered heterocycloalkyl ring, and the 5- to 6-membered heteroaryl -0959-3510.1ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected -0959-3510.1from H, C1-C6alkyl, and C1-C6haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

25. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, 6, 7, and 10 to 24 and , wherein R1is, wherein each R4is independently selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen.

26. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, 6, 7, and 10 to 24, wherein R1is, wherein R4bis C1-C6alkyl and R4ais selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6cycloalkyl, hydroxy, and halogen.

27. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, 6, 7 and 10 to 24, wherein R1is, wherein R4ais C1-C6 alkyl and R4bis selected from nitrile and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen.

28. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3is a 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2. -0959-3510.

129. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3is 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered heteroaryl ring contains 1 to 4 ring nitrogens, and wherein the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2.

30. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3is tetrazole, pyrazole, imidazole, oxazole, or pyridine, wherein R3may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3alkyl, C1-C3haloalkyl, and -C(O)NH2; optionally wherein R3is tetrazole optionally substituted with C1-C3alkyl.

31. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R3is -C(O)NHR6.

32. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6is -(CR7R8)nC(O)NRdRe.

33. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 32, wherein each of R7and R8is independently selected from H and C1-C3 alkyl.

34. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 32, wherein R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen.

35. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6is C1-C6alkyl optionally substituted with nitrile or 5- or 6- membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy. -0959-3510.

136. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6is C1-C6 alkyl optionally substituted with nitrile or tetrazole.

37. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6is phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3 alkoxy optionally substituted with 1 to 7 independently selected halogens.

38. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 31, wherein R6is cyclopropane optionally substituted with nitrile or is cyclobutane optionally substituted with nitrile.

39. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl.

40. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl.

41. > \hfihng] h_ ChkfneZ (F^)ChkfneZ (F^) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, -0959-3510.1wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 4 R4groups, wherein each R4group is independently selected from halogen, hydroxy, nitrile, -NR4aR4b, -SR4a, -S(O)2R4a, and C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl, hydroxy, and halogen; optionally wherein 2 R4groups, together with the atoms to which they are attached, form a 4- to 6- membered ring; and each R4aand R4bis independently selected from C1-C3alkyl; R2is selected from C1-C6alkyl; C1-C6haloalkyl; C1-C6hydroxyalkyl; -(C1-C3alkyl)-SO2CH3; -(C1-C6alkyl)-O-(C1-C6alkyl) optionally substituted with 1 to 13 halogens; -(C1-C6alkyl)- NR5aR5b; phenyl; C4-C6 cycloalkyl; and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl, C4-C6 cycloalkyl, and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 4 R5groups, wherein each R5group is independently selected from halogen, nitrile, -C(O)NR5aR5b, C1-C3alkyl, C1-C3haloalkyl, and C1-C3alkoxy; and each R5aand R5bis independently selected from H and C1-C3alkyl; R20is selected from H, halogen, nitrile, C1-C6alkyl, and C1-C6haloalkyl; R3is selected from -C(O)NHR6, -SO2-(C1-C3alkyl), -SO2-(C3-C6cycloalkyl), phenyl, and 5- to 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and -C(O)NH2; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; -0959-3510.1each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6 alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from oxo, halogen, hydroxy, nitrile, C1-C3 alkyl optionally substituted with 1 to 7 independently selected halogens, and C1-C3alkoxy optionally substituted with 1 to 7 independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or R11and R12together form a double bond, and R10and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

42. A compound of Formula (I) -0959-3510.1Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is -NRfRg, wherein Rfand Rgtogether with the nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally containing 1 additional ring heteroatom selected from oxygen, sulfur and nitrogen, and substituted with 1 to 3 R4groups, wherein each R4group is independently selected from nitrile and C1-C6alkyl optionally substituted with 1 to 4 substituents independently selected from hydroxy and halogen; R2is selected from C1-C6alkyl; C1-C6haloalkyl; phenyl; and 5- to 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the phenyl and the 5- to 6-membered heteroaryl ring may be optionally substituted with 1 or 2 R5groups, wherein each R5group is independently selected from halogen, nitrile, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R3is selected from |C(O)NHR6and 5- to 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the 5- to 6- membered heteroaryl ring may be optionally substituted with 1 to 3 substituents independently selected from hydroxy, nitrile, and C1-C3alkyl; R6is selected from: (i) -(CR7R8)nC(O)NRdRe, wherein n is 1 or 2; each of R7and R8is independently selected from H and C1-C3alkyl, or R7and R8together with the carbon to which they are attached form a 3- to 6-membered saturated or -0959-3510.1partially unsaturated ring optionally containing a ring heteroatom selected from oxygen, sulfur, and nitrogen; each of Rdand Reis independently selected from H and C1-C3 alkyl; (ii) C1-C6alkyl optionally substituted with nitrile or 5- or 6-membered heteroaryl ring containing 1 to 4 ring heteroatoms independently selected from oxygen and nitrogen, wherein the ring may be optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, and hydroxy; and (iii) phenyl, 3- to 6-membered saturated or partially unsaturated ring, or 5- to 6-membered heteroaryl ring, wherein the saturated or partially unsaturated ring optionally contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the heteroaryl ring contains 1 or 2 ring heteroatoms independently selected from oxygen, sulfur, and nitrogen, and wherein the phenyl, saturated or partially unsaturated ring, and heteroaryl ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, nitrile, and C1-C3 alkyl optionally substituted with one or more independently selected halogens; and each of R10, R11, R12, and R13are independently selected from H, C1-C6 alkyl, and C1-C6 haloalkyl; or any two of R10, R11, R12, and R13, together with the carbon atom(s) to which they are attached, form a 3- to 6-membered ring, and the remaining two are independently selected from H, C1-C6alkyl, and C1-C6haloalkyl, wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).

43. A compound selected from the group consisting of: [8-methoxy-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2-methyl-2- [(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl]methanone; (1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)methanone; -0959-3510.1(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-dihydropyridin-3-yl)-1-(2,2,2-triflu oroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide; (3S)-4-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-3- methyl-morpholine-3-carbonitrile; (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; (R)-1-(1-(1-hydroxy-2-methylpropan-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile; (R)-1-(1-(2,2-difluoropropyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; (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-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; (2R)-1-[8-methoxy-9-oxazol-2-yl-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2-methyl- pyrrolidine-2-carbonitrile; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl]-6-methyl-1H-pyridin-2-one; (2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-oxazol-2-yl-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; 3-[3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1- a]isoquinolin-9-yl]pyridine-2-carbonitrile; 3-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl]pyridine-2-carbonitrile; -0959-3510.1[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-methyl-2- [(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; (2R)-1-[9-(1H-imidazol-2-yl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile; (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile; [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]- [(2S)-2-methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; [(5R)-8-methoxy-5-methyl-9-(2-methyltetrazol-5-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]- [(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; (2R)-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-9-yl)-5-(trifluoromethyl)picolinonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)methanone; (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; -0959-3510.1(R)-1-(1-(5-fluoropyridin-2-yl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylpyrrolidine-2-carbonitrile; ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-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-dihydropyrrolo[2,1-a]isoquinolin-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-dihy dropyrrolo[2,1-a]isoquinolin-9-yl)picolinonitrile; ((R)-8-methoxy-5-methyl-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)methanone; ((1aR,9bR)-8-methoxy-7-(2-methyl-2H-tetrazol-5-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H- cyclopropa[c]pyrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1- yl)methanone; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-thiazol-5-yl-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; [8-methoxy-9-(2-methyltetrazol-5-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2-methyl-2- [(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; (2R)-1-[8-methoxy-9-(1H-pyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; (2R)-1-[1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile; (2R)-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl]-1-methyl-pyridin-2-one; -0959-3510.1[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1H-pyrazol-3-yl)-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-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- dihydropyrrolo[2,1-a]isoquinolin-9-yl]-1H-pyridin-2-one; 4-[3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-9-yl]-1-methyl-pyridin-2-one; 3-[3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2,2,2-trifluoroethyl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-9-yl]pyridine-2-carbonitrile; [(5R)-8-methoxy-5-methyl-9-(1-methylpyrazol-3-yl)-1-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]- [(2R)-2-methyl-2-[(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl)-2-methylazetidine-2-carbonitrile; (R)-1-(8-methoxy-6-methyl-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2-carbonitrile; ((R)-8-methoxy-5-methyl-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)methanone; ((R)-2-((R)-1-hydroxyethyl)-2-methylpyrrolidin-1-yl)((S)-8-methoxy-5-methyl-9-(1-methyl-1H-pyrazol-3-yl)-1- (thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)methanone ((1aR,9bR)-8-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-2-yl)-1a,9b-dihydro-1H- cyclopropa[c]pyrrolo[2,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1- yl)methanone; (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3- yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)methanone; [(2R)-2-[(1R) -1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[9-(1H-imidazol-2-yl)-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; (2R)-1-[9-(1H-imidazol-2-yl)-8-methoxy-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl]-2- methyl-pyrrolidine-2-carbonitrile; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; -0959-3510.1N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl- 5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2R)-2-(hydroxymethyl)-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1- (2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-(2,2-dimethylpyrrolidine-1-carbonyl)-8-methoxy-N-(1H-tetrazol-5-ylmethyl)-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)-1-(2-thienyl)-5,6- dihydropyrrolo[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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; -0959-3510.1N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-1-(4-fluorophenyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8- methoxy-5,6-dihydropyrrolo[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-dihydropyrrolo[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-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclopropyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[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-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-1-(4-fluorophenyl)-8-methoxy-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(3-cyanooxetan-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-cyanooxetan-3-yl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2- thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyano-1-methyl-ethyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-N-[(3S)-3-cyanotetrahydrofuran-3-yl]-8-methoxy-1-(2-thienyl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; -0959-3510.13-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-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-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-3-yl)-8-methoxy-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-N-(3-cyanooxetan-3-yl)-8-methoxy-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; N-(1-cyanocyclobutyl)-3-[(2R)-2-cyano-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazol-5-yl-5,6- dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-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-dihydropyridin-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-hydroxy ethyl) pyrrolidine-1- carbonyl)-1-(1,3,4-thiadiazol-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-dihydropyrrolo[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-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; -0959-3510.1(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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-(2-thienyl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; [(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; [8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2-methyl-2- [(1S)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; [(2R)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2- methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2- [(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R)-2- [(1R)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(1-methylpyrazol-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2- [(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone; [(2S)-2-[(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2- methyl-2-[(1R)-2,2,2-trifluoro-1-hydroxy-ethyl]pyrrolidin-1-yl]methanone; -0959-3510.1[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2-[1- hydroxypropyl]-2-methyl-pyrrolidin-1-yl]methanone; [1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2S)-2- [(1S)-1-hydroxyethyl]-2-methyl-pyrrolidin-1-yl]methanone; 2-cyclopropyl(hydroxy)methyl)-2-methylpyrrolidin-1-yl)(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol- 5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-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-methyl-pyrrolidine-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-methyl-pyrrolidine-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-methyl-pyrrolidine-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-methyl-pyrrolidine-1-carbonyl]-8-methoxy-N-(2-oxo-1H-pyridin-3-yl)-1-(2,2,2-trifluoroethyl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 3-[(2R)-2-cyano-2-methyl-pyrrolidine-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-methyl-pyrrolidine-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-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl]-[(2R or S)- 4,4-difluoro-2-methyl-2-[(1R or S)-1-hydroxyethyl]pyrrolidin-1-yl]methanone; N-(1-cyanocyclobutyl)-3-[(2R)-2-[(1R)-1-hydroxyethyl]-2-methyl-pyrrolidine-1-carbonyl]-8-methoxy-1-thiazol-5- yl-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-thiazol-5-yl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9-carboxamide; 2-ethyl-1-[8-methoxy-9-(1-methylpyrazol-3-yl)-1-(2-thienyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]pyrrolidine-2-carbonitrile; -0959-3510.1rel-(2R,3S)-3-hydroxy-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile; rel-(2R,3S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-3-hydroxy-2-methyl-pyrrolidine-2-carbonitrile; 2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2- azabicyclo[4.2.0]octane-1-carbonitrile; (1S,5S)-2-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)- 5-methyl-2-azabicyclo[3.2.0]heptane-1-carbonitrile; (2R,4S)-4-hydroxy-1-[8-methoxy-9-(2-methyltetrazol-5-yl)-1-propyl-5,6-dihydropyrro-lo[2,1-a]isoquinoline-3- carbonyl]-2-methyl-pyrrolidine-2-carbonitrile; and (2R,4S)-1-[1-(4-fluorophenyl)-8-methoxy-9-(2-methyltetrazol-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carbonyl]-4-hydroxy-2-methyl-pyrrolidine-2-carbonitrile; (2R,4S)-4-hydroxy-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen- 2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine- 2-carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; -0959-3510.1(S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline-3- carboxamide; (2R,4S)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-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-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl) methanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(1-methyl-2- oxo-1,2-dihydropyridin-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1- a]isoquinoline-9-carboxamide; -0959-3510.1(R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-8-methoxy-N-(2-oxo-1,2- dihydropyridin-3-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[5,1- a]isoquinoline-9-carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; ((S)-2-((R)-1,2-dihydroxy-2-methylpropyl)-2-methylpyrrolidin-1-yl)(1-(4- fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo- 1,2-dihydropyridin-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- dihydropyridin-3-yl)-1-propyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-9- carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydroimidazo[5,1- a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; -0959-3510.1(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6-dihydroimidazo[5,1- a]isoquinolin-3-yl) ((R)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-1-isobutyl-8-methoxy-N-(2- oxo-1,2-dihydropyridin-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-dihydropyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline- 9-carboxamide; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (R)-3-(2-cyano-2-methylazetidine-1-carbonyl)-8-methoxy-N-(1-methyl-2-oxo- 1,2-dihydropyridin-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-pyrazol-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (R)-3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8- methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-9-carboxamide; -0959-3510.1(1-(3,5-difluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; {(S)-2-[(S)-3,3,3-trifluoro-1-hydroxypropyl]-2-methyl-1-pyrrolidinyl}{11- methoxy-12-(2-methyl-2H-tetraazol-5-yl)-3-(2-thienyl)-6- ZsZmkb\r\ehX7.4.0.0^,êYmkb]^\Z-1(13),2,4,9,11-pentaen-5-yl}methanone; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-2-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (S)-3-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-propyl-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1-(8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; -0959-3510.1(R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)- 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (S)-3-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2,2,2-trifluoroethyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-4-methyloxazolidine-4- carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(1-methyl-1H-pyrazol-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; (R)-3-(3-(2-cyano-2-methylpyrrolidine-1-carbonyl)-1-(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)picolinonitrile; (R)-3-(3-(2-cyano-2-methylazetidine-1-carbonyl)-1-(4-fluorophenyl)-8- methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)picolinonitrile; (R)-1-(9-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-8-methoxy-1-(thiophen-2-yl)- 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; -0959-3510.1(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-dihydropyridin- 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]isoquinolin-9-yl)picolinonitrile; (8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (2R,4S)-4-hydroxy-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-8-methoxy-N-methyl-9-(2-methyl- 2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(2,2-diflu oropropyl)-8-methoxy- N-methyl-9-(2-methyl-2H-tetrazol-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-tetrazol-5-yl)-1-(1,3,4-thiadiazol-2-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide; (S)-N-(2-cyano-4,4,4-trifluorobutan-2-yl)-1-(5-fluoropyridin-2-yl)-8-methoxy- N-methyl-9-(2-methyl-2H-1,2,3-triazol-4-yl)-5,6-dihydropyrrolo[2,1- a]isoquinoline-3-carboxamide; -0959-3510.1((R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylprop-1-en-1-yl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (R)-1-(1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (R)-1-(1-(3,3-difluorocyclobutyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)- 5,6-dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-2-methylpyrrolidine-2- carbonitrile; (1-isobutyl-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6-dihydropyrrolo[2,1- a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (1-(tert-butyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydropyrrolo[2,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-3,3,3-trifluoro-1- hydroxypropyl)pyrrolidin-1-yl)methanone; (1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-3-yl)((S)-2-methyl-2-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyrrolidin-1-yl)methanone; (2R,4S)-1-(1-(4-fluorophenyl)-8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-5,6- dihydroimidazo[5,1-a]isoquinoline-3-carbonyl)-4-hydroxy-2- methylpyrrolidine-2-carbonitrile; -0959-3510.1(R)-1-(8-methoxy-9-(2-methyl-2H-tetrazol-5-yl)-1-(2-methylallyl)-5,6- dihydropyrrolo[2,1-a]isoquinoline-3-carbonyl)-2-methylazetidine-2- carbonitrile; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

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

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

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

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

49. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, for use in in treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is a fertility disorder. -0959-3510.

150. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, in the preparation of a medicament for modulating follicle-stimulating hormone receptor (FSHR) activity in a subject.

51. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-43, or a composition of claim 44, in the preparation of a medicament for treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is a fertility disorder.

52. The method of claim 47, the compound for use of claim 49, or the use of claim 51, wherein the disease or disorder is selected from hypogonadotropic hypogonadism, isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, craniopharyngiomas, combined pituitary hormone deficiency, fertile eunuch syndrome, abnormal beta subunit of LH, abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), infiltrative lesions, hemochromatosis, sarcoidosis, histiocytosis, lymphoma, lymphocytic hypophysitis, meningitis, pituitary apoplexy, hyperprolactinemia, hypothyroidism, intentional (iatrogenic) secondary hypogonadism, empty sella, pituitary infarction, Sheehan syndrome, anorexia nervosa, congenital adrenal hyperplasia, and disorders related to GnRH deficiency. -0959-3510.1

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