EA038160B1 - Estrogen receptor modulators - Google Patents

Abstract

The invention relates to compounds of Formula (I)and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cell proliferative disorders.

Description

This description relates to certain indole compounds and their pharmaceutically acceptable salts, which selectively inhibit the function of the estrogen receptor and have anti-cancer activity. This disclosure also relates to the use of said indole compounds and their pharmaceutically acceptable salts in methods of treating a human or animal body, for example, in the prevention or treatment of cancer. This description also relates to the methods and intermediates involved in the preparation of these indole compounds, and to pharmaceutical compositions containing them.

Estrogen receptor alpha (ERa, ESR1, NR3A) and estrogen receptor beta (ERp, ESR2, NR3b) are steroid hormone receptors that are members of a large family of nuclear receptors. Organized similarly to all nuclear receptors, ERa consists of six functional domains (named A to F) (Dahlman-Wright, et al., Pharmacol. Rev .. 2006, 58: 773-781), and it is classified as a ligand-dependent factor transcription, because after binding to a specific ligand (female sex steroid hormone, which is 17b estradnol (E2)), the complex binds to genomic sequences called estrogen receptor elements (ERE) and interacts with coregulators to modulate the transcription of target genes. The ERa gene is located at 6q25.1 and encodes the 595AA protein, and multiple isoforms can be generated by alternative splicing and translation initiation sites. In addition to the DNA-binding domain (domain C) and the ligand-binding domain (domain E), the receptor contains an N-terminal domain (A / B), a hinge domain (D) that connects domains C and E, and a C-terminal extension (domain F). While domains C and E from ERa and ERe are fairly conserved (96 and 55% amino acid sequence identity, respectively), conservatism of domains A / B, D, and F is low (less than 30% amino acid sequence identity). Both receptors are involved in the regulation and development of the female reproductive tract and, in addition, have functions in the central nervous system, cardiovascular system and in bone metabolism. Genomic ER action occurs in the cell nucleus when the receptor binds to the ERE directly (direct activation or classical pathway) or indirectly (indirect activation or nonclassical pathway). In the absence of a ligand, ERs bind to heat shock proteins, Hsp90 and Hsp70, and the associated chaperone mechanism stabilizes the ligand binding domain (LBD), making it accessible to the ligand. The ligand-attached ER is detached from the heat shock proteins, resulting in a conformational change in the receptor that allows dimerization, DNA binding, interaction with coactivators or corepressors, and modulation of target gene expression. In the nonclassical pathway, AP-1 and Sp-1 are alternative DNA regulatory sequences used by both isoforms of the receptor to modulate gene expression. In this example, ER does not interact with DNA directly, but through binding to other transcription factors associated with DNA, for example c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry 2003, 75: 1757-1769). The exact mechanism by which ER affects gene transcription is poorly understood, but appears to be mediated by numerous nuclear factors that are recruited by a DNA-bound receptor. The recruitment of coregulators is mainly mediated by two protein surfaces, AF2 and AF1, which are located in the E-domain and A / B-domain, respectively. AF1 is regulated by growth factors, and its activity depends on the cell environment and promoter, while AF2 activity is completely dependent on ligand binding. Although the two domains can act independently, maximum ER transcriptional activity is achieved through synergistic interactions through the two domains (Tzukerman, et al., Mol. Endocrinology. 1994, 8: 21-30). Although ERs are considered transcription factors, they can also act through non-genomic mechanisms, as evidenced by the rapid effects of ER in tissues following E2 administration at times considered too short for genomic action. It is still unclear whether the receptors responsible for the rapid action of estrogen are the same nuclear ER or other steroid receptors associated with the G-protein (Warner, et al., Steroids 2006 71: 91-95), however, a growing number of pathways induced by E2, eg the MAPK / ERK pathway and activation of endothelial nitric oxide synthase, and the PI3K / Akt pathway. In addition to ligand-dependent pathways, ERa has been shown to have ligand-independent activity mediated by AF-1, which is associated with stimulation of MAPK by mediated growth factor signaling, for example, insulin-like growth factor 1 (IGF-1) and epidermal growth factor ( EGF). AF-1 activity depends on Ser118 phosphorylation, and an example of cross-interactions between ER and growth factor-mediated signaling is the phosphorylation of Ser 118 by MAPK in response to growth factors such as IGF-1 and EGF (Kato, et al., Science. 1995,270: 1491-1494).

It has been shown that a large number of structurally different compounds bind to ER. Some compounds, such as the endogenous E2 ligand, act as receptor agonists, while others competitively inhibit E2 binding and act as receptor antagonists. Such compounds can be divided into 2 classes depending on their functional effects. Selective estrogen receptor modulators (SERMs) such as tamoxifen are characterized by the ability to act as

- 1 038160 as agonists and antagonists of the receptor, depending on the environment of the cell and the promoter, as well as on the target ER isoform. For example, tamoxifen acts as an antagonist in breast tissue, but acts as a partial agonist in bone, cardiovascular system, and uterus. All SERMs appear to act as AF2 antagonists and gain their partial agonist properties via AF1. Members of the second group, of which the fulvestrant is an example, are classified as complete antagonists and are capable of blocking estrogen activity by completely inhibiting the AF1 and AF2 domains by inducing a unique change in the conformation of the ligand binding domain (LBD) upon binding to the compound, which leads to the complete elimination of the interaction between helix 12 and the rest of the LBD, blocking cofactor recruiting (Wakeling, et al., Cancer Res .. 1991, 51: 3867-3873; Pike, et al., Structure. 2001, 9: 145-153).

In the presence of E2, intracellular ERa levels are reduced via the ubiquitin / proteasome (Ub / 26S) pathway. The ligand-attached polyubiquitinylation of ERa is catalyzed by at least three enzymes; ubiquitin activated by the ubiquitin-activating enzyme E1 is conjugated by E2 to lysine residues via an isopeptide bond via E3, which is an ubiquitin ligase, and the polyubiquitinylated ERa is then directed to the proteasome for cleavage. Although the regulation of ER-dependent transcription and proteasome-mediated cleavage of the ER are associated (Lonard, et al., Mol. Cell. 2000 5: 939-948), transcription itself is not required to cleave ERa, and the assembly of the transcription initiation complex is sufficient to to target ERa for cleavage by nuclear proteasomes. This E2-induced cleavage process is believed to be necessary to ensure its ability to rapidly activate transcription in response to the need for cell proliferation, differentiation and metabolism (Stenoien, et al., Mol. CellBiol .. 2001, 21: 4404-4412). Fulvestrant is also classified as selective estrogen receptor suppressor (SERD), a subclass of antagonists that can also induce rapid suppression of ERa along the 26S proteasome pathway. In contrast, SERMs such as tamoxifen can increase ERa levels, although the effect on transcription is similar to that observed with SERDs.

Approximately 70% of breast cancers are characterized by the expression of ER and / or progesterone receptors, indicating that the growth of such tumor cells is hormone dependent. It is believed that in the case of other cancers such as ovarian and endometrial cancers, growth also depends on ERa-mediated signaling. In these patients, therapies can suppress ER-mediated signaling either by antagonizing ligand binding to the ER, such as tamoxifen, which is used to treat early and advanced ER-positive breast cancer in both pre- and post-menopausal regimens; either by antagonizing and suppressing ERa, for example, fulvestrant, which is used to treat breast cancer in women that has progressed despite therapy with tamoxifen or aromatase inhibitors; or by blocking estrogen synthesis, such as aromatase inhibitors, which are used to treat early and advanced ER-positive breast cancer. Although these treatments have had an extremely positive impact on breast cancer treatment, a significant number of patients with ER-expressing tumors show resistance to existing de novo ER-based therapies or develop resistance to these treatments over time. Several different mechanisms have been described to explain the emergence of tamoxifen resistance in primary treatment, which mainly involve switching tamoxifen from acting as an antagonist to acting as an agonist, or through the lower affinity of some cofactors that bind to the tamoxifen-ERa complex, which is shifted due to overexpression of these cofactors, or through the formation of secondary sites that facilitate the interaction of the tamoxifen-ERa complex with cofactors that do not normally bind to the complex. Therefore, resistance may result from the proliferation of cells expressing specific cofactors that stimulate the activity of the tamoxifen-ERa complex. It is also possible that other growth factor mediated signaling pathways directly activate the ER receptor or coactivators to stimulate cell proliferation independently of ligand mediated signaling.

More recently, mutations in ESR1 have been identified as a possible resistance mechanism in tumor samples from patients with metastatic ER-positive cancer and in patient-derived xenograft (PDX) models, with frequency values ranging from 17-25%. Such mutations are predominantly, but not exclusively, in the ligand-binding domain, resulting in mutant functional proteins; examples of amino acid substitutions include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn, and Asp538Gly, with substitutions at amino acids 537 and 538 accounting for most of the substitutions currently described. Such mutations have not previously been found in genomes from primary breast cancer specimens described in the Cancer Genome Atlas database. Of 390 ER-positive primary breast cancer specimens, no mutation was found in

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ESR1 (Cancer Genome Atlas Network, 2012 Nature 490: 61-70). The mutations in the ligand-binding domain are believed to have emerged as a resistance response to aromatase inhibitor endocrine therapies, since in the absence of estradiol such mutant receptors exhibit basal transcriptional activity. The crystal structure of the ER mutated at amino acids 537 and 538 demonstrates that both mutations promoted agonist-binding ER conformation by shifting the position of helix 12 to allow for the recruitment of the coactivator and thus mimic the agonist-activated wild-type ER. Published data have demonstrated that endocrine therapies such as tamoxifen and fulvestrant can still bind to the mutant ER and inhibit transcriptional activation to some extent, and that fulvestrant is capable of cleaving the Try537Ser receptor, but more high doses (Toy et al., Nat. Genetics 2013 45: 1439-1445; Robinson et al .. Nat. Genetics 2013 45: 144601451; Li, S. et al. Cell Rep. 4.116-1130 (2013 Therefore, it is possible that some of the compounds of formula (I) or their pharmaceutically acceptable salts (described hereinafter) will be capable of suppressing and antagonizing the mutant ER, although it is not known at this stage whether ESR1 mutations are associated with an altered clinical outcome.

Regardless of which resistance mechanism or combination of mechanisms occurs, many of them are still characterized by dependence on the activity mediated by the ER, and removal of the receptor by the SERD-based mechanism is the best way to remove the ERa receptor from the cell. Fulvestrant is currently the only SERD approved for clinical use, however, despite its properties with respect to the mechanism of reaction, the pharmacological properties of the drug limit its effectiveness due to the current dose limitation of 500 mg per month, resulting in a renewal of the receptor is less than 50% in patient samples compared to complete receptor suppression observed in experiments with a breast cell line in vitro (Wardell, et al., Biochem. Pharm .. 2011, 82: 122-130). Therefore, there is a need for new agents that target the ER that have the necessary pharmaceutical properties and a SERD mechanism of action to provide increased therapeutic benefit in early, metastatic cancer and acquired resistance regimens.

Compounds according to the present disclosure have been shown to have potent anti-tumor activity, being useful in suppressing uncontrolled cell proliferation that occurs in cancer. Compounds in accordance with the present disclosure provide an anti-tumor effect by acting as a minimum as a SERD. For example, compounds according to the present disclosure can exhibit antitumor activity due to their ability to suppress estrogen receptor function in a number of different breast cancer cell lines, for example, MCF-7, CAMA-1, BT474 and / or MDA-MB breast cancer cell lines. -134. Such compounds can be expected to be more useful as therapeutic agents, in particular for the treatment of cancer.

Compounds in accordance with the present disclosure may also exhibit advantageous physical properties (e.g., lower lipophilicity, higher water solubility, higher permeability, lower plasma protein binding and / or greater chemical stability), and / or favorable profiles toxicity (eg, decreased activity against hERG), and / or favorable metabolic or pharmacokinetic profiles, compared to other known SERDs. Therefore, such compounds may be particularly useful as therapeutic agents, in particular for the treatment of cancer.

In accordance with one aspect of the present disclosure, there is provided a compound of formula (I) wherein

A represents CR ¹¹ or N;

G is CR ¹² or N;

D represents CR ¹³ or N;

E is CR ¹⁴ or N;

J is CR ¹⁹ or N;

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Q is O, NH or NMe;

R ¹ is CH2F, CHF2 or CF3;

R2 is H, Me, CH2F, CHF2 or CF3;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH2F, CHF2, CF3, CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH2F, CHF2, CF3, CN, CH2CN, CH ₂ OMe, CH2OH, COOH, or CH ₂ SO ₂ Me;

R ⁶ represents H, Me, F, CH2F, CHF2, CF3, CN, CH2CN, CH ₂ OMe, CH2OH, COOH or SO2Me;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or oxetane ring;

R ⁹ is H, Me, CH2OH, CH ₂ OMe, or F;

R ¹⁰ represents H, Me, CH2OH, CH ₂ OMe, or F;

R ¹¹ is H, F, Cl, CN, C _1-3 alkyl, or O-C _1-3 alkyl (wherein said C _1-3 alkyl groups are optionally substituted with an additional group selected from OMe, OH, F and CN);

R ¹² is H, F, Cl, CN, Me, OMe, or CHF2;

R ¹³ represents H, F, Cl, CN, Me or OMe;

R ¹⁴ represents H, F, Cl, CN, Me or OMe;

R ¹⁵ represents H, F, O or Me;

R ¹⁷ represents H, F, O or Me;

R ¹⁸ represents H, F, O or Me;

R ¹⁹ is H or F and

R ²⁰ represents H or Me;

or a pharmaceutically acceptable salt thereof.

Also described herein are pharmaceutical compositions which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.

The present description also describes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

The present description also describes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

Also described herein are combinations of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with another anticancer agent for use in the treatment of cancer.

Additional aspects of the present description will become apparent to a person skilled in the art upon reading this description.

In one embodiment, there is provided a compound of formula (I) as defined above.

In one embodiment, a pharmaceutically acceptable salt of a compound of formula (I) is provided.

In one embodiment, D is CH.

In one embodiment, E is CH.

In one embodiment, both D and E are CH.

In one embodiment, both D and E are N.

In one embodiment, one of D or E is CH and the other of D or E is N.

In one embodiment, A is CR ¹¹ .

In one embodiment, G is CR ¹²

In one embodiment, A is CR ¹¹ and G is CR ¹² .

In one embodiment, A is CR ¹¹ and G is CH.

In one embodiment, A is CH and G is CR ¹² .

In one embodiment, A is CR ¹¹ and all of D, E, and G are CH.

In one embodiment, R ^{11 is} independently selected from Me, Cl, F, or OMe.

In one embodiment, R ^{11 is} independently selected from H, F, CN, or OMe.

In one embodiment, R ^{11 is} independently selected from H or OMe.

In one embodiment, R ^{11 is} independently selected from H or F.

In one embodiment, R ^{11 is} independently selected from F, C1, or OMe.

In one embodiment, R ¹¹ is H.

In one embodiment, R ¹¹ is OMe.

In one embodiment, R ¹¹ is F.

In one embodiment, R ¹¹ is Me.

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In one embodiment, R ¹¹ is Cl.

In one embodiment, R ^{12 is} independently selected from Me, Cl, F, or CHF ₂ .

In one embodiment, R ^{12 is} independently selected from H, F, CN, or OMe.

In one embodiment, R ^{12 is} independently selected from H or OMe.

In one embodiment, R ^{12 is} independently selected from H or F.

In one embodiment, R ^{12 is} independently selected from H, Me, or F.

In one embodiment, R ¹² is H.

In one embodiment, R ¹² is OMe.

In one embodiment, R ¹² is Me.

In one embodiment, R ¹² is F.

In one embodiment, A is CR ¹¹ and R ¹¹ is H, F, CN, or OMe.

In one embodiment, G is CR ¹² and R ¹² is H, F, CN, or OMe.

In one embodiment, A is CR ¹¹ and R ¹¹ is O, F, or OMe.

In one embodiment, G is CR ¹² and R ¹² is H, Me, or F.

In one embodiment, A is CH and G is CH.

In one embodiment, A is C-F and G is C-F.

In one embodiment, A is C-F and G is CH.

In one embodiment, A is C-OMe and G is CH.

In one embodiment, A is CH and G is C-OMe.

In one embodiment, A is C-F and G is C-Me.

In one embodiment, A is C-Ci and G is C-F.

In one embodiment, Q is O or NH.

In one embodiment, Q is O.

In one embodiment, Q is NH.

In one embodiment, Q is NMe.

In one embodiment, R ¹ is CH ₂ F or CHF ₂ .

In one embodiment, R ¹ is CH ₂ F.

In one embodiment, R ¹ is CHF ₂ .

In one embodiment, R ¹ is CF3.

In one embodiment, R ² is H or Me.

In one embodiment, R ² is H.

In one embodiment, R ² is Me.

In one embodiment, R ³ is H.

In one embodiment, R ³ is Me.

In one embodiment, R ⁴ is C _1-3 alkyl, CHF 2, or cyclopropyl.

In one embodiment, R ⁴ is C _1-3 alkyl or CHF2.

In one embodiment, R ⁴ is C _1-3 alkyl, CF3, or CHF2.

In one embodiment, R ⁴ is C _1-3 alkyl.

In one embodiment, R ⁴ is Me.

In one embodiment, R ³ is H and R ⁴ is Me.

In one embodiment, R ⁴ is CHF2.

In one embodiment, R ⁴ is CF3.

In one embodiment, R ⁵ is H or Me.

In one embodiment, R ⁵ is H.

In one embodiment, R ⁵ is Me.

In one embodiment, R ⁶ is H, Me, F, CH ₂ F, CH ₂ OMe, CH ₂ OH, COOH, or SO ₂ Me.

In one embodiment, R ⁶ is H, F, or CH ₂ OH.

In one embodiment, R ⁶ is F.

In one embodiment, R ⁶ is CH ₂ OH.

In one embodiment, R ⁶ is COOH.

In one embodiment, R is H.

In one embodiment, R is Me.

In one embodiment, R is F.

In one embodiment, R ⁸ is Me or F.

In one embodiment, R ⁸ is Me.

In one embodiment, R ⁸ is F.

In one embodiment, R ⁸ is H.

In one embodiment, R ⁶ is F or CH ₂ OH and R ⁷ is H.

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In one embodiment, R ⁶ is F or CH2OH and R ⁷ is F.

In one embodiment, R ⁷ is H and R ⁸ is F.

In one embodiment, R ⁷ is F and R ⁸ is F.

In one embodiment, R ⁶ is F and R ⁷ and R ⁸ , taken together with the carbon atom to which they are attached, form a cyclopropyl ring, or a cyclobutyl ring, or an oxetane ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclobutyl ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form an oxetane ring.

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

O

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

F

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected

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In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of the group consisting of he and

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of • it and

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is

In one embodiment, both R ⁹ and R ¹⁰ are H.

In one embodiment, one of R ⁹ and R ¹⁰ is H, the other of R ⁹ and R ¹⁰ is Me, F, CH2OH, or CH2OMe.

In one embodiment, one of R ⁹ and R ¹⁰ is Me, the other of R ⁹ and R ¹⁰ is H.

In one embodiment, J is N.

In one embodiment, J is CR ¹⁹ .

In one embodiment, R ¹⁵ is H, F, or Me.

In one embodiment, R ¹⁵ is F.

In one embodiment, R ¹⁵ is H.

In one embodiment, R ¹⁷ is H or F.

In one embodiment, R ¹⁷ is F.

In one embodiment, R ¹⁷ is H.

In one embodiment, R ¹⁸ is H or F.

In one embodiment, R ¹⁸ is F.

In one embodiment, R ¹⁸ is H.

In one embodiment, R ¹⁹ is H or F.

In one embodiment, R ¹⁹ is F.

In one embodiment, R ¹⁹ is H.

In one embodiment, R ¹⁷ , R ^18, and R ¹⁹ are each H.

In one embodiment, R ²⁰ is H.

In one embodiment, R ²⁰ is Me.

In one embodiment, a compound of formula (I) is provided wherein R ² , R ³ , R ⁹ , R ¹⁰ , R ^17, and R ¹⁸ are each H;

R ¹⁵ represents H or F;

A is CR ¹¹ and R ¹¹ is H, F, CN or OMe;

G is CR ¹² and R ¹² is H, Me or F;

D represents CH;

E is CH or N;

J is CH and the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (I) is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

In a further embodiment of the present disclosure, a compound of Formula (IA) is provided,

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R ¹

(ΙΑ), where

A represents CR ¹¹ or N;

G is CR ¹² or N;

D represents CR ¹³ or N;

E is CR ¹⁴ or N;

J is CR ¹⁹ or N;

Q is O, NH or NMe;

R ¹ represents CH ₂ F, CHF2 or CF ₃ ;

R ² is H, Me, CH ₂ F, CHF _2, or CF ₃ ;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH ₂ F, CHF ₂ , CF ₃ , CN, CH2CN, CH ₂ OMe, CH ₂ OH, COOH, or CH2SO2Me;

R ⁶ is H, Me, F, CH ₂ F, CHF ₂ , CF ₃ , CN, CH2CN, CH ₂ OMe, CH ₂ OH, COOH, or SO2Me;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or oxetane ring;

R ⁹ is H, Me, CH ₂ OH, CH ₂ OMe, or F;

R ¹⁰ represents H, Me, CH ₂ OH, CH ₂ OMe, or F;

R ¹¹ is H, F, O, CN, C _1-3 alkyl, or O-C _1-3 alkyl (wherein said C _1-3 alkyl groups are optionally substituted with an additional group selected from OMe, OH, F and CN);

R ¹² is H, F, Cl, CN, Me, OMe, or CHF ₂ ;

R ¹³ represents H, F, Cl, CN, Me or OMe;

R ¹⁴ represents H, F, Cl, CN, Me or OMe;

R ¹⁵ represents H, F, O or Me;

R ¹⁷ represents H, F, Cl or Me;

R ¹⁸ is H, F, O or Me and

R ¹⁹ represents H or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment, D is CH.

In one embodiment, E is CH.

In one embodiment, both D and E are CH.

In one embodiment, both D and E are N.

In one embodiment, one of D or E is CH and the other of D or E is N.

In one embodiment, A is CR ¹¹ .

In one embodiment, G is CR ¹² .

In one embodiment, A is CR ¹¹ and G is CR ¹² .

In one embodiment, A is CR ¹¹ and G is CH.

In one embodiment, A is CH and G is CR ¹² .

In one embodiment, A is CR ¹¹ and all of D, E, and G are CH.

In one embodiment, R ^{11 is} independently selected from Me, Cl, F, or OMe.

In one embodiment, R ^{11 is} independently selected from H, F, CN, or OMe.

In one embodiment, R ^{11 is} independently selected from H or OMe.

In one embodiment, R ^{11 is} independently selected from H or F.

In one embodiment, R ^{11 is} independently selected from F, Cl, or OMe.

In one embodiment, R ¹¹ is H.

In one embodiment, R ¹¹ is OMe.

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In one embodiment, R ¹¹ is F.

In one embodiment, R ¹¹ is Me.

In one embodiment, R ¹¹ is O.

In one embodiment, R ^{12 is} independently selected from Me, Cl, F, or CHF ₂ .

In one embodiment, R ^{12 is} independently selected from H, F, CN, or OMe.

In one embodiment, R ^{12 is} independently selected from H or OMe.

In one embodiment, R ^{12 is} independently selected from H or F.

In one embodiment, R ^{12 is} independently selected from H, Me, or F.

In one embodiment, R ¹² is H.

In one embodiment, R ¹² is OMe.

In one embodiment, R ¹² is Me.

In one embodiment, R ¹² is F.

In one embodiment, A is CR ¹¹ and R ¹¹ is H, F, CN, or OMe.

In one embodiment, G is CR ¹² and R ¹² is H, F, CN, or OMe.

In one embodiment, A is CR ¹¹ and R ¹¹ is Cl, F, or OMe.

In one embodiment, G is CR ¹² and R ¹² is H, Me, or F.

In one embodiment, A is CH and G is CH.

In one embodiment, A is C-F and G is C-F.

In one embodiment, A is C-F and G is CH.

In one embodiment, A is C-OMe and G is CH.

In one embodiment, A is CH and G is C-OMe.

In one embodiment, A is C-F and G is C-Me.

In one embodiment, A is C-Ci and G is C-F.

In one embodiment, Q is O or NH.

In one embodiment, Q is O.

In one embodiment, Q is NH.

In one embodiment, Q is NMe.

In one embodiment, R ¹ is CH ₂ F or CHF ₂ .

In one embodiment, R ¹ is CH2F.

In one embodiment, R ¹ is CHF2.

In one embodiment, R ¹ is CF3.

In one embodiment, R ² is H or Me.

In one embodiment, R ² is H.

In one embodiment, R ² is Me.

In one embodiment, R ³ is H.

In one embodiment, R ³ is Me.

In one embodiment, R ⁴ is C _1-3 alkyl, CHF 2, or cyclopropyl.

In one embodiment, R ⁴ is C _1-3 alkyl or CHF ₂ .

In one embodiment, R ⁴ is C _1-3 alkyl, CF3, or CHF2.

In one embodiment, R ⁴ is C _1-3 alkyl.

In one embodiment, R ⁴ is Me.

In one embodiment, R ³ is H and R ⁴ is Me.

In one embodiment, R ⁴ is CHF2.

In one embodiment, R ⁴ is CF3.

In one embodiment, R is H or Me.

In one embodiment, R is H.

In one embodiment, R is Me.

In one embodiment, R ⁶ is H, Me, F, CH ₂ F, CH ₂ OMe, CH ₂ OH, COOH, or SO ₂ Me.

In one embodiment, R ⁶ is H, F, or CH ₂ OH.

In one embodiment, R ⁶ is F.

In one embodiment, R ⁶ is CH2OH.

In one embodiment, R ⁶ is COOH.

In one embodiment, R ⁷ is H.

In one embodiment, R ⁷ is Me.

In one embodiment, R ⁷ is F.

In one embodiment, R ⁸ is Me or F.

In one embodiment, R ⁸ is Me.

In one embodiment, R ⁸ is F.

- 9 038160

In one embodiment, R ⁸ is H.

In one embodiment, R ⁶ is F or CH 2 OH and R ⁷ is H.

In one embodiment, R ⁶ is F or CH2OH and R ⁷ is F.

In one embodiment, R ⁷ is H and R ⁸ is F.

In one embodiment, R ⁷ is F and R ⁸ is F.

In one embodiment, R ⁶ is F and R ⁷ and R ⁸ , taken together with the carbon atom to which they are attached, form a cyclopropyl ring, or a cyclobutyl ring, or an oxetane ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclobutyl ring.

In one embodiment, R ⁶ is F, and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form an oxetane ring.

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

O

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of

- 10 038160

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of he and

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is selected from the group consisting of he _and

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IA) is

In one embodiment, both R ⁹ and R ¹⁰ are H. In one embodiment, one of R ⁹ and R ¹⁰ is H, the other of R ⁹ and R ¹⁰ is Me, F, CH2OH, or CH2OMe.

In one embodiment, one of R ⁹ and R ¹⁰ is Me, the other of R ⁹ and R ¹⁰ is H.

In one embodiment, J is N.

In one embodiment, J is CR ¹⁹ .

In one embodiment, R ¹⁵ is H, F, or Me.

In one embodiment, R ¹⁵ is F.

In one embodiment, R ¹⁵ is H.

In one embodiment, R ¹⁷ is H or F.

In one embodiment, R ¹⁷ is F.

In one embodiment, R ¹⁷ is H.

In one embodiment, R ¹⁸ is H or F.

In one embodiment, R ¹⁸ is F.

In one embodiment, R ¹⁸ is H.

In one embodiment, R ¹⁹ is H or F.

In one embodiment, R ¹⁹ is F.

In one embodiment, R ¹⁹ is H.

In one embodiment, R ¹⁷ , R ^18, and R ¹⁹ are each H.

In a further embodiment of the present disclosure, there is provided a compound of formula (IB) wherein

A represents CR ¹¹ or N;

G is CR ¹² or N; D represents CR ¹³ or N;

E is CR ¹⁴ or N;

Q is O, NH or NMe;

R ¹ is CH2F, CHF2 or CF3;

R ² is H, Me, CH2F, CHF2, or CF3;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH2F, CHF2, CF ₃ , CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH2F, CHF2, CF ₃ , CN, CH2CN, CH ₂ OMe, CH2OH, COOH, or

CH2SO2Me;

R ⁶ is H, Me, F, CH2F, CHF2, CF3, CN, CH2CN, CH2OMe, CH2OH, COOH, or

- 11 038160

SO ₂ Me;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring;

R ⁹ is H, Me, CH2OH, CH2OMe, or F;

R ¹⁰ is H, Me, CH2OH, CH2OMe, or F;

R ¹¹ is H, F, Cl, CN, C _1-3 alkyl, or O-C _1-3 alkyl (wherein said C _1-3 alkyl groups are optionally substituted with an additional group selected from OMe, OH, F and CN);

R ¹² represents H, F, Cl, CN, Me or OMe;

R ¹³ represents H, F, Cl, CN, Me or OMe;

R ¹⁴ is H, F, Cl, CN, Me or OMe, and

R ¹⁵ represents H or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (IC) is provided

(IC), where

Q is O, NH or NMe;

R ¹ is CH2F, CHF2 or CF3;

R ² is H, Me, CH ₂ F, CHF _2, or CF ₃ ;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH2F, CHF2, CF ₃ , CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH2F, CHF2, CF3, CN, CH2CN, CH2OMe, CH2OH, COOH, or CH2SO2Me;

R ⁶ is H, Me, F, CH2F, CHF2, CF3, CN, CH2CN, C ^ OMe, CH2OH, COOH, or SO2Me;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring;

each of R ⁹ and R ^{10 is} independently selected from H, Me, CH2OH, CH ₂ OMe, or F, and ring Y is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (1c), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NH.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NMe.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is O.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CH2F.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CHF 2.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R2 is H.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R ³ is H.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is Me.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein R ³ is H and R ⁴ is Me.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is H.

In one embodiment, a compound of formula (IC), or a pharmaceutically acceptable salt thereof, is provided, wherein R ⁶ is H, F, or CH 2 OH.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is F and R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring, or a cyclobutyl ring, or an oxetane ring. In a further embodiment, R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring. In a further embodiment, R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclobutyl ring. In a further embodiment, R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form an oxetane ring.

In one embodiment, there is provided a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein both R ⁹ and R ¹⁰ are H.

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

- 13 038160

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is selected from the group consisting of

In one embodiment, the group —CH (R ⁵ ) —C (R ⁶ ) (R ⁷ ) (R ⁸ ) in the compound of formula (IC) is

In one embodiment, a compound of formula (ID) is provided

where

Q is O, NH or NMe;

R ¹

R2

R ³

R ⁴

R ⁹ represents CH ₂ F, CHF ₂ or CF3;

represents H or Me;

represents H or Me;

is C _1-3 alkyl;

represents H or Me;

R ¹⁰ represents H or Me;

R ^{16 is} selected from the group consisting of

and the ring Y is selected from the group consisting of

- 14 038160 or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NH.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NMe.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is O.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CH2F.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CHF ₂ .

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein R2 is H.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein R ³ is H.

In one embodiment, a compound of formula (ID), or a pharmaceutically acceptable salt thereof, is provided, wherein R4 is Me.

In one embodiment, the R ¹⁶ group in the compound of formula (ID) is selected from the group consisting of:

In one embodiment, the R ¹⁶ group in the compound of formula (ID) is selected from the group consisting of

O

In one embodiment, the R ¹⁶ group in the compound of formula (ID) is selected from the group consisting of

In one of the

In one of the

In one of the

In one of the

R ¹⁶ in the compound of the embodiment, the group of the embodiment, the group of the formula (ID) is selected from the group, co-

R ¹⁶ in the compound of formula (ID) is selected

R ¹⁶ in an embodiment, the group of the compound of the formula (ID) is selected from the group, co-group, co-group, in an embodiment, the group R ¹⁶ in

the compound of formula (ID) is selected from the group, co-

In one embodiment, the R ¹⁶ group in the compound of formula (ID) is

In one embodiment, a compound of formula (IE) is provided

where

Q is O, NH or NMe;

R ¹ is CH2F, CHF2 or CF3;

R2 is H or Me;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl;

R ⁹ represents H or Me;

R ¹⁰ represents H or Me;

R ^{16 is} selected from the group consisting of

and ring Y is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (IE), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

- 16 038160

In one embodiment, there is provided a compound of formula (IE), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, there is provided a compound of formula (IE), or a pharmaceutically acceptable salt thereof, wherein ring Y is selected from the group consisting of

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NH.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NMe.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is O.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CH2F.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CHF 2.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein R2 is H.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein R ³ is H.

In one embodiment, a compound of formula (IE), or a pharmaceutically acceptable salt thereof, is provided, wherein R4 is Me.

In one embodiment, the R ¹⁶ group in the compound of formula (IE) is selected from the group consisting of

In one embodiment, the R group in the compound of formula (IE) is selected from the group consisting of

O

In one embodiment, the R ¹⁶ group in the compound of formula (IE) is selected from the group consisting of

In one embodiment, the R ¹⁶ group in the compound of formula (IE) is selected from the group consisting of

In one embodiment, the R ¹⁶ group in the compound of formula (IE) is selected from the group consisting of

In one embodiment, the R ¹⁶ group in the compound of formula (IE) is selected from the group consisting of

In one embodiment, a compound of formula (IF) is provided

- 17 038160

(IF), where

Q is O or NH;

R ¹⁵ represents H or F;

R ^{16 is} selected from the group consisting of

and the ring Y is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (IF), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is NH.

In one embodiment, a compound of formula (IF), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is O.

In one embodiment, a compound of formula (IF), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹⁵ is H.

In one embodiment, a compound of formula (IF), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹⁵ is F.

In one embodiment, a compound of formula (IF), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹⁶ is

In one embodiment, there is provided a compound of formula (IF), or a pharmaceutically acceptable salt thereof, wherein Ring Y is

In one embodiment, a compound of formula (IF) is provided wherein Q is O or NH;

R ¹⁵ represents H or F;

R ^{16 is} selected from the group consisting of

and the ring Y is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

In a further embodiment, a compound of formula (IG) is provided

(Yu), where

A represents CR ¹¹ or N;

G is CR ¹² ;

- 18 038160

D represents CR ¹³ or N;

E is CR ¹⁴ or N;

J is CR ¹⁹ ;

Q is O or NH;

R ¹ is CH2F, CHF2, or CF ₃ ;

R ⁴ is Me, CHF2 or CF ₃ ;

R ⁷ represents H or Me;

R ⁸ is H or Me or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or cyclobutyl ring;

R ¹¹ represents H, Me, F, O or OMe;

R ¹² is H, Me, F, O, or CHF2;

R ¹³ represents H or F;

R ¹⁴ represents H or F;

R ¹⁵ represents H, F or Me;

R ¹⁷ represents H or F;

R ¹⁸ is H or F and

R ¹⁹ represents H or F;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein A is C — F, C — OMe, or C — Cl.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein G is CH, C-F, or C-Me.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein both D and E are CH.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein D is CH and E is N.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein J is CH.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹⁷ is H.

In one embodiment, there is provided a compound of formula (IG), or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ is H.

In one embodiment, there is provided a compound of formula (IG), or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is H or F.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein R ¹ is CH2F.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein R ⁴ is Me.

In one embodiment, there is provided a compound of formula (IG), or a pharmaceutically acceptable salt thereof, wherein R ⁷ is Me and R ⁸ is H.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein Q is O.

In one embodiment, a compound of formula (IG), or a pharmaceutically acceptable salt thereof, is provided, wherein A is C — F, C — Cl, or C — OMe;

G represents CH, C-Me or C-F;

both D and E are CH; or D is CH and E is N;

J represents CH;

Q is O;

R ¹ represents CH ₂ F;

R ⁴ represents Me;

R ⁷ represents H;

R ⁸ represents Me;

R ¹⁵ is H or F and both R ¹⁷ and R ¹⁸ are H.

According to a further embodiment of the present disclosure, there is provided a compound of formula (IH)

- 19 038160

R ¹

(IH), where

E is CH or N;

Q is O, NH or NMe;

R ¹ is CH2F or CHF2;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CHF 2, or CF ₃ ;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclobutyl ring;

R ¹¹ represents H, F, O or OMe;

R ¹² represents H, F, O, CHF2 or Me;

R ¹⁵ represents H or F; and

R ²⁰ represents H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, E in the compound of formula (IH) is CH and R ¹ is CH2F or CHF2; or

E in a compound of formula (IH) is N and R1 is CH2F.

According to a further embodiment of the present disclosure, there is provided a compound of formula (IJ)

R ¹

(P), where

E is CH or N;

R ¹ represents CH ₂ F or CHF ₂ ;

R ¹⁵ is H or F and

R ²⁰ represents H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, R ¹⁵ in the compound of formula (IJ) is H.

In a further embodiment, E in the compound of formula (IJ) is N.

In a further embodiment, E in the compound of formula (IJ) is CH and R ¹ is CH ₂ F or CHF ₂ ; or

E in a compound of formula (IJ) is N and R1 is CH2F.

In a further embodiment, R ¹ in the compound of formula (IJ) is CH2F.

In a further embodiment, R ¹ in the compound of formula (IJ) is CHF2.

In a further aspect, a compound of formula (IZ) is provided

- 20 038160

R ¹

(IZ), where

A represents CR ¹¹ or N;

G is CR ¹² or N;

D represents CR ¹³ or N;

E is CR ¹⁴ or N;

Q is O, NH or NMe;

R ¹ represents CH ₂ F, CHF2 or CF ₃ ;

R ² is H, Me, CH ₂ F, CHF _2, or CF ₃ ;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH ₂ F, CHF ₂ , CF ₃ , CN, CH2CN, CH ₂ OMe, CH ₂ OH, COOH, or CH2SO2Me;

R ⁶ is H, Me, F, CH2F, CHF2, CF3, CN, CH2CN, CH2OMe, CH2OH, COOH, or SO2Me;

R ⁷ represents H, Me or F;

R ⁸ represents H, Me or F; or

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring;

R ⁹ is H, Me, CH ₂ OH, CH ₂ OMe, or F;

R ¹⁰ represents H, Me, CH ₂ OH, CH ₂ OMe, or F;

R ¹¹ is H, F, Cl, CN, C _1-3 alkyl, or O-C _1-3 alkyl (wherein said C _1-3 alkyl groups are optionally substituted with an additional group selected from OMe, OH, F and CN);

R ¹² represents H, F, Cl, CN, Me or OMe;

R ¹³ represents H, F, Cl, CN, Me or OMe;

R ¹⁴ is H, F, Cl, CN, Me or OMe, and

R ¹⁵ represents H or F;

or a pharmaceutically acceptable salt thereof.

In a further aspect, a compound of formula (IZA) is provided

(IZA), where

A represents CR ¹¹ or N;

G is CR ¹² or N;

D represents CR ¹³ or N;

E is CR ¹⁴ or N;

Q is O, NH or NMe;

R ¹ is CH2F, CHF2 or CF3;

R ² is H, Me, CH2F, CHF2, or CF3;

R ³ represents H or Me;

R ⁴ is C _1-3 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH = CH ₂ , cyclopropyl or cyclobutyl;

R ⁵ is H, Me, CH2F, CHF2, CF3, CN, CH2CN, CH2OMe, CH2OH, COOH, or CH2SO2Me;

R ⁶ is H, Me, F, CH2F, CHF2, CF3, CN, CH2CN, CH2OMe, CH2OH, COOH, or SO2Me;

R ⁷ represents H, Me or F;

R ⁸ is H, Me or F or

- 21 038160

R ⁷ and R ⁸ taken together with the carbon atom to which they are attached form a cyclopropyl ring or an oxetane ring;

R ⁹ is H, Me, CH2OH, CH2OMe, or F;

R ¹⁰ is H, Me, CH2OH, CH2OMe, or F;

R ¹¹ is H, F, Cl, CN, C _1-3 alkyl, or O-C _1-3 alkyl (wherein said C _1-3 alkyl groups are optionally substituted with an additional group selected from OMe, OH, F and CN);

R ¹² represents H, F, Cl, CN, Me or OMe;

R ¹³ represents H, F, Cl, CN, Me or OMe;

R ¹⁴ represents H, F, Cl, CN, Me or OMe;

R ¹⁵ is H or F and

R ²⁰ represents H or Me;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, there is provided a compound of formula (IZ), (IZA), or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at the 1-position of the tetrahydro-1H-pyrido [3,4-b] indol-1-yl ring is of configuration S.

In a further embodiment, there is provided a compound of formula (IZ), (IZA), or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at the 1-position of the tetrahydro-1H-pyrido [3,4-b] indol-1-yl ring is of the R configuration.

In a further embodiment, there is provided a compound of formula (IZ), (IZA), or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at the 3-position of the tetrahydro-1H-pyrido [3,4-b] indol-1-yl ring is of configuration S.

In a further embodiment, there is provided a compound of formula (IZ), (IZA), or a pharmaceutically acceptable salt thereof, wherein the stereochemistry at the 3-position of the tetrahydro-1H-pyrido [3,4-b] indol-1-yl ring is of the R configuration.

In one embodiment, there is provided a compound of formula (I), wherein the compound is selected from the group consisting of

3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H- pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

N-1- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4 -b] indol 1 -yl) phenyl) -N-2- (3-fluoropropyl) ethane-1,2-diamine;

N-1- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4 -b] indol 1-yl) phenyl) -N-2- (3-fluoropropyl) -N-1 -methylethane-1,2-diamine;

3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H- pyrido [3.4b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H- pyrido [3.4b] indol-1-yl) -2-methoxyphenoxy) ethyl) propan-1 -amine;

N- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrau, dro-1H-pyrido [3,4-b ] indol-1-yl) -4methoxyphenoxy) ethyl) -3-fluoropropane-1 -amine;

3-fluoro-N- (2- (4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4-b] itzdol-1-yl) phenoxy) ethyl) propan-1-amine and

2,2-difluoro-3 - ((1R, 3R) -1- (5- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methoxyphenyl) -3-methyl-1,3,4,9tetrahydro -2H-pyrido [3,4-b] indol-2-yl) propan-1-ol; or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (I), wherein the compound is selected from the group consisting of

N- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

3-fluoro-N- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] itzdol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

N- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro- 1H-purido [3, 4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9-tetrahydro- 2Hpyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3-fluoro-N- (2- (3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indol1-yl) phenoxy) ethyl) propan-1-amine;

3-fluoro-N- (2- (4-methyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3.4-22 038160

b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (3-methyl-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (2-methyl-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (2-methyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

N- (2- (4-ethyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indol-1yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

N- (2- (4-chloro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indol 1 -yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

4- (2 - ((3-fluoropropyl) amino) ethoxy) -2 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro1H -pyrido [3,4-b] indol-1-yl) benzonitrile;

3-fluoro-N- (2- (2-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

N- (2- (2-chloro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indol 1 -yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

3-fluoro-N- (2- (4-methoxy-2-methyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (3-fluoro-4-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

3-fluoro-N- (2- (2-fluoro-4-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

N- (2- (2,5-difluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro -1H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

N- (2- (3,4-difluoro-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

N- (2- (2,5-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

3-fluoro-N- (2- (2,4,5-trifluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9 -tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

3-fluoro-N- (2- (4-fluoro-2-methyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2 - ((6 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((2 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyridin-4-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((6-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3, 4-b] indol-1-yl) pyridin-3-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((6-methyl-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-3-yl) oxy) ethyl) propan-1 -amine;

3-fluoro-N- (2 - ((4-methyl-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-3-yl) oxy) ethyl) propan-1 -amine;

3-fluoro-N- (2 - ((5-fluoro-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

N1- (3-fluoropropyl) -N2- (4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1Hpyrido [3,4-b] indol-1-yl) phenyl) ethane-1,2-diamine;

N1- (3-fluoropropyl) -N2- (6-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1Hpyrido [3,4-b] indol-1-yl) pyridin-3-yl) ethane-1,2-diamine;

N1- (3-fluoropropyl) -N2- (5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1Hpyrido [3,4-b] indol-1-yl) pyridin-2-yl) ethane-1,2-diamine;

N1- (3-fluoropropyl) -N2- (5-methoxy-6 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1Hpyrido [3,4-b] indol-1-yl) pyridin-2-yl) ethane-1,2-diamine;

3 - ((1R, 3R) -1- (2-chloro-5- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9-tetrahydro-2H- pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -6-fluoro-1- (5- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methoxyphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -1- (5 - (((R) -1 - ((3-fluoropropyl) amino) propan-2-yl) oxy) -2-methoxyphenyl) - 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -1- (5 - (((S) -1 - ((3-fluoropropyl) amino) propan-2-yl) oxy) -2-methoxyphenyl) - 3-23 038160 methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -1- (5 - ((S) -2 - ((3-fluoropropyl) amino) propoxy) -2-methoxyphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -1- (5 - ((R) -2 - ((3-fluoropropyl) amino) propoxy) -2-methoxyphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

N- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole -1-yl) -2,4-difluorophenoxy) ethyl) -3-fluoropropan-1-amine;

3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3, 4b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1 -amine;

(S) -3 - ((1R, 3R) -1- (5- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methoxyphenyl) -3-methyl-1,3,4,9-tetrahydro2H -pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-chloro-2-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid and

3-fluoro-N- (2 - ((5-methoxy-6 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (I), wherein the compound is selected from the group consisting of (S) -3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3- fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9-tetrahydro2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl-1, 3,4,9temrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -8-fluoro-3-methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -7-fluoro-3-methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -5-fluoro-3-methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3,6-dimethyl-1,3,4,9- tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (3,5-difluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3-methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (3,5-difluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -6-fluoro-3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (3,5-difluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3,6-dimethyl-1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (3,5-difluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) pyridin-4-yl) -6-fluoro-3-methyl1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3 - ((1R, 3R) -1- (2- (difluoromethyl) -3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9-tetrahydro- 2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

2- (2 - ((3-fluoro-propyl) amino) ethoxy) -6 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro1Н -pyrido [3,4-b] indol-1-yl) benzonitrile;

(4- (2 - ((3-fluoropropyl) amino) ethoxy) -2 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9- tetrahydroIII-pyrido [3, 4-b] indol-1-yl) phenyl) methanol;

3-fluoro-N- (2- (4- (methoxymethyl) -3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro -1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

3,3,3-trifluoro-N- (2- (4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

3-fluoro-N- (2- (3-fluoro-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

3-fluoro-N- (2- (2-fluoro-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3,4b] indol-1-yl) phenoxy) ethyl) propan-1-amine;

N- (2- (3 - ((1R, 3R) -1,3-dimethyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4 -b] indol-1yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

N- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

N- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2 - ((1- (methylsulfonyl) cyclopropyl) methyl) -2,3,4,9-tetragygro-1H -pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine;

N- (2- (4-chloro-2-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H -pyrido [3.4b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

- 24 038160

N- (2- (2,4-dimethyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1 -amine;

3-fluoro-N- (2- (2-fluoro-4-methyl-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1 -amine;

2,2-difluoro-3 - ((1R, 3R) -1- (2-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -6-methoxyphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

N- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole -1-yl) -2-fluoro-4-methoxyphenoxy) ethyl) -3-fluoropropan-1-amine;

3-fluoro-N- (2- (2-fluoro-3 - ((1R, 3R) -2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [ 3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1-amine;

3-fluoro-N- (2- (2-fluoro-3 - ((1R, 3R) -2 - ((3-fluoro-oxetan-3-yl) methyl) -3-methyl-2,3,4,9- tetrahydro-1Hpyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1-amine;

3 - ((1R, 3R) -1- (2-chloro-6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9- tetrahydro2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

2,2-difluoro-3 - ((1R, 3R) -6-fluoro-1- (2-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -6-methoxyphenyl) -3methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro -2H-pyrido [3,4-b] indol-2-yl) propanenitrile;

N1- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3, 4-b] indol-1-yl) phenyl) -N2- (3-fluoropropyl) ethane-1,2-diamine;

3 - ((1R, 3R) -1- (2,6-difluoro-3 - ((2 - ((3-fluoropropyl) amino) ethyl) amino) phenyl) -6-fluoro-3-methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

N1- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4b] indol-1-yl) phenyl) -N2- (3-fluoropropyl) ethane-1,2-diamine;

N1- (2-fluoro-4-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4b] indol-1-yl) phenyl) -N2- (3-fluoropropyl) ethane-1,2-diamine;

3-fluoro-N- (2 - ((3-fluoro-2 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-4-yl) oxy) ethyl) propan-1-amine;

N- (2 - ((3-chloro-2 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyridin-4-yl) oxy) ethyl) -3-fluoropropan-1-amine;

N1- (3-fluoro-2 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-purido [3,4- b] indol-1yl) pyridin-4-yl) -N2- (3-fluoropropyl) ethane-1,2-diamine;

N1- (3-fluoropropyl) -N2- (3-methyl-2 - ((1S, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9-tetrahydro- 1Hpyrido [3,4-b] indol-1-yl) pyridin-4-yl) ethane-1,2-diamine;

2,2-difluoro-3 - ((1S, 3R) -1- (4- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-2-yl) -3-methyl-1,3 , 4.9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

2,2-difluoro-3 - ((lS, 3R) -1- (3-fluoro-4- (2 - ((3-fluoro-propyl) amino) ethoxy) pyridin-2-yl) -3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

N- (2 - ((2 - ((1S, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -3fluoropyridin-4-yl) oxy) ethyl) -3-fluoropropane-1-amine;

3-fluoro-N- (2 - ((3-fluoro-2 - ((1S, 3R) -2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H -pyrido [3,4-b] indol-1-yl) pyridin-4-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((3-fluoro-2 - ((1S, 3R) -2 - ((3-fluoro-oxetan-3-yl) methyl) -3-methyl-2,3,4,9 -themrahydro-1H-pyrido [3,4-b] indol-1-yl) pyridin-4-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((5 - ((1R, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyridin-3-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

2,2-difluoro-3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl1,3,4 , 9-tetrahydro-2H-purido [3,4-b] indol-2-yl) propan-1-ol;

3 - ((1R, 3R) -1- (3-chloro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3-methyl-1,3,4,9- tetrahydro2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3-fluoro-N- (2 - ((5-methyl-6 - ((1S, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((3-methyl-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine;

N- (2 - ((3,5-difluoro-4 - ((1R, 3R) -3-methyl-2- (2,2,2-mfluoroethyl) -2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) -3-fluoropropane-1 -amine;

N- (2 - ((3,5-difluoro-4 - ((1R, 3R) -2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-purido [3, 4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) -3-fluoropropane-1 -amine;

N- (2 - ((3,5-difluoro-4 - ((1R, 3R) -6-fluoro-2 - ((1-fluorocyclopropyl) methyl) -3-methyl-2,3,4,9-tetrahydro -1Hpyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) -3-fluoropropan-1-amine;

- 25 038160

2,2-difluoro-3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

3 - ((1R, 3R) -1- (3-chloro-5-fluoro-2- (2 - ((3-fluoro-propyl) amino) ethoxy) pyridin-4-yl) -3-methyl-1,3, 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol;

3-fluoro-N- (2 - ((6-methoxy-5 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) pyridazin-3-yl) oxy) ethyl) propan-1 -amine;

3-fluoro-N- (2 - ((6 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol 1-yl) pyrimidin-4-yl) oxy) ethyl) propan-1-amine;

3-fluoro-N- (2 - ((5-methyl-6 - ((1S, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro- 1H-pyrido [3,4b] indol-1-yl) pyrimidin-4-yl) oxy) ethyl) propan-1 -amine;

2,2-difluoro-3 - ((1S, 3R) -1- (6- (2 - ((3-fluoropropyl) amino) ethoxy) -5-methylpyrimidin-4-yl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol;

3 - ((1R, 3R) -1- (fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro2H-pyrido [3,4-b] indol-2-yl) propanoic acid;

(R) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

2,2-difluoro-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid;

3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro -2H-pyrido [3,4-b] indol-2-yl) -2,2-dimethylpropanoic acid;

- (((1R, 3R) -1- (6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3 -methyl- 1,3,4,9-tetrahydro -2H-pyrido [3,4-b] indol-2-yl) methyl) cyclobutαn-1-carboxylic acid;

(R) -3 - ((1R, 3R) -6-fluoro-1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3 -methyl1,3 , 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -3-ethyl-1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1 - (2- (difluoromethyl) -6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoro-propyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1 , 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoro-propyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1 , 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (2,6-dichloro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4, 9-tetrahydro2H-pyrido [3,4-b] indol-2-yl) -2-methylnropaic acid;

(S) -3 - ((1R, 3R) -1- (2,6-dichloro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(R) -3 - ((1R, 3R) -1- (2,6-dichloro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

3 - ((1R, 3R) -1- (2-chloro-6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3-methyl-1,3,4,9- tetrahydro2H-pyrido [3,4-b] indol-2-yl) -2,2-dimethylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (3-chloro-5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3-methyl- 1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((R) -1- (6-fluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) -2-methylphenyl) -3,3-dimethyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-fluoro-3 - ((2 - ((3-fluoro-propyl) amino) ethyl) amino) -2-methylphenyl) -3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-fluoro-3 - ((2 - ((3-fluoropropyl) amino) ethyl) (methyl) amino) -2-methylphenyl) -3-methyl1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3S) -3- (difluoromethyl) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) 1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3S) -1- (2-chloro-6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3- (difluoromethyl) -1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3S) -1- (3-chloro-5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3- (difluoromethyl ) 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

(S) -3 - ((1R, 3S) -1- (6-fluoro-3- (2 - ((3-fluoro-propyl) amino) ethoxy) -2-methylphenyl) -3- (trifluoromethyl) 1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylnropanoic acid;

- 26 038160 (S) -3 - ((1R, 3S) -1- (2-chloro-6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3- (trifluoromethyl) 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3S) -1- (3-chloro-5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) pyridin-4-yl) -3- (trifluoromethyl ) -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) phenyl) -3-methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3- methyl1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) αmino) ethoxy) -2-methylphenyl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (6-fluoro-3 - ((2 - ((3-fluoropropyl) (methyl) αmino) ethyl) (methyl) αmino) -2-methylphenyl) - 3methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1- (2- (difluoromethyl) -6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) phenyl) -3-methyl - 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3S) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3- (trifluoromethyl) - 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(S) -3 - ((1R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) (methyl-d3) amino) ethoxy) -2-methylphenyl) -3 -methyl1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(R) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) αmino) ethoxy) -2-methylphenyl) -3-methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3- methyl 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(R) -3 - ((1R, 3R) -1 - (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl-d3) amino) ethoxy) -3-methylpyridin-4-yl) - 3 methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid and

N- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoro-N-methylpropαn-1-αmine;

or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (I), wherein the compound is selected from the group consisting of (2R) -3 - [(1R, 3R) -6-fluoro-1- [5-fluoro-2- [2- [3 -fluoropropyl (methyl) amino] ethoxy] -3-methyl-4-pyridyl] -3methyl-1,3,4,9-tetrahydropyrido [3,4-b] indol-2-yl] -2-methylpropanoic acid;

3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propaic acid;

3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid;

3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) butanoic acid;

(3R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3- methyl 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) butaic acid;

(3S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3- methyl 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) butaic acid;

(R) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3- methyl 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(R) -3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1, 3,4,9tetraαhydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid;

(R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) αmino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid and

3 - ((1R, 3R) -1- (fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9tetraαhydro- 2H-pyrido [3,4-b] indol-2-yl) propanoic acid;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) is provided or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the examples herein. An additional feature is any of the embodiments described in the present description, provided that any of the specific examples are excluded in isolation. An additional feature is any of the embodiments described in the present description, provided that any one or more compounds selected from the above list of examples of compounds in accordance with the present description, are excluded separately.

The C _{1 -3} alkyl group can be branched or unbranched. Examples of suitable C _1-3 alkyl groups are methyl (Me), ethyl (Et), n-propyl (n-Pr) or isopropyl (i-Pr).

- 27 038160

For the avoidance of ambiguity in a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) each of R ⁹ and R ¹⁰ may be substituted at any position on the corresponding ethyl chain to which it is linked. Therefore, by way of example only, the R ⁹ substituent can be attached at two possible positions as shown below.

Additionally, for the avoidance of ambiguity, the use of ⁿ ^^ ⁿ in the formulas herein denotes a point of attachment between different groups.

Additionally, for the avoidance of ambiguity, if multiple substituents are independently selected from a given group, then the selected substituents may provide the same substituents or different substituents from the given group.

Compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) have two or more chiral centers, and it will be understood that the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA) can be obtained, isolated and / or supplied in the presence, absence, or in addition to one or more of the other possible enantiomeric and / or diastereomeric isomers of compounds of formula (I), (IA), (IB), (IC ), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) in any relative proportions. Preparation of enantiomerically enriched / enantiomerically pure and / or diastereomerically enriched / diastereomerically pure compounds can be carried out using standard organic chemistry techniques well known in the art, for example, by synthesis from enantiomerically enriched or enantiomerically pure starting materials, using the appropriate enantiomerically enriched or enantiomerically pure catalyst during synthesis and / or by separation of a racemic or partially enriched mixture of stereoisomers, for example, by means of chiral chromatography.

For pharmaceutical use, it may be preferred to prepare a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof without the presence of other stereoisomeric forms in large quantities.

Accordingly, in one embodiment, a composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ ) or (IZA) or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) , (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof is present in the composition in a diastereomeric excess (% de) of> 90%.

In a further embodiment, the% de in the above composition is> 95%. In a further embodiment, the% de in the above composition is> 98%.

In a further embodiment, the% de in the above composition is> 99%.

In a further embodiment, a composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH) , (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof are present in the composition in an enantiomeric excess (% ee) of> 90%.

In a further embodiment, the% ee in the above composition is> 95%.

In a further embodiment, the% ee in the above composition is> 98%.

In a further embodiment, the% ee in the above composition is> 99%.

In a further embodiment, a composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomeric forms of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH) , (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof are present in the composition in an enantiomeric excess (% ee) of> 90% and a diastereomeric excess (% de) of> 90%.

In additional embodiments of the aforementioned composition,% ee and% de may have any combination of the values listed below.

% it is <5% and% de is> 80%.

% it is <5% and% de is> 90%.

% it is <5% and% de is> 95%.

% of it is <5% and% de is> 98%.

- 28,038160% it is> 95% and% de is> 95%.

% of it is> 98% and% de is> 98%.

% is> 99% and% de is> 99%.

In an additional embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient.

In one embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, optionally additionally containing one or more other stereoisomeric forms of the compound of formula (I), (IA), (IH), (IC), (ID), ( IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID) , (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, are present in the composition in an enantiomeric excess (% ee) of> 90%.

In a further embodiment, the% ee in the above composition is> 95%.

In a further embodiment, the% ee in the above composition is> 98%.

In a further embodiment, the% ee in the above composition is> 99%.

In one embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, optionally additionally containing one or more other stereoisomeric forms of the compound of formula (I), (IA), (IH), (IC), (ID), ( IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID) , (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof are present in the composition in a diastereomeric excess (% de) of> 90%.

In a further embodiment, the% de in the above composition is> 95%.

In a further embodiment, the% de in the above composition is> 98%.

In a further embodiment, the% de in the above composition is> 99%.

In one embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, optionally additionally containing one or more other stereoisomeric forms of the compound of formula (I), (IA), (IH), (IC), (ID), ( IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (IA), (IB), (IC), (ID) , (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof are present in the composition in an enantiomeric excess (% ee) of> 90% and a diastereomeric excess (% de), amounting to> 90%.

In additional embodiments of the aforementioned pharmaceutical composition,% ee and% de may have any combination of the values listed below.

% is> 95% and% de is> 95%.

% of it is> 98% and% de is> 98%.

% is> 99% and% de is> 99%.

Compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) and pharmaceutically acceptable salts thereof can be obtained, used or supplied in amorphous form, crystalline form or semi-crystalline form, and any specified compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof may be capable of forming more than one crystalline / polymorphic form, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate or other stoichiometric hydrate composition) and / or solvated forms. It should be understood that the present description covers all such solid forms of the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA) and its pharmaceutically acceptable salts.

In additional embodiments, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) is provided obtained using the methods described later in this document in the Examples section.

The present invention is intended to include all isotopes of atoms found in the compounds of the present invention. It should be understood that isotopes contemplate those atoms that have the same atomic number, but different mass numbers. For example, the isotopes of hydrogen include tritium and deuterium. Carbon isotopes include ¹³ C and ¹⁴ C. Nitrogen isotopes include ¹⁵ N. In a particular embodiment, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IZ) or (IZA) where R ² is deuterium. In a further embodiment, a compound of formula (I), (IH), (IJ) or (IZA) ^{is provided wherein R 20} is CD3.

- 29 038160

A suitable pharmaceutically acceptable salt of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is are, for example, an acid addition salt. A suitable pharmaceutically acceptable salt of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) may be, for example, an acid addition salt of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA), for example an acid addition salt formed with an inorganic or organic acid such as acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, D, L-lactic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid , hydrochloric acid, L-tartaric acid, maleic acid, malic acid, malonic acid, methanesulfonic acid, napisylic acid, phosphoric acid, saccharin, succinic acid, sulfuric acid, ntoluenesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.

An additional suitable pharmaceutically acceptable salt of a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is, for example, a salt formed in the human or animal body after administration of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ ), (IZ) or (IZA) into the specified human or animal organism.

A compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof can be obtained in the form of a co-crystalline solid form. It should be understood that a pharmaceutically acceptable co-crystal of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA) or pharmaceutically acceptable salts thereof forms an aspect of the present disclosure.

It should be understood that a suitable pharmaceutically acceptable prodrug of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) also forms an aspect of the present disclosure. Accordingly, compounds according to the present disclosure can be administered in the form of a prodrug, which is a compound that is cleaved in the human or animal body to release the compound disclosed herein. A prodrug can be used to alter the physical properties and / or pharmacokinetic properties of a compound as described herein. A prodrug can be formed if a compound as described herein contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in-vivo cleavable ester or amide derivatives of the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), ( IZ) or (IZA).

Accordingly, one aspect of the present disclosure includes such compounds of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA), as defined above in this document, if they are formed as a result of organic synthesis, and if they are formed in the human or animal body as a result of the cleavage of a prodrug based on them. Accordingly, the present disclosure includes such compounds of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) ( ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) may be a compound obtained by synthesis or a compound obtained by metabolism.

A suitable pharmaceutically acceptable prodrug of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is is a compound that, according to a reasonable medical opinion, is suitable for administration to a human or animal body without undesirable types of pharmacological activity and without excessive toxicity.

The different forms of the prodrug are described, for example, in the following documents:

a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard,

Chapter 5 Design and Application of Pro-drugs, by H. Bundgaard p. 113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews 8, 1-38 (1992);

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chern, Pharm, Bull, 32, 692 (1984);

g) T. Higuchi and V. Stella, Pro-Drugs as Novel Delivery Systems, A.C.S. Symposium Series, Volume 14 and

h) E. Roche (editor), Bioreversible Carriers in Drug Design, Pergamon Press, 1987.

In-vivo effects of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) partially can be manifested due to one or more metabolites that are formed in the human or animal body after administration of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH) , (IJ), (IZ) or (IZA). As indicated above in this document, the in-vivo effects of a compound of formula

- 30 038160 (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) can also be manifested by metabolism of the precursor compound (prodrug).

For the avoidance of ambiguity, it should be understood that if in the present description a group is denoted as 'defined above in this document' or 'as defined in this document', then said group includes the first occurring and broadest definition, as well as all alternative definitions for this group without exception. ...

In another aspect of the present disclosure, there is provided a method for preparing a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof. A suitable method is illustrated by the following exemplary method variations in which, unless otherwise indicated, A, D, E, G, Q, and R1-R ¹⁰ have any of the meanings defined hereinabove. The required starting materials can be obtained using standard organic chemistry procedures. The preparation of such starting materials is described in conjunction with the following illustrative process variations and within the scope of the accompanying examples. Alternatively, the required starting materials can be obtained using procedures similar to those illustrated, which are within the ordinary skill of a specialist in the field of organic chemistry.

Compounds of formula (I) can be prepared, for example, by the following, a) Reaction of a compound of formula (II) with a compound of formula (III) under conditions known in the art as suitable for Pictet-Spengler reactions (such as in the presence of an acid (such as acetic acid) and in a suitable solvent (e.g. toluene) and at a suitable temperature (such as 80-100 ° C) with a protecting group (P) on the nitrogen atom that can be removed under conditions known in the art, or without it.

b) If Q is O, NH or NMe, by esterification or amination of a suitable aryl halide of formula (IV), if L is, for example, halogen (such as Br), or a trifluoromethanesulfonyl (triflate) group, or a boronic acid residue, or boronate ester residue, with an alcohol or amine of formula (V) using a suitable metal catalyst (e.g. RockPhos 3rd generation precatalyst or BrettPhos 3rd generation precatalyst) in a suitable solvent (e.g. toluene, THF or DME) in the presence of a suitable base (for example, cesium carbonate or potassium carbonate) and at a suitable temperature (such as 90-120 ° C) with a protecting group (P) on the nitrogen atom, which can be removed with or without conditions known in the art.

c) If Q is O, by alkylating a suitable phenol or hydroxylheteroaryl compound of formula (VI) with an alcohol of formula (V) via Mitsunobu reaction using appropriate reagents (such as triphenylphosphine and diisopropyl (E) -diazen-1,2 dicarboxylate ) in a suitable solvent (such as DCM) with a protecting group (P) at the nitrogen atom, which can be removed with or without conditions known in the art.

d) Alkylating a suitable compound of formula (VII) wherein LG is a leaving group known in the art, for example a halide (such as Br), trifluoromethanesulfonate (triflate) or methanesulfonate (mesylate) with an amine of formula (VIII) in a suitable solvent (for example, acetonitrile) in the presence of a suitable base (for example, potassium carbonate) and when appropriate

- 31,038,160 temperature (eg 80-90 ° C) with a protecting group (P) at the nitrogen atom, which can be removed under conditions known in the art or without it.

Compounds of formula (II) can be obtained, for example, by:

a) reacting a compound of formula (IX) with an aldehyde of formula (X) in a suitable solvent (eg THF) in the presence of a suitable reducing agent (such as sodium triacetoxyborohydride) and at a suitable temperature (such as 20-30 ° C);

b) (i) reacting a compound of formula (IX) with an acid of formula (XI) under standard conditions to form an amide bond (e.g. in the presence of an amide coupling reagent (such as HATU) and a suitable base (such as triethylamine) in a suitable solvent (such as DMF)) followed by (ii) reduction of the formed amide bond using a suitable reducing agent (such as borane) in a suitable solvent (such as THF) at a suitable temperature (such as 60-70 ° C);

c) reacting a compound of formula (IX) with a compound of formula (XII) wherein LG is a suitable leaving group (e.g., a halogen atom (such as bromine or chlorine) or trifluoromethanesulfonate), in the presence of a suitable base (such as diisopropylethylamine) in a suitable solvent (eg DCM or dioxane) and at a suitable temperature (such as 20-85 ° C).

Compounds of formula (III) can be prepared by reacting a compound of formula (XIII) with an alcohol of formula (V) under conditions known in the art as suitable for Mitsunobu reactions (such as in the presence of an azodicarboxylate reagent (such as DEAD) and triphenylphosphine and in a suitable solvent (such as THF) and at a suitable temperature (such as 20-30 ° C).

Compounds of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (XIV) wherein L is a suitable functional group such as a halide (e.g. bromide or chloride), triflate, boronic acid residue or boronic ester residue. acid, under conditions known in the art as suitable for Pictet-Spengler reactions, such as in the presence of an acid (such as acetic acid) and in a suitable solvent (e.g. toluene) and at a suitable temperature (e.g. 80-100 ° C).

Compounds of formula (VI) can be prepared by reacting a compound of formula (II) with a compound of formula (XV) under conditions known in the art as suitable for Picte-Spengler reactions (such as in the presence of an acid (such as acetic acid) and in a suitable solvent (e.g. toluene) and at a suitable temperature (e.g. 80-100 ° C.) In certain aspects, X is OH (optionally protected), or X is a boronic acid residue or boronic acid ester residue, which can convert to OH using a suitable oxidizing agent (such as hydrogen peroxide) in the presence of a suitable base (such as sodium hydroxide) in a suitable solvent (such as THF).

- 32 038160

Compounds of formula (VII) can be prepared by reacting a compound of formula (VI) using standard functional group treatment, for example Mitsunobu reaction using appropriate reagents (such as triphenylphosphine and diisopropyl (E) -diazen-1,2-dicarboxylate), with 2 α-haloethanol (such as 2-bromoethan-1-ol) in a suitable solvent (such as DCM).

Alternatively, compounds of formula (VII) can be prepared by reacting a compound of formula (IV) using standard functional group treatment, for example esterification, where L is, for example, halogen (such as Br), or a trifluoromethanesulfonyl (triflate) group, or a boronic acid residue , or a boronate ester residue, using an appropriate diol (with optional monoprotection) using a suitable metal catalyst (e.g. RockPhos 3rd generation precatalyst) in a suitable solvent (e.g. toluene or DME) in the presence of a suitable base (e.g. cesium carbonate ). Then (with removal of the protective group, if necessary), the alcohol can be converted to the corresponding leaving group (eg, halide (such as Br), trifluoromethanesulfonate (triflate) or methanesulfonate (mesylate)) under standard conditions.

It should be understood that other variations of the process steps are also possible in the process variations described above.

If a pharmaceutically acceptable salt of a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is required , it can be obtained, for example, by reacting said compound with a suitable acid or a suitable base. If a pharmaceutically acceptable prodrug of a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is required , it can be obtained using a traditional procedure.

It will also be understood that in some of the reactions mentioned above in this document, it may be necessary or desirable to protect any reactive functional groups in the compounds. Cases where protection is necessary or desirable, as well as suitable methods of providing protection, are known to those skilled in the art. Traditional protecting groups can be used in accordance with standard practice (for an illustration, see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reactants contain groups such as amino, carboxy or hydroxy, protection of the group may be desirable in some of the reactions mentioned herein.

A suitable protecting group for an amino group or an alkylamino group is, for example, an acyl group, for example, an alkanoyl group such as an acetyl, alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example a benzyloxycarbonyl, or an aroyl group, for example ... The deprotection conditions for the above-mentioned protecting groups inevitably vary depending on the choice of the protecting group. For example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis using a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an alkoxycarbonyl group such as a t-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric, formic, phosphoric or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as boron tris (trifluoroacetate). A suitable alternative protecting group for the primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine or hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, an arylmethyl group, for example benzyl, or a trialkyl or diarylalkylsilane, such as TBDMS or TBDPS. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of the protecting group. For example, an acyl group such as an alkanoyl or aroyl group 33,038,160 pa can be removed, for example, by hydrolysis using a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

A suitable protecting group for the carboxy group is, for example, an esterifying group, for example, a methyl or ethyl group, which can be removed, for example, by hydrolysis using a base such as sodium hydroxide, or, for example, a tert-butyl group that can be removed, for example , by treatment with an acid such as trifluoroacetic acid, or, for example, a benzyl group, which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Protecting groups can be removed at any convenient stage of the synthesis using conventional techniques well known in the field of chemistry.

Some of the intermediates defined in this document are new, and they are presented as additional features of the present description.

Biological analyzes

The following assays were used to measure the effects of compounds as described herein.

ERa binding analysis

The ability of compounds to bind to the isolated ligand binding domain of estrogen receptor alpha (LBD ER-alpha (GST)) was evaluated in competitive assays using LanthaScreen time resolved fluorescence resonance energy transfer (TR-FRET) endpoint detection. A suitable fluorophore (Fluormone ES2, ThermoFisher, product code P2645) and recombinant human estrogen receptor alpha ligand binding domain, residues 307-554 (expressed and purified in situ) were used to measure compound binding by TR-FRET LanthaScreen endpoint. The principle of the assay is that LBD ER-alpha (GST) is added to a fluorescent ligand to form a receptor-fluorophore complex. Terbium-labeled anti-GST antibodies (product code PV3551) are used to indirectly label the receptor by binding to its GST-tag, and competitive binding is monitored by the ability of the test compound to displace fluorescent ligand, resulting in a loss of the TR-FRET signal between the Tb-tagged anti-GST antibody and the tag. The assay was performed as follows with all reagents added using a BioRAPTR FRD microfluidic workstation from Beckman Coulter.

1. Using an acoustic dispenser, dispense 120 nL of test compound into black 384-well assay plates with a small well volume.

2. Prepare 1 x LBD ER-alpha / Tb-labeled GST Ab in ES2 screening buffer and incubate for 15 min.

3. Dispense 6 μl of reagent containing 1 x LBD AR / Tb-labeled anti-GST Ab into each well of the assay plate, then dispense 6 μl of fluorophore reagent into each well of the assay plate.

4. Cover the assay plate to protect the reagents from light and evaporation and incubate at room temperature for 4 hours.

5. Provide excitation at 337 nm and measure the fluorescence signal for each well at 490 and 520 nm using BMG PhERaSTAR.

Compound was dosed directly from a compound source microplate containing serially diluted compound (4 wells containing 10, 0.1 mM, 1 μM, and 10 nM final compound, respectively) into an assay microplate using a Labcyte Echo 550. Echo 550 is a liquid dispenser that employs acoustic technology to directly transfer compound solutions in DMSO from microplate to microplate, and the system can be programmed to transfer various small volumes, on the order of nL, compound from different wells of the original plate to obtain the required serial dilution of the compound in assay plate, which is then refilled to normalize the DMSO concentration over the entire dilution range.

A total of 120 nL of compound with DMSO was added to each well, and the compounds were tested in a 12-point concentration response curve format over a final compound concentration range of 10, 2.917, 1.042, 0.2083, 0.1, 0, respectively. , 0292, 0.0104, 0.002083, 0.001, 0.0002917, 0.0001042 and 0.00001 μM. TR-FRET dose response data obtained for each compound was exported to a suitable software package (such as Origin or Genedata) for curve fitting analysis. Competitive binding of ER-alpha was expressed as an IC ₅₀ value. It was determined by calculating the concentration of the compound that was necessary to reduce the binding of the tagged compound to LBD ER-alpha by 50%.

- 34 038160

Analysis of ER suppression in MCF-7

The ability of compounds to suppress the number of estrogen receptor (ER) was assessed in an immunofluorescence assay on cells using the cell line MCF-7, obtained from carcinoma of the human breast duct. MCF-7 cells were reconstituted directly from a cryoflacon (approximately 5x10 ⁶ cells) in an assay medium (Dulbecco's modified Eagle's medium (DMEM) without phenol red; Sigma D5921) containing 2 mM L-glutamine and 5% (v / v. ) fetal calf serum treated with charcoal / dextran. Cells were harvested once using a syringe with a large gauge sterile needle 18G x 1.5 inches (1.2 x 40 mm) and the cell density was measured using a Coulter counter (Beckman). Cells were further diluted in assay media to a density of 3.75 x 10 ⁴ cells / ml and added 40 μl / well to black 384-well plates (Costar, # 3712) with clear bottom, treated for tissue culture using Thermo Scientific Matrix WellMate or Thermo Multidrop. After seeding the cells, the plates were incubated overnight at 37 ° C, 5% CO ₂ (Liconic carousel incubator). Test data was obtained using a LabCyte Echo Model 555 Mixer Reformator, which is part of an automated production cell (Integrated Echo 2 production cell). Compound stock solutions (10 mM) of the test compounds were used to provide a 384-well compound dose plate (Labcyte P-05525-CVI). 40 μl of each 10 mM compound stock solution was dispensed into the well of the first quadrant and then serial 1: 100 dilutions were made in DMSO using a Hydra II liquid dispenser (MATRIX UK) to obtain 40 μl of the diluted compound, respectively, in the wells of quadrant 2 (0 , 1 mM), 3 (1 μM) and 4 (0.01 μM). The addition of 40 μL of DMSO to the wells of row P of the original plate allowed the DMSO to be normalized over the entire dose range. To dose control wells on the original compound plate, 40 μL of DMSO was added to row O1, and 40 μL of 100 μM fulvestrant in DMSO was added to row 03.

The Echo uses acoustic technology to perform direct microplate-to-microplate transfer of DMSO compound solutions to assay plates. The system can be programmed to multi-step transferring small volumes, down to 2.5 nL, between microplates and thus serially dilute the compound in the assay plate, which is then refilled to normalize the DMSO concentration throughout the dilution range. Compounds were dispensed into cell plates, with the original compound plate prepared as above to give 12 concentration points, with a dose range of 3 μM to 3 pM, each in duplicate, using 3-fold dilutions and one final 10 -fold dilution using the Integrated Echo 2 production cell. DMSO was dosed into the maximum signal control wells to give a final concentration of 0.3%, and fulvestrant was dosed into the minimum signal control wells to give a final concentration of 100 nM, respectively. The plates were further incubated for 18-22 hours at 37 ° C, 5% CO ₂ , and then fixed by adding 20 μl of 11.1% (v / v) formaldehyde solution (in phosphate-buffered saline (PBS)) to obtain the final formaldehyde concentration 3.7% (v / v). Cells were fixed at room temperature for 20 min and then washed twice with 250 μl PBS / Proclin (PBS with biocidal preservative) using a BioTek plate washer, then 40 μl PBS / Proclin was added to all wells and the plates were stored at 4 ° C. The above fixation method was performed on an Integrated Echo 2 production cell. Immunostaining was performed using an AutoElisa automated production cell. PBS / Proclin was removed from all wells by evacuation and cells were permeabilized with 40 μl PBS containing 0.5% Tween ™ 20 (v / v) for 1 hour at room temperature. Plates were washed three times in 250 μl PBS / 0.05% (v / v) Tween 20 using Proclin (PBST with biocidal preservative) and then 20 μl 1: 1000 rabbit anti-ERa monoclonal antibody solution (SP1) (Thermofisher) was added in PBS / Tween ™ / 3% (w / v) bovine serum albumin. The plates were incubated overnight at 4 ° C (Liconic carousel incubator) and then washed three times in 250 μl PBS / 0.05% (v / v) Tween ™ 20 with Proclin (PBST). The plates were then incubated with goat anti-rabbit IgG with AlexaFluor 594 or goat anti-rabbit immunoglobulins with AlexaFluor 488 (Molecular Probes) at 20 μl / well with 1: 5000 Hoechst solution in PBS / Tween ™ / 3% (w / v .) white serum albumin for 1 hour at room temperature. The plates were then washed three times in 250 μl PBS / 0.05% (v / v) Tween ™ 20 with Proclin (PBST with biocidal preservative). 20 μl of PBS was added to each well and the plates were covered with black plate film and stored at 4 ° C before reading. Plates were read using Cellomics Arrayscan, reading the fluorescence level at 594 nm (time point 24 hours) or 488 nm (time point 5 hours) to measure the ERa receptor level in each well. The mean total intensity was normalized to the number of cells to give the total intensity per cell. The data was exported to a suitable software package (such as Origin) for curve fit analysis. The level of suppression of the ERa receptor was expressed as the IC ₅₀ value and was determined by calculating the concentration of the compound that was required to obtain a 50% reduction in the mean maximum signal of the total intensity.

The data shown in Table A was obtained (the data below may represent the result of a single experiment or the average of two or more experiments).

Table A

Example 1C ₅₀ value for ER binding (nM) 1C ₅₀ value for ER suppression (nM) 1 12 3.7 2 34 49 3 180 98 4 2.6 0.28 5 45 25 6 2.1 0.19 7 1.5 0.12 eight 1.4 0.20 nine 1,2 0.088 ten 2.9 0.23 eleven 1,2 0.14 12 0.62 0.059 13 1.6 0.22 fourteen 0.69 0.092 15 0.55 0.079 16 1.7 3.7 17 3.8 1.6 eighteen ten 6.2

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19 360 BUT twenty 1.0 0.29 21 2.6 1.6 22 1.4 0.12 23 2.7 0.5 24 2.0 0.85 25 0.88 0.25 26 0.85 0.16 27 2.7 1.6 28 2.8 0.8 29 2.0 0.44 thirty 2.1 0.32 31 5.4 7.2 32 2.7 0.38 33 1.6 0.081 34 190 - (41%) 35 1.9 1.1 36 2.6 0.35 37 12 35 38 n. and. 0.19 39 1.4 0.26 40 7.9 0.53 41 12 6.0 42 3.7 1.9 43 82 220 44 ι, ο 0.14 45 0.78 0.034 46 1.0 0.22 47 2.5 11 (81%) 48 4.4 13 49 1,2 0.15 50 ι, ο 0.81 (81%) 51 1,2 0.12 52 0.58 0.34

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53 150 - (40%) 54 5.9 ι, ο 55 4.0 0.53 56 39 fourteen 57 2.6 0.34 58 7.9 1.9 59 2,3 3.1 60 0.84 0.12 61 0.79 0.19 62 0.71 0.076 63 1.1 0.32 64 0.96 0.071 65 0.64 0.058 66 0.71 0.34 67 0.70 0.099 68 0.69 0.095 69 1.4 1.5 70 1300 180 71 3.4 2.0 (90%) 72 1.4 0.49 73 9.4 eighteen 74 31 59 75 52 58 76 ι, ο 0.21 77 7.3 6.2 78 1,3 0.12 79 1.4 0.16 80 2.0 1,2 81 > 110 0.17 82 0.80 0.042 83 1.7 0.28 (90%) 84 0.94 0.16 (83%) 85 1,3 0.089 86 0.86 0.17

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87 0.54 0.065 88 2.2 0.28 89 0.91 0.14 90 0.65 0.3 91 9.4 15 92 1.6 0,4 93 1.4 0.39 94 3.6 9.2 95 5.6 3.3 96 1.4 0.2 97 2.2 0.66 98 1.9 1,2 99 3.4 3.8 100 5.2 eleven 101 9.2 27 102 2.0 2.9 103 0.56 0.084 104 0.72 0.17 105 42 39 106 0.92 0.095 107 1,3 0.21 108 ι, θ 0.3 109 1,2 0.41 BUT 0.43 0.045 111 0.60 0.07 112 2.0 0.95 113 17 > 300 114 0.74 0.2 115 ι, ο 0.31 116 15 1.1 117 9.2 0.92 118 1,2 5.5 119 6.9 ι, ο 120 eleven 2.5

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¹ Compounds investigated in the ER suppression assay exhibit suppression values (> 90%) in the assay, unless otherwise noted, in which case% suppression is shown in parentheses, (n and = not investigated)

Western blot analysis

The ability of compounds to suppress the estrogen receptor (ER) was assessed by Western blotting using human breast cancer cell lines (MCF-7 and CAMA-1). Cells were plated in 12-well tissue culture-treated plates at 0.5 x 10 ^b / well in RPMI without phenol red containing 2 mM L-glutamine and 5% (v / v) fetal charcoal-treated calf serum (F6765, Sigma). Cells were incubated with compounds (100 nM) or a control medium (0.1% DMSO) for 48 h at 37 ° C, 5% CO2, after which they were washed once with PBS and lysed with 80 μl of buffer. for lysis (25 mM Tris / HCl, 3 mM EDTA, 3 mM EGTA, 50 mM NaF, 2 mM sodium orthovanadate, 0.27 M sucrose, 10 mM β-glycerophosphate,

- 40,038,160 mM sodium pyrophosphate, 0.5% TritonX-100, pH 6.8) on ice.

Cells were scraped off, sonicated and centrifuged (Protein Assay Kit 500-0116, DC Bio-Rad) prior to protein assay, then the samples were adjusted to a protein concentration of 1-2 mg / ml in lysis buffer containing 1 x sample buffer LDS (NP0007, Invitrogen) and 1 x NuPAGE Sample Reconstitute (NP0009, Invitrogen). The samples were boiled for 10 min at 95 ° C and then frozen at -20 ° C until the need for use.

10-20 μg protein was loaded onto 26-well Criterion gels (BioRad 345-0034). The gels were incubated at 125 V for 1 h 25 min in a rolling buffer (24 mM Tris Base Sigma, 192 mM glycine, 3.5 mM SDS prepared in distilled water). Then, at 30 V for 2 h in a blotting buffer (25 mM Tris, 192 mM glycine, 20% (v / v) methanol, pH 8.3, prepared in distilled water), the gels were transferred to a nitrocellulose membrane. The blotting membrane was stained with Ponceau S (P7170, Sigma) and excised according to the appropriate molecular weight markers.

The membranes were blocked for 1 hour at room temperature in 5% Marvel (w / v) in phosphate buffered saline containing 0.05% Tween ™ 20 (PBS / Tween). The blotting membranes were then incubated with anti-ERa rabbit monoclonal antibody (SP1) (Thermofisher) diluted 1: 1000 at 4 ° C. overnight (with gentle shaking) followed by several washes with PBS / Tween. Secondary antibody to rabbit immunoglobulins conjugated to HRP (7074, CST), diluted to a dilution of 1: 2000, was incubated for 2 h at room temperature (with gentle shaking) followed by several washes with PBS / Tween. All antibodies were prepared in 5% Marvel (w / v) in PBS / Tween.

Immunoblots were developed using Pierce WestDura chemiluminescence reagents (Thermo Scientific 34076) and developed / quantified on a G-box using Syngene software. The ERa receptor suppression value was normalized against vehicle control (0% suppression) and 100 nM fulvestrant control (100% suppression) run on the same gel.

Table B shows data obtained for selected examples (data below may represent the result of a single experiment or the average of two or more experiments).

Table B

Example Western blotting for SAMA1 % degr. ER versus Fv Western blotting for MCF7% deg. ER versus Fv 1 66 79 4 75 56 6 81 97 7 90 100 eight 93 98 nine 101 97 ten 101 94 eleven 92 94 12 89 92 13 92 83 fourteen 95 95 15 91 94 16 83 89 19 103 101

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twenty 91 88 21 95 99 22 96 96 23 95 95 35 92 94 40 70 86 44 94 95 45 93 89 46 89 83 51 93 92 55 94 89 57 88 93 58 83 76 60 97 92 61 83 94 62 96 95 63 85 94 64 98 96 65 97 94 76 85 92 88 93 90 90 93 76 92 91 93 96 100 94 97 84 89 107 98 95 BUT 83 91 111 92 84 117 92 96 121 107 85 123 90 91 124 82 93 126 89 93 127 100 96 133 86 88 137 95 90

140 86 84 141 n. and. 79 142 80 85 143 71 87 145 87 94 152 90 93

Analysis using human hepatocytes

The metabolic stability of compounds in human hepatocytes was assessed using the following protocol.

1. Prepare 10 mM stock solutions of compound and control compounds in an appropriate solvent (DMSO). The incubation medium (L-15 medium) is placed in a water bath at 37 ° C and heated for at least 15 minutes before use.

2. Add 80 μl of acetonitrile to each well of a 96 well deep well plate (block plate).

3. In a new 96-well plate, dilute 10 mM test compounds and control compounds to 100 µM by combining 198 µl acetonitrile and 2 µl 10 mM stock solution.

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4. Remove the vial containing cryopreserved (at temperatures less than -150 ° C) human hepatocytes (human hepatocytes from 10 LiverPool donors, obtained from Celsis IVT. Chicago, IL (item # S01205)) from storage, making sure the vials remain at cryogenic temperatures until the defrosting process begins. Thaw the cells as quickly as possible by placing the vial in a water bath at 37 ° C and gently shaking the vials. The vials should remain in the water bath until all ice crystals have dissolved and are no longer visible. After completion of defrosting, the vial is sprayed with 70% ethanol, the vial is transferred to a microbiological safety box.

5. Open the vial and pour the contents into a 50 ml conical tube containing thawing medium. Place a 50 ml conical tube in a centrifuge and centrifuge at 100 g for 10 minutes. After centrifugation is complete, the thawing medium is removed by evacuation and the hepatocytes are resuspended in sufficient incubation medium to yield ˜1.5 x 106 cells / 'ml.

6. Using the Cellometer Vision, cells are counted and the density of viable cells is determined. Cells with low viability (viability <80%) are unacceptable for use. The cells are diluted with the incubation medium to a working cell density of 1.0 x ^{10 6} viable cells / ml.

7. Transfer 247.5 μl of hepatocytes to each well of a 96-well cell culture plate. Place the plate on an Eppendorf Thermomixer Comfort plate shaker to heat the hepatocytes for 10 min.

8. Add 2.5 µL of 100 µM test compound or control compounds to the incubation well containing the cells, mix until a homogeneous suspension is achieved after 0.5 min, which, when reached, will define a time point of 0.5 min. After 0.5 min, 20 μl of the incubated mixture is transferred to the wells in the plate to block, followed by vortexing.

9. The plate is incubated on an Eppendorf Thermomixer Comfort plate shaker at 37 ° C at 900 rpm. After 5, 15, 30, 45, 60, 80, 100 and 120 minutes, the incubation system is stirred and at each time point, 20 μl samples of the incubated mixture are transferred to the wells in a separate plate for blocking, followed by vortexing.

10. The blocking plates are centrifuged for 20 minutes at 4000 rpm. 4 different compounds are collected in one cassette and used for LC / MS / MS analysis.

All calculations were performed using Microsoft Excel. The peak areas were determined from the obtained ion chromatograms. The in vitro intrinsic clearance (in vitro Clint, in L / min / 10 ⁶ cells) of the parent compound was determined by regression analysis of the Ln curve of the percent disappearance of the parent compound versus time. The in vitro intrinsic clearance (in vitro Cl _int , in L / min / 10 ⁶ cells) was determined from the slope value using the following equation and its values are shown in Table C:

in vitro Cl _int = kV / N

V = incubation volume (0.25 ml);

N = number of hepatocytes per well (0.25 x 10 ⁶ cells).

Table C

Example nine fourteen 55 57 121 123 126 127 143 145 151 152 157 160

Clint (μl / min / 10 ^b cells) 4 6 <1 2 <1 <1 <1 <1 4 5 <1 2 2 1

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Physical properties of logD

Lipophilicity of a drug is an important physical property that can influence many of the biological and metabolic properties of a compound, such as absorption, distribution, metabolism, excretion, and toxicity profiles of a compound. The partition coefficient between 1-octanol and an aqueous buffer, LogDO / W, at pH 7.4 is the most widely used indicator of the lipophilicity of a compound. The current LogDO / W measurement method is based on the traditional shake flask technique, but with the modification of measuring ten compounds simultaneously in mixtures using UPLC with quantitative mass spectrometry (MS) as a method for measuring relative concentrations in octanol and water. The maximum capacity is 379 working connections (48 sets of 10 connections, including three QC connections) per experiment. 2 QC samples, Medium LogD Cyclobenzapine and High LogD Nicardipine, are used with all populations to ensure proper quality. An additional QC sample, caffeine, with a low LogD value, was used and randomly assigned to all cycles. The method has been thoroughly tested against previously used shake flask techniques.

Solubility

For an oral compound to reach the site of action and for an oral compound to be absorbed from the intestine, the compound must be in solution, and therefore compounds that have high intrinsic solubility may be more suitable for pharmaceutical use. The thermodynamic solubility of the test compound is measured under standard conditions. This is a shake flask method that uses 10 mM DMSO based solutions supplied from Compound Managements' liquid storage facility and has a high throughput. The dried compounds are equilibrated in aqueous phosphate buffer (pH 7.4) for 24 hours at 25 ° C, then the portion with the dissolved compound is separated from the residue. Solutions are analyzed and quantified using UPLC / MS / MS, and QC samples are included in each run to ensure assay quality. Binding to human blood plasma protein

Binding to human plasma protein is a key factor in controlling the amount of free (unbound) drug available for binding to the target, and therefore plays an important role in the observed drug efficacy in vivo. Therefore, compounds that have a high free fraction (low plasma protein binding) may show increased efficacy relative to compounds with similar levels of activity and exposure. An automated equilibrium dialysis assay in human plasma is performed using a RED (Rapid Equilibrium Dialysis) device and sample processing. The analysis usually lasts from two to three days, including the issuance of results. After dialysis for 18 hours, samples of blood plasma and buffer are prepared for analysis by liquid chromatography and mass spectrometry. Samples are usually tested in one replicate and quantified by LC / MSMS using a 7-point calibration curve in blood plasma. The compounds are combined into plasma aggregates of no more than 10 compounds. Three reference compounds are used in each cycle: propranolol, metoprolol and warfarin. Warfarin was used as a control in each set, and propranolol and metoprolol were randomly placed in each cycle. The Excel macro for internal use is used to prepare files for the robotic station and mass spectrometer and is also used to calculate the content of the unbound fraction (fu%) in blood plasma.

Table D shows logD, solubility and plasma protein binding data obtained for selected examples (data below may represent the result of a single experiment or the average of two or more experiments).

Table D

Example LogD pH 7.4 Solubility (μM) Binding to human blood plasma protein (% free) 1 3.0 303 6.5 2 3.1 895 3.8 3 3.0 712 2.6 4 2.5 543 ten 5 3.0 357 2.8 6 3.2 154 2.2

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7 3.7 35 1.5 eight 2.6 617 5.6 nine 3.6 100 1.6 ten 3.6 67 2.0 eleven 3.4 102 0.85 13 2.6 493 3.5 fourteen 2.4 606 4.0 15 2.9 571 3.2 16 4.1 74 1,2 17 4.0 68 0.36 eighteen 4.5 27 0.55 19 4.6 5 0.49 twenty 4.6 eleven 0.24 21 4.6 3 0.10 22 4.2 0.7 0.61 23 3.4 73 3.7 24 3.7 88 0.84 25 4.3 19 0.080 26 4.6 eight 0.22 27 4.2 6 0.42 28 3.8 40 1,2 29 > 3.2 58 <3.2 thirty 4.1 39 0.72 31 4.1 40 0.41 32 4.1 55 0.52 33 4.5 eight 0.090 34 3.7 151 2.2 35 3.1 222 5.4 36 3.5 183 2 37 3.6 434 2,3 38 n. and. Η. and. 0.91 39 3.6 259 Η. and. 40 3.0 366 0.89 41 2.9 242 1.8 42 2.9 349 Η. and. 43 2.2 358 2.8

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44 3.3 278 2,3 45 3.3 227 1,2 46 2.8 462 2.4 47 2.7 488 6.1 48 2.8 307 n. and. 49 2.8 335 Η. and. 50 2.8 461 7.1 51 3.2 122 2,3 52 3.0 426 3.3 53 0.1 > 1000 80 54 0.9 > 1000 eighteen 55 0.9 875 26 56 2.7 445 4.6 57 1,3 > 1000 17 58 0,4 > 1000 38 59 0.9 > 1000 28 60 3.0 351 1.9 61 3.0 446 2.0 62 3.3 302 1,2 63 3.1 273 0.97 64 2.7 944 5.4 65 3.0 462 1.9 66 3.0 441 1,3 67 4.0 80.6 1.6 68 3.2 56.6 1,2 69 3.6 150 2.2 70 2.2 231 23 71 3.8 <1.6 0.44 72 5.2 <0.2 <0.1 73 4.4 7 0.24 74 4.1 0.9 0.61 75 4.5 0.9 0.08 76 3.1 147 4.6 77 2.4 410 5.5 78 4.0 26 0.21 79 4.8 3.9 <0.4

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80 4.5 13 0.12 81 2.6 736 2.9 82 2.9 475 1.9 83 2.9 595 2.5 84 2.4 640 6 85 3.1 224 ι, ο 86 2.9 385 2.6 87 3.1 71 1.6 88 3.4 118 0.58 89 2.7 670 <3.4 90 2.8 365 1.1 91 2.9 280 0.93 92 2.7 468 n. and. 93 4.3 0.5 0.34 94 2.4 698 7 95 2.5 869 4.6 96 2.4 960 7.1 97 1.8 > 1000 6.8 98 2,3 594 Η. and. 99 2.1 285 Η. and. 100 2.5 > 1000 Η. and. 101 3.3 329 8.4 102 3.8 251 1.4 103 2.9 660 2 104 3.0 431 2.8 105 3.4 136 1 106 3.9 264 0.34 107 3.6 120 1 108 3.2 375 2,3 109 > 3.6 176 1.9 BUT 3.1 939 Η. and. 111 3.1 469 1.4 112 3.2 92 1.5 113 4.1 <1.6 Η. and. 114 3.3 276 1.7 115 2.1 983 eleven

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116 0.3 > 1000 58 117 0.8 948 46 118 1.8 111 8.4 119 1,3 > 1000 31 120 n. and. n. and. n. and. 121 1.4 > 1000 thirty 122 1.1 > 1000 eighteen 123 1.1 954 36 124 1,3 958 fourteen 125 0.9 978 7.4 126 1,2 966 15 127 1.8 952 24 128 1.0 973 15 129 1.5 953 23 130 1.5 854 7.8 131 1,2 > 1000 32 132 0.6 914 34 133 1,2 772 16 134 0.6 > 1000 36 135 0.5 > 1000 32 136 1.1 328 2.1 137 1.4 > 1000 eleven 138 1.6 995 8.3 139 1.0 916 13 140 1.7 775 5.7 141 1.5 638 5.2 142 1.4 796 6.2 143 1.5 > 1000 28 144 n. and. n. and. n. and. 145 1.8 > 1000 15 146 1.9 887 fourteen 147 n. and. n. and. 19 148 1.5 788 ten 149 2.2 523 5.3 150 1,3 924 32 151 1.0 > 1000 45

152 1.9 860 twenty 153 1.9 > 1000 22 154 3.5 49 2.7 155 2,3 978 9.2 156 1.7 882 eighteen 157 1,2 943 29 158 1.8 > 1000 21 159 1.7 > 1000 13 160 1.7 951 32 161 1,3 > 1000 6.3 162 1.8 > 1000 27 163 0.7 > 1000 49

(n. and. = not investigated)

HERG binding assay

Potassium channels encoded by hERG (human heart specific potassium channel gene) are important for normal electrical activity of the heart. Arrhythmia can result from blockage of hERG channels by a heterogeneous group of drugs. This side effect is a common cause of unsatisfactory results in preclinical safety studies [Sanguinetti et al., Nature., 2006, 440, 463-469.], And therefore minimizing hERG blocking activity -channel can be a relevant property for drug candidates.

The purpose of the hERG binding assay is to evaluate the effects of test compounds on the voltage-gated potassium channel encoded by the human heart specific potassium channel gene (hERG) using a constitutively expressing CHO cell line on a Nanion Syncropatch 384PE automated voltage clamping system.

The analysis was performed as follows, with all reagents used at room temperature, unless otherwise indicated.

Reagent preparation includes:

1. Internal solution IC700 used for embedding into the bottom of the chip (in mM): 130 KF, 20 KCl, 1 MgCl ₂ , 10 EGTA and 10 HEPES, (all from Sigma-Aldrich; pH 7.2-7.3 s using 10 M KOH, 320 mosm) and with the addition of 25 μM escin.

2. External buffer and buffer for cells (in mM): 137 NaCl, 4 KCl, 10 HEPES, 10 D-glucose, 2 CaCl ₂ , 1 MgCl ₂ (pH 7.4, NaOH)

3. Reference buffer NMDG used to establish a stable baseline before adding test compounds: 80 NaCl, 4 KCl, 2 CaCl ₂ , 1 MgCl ₂ , 60 NMDG Cl, 5 D-glucose monohydrate, 10 HEPES (pH 7.4 NaOH 298 mOsm)

4. Contact enhancer used to improve the ability of cells to form contact: 80 NaCl, 3 KCl, 10 CaCh, 10 HEPES, I MgCh (pH 7.4 NaOH)

Cell preparations:

1. When using cell culture, cells must be incubated at 30 ° C for about 4-6 days prior to use. On the day of analysis, cells are harvested using Accutase and resuspended in 20 ml of cell buffer to a density of 0.8 to 1e6 cells / ml.

2. If ready for analysis cryovials are used, quickly thaw two cryovials at 37 ° C and slowly pipette into 23 ml of external solution.

3. Before starting the analysis, all prep. cells must be incubated for 15 minutes. in a shaker-incubator for cells, set at 10 ° C.

Preparation of compounds:

All compounds were dispensed by acoustic technology in four replicates using Labcyte Echo. A 10 mM stock solution was used to prepare 6 compound stock plates, each at a different concentration, for applying cumulative doses to cells (0.03167 mM, then 0.1 mM, then 0.3167 mM, 1 mM, 3.167 mM, 10 mM ). 90 μl of reference buffer containing 600 nl of compound is added to each well of the original plates to give final compound concentrations of 0.1, 0.39, 1.2, 3.9, 12.5 and 39.6 μM, respectively.

HERG assay (all dispensing steps were performed on a Nanion syncropatch using a liquid dosing setting)

1. Add 40 μl of external buffer to 384 well 4-channel chips with medium resistance and pour the internal buffer into the bottom of the plate.

2. Dispense 20 µl of cells into each well of the chip, followed by 20 µl of contact enhancer.

3. Remove 40 µl of reagent from each well to the washing block, leaving a residual volume of 40 µl.

4. Dispense 40 µl of reference buffer with a step of removing 40 µl after 3 minutes, repeat this step.

5. Dispense 40 μl of compound from plate 1 (0.03167 mM), record in real time with 3 min exposure, then remove 40 μl. This step is repeated for another 5 further compound plates at increasing concentrations to generate a cumulative concentration-response curve for each well of the Syncropatch chip.

The hERG-mediated currents were generated using a voltage drop protocol consisting of intermittently maintaining the voltage at -80 mV, with a step of increasing to 60 mV for 500 ms, followed by a step of decreasing to -40 mV for 500 ms in 15 s increments. The current through the hERG was automatically measured based on the leakage subtraction recording using Nanion software by recording the peak of the hERG trace current at -40 mV in 15 s increments and using the last three such responses for each concentration to construct a concentration-effect curve.

The calculation of the results is carried out using the APC package as part of Genedata. For standard normalization of well data using neutral control well groups and inhibitor control well groups as a reference, the GeneData Assay Analyzer applies the following equation to normalize signal values to the desired signal range:

N (x) = CR + x - <cr> (SR - CR) <sr> - <cr>

x is the original value of the measured signal from the well;

- 49 038160 <cr> is the average of the measured signals from the wells on the plate, which are the central standard (neutral);

<sr> is the average of the measured signals from the wells on the plate representing the scale standard (with inhibitor);

CR is the required value for the central standard (neutral), normalized to the mean;

SR is the required value for the reference scale (with inhibitor), normalized to the mean.

Table E shows hERG binding data for selected examples (data below may represent the result of a single experiment or the average of two or more experiments).

Table E

Example IC ₅₀ hERG (μM) Example 1C ₅₀ hERG (μM) 1 4.4 76 4.2 6 5.4 77 5.4 7 3.8 79 ten eight 4.6 80 ten nine 9.6 81 3.9 ten 3.6 82 4.3 eleven 5.4 83 4 12 8.2 84 2.8 13 2.6 85 4.2

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fourteen 5.1 86 3.9 15 4.6 87 2.4 17 4.1 88 4.8 eighteen 4.5 89 6.1 twenty 3.8 90 5 22 4.2 91 2.6 23 5.4 92 23 24 7 93 6.6 25 5.2 94 9.9 26 4.1 95 7.2 27 4.8 96 ten 28 3.6 97 eighteen 29 5.1 98 > 32 thirty 2,3 99 twenty 31 eleven 100 19 32 5.8 101 7.1 33 5.3 102 7.2 34 3.4 103 4.3 35 5.6 104 4.3 36 8.7 105 3.5 37 3.5 106 7.3 38 5 107 8.1 39 3.9 108 6 40 4.1 BUT 2.8 41 4.9 111 5.1 42 7.1 112 19 43 3.1 114 5.9 44 2.9 115 eleven 45 1.5 117 > 40 46 2.7 119 > 40 47 3.2 121 > 40 48 2.7 123 > 40 49 5.6 125 > 40 50 5.3 126 > 40 51 4.1 128 > 40 52 5.5 132 > 40

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53 > 40 133 > 40 54 > 40 137 > 40 55 > 40 138 > 40 57 > 40 140 > 40 58 > 40 143 > 40 59 > 40 145 > 40 60 4.4 149 > 40 61 2.7 151 > 40 62 5 152 > 40 63 4.7 154 4.3 64 6.1 156 > 40 65 9.4 157 > 40 66 5.4 158 > 40 67 5.7 159 > 40 68 2 161 > 40 69 2.7 162 > 40 70 6.3 71 5.8 73 6,7 74 12 75 7,7

Permeability

In order to maximize the absorption of the compound for oral administration, the drug should have a sufficient level of transmembrane transfer, and also avoid excretion by P-glycoprotein. The most widely used system for predicting the absorption of a compound for oral administration is to determine the level of penetration of compounds through monolayers of the human colon adenocarcinoma cell line Caco-2.

Bidirectional permeability of human Caco-2 in the direction from A to B and from B to A

To determine the bidirectional permeability (elimination and capture) of compounds in Caco-2 cells, an automated assay was used, which was performed for 2 h at pH 7.4. Samples were analyzed by LC / MS / MS to evaluate the apparent coefficients of permeability (Papp) of compounds in monolayers of Caco-2 cells, and the results are reported in units of x10 ^-6 cm / s.

The elimination rate (ER) can be determined using the following equation:

ER - Rarr (B-A) / Rarr (A-B)?

where P _apP ( _B-A ) denotes the apparent permeability ratio for the basolateral to apical direction, and P _app ( _A-B ) denotes the apparent permeability ratio for the apical to basolateral direction.

Papp for passive permeability of human Saco-2 in the direction from A to B

To determine the passive permeability of compounds in monolayers of Caco-2 cells, an automated assay was used, which was carried out for 2 h at pH 6.5 on the apical side and pH 7.4 on the basolateral side. The Caco-2 AB inhibition assay is performed using chemical inhibition in Caco-2 cells of three major efflux transporters: ABCB1 (P-gp), ABCG2 (BCRP), and ABCC2 (MRP2). Incubation of both the apical and basolateral sides is carried out using a mixture of inhibitors (50 μM quinidine, 20 μM sulfasalazine and 100 μM benzbromarone). Samples were analyzed by LC / MS / MS to evaluate the apparent coefficients of permeability (Papp) of compounds in monolayers of Caco-2 cells, and the results are reported in units of x10 ^-6 cm / s.

Table F shows the permeability data obtained for the selected examples (the data below may represent the result of a single experiment or the average of two or more experiments).

- 52 038160

Table F

Example Papp for bidirectional permeability Saco-2 (x10 ' ⁶ cm / s) Percentage of elimination FOR bidirectional permeability of Saco-2 Rarr for passive permeability Saco-2 (x10 ' ⁶ cm / s) nine 1.0 1.0 n. and. ten 1.4 1.6 n. and. eleven 3.6 1.4 Ή. AND. fourteen 4.4 1,3 13 52 8.8 1, o n. and. 55 0.55 23 <0.7 57 0.15 105 <1.2 59 0.035 480 <0.3 64 2.6 6.1 n. and. 76 6.4 0.55 n. and. 117 0.27 34 <0.3 119 0.85 25 3.5 121 0.20 58 n. and. 122 0.58 40 <1.0 123 1.1 16 <1.0 124 1.1 23 1.9 125 0.13 130 <0.6 126 0.46 52 1,2 127 0.43 48 2.0 133 0.29 51 2.5 137 0.35 64 4.6 138 0.16 94 1.8 139 0.26 54 <0.9 140 0.51 36 4.0 141 0.54 36 3.4 142 0.34 40 3.2 143 3.2 eleven 3.3 144 0.50 35 4.0 145 5.6 3.4 17 151 2.2 9.5 4.3 152 eleven 2.2 16 155 7.3 2.6 23 156 4.6 4.2 9.2 157 3.6 5.6 12 160 4.4 6.4 4.2

(n. and. = not investigated)

In accordance with a further aspect of the present disclosure, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined above in this document, in combination with a pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents, granulating agents and disintegrating agents, binders, lubricants, preservatives, and antioxidants. An additional suitable pharmaceutically acceptable excipient may be a hedating agent. Tablet formulations may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in any case using conventional coating agents and procedures well known. from the prior art.

Compositions for oral administration may alternatively be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil.

Aqueous suspensions typically contain the active ingredient in finely divided form together with one or more suspending, dispersing or wetting agents

- 53 038160 funds. Aqueous suspensions may also contain one or more preservatives, antioxidants, colors, flavors and / or sweeteners.

Oily suspensions can be formulated by suspending the active ingredient in vegetable oil or mineral oil. Oily suspensions may also contain a thickening agent. Sweeteners such as those set forth above and flavoring agents can be added to provide an oral preparation with an attractive taste. Such compositions can be preserved by the addition of an antioxidant.

Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. Additional auxiliaries such as sweeteners, flavors and colors may also be present.

Pharmaceutical compositions in accordance with the present disclosure can also be presented in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, or a mixture of any of these. Emulsions can also contain sweeteners, flavors and preservatives.

Syrups and elixirs can be formulated with sweeteners and can also contain an emollient, preservative, flavoring and / or coloring agent.

The pharmaceutical compositions can also be presented in the form of a sterile injectable aqueous or oily suspension, which can be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent system.

Compositions to be administered by inhalation may be in the form of a conventional pressurized aerosol for dispensing the active ingredient in the form of an aerosol containing fine solid particles or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used, and the aerosol device is conveniently arranged to dispense a metered amount of active ingredient. Dry powder inhalers may also be suitable.

For additional compilation information, the reader is referred to Chapter 25.2 of Volume 5 of the Comprehensive Medicinal Chemistry (Corwin Hansch; editorial board chairman), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a unit dosage form will inevitably vary depending on the recipient being treated and the particular route of administration. For example, oral administration to humans will generally require administration of, for example, 1 mg to 2 g of active agent (more suitably 100 mg to 2 g, such as 250 mg to 1.8 g, such as , from 500 mg to 1.8 g, in particular from 500 mg to 1.5 g, for the sake of convenience from 500 mg to 1 g), formulated as a mixture with an appropriate and appropriate amount of excipients, which may vary from about 3 to about 98 percent by weight of the total composition. It should be understood that in the event that a large dose is required, several dosage forms may be required, for example, two or more tablets or capsules, with the dose of the active ingredient dispersed therebetween for convenience sake. Typically, unit dosage forms will contain from about 10 mg to 0.5 g of a compound as described herein, although a unit dosage form may contain up to 1 g. For convenience, a unit solid dosage form may contain from 1 mg to 300 mg of active ingredient. ...

The dosage size of the compounds as described herein for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the disease condition, the age and sex of the animal or patient, and the route of administration in accordance with well-known medical principles.

When the compounds are used according to the present disclosure for therapeutic or prophylactic purposes, they are usually administered so that the daily dose is in the range of, for example, 1 to 100 mg / kg body weight, optionally in divided doses. Typically, when using the parenteral route, lower doses will be administered. Thus, for example, for intravenous administration, a dose in the range of, for example, 1 to 25 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 1 to 25 mg / kg body weight will be used. However, oral administration is preferred, in particular in the form of tablets.

In one aspect of the present description, the compounds according to the present description or their pharmaceutically acceptable salts are administered in the form of tablets containing from 10 to 100 mg of the compound according to the present description (or a pharmaceutically acceptable salt thereof), where to achieve

- 54 038160 of the required dose, depending on the need, one or more tablets are administered.

As noted above, ERa signaling is known to induce tumor formation through one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenesis events, and mediating cancer cell motility, migration and invasiveness. The present inventors have found that compounds according to the present disclosure have potent antitumor activity, which is believed to be achieved by antagonizing and suppressing ERa, which is involved in the signaling steps that mediate tumor cell proliferation and survival, as well as invasiveness. and the ability to migrate in metastatic tumor cells.

Accordingly, the compounds according to the present disclosure may be of value as antitumor agents, in particular as selective inhibitors of proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells, leading to suppression of tumor growth and survival and suppression of the growth of metastatic tumors. In particular, compounds according to the present disclosure may be of value as antiproliferative and antiinvasive agents in containing and / or treating a disease characterized by the presence of a solid tumor. In particular, the compounds according to the present disclosure may be useful in the prevention or treatment of those tumors that are sensitive to the suppression of ERa function, which are involved in the signaling steps that lead to the proliferation and survival of tumor cells, as well as the ability to migrate and invasiveness. in metastatic tumor cells. In addition, compounds according to the present disclosure may be useful in the prevention or treatment of those tumors for which it is mediated solely or partially by ERa antagonism and suppression, i. E. the compounds can be used to produce an ERa inhibitory effect in a warm-blooded animal in need of such treatment.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use as a medicament in a warm-blooded animal such as a human.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in obtaining an antiproliferative effect in a warm blooded animal such as a human.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in a warm-blooded animal, such as a human, as an anti-invasive agent in containing and / or treating a disease characterized by the presence of a solid tumor.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, to obtain an antiproliferative effect in a warm blooded animal such as a human.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in obtaining an antiproliferative effect in a warm-blooded animal such as a human.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in a warm-blooded animal, such as a human, as an anti-invasive agent in containing and / or treating a disease characterized by the presence of a solid tumor.

According to a further aspect of the present disclosure, there is provided a method of obtaining an antiproliferative effect in a warm blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

In accordance with a further aspect of the present disclosure, there is provided a method of obtaining an anti-invasive effect by containing and / or treating a disease characterized by the presence of a solid tumor in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount

- 55 038160 a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or its a pharmaceutically acceptable salt as defined hereinabove.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the prevention or treatment of cancer in a warm-blooded animal, such as a human.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the prevention or treatment of cancer in a warm-blooded animal, such as a human.

According to a further aspect of the present disclosure, there is provided a method for preventing or treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC) , (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the prevention or treatment of a disease characterized by the presence of a solid tumor in a warm-blooded animal such as a human.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the prevention or treatment of a disease characterized by the presence of a solid tumor in a warm-blooded animal such as a human.

According to a further aspect of the present disclosure, there is provided a method for preventing or treating a disease characterized by the presence of a solid tumor in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), ( IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined above, for use in the prevention or treatment of tumors that are sensitive to suppression of ERa function, which are involved in the signaling steps involved in the proliferation, survival, invasiveness and migration of tumor cells.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament intended for use in the prevention or treatment of tumors that are susceptible to suppression of ERa function, which are involved in the signaling steps involved in proliferation, survival , invasiveness and ability to migrate tumor cells.

In accordance with a further aspect of the present disclosure, there is provided a method for preventing or treating tumors that are sensitive to suppression of ERa function that are involved in the signaling steps of proliferation, survival, invasiveness, and the ability to migrate tumor cells, which comprises administering to said animal an effective amount a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof defined earlier in this document.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in providing an ERa inhibitory effect.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in providing an ERa inhibitory effect.

According to a further aspect of the present disclosure, there is also provided a method of providing an ERa inhibitory effect, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF ), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

- 56 038160

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in providing a selective inhibitory effect on ERa.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in providing a selective inhibitory effect on ERa.

In accordance with a further aspect of the present disclosure, there is also provided a method of providing a selective inhibitory effect on ERa, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), ( IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

This document describes compounds that can bind to the ligand-binding domain of ERa and are selective disruptors of the estrogen receptor. Biochemical and cellular assays have shown that compounds according to the present disclosure are active in binding to estrogen receptors and reduce cellular levels of ERa, and therefore may be useful in the treatment of estrogen-sensitive diseases or conditions (including diseases characterized by the emergence of resistance to endocrine therapy drugs), i.e. for use in the treatment of breast and gynecological cancers (including endometrium, ovarian and cervical cancers) and cancers expressing ERa proteins with mutations that may be de novo mutations or those resulting from treatment with more an early endocrine therapy drug such as an aromatase inhibitor.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the treatment of breast cancer or gynecological cancers.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the treatment of breast, endometrial, ovarian, or cervical cancer.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the treatment of breast cancer.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the treatment of breast cancer where the cancer cells have developed resistance to one or more other endocrine therapy drugs.

In accordance with a further aspect of the present disclosure, there is provided a method of treating breast cancer or gynecological cancers, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), ( IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

In accordance with a further aspect of the present disclosure, there is provided a method of treating breast, endometrial, ovarian, or cervical cancer, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE ), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

In accordance with a further aspect of the present disclosure, there is provided a method of treating breast cancer, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

According to a further aspect of the present disclosure, there is provided a method of treating breast cancer, wherein the cancer cells have developed resistance to one or more other endocrine therapy drugs, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC ), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the treatment of breast cancer or gynecological cancers.

In accordance with a further aspect of the present disclosure, the use of a co-57 038160 combination of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ) is provided. , (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the treatment of breast, endometrial, ovarian, or cervical cancer.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the treatment of breast cancer.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the treatment of breast cancer, where the cancer cells have developed resistance to one or more other endocrine therapy drugs.

In one feature of the present disclosure, the cancer to be treated is breast cancer. In an additional aspect of this trait, breast cancer is estrogen receptor positive (ER positive). In one embodiment of this aspect, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) ) or a pharmaceutically acceptable salt thereof is administered in combination with another anti-cancer agent, such as the anti-hormonal agent as defined herein.

According to a further aspect of the present disclosure, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove, for use in the treatment of ER-positive breast cancer.

According to a further aspect of the present disclosure, there is provided a method of treating ER-positive breast cancer, which comprises administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF ), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, as defined hereinabove.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof, as defined hereinabove, in the manufacture of a medicament for use in the treatment of ER-positive breast cancer.

The anticancer treatment as defined herein can be used as monotherapy or can include, in addition to using compounds as described herein, conventional surgery or radiation therapy or chemotherapy.

Such chemotherapy may involve the use of one or more of the following categories of antineoplastic agents:

(i) other antiproliferative / antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (for example, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, chlormethine, melphalan, chlorambucil, busulfan, temozolomide and nitrosoureas); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antineoplastic antibiotics (eg, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, as well as taxoids such as taxol and taxotere and polo kinase inhibitors) and topoisomerase inhibitors (eg epipodophyllotoxins such as etoposide and tenena amsacrine, topotecan, and camptothecin);

(ii) antihormonal agents such as antiestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and idoxifene), progestogens (eg megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorozole and exemestane);

(iii) inhibitors of growth factor function and their downstream signaling pathways: included Ab modulators of any growth factor or growth factor receptor targets reviewed by Stern et al. Critical Reviews in Oncologv / Haematology. 2005, 54, pp11-29); also includes small molecule inhibitors of such targets, for example, kinase inhibitors - examples include trastuzumab, which is an anti-erbB2 antibody [Herceptin ™], panitumumab, which is an antibody to EGFR, cetuximab, which is an antibody to EGFR [erbitux, C225 inhibitors], and including inhibitors of the erbB family of receptors, such as inhibitors of tyrosine kinases belonging to the epidermal growth factor receptor (EGFR / erbB1) family, such as gefitinib or erlotinib, inhibitors of tyrosine kinase erbB2, such as lapatinib, and mixed inhibitors of erbl / 2, ; similar strategies are available for other classes of growth factors and their receptors, for example inhibitors of the hepatocyte growth factor family or their receptors, including c-met and ran; insulin inhibitors and the family of insulin growth factors or their receptors (IGFR, IR),

- 58 038160 inhibitors of the platelet growth factor family or their receptors (PDGFR) and inhibitors of signal transduction mediated by other receptor tyrosine kinases such as c-kit, AnLK and CSF-1R; also included are modulators that target signal proteins in the PI3 kinase signaling pathway, for example inhibitors of PI3 kinase isoforms such as P13K-α / β / γ and ser / thr kinases such as AKT, mTOR (such as AZD2014), PDK, SGK, PI4K or PIP5K; also included are inhibitors of serine-threonine kinases not listed above, for example, raf inhibitors such as vemurafenib, MEK inhibitors such as selumetinib (AZD6244), Ab1 inhibitors such as imatinib or nilotinib, Btk inhibitors such as ibrutinib, such as phytarafenib inhibitors , aurorakinase inhibitors (eg AZD1152), inhibitors of other ser / thr kinases such as JAK species, STAT species and IRAK4, and cyclin dependent kinase inhibitors, such as CDK1, CDK7, CDK9 and CDK4 / 6 inhibitors such as palbociclib;

iv) modulators of DNA damage signaling pathways, eg PARP inhibitors (eg olaparib), ATR inhibitors or ATM inhibitors;

v) modulators of signaling pathways of apoptosis and cell death, such as modulators of the Bcl family (eg, ABT-263 / navitoclax, ABT-199);

(vi) anti-angiogenic agents, such as agents that inhibit the effects of vascular endothelial growth factor [e.g. bevacizumab, which is an antibody to vascular endothelial cell growth factor (Avastin ™), and, for example, a VEGF receptor tyrosine kinase inhibitor such as sorafenib, axitinib, pazopanib , sunitinib and vandetanib, as well as compounds acting through other mechanisms (eg, linomide, inhibitors of the function of integrin avaaa3 and angiostatin)];

(vii) vascular damaging agents such as combretastatin A4;

(viii) anti-invasive agents, for example, c-Src family kinase inhibitors such as dasatinib (J. Med. Chem .. 2004, 47, 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat , inhibitors of urokinase-type plasminogen activator receptor function or anti-heparanase antibodies;

(ix) immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of tumor cells in a patient, such as transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte macrophage colony stimulating factor, approaches to reduce T -cellular tolerance, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies. Specific examples include monoclonal antibodies that target PD-1 (eg, BMS-936558) or CTLA4 (eg, ipilimumab and tremelimumab);

(x) types of antisense or RNAi-based therapies, for example, directed to the listed targets;

(xi) gene therapy approaches, including, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-mediated enzyme prodrug therapy) approaches such as cytosine deaminase, or thymidine kinase approaches , and approaches to increasing patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy.

Accordingly, in one embodiment, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or ( IZA) or a pharmaceutically acceptable salt thereof and an additional anticancer agent for the joint treatment of cancer.

In accordance with this aspect of the present disclosure, there is provided a combination suitable for use in the treatment of cancer comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH) ), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof and another antineoplastic agent, in particular any of the antineoplastic agents listed in items (i) to (xi) above. In particular, the use of the antineoplastic agents listed in items (i) to (xi) above constitutes the standard of care for the particular type of cancer to be treated; a person skilled in the art will understand the meaning of the term standard of care.

Therefore, in a further aspect of the present disclosure, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof in combination with another antineoplastic agent, in particular an antineoplastic agent selected from those listed in items (i) to (xi) above in this document.

In a further aspect of the present disclosure, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is provided ) or a pharmaceutically acceptable salt thereof in combination with another antineoplastic agent, in particular an antitumor agent selected from those listed in (i) above.

In a further aspect of the present disclosure, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is provided ) or a pharmaceutically acceptable salt thereof and any of the pro 59 038160 antineoplastic agents listed in n. (i) above.

In a further aspect of the present disclosure, a combination suitable for use in the treatment of cancer is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof and a taxoid such as, for example, Taxol or Taxotere, especially Taxotere.

In a further aspect of the present disclosure, a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) is provided ) or a pharmaceutically acceptable salt thereof in combination with another antineoplastic agent, in particular, an antitumor agent selected from those listed in item (i) above in this document.

In a further aspect of the present disclosure, a combination suitable for use in the treatment of cancer is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof and any of the anti-hormonal agents listed in (p) above, for example, any of the antiestrogens listed in (p) above, or, for example , of the aromatase inhibitors listed in (n) above.

In a further aspect of the present disclosure, a combination suitable for use in the treatment of cancer is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof and an mTOR inhibitor such as AZD2014.

In a further aspect of the present disclosure, a combination suitable for use in the treatment of cancer is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof and a PI3Ka inhibitor such as compound 1 (4- (5- (5-amino-6- (5-tert-butyl-1,3,4- oxadiazol-2-yl) pyrazin-2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidin-1-yl) -3-hydroxypropan-1-one, or a pharmaceutically acceptable salt.

In a further aspect of the present disclosure, a combination suitable for use in the treatment of cancer is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA); or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor such as palbociclib.

In one aspect, the above combination of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof with the antitumor agent listed in (p) above, or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as compound 1- (4- (5- (5-amino-6 - (5-tert-butyl-1,3,4-oxadiazol-2-yl) pyrazin-2-yl) -1ethyl-1H-1,2,4-triazol-3-yl) piperidin-1-yl) - 3-hydroxynropan-1-one), or a CDK4 / 6 inhibitor (such as palbociclib) is suitable for use in the treatment of breast or gynecological cancers such as breast, endometrial, ovarian or cervical cancer, in particular breast cancer gland, such as ER-positive breast cancer.

Whenever the term combination is used herein, it should be understood to refer to simultaneous, separate or sequential administration. In one aspect of the present disclosure, the combination refers to simultaneous administration. In another aspect of the present disclosure, the combination refers to separate administration. In a further aspect of the present disclosure, the combination refers to sequential administration. If the administration is sequential or separate, then the delay in the administration of the second component should not be such that the beneficial effect of the combination is lost. If a combination of two or more components is administered separately or sequentially, it will be appreciated that the dosage regimen for each component may be different from and independent of the dosage regimens of the other components. For convenience, compounds as described herein are dosed once a day.

According to a further aspect of the present disclosure, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA) a pharmaceutically acceptable salt thereof in combination with an antineoplastic agent selected from those listed in items (i) to (xi) above in this document, in combination with a pharmaceutically acceptable excipient.

In accordance with a further aspect of the present disclosure, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA) a pharmaceutically acceptable salt thereof in combination with any of the antihormonal agents listed in (n) above, for example, any of the antiestrogens listed in (n) above, or, for example, inhibitors aromatase listed in item (n) above, in combination with a pharmaceutically acceptable excipient.

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof and an mTOR inhibitor such as AZD2014 in combination with a pharmaceutically acceptable excipient.

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof and a PI3Ka inhibitor such as compound 1- (4- (5- (5-amino-6- (5-tert-60 038 160 butyl-1,3,4-oxadiazole-2 -yl) pyrazin-2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidin-1-yl) -3-hydroxypropan-1-one, in combination with a pharmaceutically acceptable excipient ...

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor (such as palbociclib) in combination with a pharmaceutically acceptable excipient.

According to a further aspect of the present disclosure, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with an antineoplastic agent selected from those listed in (i) - (xi) above in this document, in combination with a pharmaceutically acceptable adjuvant for use in treatment cancer.

In accordance with a further aspect of the present disclosure, a pharmaceutical composition is provided that comprises a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, in combination with any of the anti-hormonal agents listed in (p) above, for example, any of the antiestrogens listed in (p) above, or, for example, from the aromatase inhibitors listed in (i) above, in combination with a pharmaceutically acceptable excipient for use in the treatment of cancer.

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof and an mTOR inhibitor such as AZD2014 in combination with a pharmaceutically acceptable adjuvant for use in the treatment of cancer.

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof and a PI3Ka inhibitor such as compound 1- (4- (5- (5-amino-6- (5-tert-butyl-1,3,4-oxadiazol-2-yl) pyrazine -2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidin-1-yl) -3-hydroxypropan-1-one, in combination with a pharmaceutically acceptable auxiliary for use in treatment cancer.

In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) ) or (IZA) or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor (such as palbociclib) in combination with a pharmaceutically acceptable adjuvant for use in the treatment of cancer.

In one aspect, the above pharmaceutical compositions based on a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof with the antitumor agent listed in (i) above, or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as compound 1- (4- (5- (5- amino-6- (5-tert-butyl-1,3,4-oxadiazol-2yl) nurazin-2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidine-1- yl) -3-hydroxypropan-1-one), or a CDK4 / 6 inhibitor (such as palbociclib) are suitable for use in the treatment of breast or gynecological cancers such as breast, endometrial, ovarian or cervical cancer, in particular breast cancer such as ER-positive breast cancer.

In accordance with another feature of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with an antineoplastic agent selected from those listed in items (I) to (xi) above in this document, in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such As a person.

According to a further aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with any of the anti-hormonal agents listed in (i) above, for example, any of the antiestrogens listed in (i) above, or, for example, of the aromatase inhibitors listed in m (ii) above, in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as a human.

In a further aspect of the present disclosure, the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA) or a pharmaceutically acceptable salt thereof in combination with an mTOR inhibitor such as AZD2014 in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal, such as a human.

In a further aspect of the present disclosure, the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or ( IZA) or a pharmaceutically acceptable salt thereof in combination with a PI3Ka inhibitor such as compound 1- (4- (5- (5-amino-6- (5-tert-butyl-1,3,4oxadiazol-2-yl) pyrazine- 2-yl) -1-ethyl-1H- 1,2,4-triazol-3-yl) piperidin-1-yl) -3-hydroxypropan-1-one, in the manufacture of a medicinal product intended for use in the treatment of cancer in a warm-blooded animal such as a human.

In a further aspect of the present disclosure, the use of a compound of formula

- 61 038160 (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or its pharmaceutically acceptable salts in combination with a CDK4 / 6 inhibitor (such as palbociclib) in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as a human.

In one aspect, the above-mentioned uses of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) ) or a pharmaceutically acceptable salt thereof in combination with the antitumor agent listed in (p) above, or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as compound 1- (4- (5- (5- amino-6- (5-tert-butyl-1,3,4-oxadiazol-2yl) pyrazin-2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidine-1 - yl) -3-hydroxypropan-1-one), or a CDK4 / 6 inhibitor (such as palbociclib) are suitable for use in the manufacture of a medicament for the treatment of breast cancer or gynecological cancers such as breast cancer, endometrial cancer, ovarian or cervical cancer, in particular breast cancer such as ER-positive breast cancer.

Therefore, in an additional feature of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), ( ID), (IH), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof, in combination with an antineoplastic agent selected from the agents listed in items (i) - (xi ) earlier in this document.

According to a further aspect of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), ( ID), (IH), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with any of the anti-hormonal agents listed in (and) above, for example, any from the antiestrogens listed in (i) above, or, for example, from the aromatase inhibitors listed in (i) above.

In a further aspect of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID) , (IH), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof in combination with an mTOR inhibitor such as AZD2014.

In a further aspect of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID) , (IH), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof in combination with a PI3Ka inhibitor such as compound 1- (4- (5- (5-amino -6- (5-tert-butyl-1,3,4-oxadiazol-2-yl) pyrazin-2-yl) -1-ethyl-1H1,2,4-triazol-3-yl) piperidin-1-yl ) -3-hydroxypropane-1-one.

In a further aspect of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID) , (IH), (IF), (IH), (IJ), (IZ) or (IZA), or a pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor (such as palbociclib).

In one aspect, the above combinations, pharmaceutical compositions, uses and methods for treating cancer are methods for treating breast or gynecological cancers such as breast, endometrial, ovarian or cervical cancers, in particular breast cancers such as ER- positive breast cancer.

In accordance with a further aspect of the present disclosure, a kit is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), ( IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with an antineoplastic agent selected from those listed in items (i) - (xi) above in this document.

In accordance with a further aspect of the present disclosure, a kit is provided comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), ( IZ) or (IZA) or a pharmaceutically acceptable salt thereof in combination with an antineoplastic agent selected from those listed in items (i) or (ii) above in this document.

In accordance with a further aspect of the present disclosure, a kit is provided comprising:

a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or pharmaceutically an acceptable salt in the form of a first unit dosage form;

b) an antineoplastic agent selected from those listed in items (i) to (xi) above in this document, in the form of a second unit dosage form; and

c) a container means for containing said first and second dosage forms.

In accordance with a further aspect of the present disclosure, a kit is provided comprising:

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a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or pharmaceutically an acceptable salt in the form of a first unit dosage form;

b) an antineoplastic agent selected from those listed in items (i) - (ii) above in this document, in the form of a second unit dosage form; and

c) a container means for containing said first and second dosage forms.

In accordance with a further aspect of the present disclosure, a kit is provided comprising:

a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or pharmaceutically an acceptable salt in the form of a first unit dosage form;

b) an antineoplastic agent selected from the antineoplastic agents listed in (n) above, an mTOR inhibitor (such as AZD2014), a PI3Kα inhibitor such as compound 1- (4- (5- (5-amino6- (5- tert-butyl-1,3,4-oxadiazol-2-yl) purazin-2-yl) -1-ethyl-1H-1,2,4-triazol-3-yl) piperidin-1-yl) -3hydroxypropan- 1-one, and a CDK4 / 6 inhibitor such as palbociclib, as a second unit dosage form, and

c) a container means for containing said first and second dosage forms.

The combination therapy described above can be carried out in addition to standard treatment, usually carried out in accordance with his usual schedule of administration.

Although compounds of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) are advantageously of value in as therapeutic agents for use in warm-blooded animals (including humans), they are also applicable in all cases where it is necessary to suppress the function of ER-α. Thus, they are applicable as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

Personalized healthcare

Another aspect of the present disclosure is based on the identification of the relationship between the status of the gene encoding ERa and the potential susceptibility to treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA). In particular, ERa gene status may indicate that the patient is less likely to respond to existing hormone therapy (such as aromatase inhibitors), at least in part because some ERa mutations are thought to arise as mechanisms of resistance to existing treatments. SERD, in particular SERD, which can be administered orally in potentially large doses without undue inconvenience, can therefore be advantageously used to treat patients with ERa mutations who may be resistant to other therapies. Thus, it provides opportunities, methods and tools for selecting patients for treatment with a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), ( IJ), (IZ) or (IZA), in particular, cancer patients. This description relates to tools and methods for patient selection (including personalized medicine). The selection is based on whether the tumor cells to be treated contain the wild-type or mutant ERa gene. The status of the ERa gene can therefore be used as a biomarker to indicate that the choice of SERD treatment may be appropriate. For the avoidance of ambiguity, it is believed that compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) described herein are characterized by similar activity against the wild-type ERa gene and the mutant ERa gene, at least the ERa gene with mutations identified at the filing date of this application.

There is a clear need for biomarkers that will expand the category or select patients whose tumors will respond to SERD treatment, such as a compound of formula (I), (IA), (IB), (IC), (ID), (IE ), (IF), (IH), (IJ), (IZ) or (IZA). Patient selection biomarkers that identify patients most likely to respond to one drug over others are ideal for cancer treatment because they reduce the incidence of unnecessary treatment for patients with non-responsive tumors and the potential side effects of such drugs.

A biomarker can be described as a characteristic parameter that can be objectively measured and assessed as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to therapeutic intervention. A biomarker is any identifiable and measurable indicator associated with a specific condition or disease for which there is a correlation between the presence or level of a biomarker and some aspect of the condition or disease (including the presence, level or change in level, type, stage of the condition or disease, predisposition to it or the ability to respond to a drug used to treat a condition or disease). Correlation can be qualitative, quantitative, or both qualitative and quantitative. Typically, a biomarker is a compound, a fragment of a compound, or a group of compounds. Such compounds can be any compound found or produced in the body, including proteins (and peptides), nucleic acids, and other compounds.

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Biomarkers can have predictive potential and, as such, can be used to predict or determine the presence, level, type or stage of specific conditions or diseases (including the presence or level of specific microorganisms or toxins), predisposition (including genetic predisposition) to specific conditions or disease or response to specific treatments (including drug treatments). It is believed that biomarkers will play an increasingly important role in future drug discovery and development by improving the effectiveness of research and development programs. Biomarkers can be used as diagnostic tools, indicators of disease progression, indicators of treatment, and predictors of clinical outcome. For example, various biomarker research projects are attempting to identify markers for certain cancers and certain cardiovascular and immunological diseases. The development of new validated biomarkers is believed to result in both significant reductions in health care and drug development costs and significant improvements in the treatment of a wide range of diseases and conditions.

A biomarker may be required for optimal planning of clinical trials and to obtain the most complete information from these trials. The marker can be measurable in mimic and tumor tissues. Ideally, these markers will also correlate with efficacy and thus ultimately can be used for patient selection.

Thus, the technical problem underlying this aspect of the present disclosure is to define a method for stratifying patients by treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF ), (IH), (IJ), (IZ) or (IZA). This technical problem is solved by providing for the embodiments described in this document in the claims and / or in the description.

Tumors that contain wild-type ERa are believed to be susceptible to treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), ( IJ), (IZ) or (IZA), for example, as a first-line treatment. Tumors may also respond to treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) ) as second-line, third-line or follow-up therapy, and this can be used, in particular, if tumors contain mutant ERa and can thus be resistant to existing therapies such as AI. In the treatment of resistant tumors, a higher dose of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), ( IZ) or (IZA) than tumors expressing the wild-type receptor.

Provided herein is a method for determining the sensitivity of cells to a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA). This method includes determining the status of the ERa gene in these cells. A cell is defined as sensitive to a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) if it inhibits an increase in the number of cells in a cell growth assay (by inhibiting cell proliferation and / or by increasing the rate of cell death). The methods described herein are useful for predicting which cells are more likely to respond to a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) , (IH), (IJ), (IZ) or (IZA) by inhibiting growth.

The tumor characterizing sample can be an actual isolated tumor sample, or it can be a sample that has been further processed, for example, a sample of PCR amplified nucleic acid from a tumor sample.

Definitions

In this section on Personalized Care, the following is accepted.

An allele refers to a specific form of a genetic locus that differs from other forms in its specific nucleotide or amino acid sequence.

Amplification reactions are nucleic acid reactions that result in the specific amplification of target nucleic acids among non-target nucleic acids. Polymerase chain reaction (PCR) is a well-known amplification reaction.

As used herein, cancer refers to neoplastic growth resulting from the transformation of cells into a neoplastic phenotype. Genetic mutation is often involved in this cell transformation.

A gene is a segment of DNA that contains all the information necessary for the regulated biosynthesis of an RNA product, including a promoter, exons, introns, and other expression control sequence elements that can be located within the 5 'or 3' flanking regions ( but not in the transcribed parts of the gene).

Gene status refers to whether a gene is wild-type or not (i.e., mutant).

A label refers to a composition capable of producing a detectable signal indicative of the presence of a target polynucleotide in a sample to be analyzed. Suitable labels include radioactive isotopes, nucleotide chromophores, enzymes, substrates, fluorescent molecules, chemiluminescence moieties, magnetic particles, bioluminescent moieties, and the like. Thus, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical methods.

A nonsynonymous change refers to a change (variation) in the coding sequence of a gene or overlapping region that results in a different (altered) polypeptide sequence. These changes may or may not affect protein function and include missense variants (where one amino acid is substituted for another), nonsense variants (where the result is polypeptide truncation due to premature stop codon formation), and insertion-deletion options.

Synonymous change refers to a change (variation) in the coding sequence of a gene that does not affect the sequence of the encoded polypeptide. These changes can indirectly affect protein function (for example, by altering gene expression), but in the absence of evidence to the contrary, they are generally considered harmless.

Nucleic acid refers to single-stranded or double-stranded DNA and RNA molecules, including naturally occurring nucleic acids found in nature and / or modified artificial nucleic acids having modified backbones or nucleic bases, as is known in the art.

A primer refers to a single-stranded DNA oligonucleotide sequence capable of acting as an initiation point for synthesizing a primer extension product that is complementary to the nucleic acid strand to be copied. The length and sequence of the primer must be such that it can prime the synthesis of extension products. A typical primer is at least about 7 nucleotides in length and is substantially complementary to the target sequence, but slightly longer primers are preferred. Typically, primers are about 15-26 nucleotides in length, but longer or shorter primers can also be used.

A polymorphic site is a position at a locus at which at least two alternative sequences are found in a population.

Polymorphism refers to a sequence change observed in an individual at a polymorphic site. The types of polymorphism include nucleotide substitutions, insertions, deletions, and microsatellites and may, but need not be, cause detectable differences in gene expression or protein function. In the absence of evidence of an effect on protein expression or function, common polymorphism types, including nonsynonymous variants, are generally considered to be included in wild-type gene sequencing. A catalog of human polymorphism types and related annotations, including validation, frequency of observation, and disease association, is maintained by the NCBI (dbSNP: http://www.ncbi.nlm.nih.gov/projects/SNP/). It should be noted that the term polymorphism when used in relation to gene sequences should not be confused with the term polymorphism when used in relation to the solid form of the compound, that is, the crystalline or amorphous nature of the compound. A person skilled in the art will understand the intended meaning from its context.

Probe refers to sequence-specific single-stranded oligonucleotides that have a sequence exactly complementary to the target allele sequence to be detected.

Response is determined by measurements made in accordance with the criteria for evaluating the response of solid tumors (RECIST), which classifies patients into two main groups: those showing a partial response or stabilization of the disease, and those showing signs of disease progression.

Stringent hybridization conditions refer to overnight incubation at 42 ° C in a solution containing 50% formamide, 5x SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10 % dextran sulfate and 20 pg / ml denatured hydrodynamically shear dehydrated DNA from salmon milk, followed by washing the filters in 0.1 x SSC at approximately 65 ° C.

Survival encompasses overall survival and progression-free survival in a patient.

Overall survival (OS) is defined as the time from initiation of drug administration to death for any reason. Progression-free survival (PFS) is defined as the time from initiation of drug administration to the first manifestation of disease progression or death from any cause.

In accordance with one aspect of the present disclosure, there is provided a method of selecting patients for treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ) , (IZ) or (IZA), the method comprising obtaining from a patient a sample that contains tumor cells; determining whether the ERa gene in a patient sample containing tumor cells is a wild-type

- 65 038160 type or mutant; and selecting a patient for treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) Based on this.

The method may or may not include the step of actually taking a sample from the patient. Thus, in accordance with one aspect of the present disclosure, there is provided a method of selecting patients for treatment with a compound of formula (I), (IA), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA), the method comprising determining whether the ERa gene in a sample containing tumor cells previously isolated from a patient's body is wild-type or mutant; and selecting a patient for treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) Based on this.

In one embodiment, the patient is selected for treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) if the tumor cell DNA contains the mutant ERa gene. In other embodiments, a patient whose tumor cell DNA contains a wild-type ERa gene is selected for treatment with a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), ( IH), (IJ), (IZ) or (IZA).

For the purposes of this disclosure, wild-type gene status is intended to indicate normal or appropriate gene expression and normal function of the encoded protein. In contrast, mutant status is intended to indicate the expression of a protein with altered function in accordance with the known roles of mutant ERa genes in cancer (as described herein). Any number of genetic or epigenetic changes, including but not limited to mutation, amplification, deletion, genomic rearrangement, or changes in the methylation profile, can result in mutant status. However, if such changes, in spite of everything, lead to the corresponding expression of a normal protein or a functionally equivalent variant, then the status of the gene is considered to be wild-type status. Examples of variants that do not typically result in a functional gene mutant status include synonymous coding variants and types of common polymorphisms (synonymous or nonsynonymous). As discussed below, the status of a gene can be assessed by functional analysis, or it can be inferred from the nature of the detected deviations from the reference sequence.

In certain embodiments, the wild-type or mutant status of the ERa gene is determined by the presence or absence of nonsynonymous nucleic acid changes in the genes. The observed nonsynonymous changes, corresponding to known types of common polymorphism without annotated functional effects, do not contribute to the emergence of the mutant status of the gene.

Other changes in the ERa gene that indicate mutant status include splice site changes that reduce recognition of the intron-exon boundary during pre-mRNA-to-mRNA conversion. This can lead to exon skipping or normal incorporation of the intron sequence into the spliced mRNA (intron retention or the use of hidden splicing boundaries). In turn, this can lead to the production of an aberrant protein with insertions and / or deletions relative to the normal protein. Thus, in other embodiments, a gene is mutated if a variant is present that alters the recognition sequence of a splice site at the intron-exon interface.

In the case of ESR1, reference sequences are available for gene (GenBank accession: NG008493), mRNA (GenBank accession: NM_000125) and protein (GenBank accession: NP000116 or Swiss-Prot accession: P03372). One skilled in the art will be able to determine the status of the ESR1 gene, i. E. whether a particular ESR1 gene is a wild-type gene or a mutant gene, based on a comparison of the DNA or protein sequence with the wild-type one.

It will be apparent that the gene and mRNA sequences disclosed for the ERa gene are exemplary sequences. In normal individuals, there are two copies of each gene, maternal and paternal copies, which are likely to have some sequence differences; moreover, there are numerous allelic variants of a given gene sequence in the population. Other sequences that are considered wild-type include those that have one or more synonymous changes in the nucleic acid sequence (and these changes do not change the sequence of the encoded protein), nonsynonymous types of common polymorphism (for example, types of polymorphism in germ-line cells) that change protein sequence, but not affecting protein function, and changes in intron sequences not affecting the splicing site.

To determine the status of the ERa gene, there are many techniques available to the person skilled in the art. Gene status can be determined by determining the nucleic acid sequence. This can be done by direct sequencing of the full-length gene or by analyzing specific sites in the gene, for example, sites that are frequently mutated.

Samples

The patient sample to be tested for gene status can be any sample containing tumor tissue or tumor cells obtained or obtained from an individual. For convenience, the test sample is a blood sample, oral swab, biopsy, or other biological fluid or tissue obtained from an individual. Specific examples include circulating tumor cells, circulating DNA in plasma or serum, cells isolated from ascitic fluid from patients suffering from ovarian cancer, pulmonary sputum from patients with lung tumors, fine-needle punctate obtained from a patient suffering from breast cancer, urine , peripheral blood, cell scraping, hair follicle, pinch biopsy skin sample, or buccal epithelium sample.

It will be understood that the test sample may equally be a nucleic acid sequence corresponding to the sequence in the test sample, which means that all or part of a region in a nucleic acid sample can be first amplified prior to analysis using any convenient technique, for example, polymerase chain reaction (PCR). The nucleic acid can be genomic DNA or fractionated or total cellular RNA. In specific embodiments, the RNA is total cellular RNA and is used directly as a template for labeling the first strand of cDNA using random primers or poly-A containing primers. The nucleic acid or protein in the test sample can be extracted from the sample according to standard techniques (see Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th Edition, Volume 1-3, ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY).

The diagnostic methods of the present disclosure can be performed using a sample previously obtained from an individual or patient. Such samples can be preserved by freezing or fixing and embedded in formalin / paraffin or other media. Alternatively, you can obtain and use a fresh sample containing tumor cells.

The methods in accordance with the present description can be applied using cells from any tumor. Suitable tumors for treatment with a compound of formula (I) (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) have been described earlier in this document.

Methods for detecting nucleic acids

As used herein, the detection of mutant ERa nucleic acids can be used to guide drug treatment. Since mutations in these genes occur at the DNA level, the methods described herein can be based on detecting mutations or variations in genomic DNA as well as transcripts and proteins themselves. It may be desirable to confirm mutations in genomic DNA by analyzing transcripts and / or polypeptides to ensure that the identified mutation is in fact expressed in the subject.

One of ordinary skill in the art will appreciate that there are a large number of analytical procedures that can be used to detect the presence or absence of nucleotide variants at one or more positions in a gene. Typically, detection of allelic variation requires a mutation discrimination technique, optionally an amplification reaction (such as based on polymerase chain reaction) and optionally a signal generating system. There are a large number of mutation detection techniques available in the art and can be used in combination with a signal generating system, many of which are available in the art. A review of the many methods for detecting allelic variation is given in Nollau et al., Clin. Chem .. 1997, 43, 1114-1120; Anderson SM. Expert Rev Mol Diagn .. 2011, 11, 635-642; Meyerson M. et al. Nat Rev Genet .. 2010,11, 685-696; and in standard guidelines such as Laboratory Protocols for Mutation Detection, ed. U. Landegren, Oxford University Press, 1996, and PCR, 2nd Edition, Newton & Graham, BIOS Scientific Publishers Limited, 1997.

As indicated above, the determination of the presence or absence of a particular variation or multiple variations in the ERa gene in a patient suffering from cancer can be performed in various ways. Such tests are usually performed using DNA or RNA collected from biological samples, for example, biopsies of tissues, urine, feces, sputum, blood, cells, tissue scrapings, breast punctates, or other cellular materials, and can be performed in a variety of ways, including without limitations of PCR, hybridization with allele-specific probes, enzymatic detection of mutations, chemical cleavage of mismatch sites, mass spectrometry or DNA sequencing, including minisequencing.

Suitable mutation detection techniques include Amplification System for Mutation Identification (ARMS), Amplification System for Linear Extension Mutation (ALEX), Competitive Oligonucleotide Priming System (COPS), Taqman, molecular beacons, restriction fragment length polymorphism (RFLP), as well as PCR with the introduction of restriction sites and fluorescence resonance energy transfer (FRET).

In specific embodiments, the method used to determine the nucleotide (s) in the biomarker gene is selected from allele-specific amplification (allele-specific PCR), such as amplification system for mutation identification (ARMS), sequencing, allelic discriminant analysis, hybridization, restriction length polymorphism - 67,038,160 fragments (RFLP) or oligonucleotide probe ligation assay (OLA).

In certain embodiments, hybridization with allele-specific probes can be accomplished using: (1) allele-specific oligonucleotides bound to a solid phase (e.g., glass, silicon, nylon membranes) in a labeled probe solution, such as in many applications DNA chips; or (2) a linked sample (often cloned DNA or DNA amplified by PCR) in solution with labeled oligonucleotides (either allele specific or short to allow hybridization sequencing). A set of variations can be included in diagnostic tests, often on a solid support, allowing more than one variation to be detected at a time. Such hybridization probes are well known in the art (see, for example, Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th edition, volume 1-3, ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York) and may span two or more sites with variations.

Thus, in one embodiment, detecting the presence or absence of at least one mutation comprises contacting an ERa nucleic acid containing the putative mutation site with at least one nucleic acid probe. Under selective hybridization conditions, the probe preferably hybridizes to a nucleic acid sequence containing a site of variation and containing complementary nucleotide bases at a site of variation. Hybridization can be detected with a detectable label using labels known to a person skilled in the art. Such labels include, but are not limited to, radioactive, fluorescent, staining, and enzymatic labels.

In another embodiment, detecting the presence or absence of at least one mutation comprises contacting an ERa nucleic acid containing the putative mutation site with at least one nucleic acid primer. Under selective hybridization conditions, the primer preferably hybridizes to a nucleic acid sequence containing a site of variation and containing complementary nucleotide bases at a site of variation.

Oligonucleotides used as primers for specific amplification may contain a nucleotide base complementary to the mutation in question at the center of the molecule (such that amplification is dependent on differential hybridization; see, for example, Gibbs, et al., 1989. Nucl. Acids Res .. 17.2437-248) or at the very edge of the 3'-end of a single primer, where, under appropriate conditions, mismatch of bases can prevent or reduce polymerase-mediated chain elongation (see, for example, Prossner, 1993, Tibtech. 11 238) ...

In yet another embodiment, detecting the presence or absence of at least one mutation comprises sequencing at least one nucleic acid sequence and comparing the resulting sequence to a known wild-type nucleic acid sequence.

Alternatively, the presence or absence of at least one mutation provides for the determination of the sequence of at least one nucleic acid using mass spectrometry.

In one embodiment, detecting the presence or absence of at least one variation in a nucleic acid involves performing a polymerase chain reaction (PCR). The target nucleic acid sequence containing the intended variation is amplified, and the nucleotide sequence of the amplified nucleic acid is determined. Determining the nucleotide sequence of the amplified nucleic acid involves sequencing at least one segment of the nucleic acid. Alternatively, the amplification products can be analyzed by any method suitable for separating amplification products according to their size, including automatic and manual gel electrophoresis and the like.

Mutations in genomic nucleic acid are predominantly detected using techniques based on changes in the mobility of amplified nucleic acid fragments. For example, Chen et al., Anal Biochem 1996. 239. 61-9, describes the detection of single base mutations by competitive mobility analysis. In addition, assay systems based on the method of Marcelino et al., BioTechniques 1999, 26, 1134-1148 are commercially available.

In a specific example, capillary heteroduplex (hybridization) analysis based on changes in the mobility of duplex nucleic acids in capillary systems as a result of base mismatch can be used to detect mutations.

To obtain nucleic acids from samples for analysis, amplification of nucleic acids is usually required. Many amplification methods rely on an enzymatic chain reaction (such as polymerase chain reaction, ligase chain reaction, or self-sustaining sequence replication) or on the replication of all or part of the vector into which it has been cloned. Preferably, the amplification in accordance with the present disclosure is exponential amplification, an example of which is the polymerase chain reaction.

- 68 038160

Many methods for amplifying targets and signals are described in the literature, for example, general reviews of these methods are given in Landegren, U., et al., Science. 1988 242 229-237 and Lewis, R., Genetic Engineering News 1990, 20, 54-55. Such amplification methods can be used in the methods according to the description provided by the present inventors, and they include polymerase chain reaction (PCR), in situ PCR, ligase amplification reaction (LAR), hybridization with ligase, QP bacteriophage replicase, transcriptional mediated amplification system (TAS), genomic amplification with transcript sequencing (GAWTS), nucleic acid sequence based amplification (NASBA), and in situ hybridization. Primers suitable for use in various amplification techniques can be prepared according to methods known in the art.

Polymerase chain reaction (PCR) is a nucleic acid amplification technique described, inter alia, in US Pat. Nos. 4,683,195 and 4,683,202. PCR consists of repeated cycles of primer extension reactions caused by DNA polymerase. The target DNA is heat denatured and two oligonucleotides that are located at both ends of the target sequence on opposite strands of the DNA to be amplified hybridize. These oligonucleotides become primers for use with DNA polymerase. DNA is copied by extending the primer to produce a second copy of both strands. By repeating the cycle of heat denaturation, hybridization and primer extension, the target DNA can be amplified a million or more times in approximately two to four hours. PCR is a molecular biology tool that must be used in conjunction with detection techniques to determine the results of amplification. The advantage of PCR is that it increases sensitivity by amplifying the number of target DNA by 1 million to 1 billion times in about 4 hours. PCR can be used to amplify any known nucleic acid for diagnostic purposes (Mok et al., Gvnaecologic Oncology . 1994, 52: 247-252).

Allele-specific amplification techniques such as the Amplification System for Mutation Identification (ARMS ™) (Newton et al., Nucleic Acids Res .. 1989, 17, 2503-2516) can also be used to detect single base mutations. Under appropriate conditions for PCR amplification, for the preferred amplification of perfectly matching alleles (Newton et al., 1989, above), a base pair mismatch occurring at the 3'-end of the primer is sufficient to distinguish closely related molecules. The amplification system, which uses the primers described above, is based on the fact that oligonucleotides with mismatched residues at the 3 'end will not function as primers for PCR under appropriate conditions. This amplification system allows genotyping solely by examining reaction mixtures after agarose gel electrophoresis.

Analysis of amplification products can be performed using any method capable of separating amplification products according to their size, including automatic and manual gel electrophoresis, mass spectrometry, and the like.

Methods for isolating, amplifying, and analyzing nucleic acid are common to those of skill in the art, and examples of protocols can be found, for example, in Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th Edition, Volume 1 -3, ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY A particularly useful source of protocols for methods used in PCR amplification is PCR (Basics: From Background to Bench). M. J. McPherson, S. G. Mailer, R. Beynon, C. Howe, Springer Verlag; 1st edition (October 15, 2000), ISBN: 0387916008.

Also provided herein are predictive and diagnostic kits containing degenerate primers for amplifying a target nucleic acid sequence from the ERa gene and instructions including an amplification protocol and analysis of the results. Alternatively, the kit may also contain buffers, enzymes, and containers for performing amplification and analyzing amplification products. The kit can also be a component of a screening or diagnostic kit containing other tools such as DNA microarrays or other supports. Preferably, the kit also provides one or more templates with controls such as nucleic acids isolated from normal tissue samples and / or rows of samples representing different variations in reference genes.

In one embodiment, the kit includes two or more pairs of primers, each pair is suitable for amplifying a separate region of a reference gene (ERa) (each region is a site of possible variation), thus providing a kit for assay in a biological sample for the expression of several variations in a gene in one reaction or in several parallel reactions.

The primers in the kits can be labeled, eg, fluorescently labeled, to aid in the detection of amplification products and subsequent analysis of variations in the nucleic acid. The kit can also provide for the detection of more than one variation in one test 69 038160 lysis. Therefore, the combination kit will contain primers suitable for amplifying different segments of the reference gene. Primers can be labeled differentially, for example using different fluorescent labels, to differentiate between different variations.

In another aspect, the present disclosure provides a method of treating a patient suffering from cancer, comprising assigning the ERa gene in the patient's tumor cells the status of a mutant gene or a wild-type gene and, if the ERa gene is mutant, administering to the patient an effective amount of a compound of formula (I), (IA ), (IH), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA).

As used herein, the terms effective and efficacy encompass both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a treatment to provide a desired biological effect in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects at the cellular, organ and / or body level (often referred to as side effects) resulting from the administration of a therapeutic agent. Less effective means that the treatment results in a therapeutically less significant level of pharmacological efficacy and / or a therapeutically higher level of adverse physiological effects.

In accordance with another aspect of the present disclosure, there is provided the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof for the treatment of a patient suffering from cancer, whose tumor cells have been identified as containing the mutant ERa gene.

In accordance with another aspect of the present disclosure, there is provided a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ), or (IZA) or a pharmaceutically acceptable salt thereof for the treatment of cancers in which tumor cells are identified as carrying the mutant ERa gene.

In accordance with another aspect of the present disclosure, there is provided a method for treating cancers in which tumor cells are identified as carrying a mutant ERa gene, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ), (IZ) or (IZA) or a pharmaceutically acceptable salt thereof.

In still several additional embodiments, the implementation of the present description relates to a pharmaceutical composition containing a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IH), (IJ ), (IZ) or (IZA), intended for use in the prevention and treatment of cancer with tumor cells identified as carrying the mutant ERa gene.

For all of the above aspects, detectable / detectable mutant forms of ERa are those at any position throughout the gene.

For all of the above, when used as an example of a tumor such as breast cancer, specific identified / identified ERa mutants are those with mutations at Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly.

Examples of

The present description will be further illustrated in the following examples, in which, as a rule, the following was adhered to:

(i) Operations were carried out at ambient temperature, ie in the range of 17-25 ° C and in an atmosphere of an inert gas such as nitrogen, unless otherwise indicated.

(ii) Evaporation was carried out by rotary evaporation or using Genevac equipment or a Biotage v10 in vacuo evaporator, and product isolation procedures were followed after removal of residual solids by filtration.

(iii) Purification operations using flash chromatography were performed on an automated Teledyne Isco CombiFlash Rf or Teledyne Isco CombiFlash Companion using pre-filled RediSep Rf Gold columns (20-40 μm, spherical particles), GraceResolv cartridges (Davisil silicon dioxide) or Silicycle cartridges (40-63 microns).

(iv) Preparative chromatography was performed on a Gilson preparative HPLC with UV collection system or by supercritical liquid chromatography performed on a Waters Prep 100 SFC-MS with MS and UV collection system or a Thar MultiGram III SFC with UV collection system. collection system.

(v) Chiral preparative chromatography was performed on a Gilson device with UV collection system (233 injector / fraction collector, 333 and 334 pumps, 155 UV detector) or on a VarianPrep Star device (2 x SD1 pumps, 325 UV detector, 701 collectors fractions) with a pump working with a Gilson 305 injector.

(vi) Output values, if any, were not necessarily the maximum attainable.

(vii) Typically, the structures of the final products of formula (I) were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured by delta

- 70 038160 scale [proton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz) or Bruker Avance 400 (400 MHz)]; measurements were carried out at ambient temperature, unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of triplets; bs, wide signal.

(viii) Typically, the final products of formula (I) were also characterized by liquid chromatography mass spectroscopy (LCMS or UPLC); UPLC was performed using a Waters UPLC equipped with a Waters SQ mass spectrometer (column temperature 40, UV = 220-300 nm, mass spectrometry = ESI with positive / negative charge switching) at a flow rate of 1 ml / min, using a solvent system from 97% A + 3% B up to 3% A up to 97% B in 1.50 min (total cycle time with equilibration to baseline, etc. 1.70 min), where A = 0.1% formic acid c water (for acid work) or 0.1% ammonia in water (for base work), B = acetonitrile. For acid analysis, the column used was a Waters Acquity HSS T3, 1.8 µm, 2.1 x 50 mm, for the main analysis, the column used was a Waters Acquity BEN 1.7 µm, 2.1 x 50 mm; LCMS was performed using a Waters Alliance HT (2795) system equipped with a Waters ZQ ESCi mass spectrometer and a Phenomenex Gemini-NX column (50 x 2.1 mm, 5 μm) at a flow rate of 1.1 ml / min, from 95% A up to 95% B in 4 min with a hold of 0.5 min. The modifier was kept constant at 5% C (50:50 acetonitrile: water 0.1% formic acid) or D (50:50 acetonitrile: water 0.1% ammonium hydroxide (0.88 SG) depending on whether acidic or basic method.

(ix) Ion exchange purification was typically performed using an SCX-2 cartridge (Biotage, propyl sulfonic acid functionalized silica. Manufactured using a trifunctional silane. No end group blocking).

(x) The purity of the intermediate was assessed by thin layer chromatography, mass spectrometric, HPLC (high performance liquid chromatography) and / or NMR analysis.

(xi) RockPhos 3rd Generation Precatalyst supplied by Strem Chemicals Inc. and Sigma-Aldrich.

(xii) The following abbreviations were used:

Ason acetic acid drive. 3rd Generation Precatalyst Brettphos water [(2-di-cyclohexylphosphino-3,6- dimethoxy- 2 ', 4', 6'-triisopropyl-1, G-biphenyl) -2- (2'-amino-1, Gbiphenyl)] palladium (P) methanesulfonate Cbz CDC1 ₃ Conc. DCM benzyloxycarbamate deuterochloroform concentrated dichloromethane DIPEA diisopropylethylamine DMF N, M-d and meth yl for r m m id DMSO EtOAc HPLC MeCN dimethyl sulfoxide ethyl acetate high performance liquid chromatography acetonitrile MeOH methanol 3rd Generation Precatalyst RockPhos [(2-di- / ure / i-butylphosphino-3- methoxy-6- methyl-2 ', 4', 6 '-triisopropyl-1,1' -biphenyl) -2 - (2-aminobiphenyl)] palladium (P) methanesulfonate to. t. room temperature saturate saturated

sol. TBAF solution tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TFA trifluoroacetic acid THF tetrahydro furan Xphos 2nd Generation Precatalyst chlorine (2-dicyclohexylphosphino-2 ', 4', 6'- triisopropyl-1,1'-biphenyl) [2 - (2'-amino-1, Gbiphenyl)] palladium (P)

- 71 038160

Example 1.3-Fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro -1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propane-1 -amine

2,2,2-Trifluoroacetic acid (0.33 ml, 4.35 mmol) was added to a stirred solution of tert-butyl- (2- (3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl ) methyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indol1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (67 mg, 0.12 mmol) in DCM (3.3 ml) at -5 ° C under nitrogen. The resulting mixture was stirred at -5 ° C for 1 h. Saturated NaHCO ₃ solution (5 ml) was carefully added and the mixture was extracted with DCM (3 x 10 ml). The combined organics were dried and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the required compounds were evaporated to dryness to give 3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl- 2,3,4,9tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine (35 mg, 63%) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ , 22 ° C): 1.16 (3H, d), 1.83-1.95 (2H, m), 2.60 (1H, dd), 2.77- 2.86 (3H, m), 2.88-3 (3H, m), 3.10-3.21 (1H, m), 3.29-3.39 (1H, m), 3.98- 4.05 (2H, m), 4.40 (1H, dd), 4.48 (1H, t), 4.58 (1H, t), 4.59-4.74 (2H, m), 4 , 82 (1H, dd), 4.97 (1H, s), 6.78-6.83 (2H, m), 6.87 (1H, d), 7.10-7.23 (3H, m ), 7.27-7.30 (1H, m), 7.54 (1H, d), 7.61 (1H, s). mass / charge: ES + [M + H] + 470.

Tert-butyl- (2- (3 - ((1 R, 3R) -2 - ((3-fluoroxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H- pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Obtaining (3-fluorooxetan-3-yl) methyltrifluoromethanesulfonate

F

V-o

2,6-Lutidine (0.441 ml, 3.79 mmol) was added to a stirred solution of (3-fluorooxetane-3yl) methanol (335 mg, 3.16 mmol) in anhydrous DCM (15 ml) at -10 ° C. Then, trifluoromethanesulfonic anhydride (0.560 mL, 3.32 mmol) was added dropwise with a syringe over 3 min and the reaction mixture was allowed to stir at -10 ° C for 40 min. The cooling bath was removed and the solution was washed sequentially with cold aqueous HCl (1N; 2x5 ml) and saturated aqueous NaHCO ₃ (2x5 ml), then dried over MgSO ₄ , filtered and concentrated under reduced pressure. Drying in vacuo afforded (3fluoroxetan-3-yl) methyl trifluoromethanesulfonate (431 mg, 57%) as a pale yellow oil which was used without further purification.

¹ H NMR (300 MHz, CDCl3, 27 ° C) 4.53-4.67 (2H, m), 4.79-4.95 (4H, m).

Obtaining (R) -N - ((3-fluorooxetane-3-yl) methyl) -1 - (1 N-indol-3-yl) propan-2-amine

A solution of (3-fluorooxetan-3-yl) methyltrifluoromethanesulfonate (431 mg, 1.81 mmol) in DCM (3 ml) was added dropwise to a stirred solution of (R) -1- (1H-indol-3-yl) propan-2 α-amine (287 mg, 1.65 mmol) and diisopropylethylamine (0.345 ml, 1.97 mmol) in DCM (7 ml) at ambient temperature. The reaction mixture was stirred for 8 h and then diluted with DCM and washed with water. The phases were separated and the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 30 to 100% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to give (R) -N - ((3-fluorooxetane-3yl) methyl) -1- (1H-indol-3-yl) propan-2-amine (384 mg, 89%) as a colorless resin.

1H NMR (300 MHz, CDCl3, 27 ° C) 1.12 (3H, d), 2.82 (2H, dd), 2.95-3.07 (3H, m), 3.12 (1H, t ), 4.49 (2H, ddd), 4.67 (1H, dd), 4.70-4.78 (1H, m), 6.92 (1H, d), 7.05-7.14 ( 1H, m), 7.18 (1H, td), 7.29 (1H, d), 7.59 (1H, d), 8.34 (1H, br s). mass / charge: ES + [M + H] + 263.

Obtaining (1R, 3R) -1- (3-bromophenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H- 72 038160 pyrido [ 3,4-b] indole

Acetic acid (1.0 ml) was added to a stirred solution of (R) -N - ((3-fluoro-oxetane-3yl) methyl) -1- (1H-indol-3-yl) propan-2-amine (700 mg, 2 , 67 mmol) and 3-bromobenzaldehyde (311 μl, 2.67 mmol) in toluene (9.3 ml). The resulting mixture was heated to 90 ° C and stirred for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM (50 ml) and 1M NaOH (25 ml). The layers were separated and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (25 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica, elution gradient 0 to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to give (1R, 3R) -1- (3-bromophenyl) -2 - ((3fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H -pyrido [3,4-b] indole (809 mg, 71%) as a white solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.18 (3H, d), 2.60 (1H, dd), 2.79 (1H, dd), 2.92 (1H, t), 3.18 (1H, dd), 3.23-3.30 (1H, m), 4.37 (1H, dd), 4.69 (2H, ddd), 4.86 (1H, dd), 5 , 02 (1H, s), 7.11-7.23 (4H, m), 7.31 (1H, d), 7.35 (1H, s), 7.40 (1H, dd), 7, 55 (1H, d), 7.64 (1H, s). mass / charge: ES + [M + H] + 429.

Obtaining tert-butyl-3-fluoropropyl (2-hydroxyethyl) carbamate

Vos

A solution of 1-iodo-3-fluoropropane (7.0 g, 37 mmol) in acetonitrile (10 ml) was added to a suspension of ethanolamine (4.50 ml, 74.5 mmol) and potassium carbonate (25.7 g, 186 mmol) in acetonitrile (60 ml). The mixture was stirred at room temperature for 5 h and then diluted with DCM (20 ml). The mixture was cooled to 0 ° C and di-tert-butyldicarbonate (19.0 mL, 81.9 mmol) was added. The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica, gradient elution from 0 to 4% methanol in DCM, to give tert-butyl (3-fluoropropyl) (2hydroxyethyl) carbamate (3.82 g, 46 %) as a colorless oil.

1H NMR (300 MHz, DMSO-d ₆ ): 1.4 (9H, s), 1.70-2.00 (2H, m), 3.10-3.20 (2H, m), 3.30 (2H, d), 3.50 (2H, d), 4.30-4.60 (2H, m), 4.60 (1H, br t). mass / charge: ES + [M + Na] + 244.

Preparation of tert-butyl- (2- (3 - ((1 R, 3R-2 - ((3-fluoroxetane-3-yl) methyl-3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate

(1 R, 3R) -1 - (3-bromophenyl) -2 - ((3-fluorooxetane-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3 , 4b] indole (100 mg, 0.23 mmol), cesium carbonate (190 mg, 0.58 mmol) and 3rd generation RockPhos (19.75 mg, 0.02 mmol) were loaded into the flask and the flask was evacuated and again filled it with nitrogen 3 times. A solution of tert-butyl (3-fluoropropyl) (2-hydroxyethyl) carbamate (103 mg, 0.47 mmol) in degassed toluene (0.78 ml) was added and the reaction mixture was heated to 90 ° C for 16 h. After cooling the reaction mixture was partitioned between water (20 ml) and EtOAc (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in heptane. Fractions containing product were combined and concentrated in vacuo to give tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) 3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (77 mg, 58%) as a white solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.16 (3H, d), 1.35-1.51 (9H, m), 1.97 (2H, s), 2.52-2 , 65 (1H, m), 2.84 (1H, dd), 2.88-2.98 (1H, m), 3.15 (1H, dd), 3.32-3.44 (3H, m ), 3.49-3.60 (2H, m), 3.97-4.09 (2H, m), 4.40 (2H, dd), 4.50 (1H, s), 4.57- 4.66 (1H, m), 4.65-4.73 (1H, m), 4.75-4.84 (1H, m), 4.95 (1H, s), 6.76-6, 84 (2H, m), 6.86 (1H, d), 7.09-7.18 (2H, m), 7.20 (1H, t), 7.28 (1H, d), 7.53 (1H, d), 7.66 (1H, s). mass / charge: ES + [M + H] + 570.

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Example 2.N-1- (3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl) methyl-3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) phenyl) -N-2- (3-fluoropropyl) ethane-1,2-diamine

Benzyl- (2 - ((3 - ((1 R, 3R) -2 - ((3-fluoroxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4b] indol-1-yl) phenyl) amino) ethyl) (3-fluoropropyl) carbamate (55 mg, 0.09 mmol) and 10% palladium on carbon (19.4 mg, 0.02 mmol) in ethanol (1 ml) was stirred under a hydrogen atmosphere at 21 ° C. for 30 minutes. The mixture was diluted with DCM (20 ml) and the solids were filtered through celite while washing the filter cake with DCM (10 ml). The combined organics were combined and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the required compounds were evaporated to dryness to give N- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9 -tetrahydro1H-pyrido [3,4-b] indol-1-yl) phenyl) -N2- (3-fluoropropyl) ethane-1,2-diamine (25 mg, 59%) as a white solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.15 (3H, d), 1.79-1.92 (2H, m), 2.59 (1H, dd), 2.75 (2H , t), 2.82-3.00 (4H, m), 3.06-3.20 (3H, m), 3.36-3.45 (1H, m), 4.05 (1H, s ), 4.39-4.49 (2H, m), 4.54-4.64 (2H, m), 4.69 (1H, dd), 4.78 (1H, dd), 4.88 ( 1H, s), 6.51-6.57 (2H, m), 6.62 (1H, d), 7.08-7.18 (3H, m), 7.26 (1H, s), 7 , 53 (1H, d), 7.57 (1H, s). mass / charge: ES + [M + H] + 469.

Benzyl- (2 - ((3 - ((1 R, 3R) -2 - ((3-fluoroxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4b] indol-1-yl) phenyl) amino) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Obtaining benzyl- (2 - ((tert-butoxycarbonyl) amino) ethyl) (3-fluoropropyl) carbamate%

WITH)

A solution of 1-iodo-3-fluoropropane (3.52 g, 18.7 mmol) in acetonitrile (5 ml) was added to a suspension of tert-butyl (2-aminoethyl) carbamate (5.0 g, 31 mmol) and potassium carbonate (8.63 g, 62.4 mmol) in acetonitrile (30 ml). The mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and then DCM (50 ml) was added. The solution was cooled to 0 ° C and DIPEA (7.10 ml, 40.7 mmol) was added followed by the slow dropwise addition of benzyl chloroformate (4.56 ml, 32.0 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 80% ethyl acetate in hexane to give benzyl- (2 - ((tert-butoxycarbonyl) amino) ethyl) (3-fluoropropyl) carbamate (2.1 g , 21%) as oil.

¹ H NMR (300 MHz, DMSO-d ₆ ,, 27 ° C): 1.37 (9H, s), 1.74-1.98 (2H, m), 3.01-3.13 (2H, m), 3.19-3.41 (4H, m), 4.29-4.63 (2H, m), 5.07 (2H, s), 6.88 (1H, br. s), 7 , 30-7.39 (5H, m).

Obtaining benzyl- (2-aminoethyl) (3-fluoropropyl) carbamate

Trifluoroacetic acid (3.48 ml, 45.1 mmol) was added to a solution of benzyl- (2 - ((tert-butoxycarbonyl) amino) ethyl) (3-fluoropropyl) carbamate (1.6 g, 4.5 mmol) in DCM (16 ml) and stirred at room temperature for 1 hour. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give benzyl- (2-aminoethyl) (3-fluoropropyl) carbamate (1.1 g, 98%) as a light yellow solid.

1H NMR (300 MHz, DMSO-d6, 27 ° C): 1.73-1.98 (2H, m), 2.88 (2H, br.s), 3.37 (4H, q), 4, 45 (2H, dt), 5.09 (2H, s), 6.43 (2H, br. S), 7.25-7.49 (5H, m).

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Obtaining benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl-3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3,4 -B] indol-1-yl) phenyl) amino) ethyl) (3-fluoropropyl) carbamate

BrettPhos Pd G3 (42.2 mg, 0.05 mmol) was added to the degassed mixture (1R, 3R) -1- (3-bromophenyl) 2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (200 mg, 0.47 mmol), benzyl- (2-aminoethyl) (3-fluoropropyl) carbamate (154 mg, 0, 61 mmol) and potassium carbonate (129 mg, 0.93 mmol) in THF (4.3 ml) at 21 ° C. The resulting mixture was heated to 70 ° C and stirred at 70 ° C for 16 hours. The mixture was allowed to cool to room temperature, concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica, elution gradient 0 to 80% EtOAc in heptane. Pure fractions were evaporated to dryness to give benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetane-3yl) methyl) -3-methyl-2,3,4,9-tetrahydro -1 H-pyrido [3, 4-b] indol-1-yl) phenyl) amino) ethyl) (3-fluoropropyl) carbamate (110 mg, 39%) as a yellow oil.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.15 (3H, d), 1.90 (2H, s), 2.59 (1H, dd), 2.81-2.99 (2H, m), 3.04-3.17 (1H, m), 3.19-3.61 (8H, m), 4.33-4.62 (4H, m), 4.66-4.91 ( 3H, m), 5.14 (2H, d), 6.32-6.70 (3H, m), 7.07-7.15 (2H, m), 7.23 (1H, d), 7 , 28-7.39 (6H, m), 7.49-7.56 (1H, m), 7.66 (1H, d). mass / charge: ES + [M + H] + 603.

Example 3. N-1- (3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H- pyrido [3, 4-b] indol-1-yl) phenyl) -N-2- (3-fluoropropyl) -N-1 -methylethane-1,2-diamine

A solution of benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol-1-yl) phenyl) (methyl) amino) ethyl) (3-fluoropropyl) carbamate (55.5 mg, 0.09 mmol) in ethanol (2 ml) was hydrogenated in a hydrogenation apparatus H -Cube using a 30 mm cartridge containing 10% palladium on carbon at 21 ° C, 30 bar and a flow rate of 1 ml / minute for 30 minutes. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the required compounds were evaporated to dryness to give N- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9tetrahydro - 1 H-pyrido [3,4-b] indol-1-yl) phenyl) -N2- (3-fluoropropyl) ^ 1 -methylethane-1,2-diamine (1.5 mg, 3%) as white solid matter.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.16 (3H, d), 1.74-1.88 (2H, m), 2.60 (1H, dd), 2.70 (2H , t), 2.78 (2H, t), 2.87 (1H, dd), 2.91 (3H, s), 2.92-2.99 (1H, m), 3.06-3, 18 (1H, m), 3.35-3.45 (3H, m), 4.40-4.49 (2H, m), 4.53 (1H, t), 4.60 (1H, dd) , 4.69 (1H, dd), 4.78 (1H, dd), 4.90 (1H, s), 6.56 (1H, d), 6.67 (1H, dd), 6.75 ( 1H, s), 7.07 7.17 (3H, m), 7.26 (1H, s), 7.52 (1H, d), 7.61 (1H, s). mass / charge: ES + [M + H] + 483.

Benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3 , 4b] indol-1-yl) phenyl) (methyl) amino) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Obtaining benzyl- (2 - ((3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1Hpyrido [3 , 4-b] indol-1-yl) phenyl (methyl) amino) ethyl) (3-fluoropropyl) carbamate

Iodomethane (6.25 μL, 0.10 mmol) was added to a suspension of potassium carbonate (18.9 mg, 0.14 mmol) in

- 75 038160 solution of benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H -pyrido [3,4-b] indol-1-yl) phenyl) amino) ethyl) (3-fluoropropyl) carbamate (55 mg, 0.09 mmol) in DMF (1 ml). The resulting mixture was heated at 50 ° C for 3 hours. Additional iodomethane (6.25 μl, 0.10 mmol) was added and the mixture was stirred at 50 ° C for 16 hours. The mixture was diluted with EtOAc (20 ml) and water (10 ml). The layers were separated and the organic layer was washed with water (2 x 10 ml) and saturated aqueous sodium chloride solution (10 ml). The organic layer was dried and concentrated to give benzyl- (2 - ((3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9- tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenyl) (methyl) amino) ethyl) (3-fluoropropyl) carbamate (56 mg, 100%) as an orange oil which was used without further purification. Mass / charge: ES + [M + H] + 617.

Example 4. 3-Φτορ-Ν- (2- (3 - ((1 R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9- tetrahydro-1Hpyrido [3, 4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1-amine

tert-Butyl- (2- (3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H- pyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (220 mg, 0.37 mmol) was dissolved in DCM (3.5 ml) and treated with TFA (0.28 ml, 3.7 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 5 hours, and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ , dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC (Xbridge C18 column, 5 μm silica, 19 mm diameter, 100 mm long, 20 ml / min) eluting with 50 to 80% acetonitrile in water containing 0.2% NH ₄ OH (pH 10) for 6 min. The fractions containing the product were combined and concentrated under reduced pressure to give 3-fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3fluorooxetane-3-yl) methyl) -3 -methyl-2 , 3,4,9-tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) propan-1-amine (183 mg, 60%) as a white foam.

¹ H NMR (300 MHz, DMSO-d6, 27 ° C): 1.07 (3H, d), 1.53-1.79 (3H, m), 2.52-2.60 (2H, m) , 2.62-2.89 (4H, m), 3.03-3.36 (3H, m), 3.75 (2H, t), 3.80 (3H, s), 4.38-4 , 74 (4H, m), 4.42 (2H, dt), 5.36 (1H, s), 6.13 (1H, d), 6.82 (1H, dd), 6.94 (3H, s), 7.16 -7.23 (1H, m), 7.43 (1H, d), 10.50 (1H, s). mass / charge: ES + [M + H] + 500.

Tert-butyl- (2- (3 - ((1 R, 3R) -2 - ((3-fluoroxetane-3-yl) methyl) -3 -methyl-2,3,4,9-tetrahydro-1 H- pyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate as a starting material was prepared as described below.

Obtaining (1 R, 3R) -1 - (5-bromo-2-methoxyphenyl) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl-2,3,4,9tetrahydro-1 H- pyrido [3,4-b] indole

(R) -N - ((3-fluorooxetan-3-yl) methyl) -1- (1H-indol-3-yl) propan-2-amine (346 mg, 1.32 mmol; prepared according to the procedure for Example 1) and 5-bromo-2-methoxybenzaldehyde (265 mg, 1.23 mmol) were dissolved in toluene (6.0 ml). Acetic acid (0.67 ml) was added and the reaction mixture was heated at 80 ° C for 18 h. The reaction mixture was then diluted with EtOAc and neutralized with saturated aqueous NaHCO3 solution. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to give (1R, 3R) -1- (5-bromo-2-methoxyphenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3methyl-2 , 3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (513 mg, 91%) as light yellow foam.

¹ H NMR (300 MHz, DMSO-d ₆ , 27 ° C): 1.09 (3H, d), 2.52-2.61 (1H, m) 2.62-2.88 (2H, m) , 3.06-3.29 (2H, m), 3.87 (3H, s), 4.34-4.79 (4H, m), 5.38 (1H, s), 6.61 (1H , d), 6.94-7.09 (3H, m), 7.19-7.27 (1H, m), 7.39-7.51 (2H, m), 10.56 (1H, s ). mass / charge: ES + [M + H] + 459.

Preparation of tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3 , 4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate

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(1R, 3R) -1- (5-bromo-2-methoxyphenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3 , 4-b] indole (250 mg, 0.54 mmol), tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (181 mg, 0.82 mmol) and cesium carbonate (355 mg, 1.09 mmol) was suspended in toluene (3 ml) in a 25 ml pear-shaped flask dried in an oven. The suspension was degassed (evacuated and filled with nitrogen) and then RockPhos 3rd generation pre-catalyst (18 mg, 0.02 mmol) was added. Provide a condenser for the reaction mixture and heat it at 90 ° C for 3 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to give tert-butyl- (2- (3 - ((1 R, 3R) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl -2,3,4,9-tetrahydro-1Hpyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (220 mg, 67%) as a yellow foam.

1H NMR (300 MHz, DMSO-d6, 27 ° C): 1.08 (3H, d) 1.17-1.39 (9H, m), 1.61-1.86 (2H, m), 2 , 53-2.63 (1H, m), 2.65-2.90 (2H, m), 3.06-3.30 (4H, m), 3.32-3.45 (2H, m) , 3.75-3.90 (5H, m), 4.31 (2H, dt), 4.42-4.76 (4H, m), 5.37 (1H, s), 6.13 (1H , d), 6.72-6.91 (1H, m), 6.91-7.10 (3H, m), 7.13-7.28 (1H, m), 7.44 (1H, d ), 10.50 (1H, s). mass / charge: ES + [M + H] + 600.

Example 5. 3-Φτορ-Ν- (2- (3 - ((1 R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9- tetrahydro-1Hpyrido [3,4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) propan-1-amine

Tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-Spirido [3, 4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (168 mg, 0.28 mmol) was dissolved in DCM (2.5 ml) and treated with TFA (0.22 ml, 2.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ solution, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (Xbridge C18 column, 5 μm silica, 19 mm diameter, 100 mm long, 20 ml / min.) Eluting with 50 to 80% acetonitrile in water containing 0, 2% NH4OH (pH 10) for 6 minutes. The fractions containing the product were combined and concentrated under reduced pressure to give 3 fluoro-N- (2- (3 - ((1R, 3R) -2 - ((3-fluoro-oxetan-3-yl) methyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) propan-1-amine (63 mg, 45%) as a white foam.

¹ H NMR (300 MHz, DMSO-d6, 27 ° C): 1.08 (3H, d), 1.67-1.92 (3H, m), 2.52-2.63 (1H, m) , 2.63-2.88 (4H, m), 2.91-2.99 (2H, br m), 3.07-3.35 (2H, m), 3.85 (3H, s), 3.97-4.12 (2H, m), 4.30-4.70 (6H, m), 5.32 (1H, s), 6.21 (1H, dd), 6.86 (1H, t), 6.91-7.07 (3H, m), 7.17-7.26 (1H, m), 7.42 (1H, d), 10.50 (1H, s). mass / charge: ES + [M + H] + 500.

Tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluoroxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [ 3,4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Obtaining (1R, 3R) -1- (3-bromo-2-methoxyphenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1H- pyrido [3,4-b] indole

(R) -N - ((3-fluorooxetan-3-yl) methyl) -1- (1H-indol-3-yl) propan-2-amine (345 mg, 1.32 mmol) and 3-bromo2-methoxybenzaldehyde (297 mg, 1.38 mmol) was dissolved in toluene (6 ml) and treated with AcOH (0.67 ml). The reaction mixture was heated at 80 ° C for 18 h and then diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in hexanes. The fractions containing the desired product were pooled and

- 77 038160 was concentrated under reduced pressure to give (1R, 3R) -1- (3-bromo-2-methoxyphenyl) -2 - ((3fluorooxetan-3-yl) methyl) -3-methyl-2,3,4, 9-tetrahydro-3-pyrido [3,4-b] indole (438 mg, 73%) as a yellow foam.

1H NMR (300 MHz, DMSO-d6, 27 ° C): 1.11 (3H, d) 2.53-2.66 (1H, m) 2.70-2.93 (2H, m) 3.16 -3.35 (2H, m) 3.91 (3H, s) 4.33-4.75 (4H, m) 5.36 (1H, s) 6.63 (1H, dd) 6.89-7 , 09 (3H, m) 7.20-7.28 (1H, m) 7.46 (1H, d) 7.56 (1H, dd) 10.59 (1H, s). mass / charge: ES + [M + H] + 459.

Preparation of tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3 , 4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate ο ^ ο

HI Ε 1 ^Λ (1R, 3R) -1- (3-bromo-2-methoxyphenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9-tetrahydro -Spirido [3,4-b] indole (240 mg, 0.52 mmol), tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (173 mg, 0.78 mmol; prepared according to the procedure according to Example 1) and cesium carbonate (340 mg, 1.04 mmol) were suspended in toluene (3 ml) in a 25 ml pear-shaped flask dried in an oven. The slurry was degassed (by evacuation and backfilled with nitrogen) and then treated with RockPhos 3rd generation precatalyst (18 mg, 0.02 mmol). The reaction flask was equipped with a condenser and heated at 90 ° C for 3 h. The mixture was then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in hexanes. The fractions containing the desired product were combined and concentrated under reduced pressure to give tert-butyl- (2- (3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl- 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -2-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (168 mg, 54%) as yellow foam ...

1H NMR (300 MHz, DMSO-d6, 27 ° C): 1.09 (3H, d), 1.41 (9H, s), 1.80-1.99 (2H, m), 2.53- 2.65 (1H, m), 2.66-2.90 (2H, m), 3.10-3.36 (2H, m), 3.42 (2H, t), 3.53-3, 70 (2H, m), 3.84 (3H, s), 4.06-4.20 (2H, br m), 4.314.72 (6H, m), 5.33 (1H, s), 6, 23 (1H, dd), 6.86 (1H, t), 6.92-7.09 (3H, m), 7.17-7.28 (1H, m), 7.39-7.49 ( 1H, m), 10.52 (1H, s). mass / charge: ES + [M + H] + 600.

Example 6.N- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4- b] indol1-yl) -4-methoxyphenoxy) ethyl) -3 -fluoropropane-1 -amine

2,2,2-Trifluoroacetic acid (0.5 ml, 0.13 mmol) was added to a solution of tert-butyl- (2- (3 ((1R, 3R) -2- (2,2-difluoroethyl) -3- methyl 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (76 mg, 0.13 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, redissolved in MeOH and loaded onto a pre-wetted (with MeOH) SCX-2 cartridge. The cartridge was washed with MeOH (50 ml) and the product was eluted with 1 M NH ₃ in MeOH solution (30 ml). The resulting residue was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 30 mm diameter, 100 mm long) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give N- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl2,3,4,9-tetrahydro-1H -pyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) -3-fluoropropan-1-amine (5.0 mg, 8%) as a colorless oil.

1H NMR (500 MHz, CDCl3, 27 ° C): 1.16 (3H, d), 1.77-1.91 (2H, m), 2.55-2.64 (2H, m), 2, 69-2.8 (3H, m), 2.88 (2H, dd), 2.92-2.98 (1H, m), 2.98-3.09 (1H, m), 3.45- 3.53 (1H, m), 3.89 (2H, t), 3.92 (3H, s), 4.44 (1H, t), 4.53 (1H, t), 5.29 (1H , s), 5.86 (1H, tdd), 6.67 (1H, d), 6.78 (1H, dd), 6.89 (1H, d), 7.07-7.16 (2H, m), 7.23 (1H, ddd), 7.49-7.54 (1H, m), 7.69 (1H, s). mass / charge: ES + [M + H] + 476.

Tert-Butyl- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b ] indol-1yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Preparation of 2,2-difluoroethyl trifluoromethanesulfonate

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Trifluoromethanesulfonic anhydride (3.97 ml, 23.5 mmol) was added dropwise to a solution of 2,2-difluoroethan-1-ol (1.75 g, 21.3 mmol) in DCM (40 ml at) at -10 ° C (salt / ice bath). Then added lutidine (2.98 ml, 25.6 mmol) and the reaction mixture was stirred for 1 h at -10 ° C. Then the reaction mixture was quenched with water and the layers were separated. The organic layer was washed with water and then dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2,2-difluoroethyl trifluoromethanesulfonate (3.10 g, 67.9%) as a colorless liquid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 4.57 (2H, td), 6.03 (1H, tt).

Obtaining (R) -N- (2,2-difluoroethyl) -1- (1Н-indol-3-yl) propan-2-amine n

HN ^ V ^F qAa, ί (R) -1- (1H-indol-3-yl) propan-2-amine (5 g, 28.69 mmol) was added to a solution of 2,2 difluoroethyl trifluoromethanesulfonate (7.07 g, 33, 00 mmol) and DIPEA (7.44 ml, 43.04 mmol) in chloroform (100 ml) and the reaction mixture was stirred at 60 ° C for 16 hours. Allow the reaction mixture to cool and concentrate in vacuo. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 40% EtOAc in heptane to give (R) -N- (2,2-difluoroethyl) -1- (1H-indol-3-yl) propan-2 α-amine (4.22 g, 62%) as a yellow oil.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.12 (3H, d), 2.73-3.17 (5H, m), 3.47 (1H, s), 5.77 (1H , tt), 7.01 (1H, d), 7.06-7.17 (1H, m), 7.17-7.23 (1H, m), 7.3-7.42 (1H, m ), 7.59 (1H, d), 8.11 (1H, s). mass / charge: ES- [NH] 237.

Obtaining (1R, 3R) -1- (5-bromo-2-methoxyphenyl) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3,4-b ] indole

Acetic acid (1.23 ml) was added to a stirred solution of (R) -N- (2,2-difluoroethyl) -1- (1Hindol-3-yl) propan-2-amine (730 mg, 3.06 mmol) and 5-bromo-2-methoxybenzaldehyde (659 mg, 3.06 mmol) in toluene (11 ml). The resulting mixture was heated at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, redissolved in MeOH and loaded onto a pre-wetted (with MeOH) SCX-2 cartridge. The cartridge was washed with MeOH (50 ml) and the product was eluted with 1 M NH ₃ in MeOH solution (50 ml). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 20% EtOAc in heptane. The fractions containing the product were combined and concentrated under reduced pressure to give (1R, 3R) -1- (5-bromo-2-methoxyphenyl) -2- (2,2-difluoroethyl) -3-methyl-2,3,4 , 9-tetrahydro-1H-pyrido [3,4-b] indole (429 mg, 32%) as a white solid.

1H NMR (500 MHz, CDCl3, 27 ° C): 1.13 (3H, d), 2.56 (1H, ddd), 2.61-2.75 (1H, m), 2.89 (1H, ddd), 3.02 (1H, qd), 3.33-3.47 (1H, m), 3.90 (3H, s), 5.25 (1H, s), 5.88 (1H, tdd ), 6.81 (1H, d), 7.05-7.15 (3H, m), 7.16-7.22 (1H, m), 7.33 (1H, dd), 7.51 ( 1H, dd), 7.57 (1H, s). mass / charge: ES- [N-H] -433.

Obtaining tert-butyl- (2- (3 - ((1 R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3, 4b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate

RockPhos Pd G3 (11.6 mg, 0.01 mmol) was added to the degassed suspension of (1R, 3R) -1- (5-6pom-2methoxyphenyl) -2- (2,2-difluoroethyl) -3-methyl-2, 3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (120 mg, 0.28 mmol), tert-butyl (3-fluoropropyl) (2-hydroxyethyl) carbamate (122 mg, 0, 55 mmol) and cesium carbonate (225 mg, 0.69 mmol) in anhydrous toluene (2.76 ml) and the reaction mixture was heated to 90 ° C for 1 h.The reaction mixture was cooled to room temperature and quenched with water (5 ml) , was diluted with EtOAc (5 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3x5 ml) and the combined organic layers were dried with MgSCO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain tert-butyl- (2- (3 - ((1R, 3R) -2- (2,2-difluoroethyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3,4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (82 mg, 52%) as a colorless gum.

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1H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.15 (3H, d), 1.38 (9H, s), 1.79-1.99 (2H, m), 2.58 (1H , dd), 2.65-2.82 (1H, m), 2.89-3.11 (2H, m), 3.32 (2H, t), 3.4-3.53 (3H, m ), 3.84-3.95 (5H, m), 4.22-4.50 (2H, m), 5.27 (1H, s),

5.70-6.01 (1H, m), 6.66 (1H, d), 6.76 (1H, dd), 6.88 (1H, d), 7.09 (2H, pd), 7 , 20 (1H, dd), 7.50 (1H, d), 7.80 (1H, s). mass / charge: ES- [N-H] - 574

Example 7. 3-Fluoro-N- (2- (4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9- tetrahydro-1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propane-1 -amine

To a solution of tert-butyl- (3-fluoropropyl) (2- (4-methoxy-3 - ((1R, 3R) -3 -methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9 -tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) carbamate (62 mg, 0.10 mmol) in DCM (4 ml), trifluoroacetic acid (0.5 ml, 0, 10 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, redissolved in MeOH and loaded onto a pre-wetted (with MeOH) SCX-2 cartridge (5 g). The cartridge was washed with MeOH (50 ml) and the product was eluted with 1 M NH ₃ in MeOH solution (30 ml). The resulting residue was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 30 mm diameter, 100 mm long) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give 3-fluoro-N- (2- (4-methoxy-3 - ((1R, 3R) -3-methyl2- (2,2,2-trifluoroethyl) -2 , 3,4,9-tetrahydro-3-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine (17 mg, 33%) as a colorless oil.

1H NMR (500 MHz, CDCl3, 27 ° C): 1.18 (3H, d), 1.77-1.89 (2H, m), 2.60 (1H, ddd), 2.73 (2H, t), 2.86-2.9 (2H, m), 2.92-3.02 (2H, m), 3.24 (1H, dq), 3.61 (1H, td), 3.90 (6H, m), 4.48 (2H, dt), 5.36 (1H, s), 6.76-6.81 (2H, m), 6.87-6.92 (1H, m), 7.06-7.15 (2H, m), 7.22 (1H, ddd), 7.48-7.54 (1H, m), 7.83 (1H, s). mass / charge: ES + [M + H] + 494.

Tert-butyl- (3-fluoropropyl) (2- (4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b] ingol-1-yl) phenoxy) ethyl) carbamate, used as a starting material, was prepared as described below.

Preparation of 2,2,2-trifluoroethyl trifluoromethanesulfonate o

F ₃ CS-0 О CF ₃

Trifluoromethanesulfonic anhydride (3.14 ml, 18.6 mmol) was added dropwise via syringe over 5 minutes to a stirred solution of 2,2,2-trifluoroethan-1-ol (1.23 ml, 16.9 mmol) and 2,6-dimethylpyridine (2.36 ml, 20.3 mmol) in DCM (50 ml) at -10 ° C. After 2 h, the reaction mixture was washed sequentially with an aqueous solution of HCl (1 N; 2 x 30 ml) and a saturated aqueous solution of NaHCO ₃ (20 ml). The organic layer was then dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.92 g, 23%) as a red oil. 'And NMR (300 MHz, CDCl ₃ , 27 ° C): 4.69 (2H, q).

Preparation of (R) -1 - (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine

2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.91 g, 13.29 mmol) was added to a solution of (R) -1- (1Hindol-3-yl) propan-2-amine (2.32 g, 13.29 mmol) and DIPEA (3.44 ml, 19.93 mmol) in 1,4-dioxane (30 ml) and the reaction mixture was stirred at 85 ° C for 4 hours. The reaction mixture was cooled and concentrated in vacuo. The crude product was purified by flash chromatography on silica, elution gradient 0 to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to give (R) -1- (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine (2.81 g, 83%) in the form of a colorless oil.

'H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.14 (3H, d), 2.81-2.88 (2H, m), 3.11-3.22 (3H, m), 7.06 (1H, d), 7.12 (1H, ddd), 7.21 (1H, ddd), 7.37 (1H, dt), 7.60 (1H, ddd), 8.01 (1H , s). mass / charge: ES- [N-H] - 255.

Obtaining (1R, 3R) -1- (5-bromo-2-methoxyphenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro1 H-pyrido [3, 4-b] indole

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Acetic acid (1.06 ml) was added to a stirred solution of (R) -1- (1H-indol-3-yl) -N- (2,2,2trifluoroethyl) propan-2-amine (680 mg, 2.65 mmol ) and 5-bromo-2-methoxybenzaldehyde (571 mg, 2.65 mmol) in toluene (9.55 ml). The resulting mixture was heated at 90 ° C for 16 h. The reaction mixture was concentrated in vacuo, redissolved in MeOH and loaded onto a pre-wetted (with MeOH) SCX-2 cartridge (5 g). The cartridge was washed with MeOH (50 ml) and the product was eluted with 1 M NH ₃ in MeOH solution (50 ml). The filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to give (1 R, 3R) -1 - (5-bromo-2-methoxyphenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9 -tetrahydro-1 H-pyrido [3,4b] indole (681 mg, 57%) as a colorless gum.

Ή NMR (500 MHz, CDCl ₃ , 27 ° С): 1.17 (3H, d), 2.58 (1H, ddd), 2.82 - 3.01 (2H, m), 3.23 (1H , dq), 3.52 (1H, td), 3.92 (3H, s), 5.36 (1H, s), 6.83 (1H, d), 7.07-7.17 (3H, m), 7.19-7.24 (1H, m), 7.34 (1H, dd), 7.49-7.55 (1H, m), 7.68 (1H, s). mass / charge: ES- [M + H] + 453

Preparation of tert-butyl- (3-fluoropropyl) (2- (4-methoxy-3 - ((1 R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9 -tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) carbamate

RockPhos Pd G3 (11.57 mg, 0.01 mmol) was added to the degassed suspension of (1R, 3R) -1- (5-6pom-2methoxyphenyl) -3-methyl-2- (2,2,2-trifluoroethyl) - 2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indole (125 mg, 0.28 mmol), tert-butyl (3-fluoropropyl) (2-hydroxyethyl) carbamate (122 mg , 0.55 mmol) and cesium carbonate (225 mg, 0.69 mmol) in toluene (2.76 ml) and the reaction mixture was heated to 90 ° С for 1 h. The reaction mixture was cooled to room temperature and quenched with water (5 ml), diluted with EtOAc (5 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3x5 ml) and the combined organic layers were dried over MgSCO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain tert-butyl- (3fluoropropyl) (2- (4-methoxy-3 - ((1 R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2 , 3,4,9-tetrahydro-1 H-pyrido [3,4b] indol-1-yl) phenoxy) ethyl) carbamate (69.0 mg, 42%) as a colorless oil.

Ή NMR (500 MHz, CDCl3, 27 ° С): 1.19 (3H, d), 1.40 (9H, s), 1.81-1.99 (2H, m), 2.61 (1H, dd), 2.89-3.07 (2H, m), 3.24 (1H, dq), 3.32-3.39 (2H, m), 3.41-3.57 (2H, m) , 3.63 (1H, h), 3.85-3.97 (5H, m), 4.39 (2H, d), 5.35 (1H, s), 6.72-6.83 (2H , m), 6.90 (1H, d), 7.04-7.16 (2H, m), 7.2-7.24 (1H, m), 7.46-7.55 (1H, m ), 7.83 (1H, s). mass / charge: ES- [M-H] - 592.

Example 8 2,2-Difluoro-3 - ((1R, 3R) -1- (5- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methoxyphenyl) -3-methyl1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propan-1-ol

To a solution of tert-butyl- (2- (3 - ((1R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro1H-pyrido [3 , 4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (152 mg, 0.25 mmol) in DCM (4 ml), trifluoroacetic acid (0.5 ml, 0, 25 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, redissolved in MeOH and loaded onto a pre-wetted (with MeOH) SCX-2 cartridge. The cartridge was washed with MeOH (50 ml) and the product was eluted with 1M NH ₃ in MeOH solution (50 ml). The resulting residue was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 30 mm diameter, 100 mm long) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give 2,2-difluoro-3 - ((1R, 3R) -1- (5- (2 ((3-fluoropropyl) amino) ethoxy) -2-methoxyphenyl) - 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) propan-1-ol (62 mg, 49%) as a colorless oil.

- 81 038160 ¹ H NMR (500 MHz, CDCl3, 27 ° C): 1.18 (3H, d), 1.74-1.88 (2H, m), 2.58-2.67 (1H, m ), 2.70 (2H, t), 2.79-3 (4H, m), 3.08-3.23 (1H, m), 3.57-3.81 (3H, m), 3, 82-3.91 (6H, m), 4.04 (1H, s), 4.41 (1H, t), 4.50 (1H, t), 5.35 (1H, s), 6.60 (1H, d), 6.79 (1H, dd), 6.86 (1H, d), 7.06-7.15 (2H, m), 7.15-7.22 (1H, m), 7.45-7.58 (1H, m), 7.87 (1H, s). mass / charge: ES + [M + H] + 506.

Tert-butyl- (2- (4 - ((1R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3 , 4-b] indol-1-yl) -3,5-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate used as a starting material was prepared as described below.

Preparation of 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropan-1-ol

NaH in mineral oil (60 wt%; 343 mg, 8.58 mmol) was added in one portion to a stirred solution of 2,2-difluoropropane-1,3-diol (874 mg, 7.80 mmol) in THF (32 ml) at 0 ° C. Allow the reaction mixture to warm to room temperature and stir at room temperature for 2 hours. Warm the reaction mixture to 0 ° C. again and add tert-butyldiphenylchlorosilane (2.0 mL, 7.8 mmol) dropwise via syringe. Allow the reaction mixture to warm to room temperature over 1 h, then quench it with water and extract with EtOAc. The organic layer was dried with Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica eluting with isocratic 5% ethyl acetate in hexanes to give 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropan-1-ol (1.94, 71%) as colorless oil.

1H NMR (300 MHz, CDCl ₃ , 27 ° C): 1.03-1.14 (9H, s), 3.87-3.93 (4H, m), 7.37-7.44 (6H, m), 7.64-7.66 (4H, m).

Preparation of 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyltrifluoromethanesulfonate

A solution of 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropan-1-ol (1.94 g, 5.55 mmol) and 2.6 dimethylpyridine (1.94 ml, 16.6 mmol) in DCM ( 18 ml) was cooled to -10 ° C (salt / ice bath). Trifluoromethanesulfonic anhydride (1.88 mL, 11.1 mmol) was slowly added dropwise over 10 minutes. The reaction mixture was kept under these conditions for 2 hours. Then the reaction mixture was washed with water, aqueous HCl solution (1N, 100 ml) and saturated aqueous sodium bicarbonate solution. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl trifluoromethanesulfonate (2.68 g, 100%) as a red oil.

¹ H NMR (300 MHz, CDCl3, 27 ° C): 1.03-1.14 (9H, s), 3.90 (2H, t), 4.76 (2H, t), 7.39-7 , 56 (6H, m), 7.597.75 (4H, m).

Preparation of (R) -N- (1- (1 H-indol-3-yl) propan-2-yl) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropane-1-amine

3 - ((Tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl trifluoromethanesulfonate (481 mg, 1.00 mmol) was added to a stirred solution of (R) -1- (1H-indol-3-yl) propan-2-amine ( 174 mg, 1.00 mmol) in 1,4 dioxane (3 ml) followed by the addition of DIPEA (0.244 ml, 1.40 mmol). The reaction mixture was stirred at 85 ° C for 5 hours. The reaction mixture was poured into a mixture of DCM and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 35% ethyl acetate in hexanes, to give (R) -N- (1- (1H-indol-3yl) propan-2-yl) -3- ( (tert-butyldiphenylsilyl) oxy) -2,2-difluoropropan-1-amine (465 mg, 92%). Mass / charge: ES + [M + H] + 507.

Obtaining (1R, 3R) -1- (5-bromo-2-methoxyphenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -3 -methyl-2,3,4, 9-tetrahydro-1 H-pyrido [3,4-b] indole

- 82 038160

Acetic acid (545 μl) was added to a stirred solution of (R) -N- (1- (1H-indol-3yl) propan-2-yl) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropane- 1-amine (690 mg, 1.36 mmol) and 5-bromo-2-methoxybenzaldehyde (293 mg, 1.36 mmol) in toluene (4.90 ml). The reaction mixture was heated to

90 ° C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, redissolved in MeOH and loaded onto a pre-moistened (with MeOH) SCX-2 cartridge. The cartridge was washed with MeOH (50 ml) and the product was eluted with 1 M NH ₃ in MeOH solution (50 ml). The filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to give (1R, 3R) -1- (5-6pom-2methoxyphenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -3-methyl-2 , 3,4,9-tetrahydro-1Hpyrido [3,4-b] indole (395 mg, 41%) as a white solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C): 0.96 (9H, s), 1.12 (3H, d), 2.50 (1H, ddd), 2.67-2.79 (2H , m), 3.16 (1H, ddd), 3.38-3.47 (1H, m), 3.61-3.71 (4H, m), 3.96 (1H, dt), 5, 33 (1H, s), 6.66 (1H, d), 6.99-7.07 (2H, m), 7.08 (1H, d), 7.14 (1H, dt), 7.25 (5H, tt), 7.29-7.35 (2H, m), 7.4-7.46 (1H, m), 7.52-7.59 (4H, m), 7.73 (1H , s). mass / charge: ES + [M + H] + 703.

Obtaining tert-butyl- (2- (3 - ((1R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro1 H-pyrido [3 , 4-b] indol-1-yl) -4-methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate

RockPhos Pd G3 (22.66 mg, 0.03 mmol) was added to the degassed suspension of (1R, 3R) -1- (5-6pom-2methoxyphenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2, 2-difluoropropyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3,4-b] indole (380 mg, 0.54 mmol), tert-butyl- (3-fluoropropyl) (2- hydroxyethyl) carbamate (239 mg, 1.08 mmol) and cesium carbonate (440 mg, 1.35 mmol) in toluene (5.4 ml) and the reaction mixture was heated to 90 ° C for 1 h. The reaction mixture was cooled to room temperature. temperature and quenched with water (5 ml), diluted with EtOAc (5 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3x5 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. A solution of 1.0 M TBAF in THF (10 ml) was added and stirred for 30 min. The reaction mixture was quenched with water (10 ml), diluted with EtOAc (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain tert-butyl- (2- (3 - ((1R, 3R) -2 (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9- tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -4methoxyphenoxy) ethyl) (3-fluoropropyl) carbamate (160 mg, 49%) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ , 27 ° C): 1.21 (3H, d), 1.39 (9H, s), 1.8 - 1.99 (2H, m), 2.65 ( 1H, dd), 2.86 - 3.03 (2H, m), 3.12 3.25 (1H, m), 3.3 - 3.37 (2H, m), 3.42 - 3.57 (2H, m), 3.62 - 3.83 (4H, m), 3.84 -4.03 (5H, m), 4.34 (1H, s), 4.44 (1H, s), 5.35 (1H, s), 6.62 (1H, d), 6.81 (1H, dd), 6.90 (1H, d), 7.07-7.17 (2H, m), 7 , 21 - 7.25 (1H, m), 7.5 7.54 (1H, m), 7.68 (1H, s). mass / charge: ES + [M + H] + 606.

Example 9

Obtaining N- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-Spirido [ 3, 4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1 -amine

A solution of tert-butyl- (2- (2,4-difluoro-3 - ((1 R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro -1Hpyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (0.30 g, 0.50 mmol) in formic acid (4 ml, 104 mmol) was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% methanol in dichloromethane. The fractions containing the product were combined and concentrated under reduced pressure to give a yellow foam solid (131 mg). The material was further purified by preparative SFC (column: CHIRALPAK IG, 5 μm, 21.2 mm in diameter, 250 mm in length, 5 ml / min, flow rate) eluting with isocratic 20% methanol (containing 0.2% NH4OH ) in CO ₂ to give N- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9- tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine (0.080 g, 32%) as a pale yellow solid.

1H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.13 (3H, d), 1.67-1.84 (3H, m), 2.57-2.70 (3H, m), 2.74-2.79 (3H, m), 2.92-3.11 (1H, m), 3.35-3.67 (2H, m), 4.03 (2H, t), 4, 47 (2H, dt), 5.31 (1H, s), 6.93-7.05 (3H, m), 7.14-7.23 (2H, m), 7.42 (1H, d) , 10.64 (1H, s). mass / charge: ES + [M + H] + 500.

The procedures used to obtain tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2trifluoroethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate starting material are described below.

Obtaining (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro1 H-pyrido [ 3,4-b] indole

A mixture of (R) -1- (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine (0.50 g, 1.95 mmol) and c-2,6 difluorobenzaldehyde (0.453 g, 2.05 mmol) in toluene (10 ml) and acetic acid (1 ml) was stirred at 100 ° C for 5 hours. The reaction mixture was then allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was treated with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% ethyl acetate in hexanes, to give (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -3-methyl-2 ( 2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (0.85 g, 95%) as a white foam solid.

1H NMR (300 MHz, DMSO-d6, 27 ° C) 1.13 (3H, d), 2.65 (1H, dd), 2.88 (1H, brdd), 2.93-3.12 (1H , m), 3.35-3.47 (1H, m), 3.47-3.67 (1H, m), 5.35 (1H, s), 6.92-7.15 (3H, m ), 7.22 (1H, d), 7.44 (1H, d), 7.68-7.78 (1H, m), 10.66 (1H, s). mass / charge: ES + [M + H] + 459.

Preparation of tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro1 H -pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate

A mixture of (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1Hpyrido [3 , 4-b] indole (0.30 g, 0.65 mmol), tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (0.289 g, 1.31 mmol), RockPhos 3rd generation precatalyst ( 0.027 g, 0.03 mmol) and cesium carbonate (0.532 g, 1.63 mmol) were evacuated and filled with nitrogen (3x). Toluene (3.5 ml) was added and the mixture was evacuated again and backfilled with nitrogen (2x). The resulting suspension was stirred at 90 ° C for 2.3 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 30% ethyl acetate in hexanes, to give tert-butyl- (2- (2,4-difluoro-3 ((1R, 3R) -3-methyl- 2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3fluoropropyl) carbamate (0.30 d, 77%) as a pale yellow foam.

1H NMR (300 MHz, DMSO-d6, 27 ° C) 1.03-1.19 (3H, d), 1.34-1.40 (9H, m), 1.71-1.97 (2H, m), 2.63 (1H, dd), 2.70-3.13 (2H, m), 3.36-3.63 (4H, m), 4.09 (2H, brt), 4.41 (2H, dt), 5.31 (1H, s), 6.88-7.08 (3H, m), 7.137.31 (2H, m), 7.42 (1H, d), 10.63 ( 1H, s). (The multiplet corresponding to two hydrogen atoms is covered by a peak of water), mass / charge: ES + [M + H] + 600.

Example 10. Obtaining 3-fluoro-N- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9tetrahydro -1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) propane-1 -amine

- 84 038160

A solution of tert-butyl- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-Spirido [ 3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (0.59 g, 1.01 mmol) in formic acid (4 ml, 104 mmol) was stirred at room temperature for 24 h and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% methanol in dichloromethane. The fractions containing the product were concentrated under reduced pressure to give a pale yellow foam solid (425 mg). This material was further purified by preparative SFC (column: CHIRALPAK IG, 5 μm, 21.2 mm in diameter, 250 mm in length, 4 ml / min, flow rate) eluting with isocratic 15% methanol (containing 0.2% NH4OH) in an excess of CO ₂ to give 3-fluoro-N- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2trifluoroethyl) -2,3,4 , 9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine (0.35 g, 71%) as a pale yellow solid.

Ή NMR (300 MHz, DMSO-d6, 27 ° С) 1.10 (3H, d), 1.53-1.83 (3H, m), 2.56-2.83 (4H, m), 2 , 88-3.13 (1H, m), 3.14-3.30 (1H, m), 3.44-3.61 (1H, m), 3.81 (2H, brt), 4.42 (2H, dt), 5.28 (1H, s), 6.16 (1H, dd), 6.91 (1H, dt), 6.96-7.04 (1H, m), 7.07 ( 1H, td), 7.17 (1H, t), 7.27 (1H, d), 7.47 (1H, d), 10.70 (1H, s). (The multiplet corresponding to two hydrogen atoms is overlapped by DMSO). mass / charge: ES +, [M + H] 482.

The procedures used to obtain tert-butyl- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2trifluoroethyl) -2,3,4,9-tetrahydro- 1 H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate starting material are described below.

Obtaining (1R, 3R) -1- (5-bromo-2-fluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9-tetrahydro-1Hpyrido [3,4- b] indole

A mixture of (R) -1- (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine (0.30 g, 1.17 mmol) and 5-bromo-2fluorobenzaldehyde (0.250 g, 1.23 mmol) in toluene (6 ml) and acetic acid (0.67 ml) was stirred at 100 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was increased in basicity with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% ethyl acetate in hexanes, to give (1R, 3R) -1- (5-bromo-2-fluorophenyl) -3-methyl-2 (2, 2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (0.51 g, 99%) as a white foam solid.

Ή NMR (300 MHz, DMSO-d ₆ , 27 ° С) 1.10 (3H, d), 2.60 (1H, dd), 2.77 (1H, dd), 3.97-3.08 ( 1H, m), 3.133.28 (1H, m), 3.40-3.69 (1H, m), 5.31 (1H, s), 6.73 (1H, dd), 6.97-7 , 04 (1H, m), 7.09 (1H, td), 7.29 (2H, d), 7.49 (1H, d), 7.57 (1H, ddd), 10.71 (1H, s). mass / charge: ES + [M + H] + 441.

Preparation of tert-butyl- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1Hpyrido [ 3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate

A flask containing a mixture of (1R, 3R) -1- (5-bromo-2-fluorophenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9tetrahydro-1H-pyrido [ 3,4-b] indole (0.510 g, 1.16 mmol), tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (0.511 g, 2.31 mmol), RockPhos 3rd generation precatalyst (48 mg, 0.060 mmol) and cesium carbonate (0.941 g, 2.89 mmol) were evacuated and filled with nitrogen (3x). Toluene (6 ml) was added and the reaction flask was evacuated again and filled with nitrogen (2x). The resulting suspension was stirred at 90 ° C for 2.3 hours and then allowed to cool to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 30% ethyl acetate in hexanes, to give tert-butyl- (2- (4-fluoro-3 - ((1R, 3R) -3-methyl-2 - (2,2,2-trifluoroethyl) -2,3,4,9- 85 038160 tetrahydro-III-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate ( 0.595 g, 89%) as a pale yellow foamy solid.

1H NMR (300 MHz, DMSO-d6, 27 ° C) 1.09 (3H, d), 1.16-1.42 (9H, m), 1.60-1.90 (2H, m), 2 , 57-2.82 (1H, m), 3.01 (1H, br dd), 3.19 (2H, t), 3.22-3.28 (1H, m), 3.34-3, 64 (3H, m), 3.87 (2H, brt), 4.32 (2H, dt), 5.28 (1H, s), 6.14 (1H, dd), 6.86-6.96 (1H, br m), 6.96-7.02 (1H, m), 7.06 (1H, td), 7.17 (1H, t), 7.26 (1H, d), 7.47 (1H, d), 10.67 (1H, s). mass / charge: ES + [M + H] + 582.

Example 11. Obtaining 3-fluoro-N- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4 , 9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine

A solution of tert-butyl- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (0.21 g, 0.34 mmol) in formic acid (4.0 ml, 104 mmol ) was stirred at room temperature for 20 h and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% methanol in dichloromethane. The fractions containing the product were concentrated under reduced pressure to give a yellow foam solid (120 mg). This solid was further purified by preparative SFC ((S, S) Whelk-O1 column, 5 μm, 21.2 mm in diameter, 250 mm in length, 4.0 ml / min, flow rate) eluting with an isocratic 25 % methanol (containing 0.2% NH4OH) in СО ₂ to give 3-fluoro-N- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2 (2, 2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) propan-1-amine (0.10 g, 57% ) as a pale yellow solid.

'H NMR (300 MHz, DMSO-d6, 27 ° C) 1.10 (3H, d), 1.61-1.81 (3H, m), 2.54-2.67 (3H, m), 2.76 (2H, br t) 2.86-3.03 (2H, m), 3.35-3.52 (2H, m), 3.79 (3H, s), 3.85-3, 98 (2H, m), 4.44 (2H, dt), 5.41 (1H, s), 6.83 (1H, dd), 6.96 (2H, doublet quinn), 7.11 (1H, t), 7.15-7.20 (1H, m), 7.35-7.43 (1H, m), 10.45 (1H, s). mass / charge: ES + [M + H] + 512.

Procedures used to prepare tert-butyl- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2 (2,2,2-trifluoroethyl) -2,3,4 , 9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate starting material are described below.

Obtaining (1R, 3R) -1- (3-bromo-2-fluoro-6-methoxyphenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9tetrahydro-1 H- pyrido [3,4-b] indole

F F

A mixture of (R) -1- (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine (0.20 g, 0.78 mmol) and 3-bromo-2fluoro -6-methoxybenzaldehyde (0.191 g, 0.820 mmol) in toluene (4 ml) and acetic acid (0.44 ml) was stirred at 100 ° C for 5 h. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure ... The resulting residue was increased in basicity with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% ethyl acetate in hexanes, to give (1R, 3R) -1- (3-bromo-2-fluoro-6methoxyphenyl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (0.32 g, 87%) as a white foam solid.

'H NMR (300 MHz, DMSO-d6, 27 ° C) 1.10 (3H, d), 2.62 (1H, dd), 2.72-2.99 (2H, m), 3.38- 3.57 (2H, m), 3.86 (3H, s), 5.45 (1H, s), 6.92-7.03 (3H, m), 7.15-7.23 (1H, m), 7.37-7.44 (1H, m), 7.64 (1H, dd), 10.48 (1H, s). mass / charge: ES + [M + H] + 471.

Obtaining tert-butyl- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9tetrahydro- 1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate

A flask containing a mixture of (1R, 3R) -1- (3-bromo-2-fluoro-6-methoxyphenyl) -3-methyl-2- (2.2.2- 86 038160 trifluoroethyl) -2.3.4, 9-tetrahydro-III-pyrido [3,4-b] indole (0.32 g, 0.68 mmol), tert-butyl- (3fluoropropyl) (2-hydroxyethyl) carbamate (0.225 g, 1.02 mmol), RockPhos 3rd generation pre-catalyst (28 mg, 0.030 mmol) and cesium carbonate (0.553 g, 1.70 mmol) were evacuated and filled with nitrogen (3x). Toluene (3.5 ml) was added and the flask was evacuated again and filled with nitrogen (2x). The resulting suspension was stirred at 90 ° C for 2.3 hours and then allowed to cool to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 30% ethyl acetate in hexanes, to give tert-butyl- (2- (2-fluoro-4-methoxy-3 - ((1R, 3R) -3 -methyl-2- (2,2,2trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate ( 0.22 g, 52%) as a pale yellow foam solid.

¹ H NMR (300 MHz, DMSO-d6, 27 ° С) 1.10 (3H, d), 1.34 (9H, br s), 1.63-1.96 (3H, m), 2.54 -2.69 (1H, m), 2.87-2.97 (1H, m), 3.18-3.28 (2H, m), 3.46-3.49 (4H, m), 3 , 78 (3H, s), 3.89-4.03 (2H, m), 4.35 (2H, dt), 5.41 (1H, br d), 6.82 (1H, dd), 6 , 96 (2H, quinn), 7.12 (1H, t), 7.18 (1H, dd), 7.37-7.41 (1H, m), 10.43 (1H, s). mass / charge: ES + [M + H] +612.

Example 12. Obtaining 3-fluoro-N- (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4, 9tetrahydro-III-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1 -amine

F F

Trifluoroacetic acid (0.96 ml, 12 mmol) was added to a solution of tert-butyl- (3-fluoropropyl) (2 ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2.2 , 2-trifluoroethyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1yl) pyridin-2-yl) oxy) ethyl) carbamate (370 mg, 0.62 mmol) in DCM (5.2 ml). The mixture was stirred at room temperature for 16 hours. Saturated aqueous NaHCO ₃ (25 ml) was carefully added and after the addition was complete, the mixture was extracted with DCM (3 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative SFC (column: (S, S) Whelk-O1, 5 μm, 21.2 mm in diameter, 250 mm in length, 70 ml / min, flow rate) eluting with isocratic 25% methanol ( containing 0.2% NH4OH) in CO ₂ . The fractions containing the product were concentrated under reduced pressure to give 3-fluoro-N- (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2trifluoroethyl) -2 , 3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) propan-1-amine (109 mg, 35%) as yellow foamy solid.

¹ H NMR (300 MHz, DMSO-d ₆ , 27 ° С) 1.10 (3H, d), 1.64-1.79 (3H, m), 2.52-2.64 (3H, m) , 2.71-2.78 (3H, m), 2.93-3.08 (1H, m), 3.22-3.28 (1H, m), 3.44-3.60 (1H, m), 3.90 (3H, s), 4.13 (2H, brt), 4.43 (2H, dt), 5.31 (1H, s), 5.92 (1H, s), 6, 96-7.03 (1H, m), 7.03-7.10 (1H, m), 7.24 (1H, d), 7.45 (1H, d), 7.92 (1H, s) , 10.61 (1H, s). mass / charge: ES + [M + H] + 495.

Preparation of tert-butyl- (3-fluoropropyl) (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9 -tetrahydro-1H-pyrido [3,4-b] ingol-1-yl) pyridin-2-yl) oxy) ethyl) carbamate starting material is described below.

Obtaining (1R, 3R) -1- (2-chloro-5-methoxypyrigin-4-yl) -3-methyl-2- (2,2,2-trifluoroethyl) -2,3,4,9tetrahydro-1 H- pyrido [3,4-b] indole

Acetic acid (1.33 ml) was added to a stirred solution of (R) -1- (1H-ingol-3-yl) -N- (2,2,2trifluoroethyl) propan-2-amine (855 mg, 3.34 mmol ) and 2-chloro-5-methoxyisonicotinaldehyde (572 mg, 3.34 mmol) in toluene (11.6 ml). The resulting mixture was heated at 90 ° C for 5 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was redissolved in dichloromethane. This solution was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica eluting with 0-75% ethyl acetate in hexanes. The fractions containing the product were concentrated under reduced pressure to give (1R, 3R) -1- (2-chloro-5-methoxypyridin-4-yl) -3methyl-2- (2,2,2-trifluoroethyl) -2.3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indole (1.28 g, 97%) as a colorless gum.

¹ H NMR (300 MHz, DMSO-d6, 27 ° C) 1.09 (3H, d), 2.60 (1H, dd), 2.80 (1H, dd), 2.90-3.08 ( 1H, m), 3.193.28 (1H, m), 3.38-3.63 (1H, m), 3.99 (3H, s), 5.33 (1H, s), 6.54 (1H , s), 6.97-7.04 (1H, m) 7.05-7.11 (1H, m),

- 87 038160

7.24-7.29 (1H, m), 7.48 (1H, d), 8.27 (1H, s), 10.59 (1H, s). mass / charge: ES + [M + H] + 410.

Preparation of tert-butyl- (3-fluoropropyl) (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2-trifluoroethyl) 2,3,4,9 -tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) pyridin-2-yl) oxy) ethyl) carbamate

RockPhos 3rd generation precatalyst (64.6 mg, 0.08 mmol) was added to the degassed suspension of (1R, 3R) -1- (2-bromo-5-methoxypyridin-4-yl) -3-methyl-2- ( 2,2,2-trifluoroethyl) -2,3,4,9-tetrahydro-Spirido [3,4-b] indole (350 mg, 0.77 mmol) and cesium carbonate (628 mg, 1.93 mmol) in toluene (7.7 ml) and the reaction mixture was heated at 90 ° C for 16 hours. Then the reaction mixture was cooled to room temperature and quenched with water (15 ml). The mixture was diluted with EtOAc (15 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 15 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 50% EtOAc in hexane. Fractions containing product were concentrated under reduced pressure to give tert-butyl- (3-fluoropropyl) (2 - ((5-methoxy-4 - ((1R, 3R) -3-methyl-2- (2,2,2 -trifluoroethyl) -2,3,4,9tetrahydro-1H-pyrido [3,4-L] indol-1-yl) pyridin-2-yl) oxy) ethyl) carbamate (370 mg, 81%) as colorless oils.

¹ H NMR (300 MHz, DMSO-d6, 27 ° C): 1.09 (3H, d), 1.14-1.35 (9H, m), 1.67-1.85 (2H, m) , 2.54-2.61 (1H, m), 2.69-2.76 (1H, m), 2.96-3.04 (1H, m), 3.17-3.29 (3H, m), 3.35-3.57 (3H, m), 3.90 (3H, s), 4.09-4.25 (2H, m), 4.33 (2H, dt), 5.31 (1H, s), 5.90 (1H, s), 6.93-7.09 (2H, m), 7.22-7.26 (1H, m), 7.46 (1H, d), 7.91 (1H, s), 10.58 (1H, s). mass / charge: ES + [M + H] + 595.

Example 13. Obtaining N- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4, 9tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropane-1-amine

Formic acid (5 ml) was added to tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetane-3yl) methyl) -3-methyl-2, 3,4,9-tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate (0.15 g, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by ion exchange chromatography using an SCX-2 cartridge and eluting with ammonia in methanol (3N). The fractions containing the product were combined and concentrated under reduced pressure. The resulting residue was further purified by flash chromatography on silica, elution gradient from 5 to 10% MeOH in DCM. The fractions containing the product were concentrated under reduced pressure to give N- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3methyl-2 , 3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) -3-fluoropropan-1-amine (84 mg, 67%) as a white solid.

1H NMR (400 MHz, DMSO-de, 27 ° С) 1.10 (3H, d), 1.65-1.83 (2H, m), 2.58-2.65 (3H, m), 2 , 70-2.88 (4H, m), 3.17-3.27 (1H, m), 3.33-3.42 (1H, m), 4.01 (2H, t), 4.27 (1H, dd), 4.40 (1H, t), 4.42-4.60 (4H, m), 5.27 (1H, s), 6.87-7.03 (3H, m), 7.10-7.22 (2H, m), 7.40 (1H, d), 10.60 (1H, s). mass / charge: ES + [M + H] + 506.

Procedures used to prepare tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetane-3yl) methyl) -3-methyl-2,3,4 , 9-tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate starting material are described below.

Obtaining (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9tetrahydro-1 H -pyrido [3,4-b] indole o

3-bromo-2,6-difluorobenzaldehyde (0.973 g, 4.40 mmol) was added to a solution of (R) -N - ((3-fluorooxetan3-yl) methyl) -1- (1H-indol-3-yl) propane -2-amine (1.1 g, 4.2 mmol) in toluene (18 ml) and acetic acid (2 ml) and the reaction mixture was heated at 80 ° C for 18 h. Then the reaction mixture was concentrated under reduced pressure and the resulting the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 5% to 50% EtOAc in hexane. The fractions containing the product were concentrated under reduced pressure to give (1R, 3R) -1- (3-6pom-2,6 difluorophenyl) -2 - ((3-fluorooxetane-3-yl) methyl) -3 -methyl-2, 3,4,9-tetrahydro-1 H-pyrido [3,4-b] indole (1.4 g,

72%) as a white solid.

1H NMR (500 MHz, DMSO-d6, 27 ° С) 1.11 (3H, d), 2.59 (1H, dd), 2.71-2.85 (2H, m), 3.20-3 , 29 (1H, m), 3.32-3.39 (1H, m), 4.28 (1H, dd), 4.44-4.61 (3H, m), 5.30 (1H, s ), 6.93-6.98 (1H, m), 6.99-7.04 (1H, m), 7.057.12 (1H, m), 7.20 (1H, d), 7.41 ( 1H, d), 7.74 (1H, td), 10.64 (1H, s). mass / charge: ES + [M + H] + 465.

Preparation of tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3-fluorooxetan-3-yl) methyl) -3-methyl-2,3,4,9tetrahydro -1 H-pyrido [3, 4-b] indol-1-yl) phenoxy) ethyl) (3-fluoropropyl) carbamate

O p

O— / / N— / n

Toluene (4.5 ml) was added to a mixture of (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -2 - ((3-fluorooxetane-3yl) methyl) -3-methyl-2,3 , 4,9-tetrahydro-1H-pyrido [3,4-b] indole (0.25 g, 0.54 mmol) and tert-butyl (3fluoropropyl) (2-hydroxyethyl) carbamate (0.238 g, 1.07 mmol). The reaction flask was evacuated and filled with nitrogen.

Cesium carbonate (0.438 g, 1.34 mmol) and 3rd generation RockPhos precatalyst (0.046 g, 0.05 mmol) were added and the reaction mixture was again subjected to vacuum conditions and then filled with nitrogen. The reaction mixture was heated at 100 ° C for 1 h before being cooled to room temperature and filtered through celite using a DCM wash. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica, elution gradient from 2 to 10% MeOH in DCM. The fractions containing the product were concentrated under reduced pressure to give tert-butyl- (2- (2,4-difluoro-3 - ((1R, 3R) -2 - ((3fluorooxetane-3-yl) methyl) -3 -methyl -2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) phenoxy) ethyl) (3 fluoropropyl) carbamate (151 mg, 46%) as a solid.

1H NMR (500 MHz, DMSO-d6, 27 ° С) 1.10 (3H, d), 1.33-1.39 (9H, m), 1.78-1.89 (2H, m), 2 , 58 (1H, br dd), 2.72-2.84 (2H, m), 3.18-3.30 (3H, m), 3.34-3.40 (2H, m), 3, 45-3.53 (2H, m), 4.07 (2H, brt), 4.28 (1H, brdd), 4.35 (1H, t), 4.42-4.58 (3H, m) , 5.27 (1H, s), 6.91-6.97 (2H, m), 6.97-7.02 (1H, m), 7.13-7.21 (2H, m), 7 , 40 (1H, d), 10.60 (1H, s). mass / charge: ES + [M + H] + 606.

Example 14 3 - ((1 R, 3R) -1 - (2,6-difluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3 -methyl-1,3,4, 9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol

Tert-butyl- (2- (3 - ((1 R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate (0.55 g, 0.90 mmol) was dissolved in formic acid (5 ml). The reaction mixture was heated to 40 ° C for 1 hour and the reaction mixture was evaporated. The crude product was purified by flash chromatography on reverse phase silica (Puriflash HP C18, 30 μ silica, 120 g) using mixtures of water (containing 1% NH ₃ ) and decreasing polarity MeCN as eluents to give 3- ( (1R, 3R) -1 - (2,6-difluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol as foam (0.230 g, 50%).

1H NMR (500 MHz, CDCl3, 27 ° С) 1.18 (3H, d), 1.82-1.93 (2H, m), 2.68 (1H, ddd), 2.80 (2H, t ), 2.83-2.93 (1H, m), 2.96-3.01 (2H, m), 3.11 (1H, ddd), 3.25 (1H, dt), 3.61- 3.78 (3H, m), 4.06-4.12 (2H, m), 4.52 (2H, dt), 5.29 (1H, s), 6.84 (1H, td), 6 , 96 (1H, td), 7.09-7.16 (2H, m), 7.21-7.24 (1H, m), 7.45 (1H, s), 7.50-7.54 (1H, m) (2 H did not appear). mass / charge: ES- [N-H] - 510.

Tert-butyl- (2- (3 - ((1 R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate was prepared as follows.

Obtaining (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2difluoropropyl) -3 -methyl-2,3,4, 9-tetrahydro-1 H-pyrido [3,4-b] indole

- 89 038160

To a solution of (R) -N- (1- (1 H-indol-3-yl) propan-2-yl) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2 difluoropropan-1-amine (1.12 g, 2.21 mmol) in toluene (15 ml) and acetic acid (1.67 ml) was added 3-bromo-2,6-difluorobenzaldehyde (0.624 g, 2.82 mmol). The solution was heated to 90 ° C and stirred for 16 hours. The reaction mixture was evaporated and the residue was partitioned between DCM and 2M NaOH (50 ml each). The organic phase was evaporated and the crude product was purified by flash chromatography on silica, elution gradient from 0 to 25% EtOAc in heptane to give (1 R, 3R) -1 - (3-bromo-2,6-difluorophenyl) -2- ( 3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -3-methyl2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (1.070 g, 68%) as white foam.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.05 (9H, s), 1.16 (3H, d), 2.61 (1H, ddd), 2.71-2.81 (1H , m), 2.99 (1H, ddd), 3.25-3.38 (1H, m), 3.57-3.69 (2H, m), 3.91-4.01 (1H, m ), 5.36 (1H, s), 6.65-6.71 (1H, m), 7.08-7.16 (2H, m), 7.21-7.25 (1H, m), 7.36-7.44 (8H, m), 7.51-7.55 (1H, m), 7.60-7.66 (4H, m).

Preparation of tert-butyl- (2- (3 - ((1R, 3R) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -3methyl-2,3,4,9-tetrahydro -1Н-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate

RockPhos Pd G3 (0.063 g, 0.08 mmol) was added to the degassed suspension of (1R, 3R) -1- (3-6pom-2,6difluorophenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2, 2-difluoropropyl) -3-methyl-2,3,4,9-tetrahydro-Spirido [3,4-b] indole (1.07 g, 1.51 mmol), tert-butyl- (3-fluoropropyl) ( 2-hydroxyethyl) carbamate (0.667 g, 3.02 mmol) and cesium carbonate (1.23 g, 3.77 mmol) in toluene (15 ml) and the reaction mixture was heated to 90 ° C for 5 h. the mixture to room temperature and it was diluted with water (15 ml). DCM (30 ml) was added and the organic phase was separated and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 50% EtOAc in heptane to give tert-butyl- (2- (3 - ((1R, 3R) -2- (3 - ((tert-butyldiphenylsilyl) oxy ) -2,2-difluoropropyl) -3-methyl-2,3,4,9-tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) 2,4-difluorophenoxy) ethyl) (3 -fluoropropyl) carbamate (0.850 g, 66%) as a beige foam.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.04 (9H, s), 1.15 (3H, d), 1.43 (9H, s), 1.84-1.99 (2H, m ), 2.60 (1H, dd), 2.74-2.85 (1H, m), 3.00 (1H, ddd), 3.23-3.34 (1H, m), 3.35- 3.41 (2H, m), 3.45-3.62 (3H, m), 3.65-3.72 (1H, m), 3.93-4.09 (3H, m), 4, 33-4.49 (2H, m), 5.33 (1H, s), 6.62 (1H, s), 6.77-6.85 (1H, m), 7.07-7.14 ( 2H, m), 7.207.23 (1H, m), 7.33-7.44 (6H, m), 7.49-7.52 (1H, m), 7.56 (1H, s), 7 , 58-7.66 (4H, m). mass / charge: ES + [M + H] + 850.

Preparation of tert-butyl- (2- (3 - ((1R, 3R) -2- (2,2-difluoro-3-hydroxypropyl) -3-methyl-2,3,4,9-tetrahydro1 H-pyrido [3 , 4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate

Tetrabutylammonium fluoride (1.0 M in THF) (1.50 ml, 1.50 mmol) was added to a solution of tert-butyl (2- (3 - ((1R, 3R) -2- (3 - ((tert-butyldiphenylsilyl ) oxy) -2,2-difluoropropyl) -3-methyl-2,3,4,9-tetrahydro-1Hpyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3 -fluoropropyl) carbamate (0.850 g, 1.00 mmol) in tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 90 minutes and then the reaction mixture was evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 80% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give tert-butyl- (2- (3 - ((1R, 3R) -2- (2,2 difluoro-3-hydroxypropyl) -3-methyl-2,3,4, 9-tetrahydro-III-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate (0.550 g, 90%) as a colorless foam.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.18 (3H, d), 1.44 (9H, s), 1.88-2.02 (2H, m), 2.69 (1H, ddd ), 2.83-2.93 (1H, m), 3.13 (1H, dd), 3.21-3.32 (2H, m), 3.39-3.44 (2H, m), 3.47-3.79 (6H, m), 4.16 (1H, s), 4.45 (2H, dt), 5.28 (1H, s), 6.82 (1H, td), 6 , 96 (1H, s), 7.08-7.15 (2H, m), 7.23 (1H, d), 7.49-7.65 (2H, m). mass / charge: ES + [M + H] + 612.

Example 15 3 - ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol

A solution of TBAF (1M B THF) (1.58 ml, 1.58 mmol) was added to tert-butyl- (2- (3 - ((1R, 3R) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2 , 2-difluoropropyl) -6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) ( 3-fluoropropyl) carbamate (275 mg, 0.32 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (10 ml) and washed with saturated aqueous sodium chloride solution (10 ml). The aqueous layer was extracted with DCM (10 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was passed through a silica plug eluting with EtOAc / heptane 1: 1. Fractions containing product were evaporated to give the crude title compound as a pale yellow gum (~ 200 mg). The residue was dissolved in formic acid (2 ml) and stirred at 40 ° C for 1 hour. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length ) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness. The sample was dissolved in MeOH and further purified using SFC: Column: Phenomenex A1, 30x250 mm, 5 μm; mobile phase: 20% MeOH + 0.1% NH ₃ /80% sc CO ₂ ; flow rate: 100 ml / min; temperature: 40 ° C; BPR: 120 bar to give 3 ((1R, 3R) -1- (2,6-difluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3-methyl-1 , 3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2,2-difluoropropan-1-ol (72.6 mg, 77%) as a colorless solid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.18 (3H, d), 1.82-1.95 (2H, m), 2.62 (1H, dd), 2.80 (2H, t), 2.87 (1H, dd), 2.97-3.01 (2H, m), 3.07 (1H, dd), 3.19-3.28 (1H, m), 3.56 -3.82 (2H, m), 4.04-4.17 (2H, m), 4.52 (3H, dt), 5.28 (1H, s), 6.82-6.91 (2H , m), 6.97 (1H, td), 7.14 (2H, td), 7.43 (1H, s); mass / charge: ES + [M + H] + 530.

Tert-butyl- (2- (3 - ((1R, 3R) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -6-fluoro-3methyl-2,3,4, 9-tetrahydro-1H-pyrido [3,4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate as a starting material was prepared as described below.

Tert-butyl- (R) - (1- (5-fluoro-1H-indol-3-yl) propan-2-yl) carbamate

5-Fluoro-III-indole (9.34 g, 69.11 mmol) was dissolved in DCM (470 ml) and cooled to -78 ° C. A solution of methylmagnesium bromide (23.50 ml, 70.50 mmol) was added dropwise over 10 min, then tert-butyl (R) -4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2 was added dropwise , 2-dioxide (6.56 g, 27.65 mmol) in DCM (15 ml). The reaction mixture was stirred at -78 ° C for 30 min, then allowed to warm to 0 ° C for 2 h. 1M ice-cold aqueous citric acid solution (80 ml) was added and the biphasic mixture was stirred for 10 min. The layers were separated, then the aqueous layer was extracted with DCM (2 x 100 ml). The combined organics were washed with H ₂ O (50 ml), saturated aqueous sodium chloride solution (50 ml), then dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain tert-butyl- (R) - (1- (5-fluoro-1H-indol-3-yl) propan-2-yl) carbamate (5.56 g, 69%) as brown solid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.12 (3H, d), 1.43 (9H, s), 2.87 (2H, td), 3.93-4.08 (1H, m ), 4.36-4.51 (1H, m), 6.93 (1H, td), 7.05 (1H, d), 7.23-7.29 (2H, m), 8.11 ( 1H, s); mass / charge: ES- [M + H] + 291.

- 91 038160 (R) -1 - (5-fluoro-1 N-indol-3-yl) propan-2-amine

To a solution of tert-butyl- (R) - (1- (5-fluoro-1H-indol-3-yl) propan-2-yl) carbamate (5.5 g, 18.81 mmol) in DCM (40 ml) trifluoroacetic acid (1.45 mL, 18.81 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, redissolved in methanol and loaded onto a pre-wet (methanol) SCX-2 cartridge. The cartridge was washed with methanol (250 ml), the product was eluted with 1 M NH ₃ in methanol solution (250 ml) and concentrated in vacuo to give (R) -1- (5-fluoro-1H-indol-3-yl) propan- 2-amine (3.56 g, 98%) as a yellow solid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.16 (3H, d), 2.62 (1H, dd), 2.82 (1H, dd), 3.27 (1H, ddt), 6, 9-7.01 (1H, m), 7.09 (1H, s), 7.22-7.32 (2H, m), 8.16 (1H, s); mass / charge: ES + [N-H] - 191.

(R) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoro-N- (1- (5-fluoro-1H-indol-3-yl) propan-2-yl) propan-1-amine

3 - ((Tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl trifluoromethanesulfonate (1.44 g, 2.99 mmol) was added to a solution of (R) -1- (5-fluoro-1H-indol-3-yl) propane -2-amine (0.500 g, 2.6 mmol) and DIPEA (0.674 ml, 3.90 mmol) in 1,4-dioxane (9.73 ml). The reaction mixture was heated to 80 ° C for 6 hours. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The organic phase was dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain (R) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoro-N- (1 - (5-fluoro-1 H-indol-3-yl) propane- 2-yl) propan-1-amine (1.13 g, 83%) as a colorless gum.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.04 (9H, s), 1.11 (3H, d), 2.68-2.77 (1H, m), 2.81 (1H, dd), 3.02-3.26 (3H, m), 3.74-3.88 (2H, m), 6.93 (1H, td), 7.03 (1H, d), 7.18 -7.25 (2H, m), 7.38 (4H, ddd), 7.4-7.49 (2H, m), 7.65 (4H, dq), 7.85 (1H, s); mass / charge: ES + [M + H] + 525.

(1R, 3R-1- (3-bromo-2,6-difluorophenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -6fluoro-3-methyl-2,3, 4,9-tetrahydro-1H-pyrido [3,4-b] indole f-ΛΑ Η \) - Br, / ΐχ-Ν Υ— / LDCP 4 ^F Py _z Ph Q-S '^ Z

Ph \ (R) -3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoro-N- (1- (5-fluoro-1H-indol-3-yl) propan-2-yl) propan-1 α-amine (352 mg, 0.67 mmol) and 3-bromo-2,6-difluorobenzaldehyde (155 mg, 0.70 mmol) were heated in toluene (3.02 ml) / acetic acid (0.33 ml) to 80 ° C for 4 h. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (25 ml) and washed with saturated NaHCO ₃ solution (25 ml), then dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 25% EtOAc in heptane. Pure fractions were evaporated to dryness to give (1R, 3R) -1- (3-bromo-2,6-difluorophenyl) -2 (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -6- fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole (483 mg, 99%) as a colorless solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.05 (9H, s), 1.16 (3H, d), 2.54 (1H, dd), 2.76 (1H, td), 2 , 89-2.98 (1H, m), 3.29 (1H, ddd), 3.56-3.69 (2H, m), 3.95 (1H, ddd), 5.35 (1H, s ), 6.70 (1H, td), 6.88 (1H, td), 7.11-7.18 (2H, m), 7.34-7.47 (8H, m), 7.6- 7.67 (4H, m); mass / charge: ES + [M + H] + 727.

tert-Butyl- (2- (3 - ((1 R, 3R) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -6-fluoro-3-methyl-2,3 , 4,9-tetrahydro-1 H-pyrido [3, 4-b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate

- 92 038160

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (137 mg, 0.62 mmol) was added to toluene (2.06 ml) in a flask containing (1R, 3R) -1 - (3-bromo- 2,6-difluorophenyl) -2- (3 - ((tert-butyldiphenylsilyl) oxy) -2,2difluoropropyl) -6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3, 4-b] indole (300 mg, 0.41 mmol), cesium carbonate (268 mg, 0.82 mmol) and Rockphos 3rd generation precatalyst (18.65 mg, 0.02 mmol). The reaction mixture was degassed, then heated to 90 ° C for 2 h. After cooling, the reaction mixture was diluted with EtOAc (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The organic phase was dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain tert-butyl- (2- (3 - ((1R, 3R) -2- (3 ((tert-butyldiphenylsilyl) oxy) -2,2-difluoropropyl) -6-fluoro-3 -methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4b] indol-1-yl) -2,4-difluorophenoxy) ethyl) (3-fluoropropyl) carbamate as a beige solid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.04 (9H, s), 1.15 (3H, d), 1.43 (9H, s), 1.91 (2H, d), 2 , 53 (1H, dd), 2.79 (1H, q), 2.92-3 (1H, m), 3.21-3.35 (1H, m), 3.35-3.4 (1H , m), 3.41-3.54 (2H, m), 3.53-3.63 (2H, m), 3.63-3.74 (1H, m), 3.89-4.01 (1H, m), 4.03 (1H, s), 4.09 (1H, d), 4.37 (1H, d), 4.46 (1H, s), 5.31 (1H, s) , 6.63 (1H, s), 6.76-6.89 (2H, m), 7.06-7.12 (1H, m), 7.14 (1H, dd), 7.33-7 , 47 (6H, m), 7.60 (3H, ddd), 7.63-7.68 (2H, m).

Example 55 (S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (235 mg, 1.06 mmol) in anhydrous toluene (4.25 ml) was added to a flask containing methyl- (S) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -3methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2- methyl propanoate (402 mg, 0.85 mmol), cesium carbonate (553 mg, 1.70 mmol) and Rockphos 3rd generation precatalyst (38.5 mg, 0.04 mmol). The reaction mixture was degassed, then heated to 90 ° C for 4 h. An additional portion of tert-butyl (3-fluoropropyl) (2-hydroxyethyl) carbamate (235 mg, 1.06 mmol) and 3rd generation Rockphos precatalyst ( 38.5 mg, 0.04 mmol) and the reaction mixture was heated to 90 ° C overnight. The residue was dissolved in THF (3 ml) / MeOH (3 ml) and then 2N hydrochloric acid was added. NaOH solution (1.5 ml). The reaction mixture was stirred for 3 h, then diluted with EtOAc (20 ml) and water (20 ml). The pH was adjusted to ~ 6 by adding 2N HCl. HCl solution and the layers were separated. The aqueous layer was extracted with EtOAc (20 ml), then the combined organics were evaporated. The residue was dissolved in formic acid (2 ml) and stirred at 40 ° C for 1 hour. The volatiles were evaporated, then the residue was partitioned between DCM (20 ml) and water (20 ml). The desired product was observed exclusively in the aqueous phase. The aqueous phase was evaporated, then the crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm diameter, 100 mm long) using mixtures of water (containing 0.1% NH ₃ ) and MeCN with decreasing polarity in as eluents. The fractions containing the desired compound were evaporated to dryness to give (S) -3 ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl ) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (83 mg, 20%) as a pale yellow solid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 0.86 (3H, d), 1.20 (3H, d), 1.82-1.97 (5H, m), 2.68-2, 80 (3H, m), 2.83 (3H, t), 2.94-3.07 (2H, m), 3.21 (1H, dd), 3.42 (2H, s), 3.54 -3.65 (1H, m), 4.02 (1H, q), 4.40 (1H, t), 4.50 (1H, t),

5.47 (1H, s), 6.18 (1H, s), 6.77 (1H, dd), 6.89 (1H, t), 7.09 (2H, td), 7.14-7 , 22 (1H, m), 7.48-7.52 (1H, m), 7.82 (1H, s). mass / charge: ES + [M + H] + 500.

Methyl- (S) -3 - ((1H, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3 , 4b] indol-2-yl) -2-methylpropanoate used as a starting material was prepared as described below.

Methyl- (S) -2-Methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate

Added trifluoromethanesulfonic anhydride (3.53 ml, 21.00 mmol), then 2.6 dimethylpyridine (2.56 ml, 22.00 mmol) to a solution of methyl (S) -3-hydroxy-2-methylpropanoate (2.36 g, 20.0 mmol) in DCM (74 ml) at 5 ° C. The reaction mixture was stirred for 1 hour, then washed with 2N HCl. HCl solution (50 ml). The organic phase was washed with saturated aqueous sodium chloride solution (50 ml), then dried over Na ₂ SO ₄ and evaporated to give methyl (S) -2-methyl-3 (((trifluoromethyl) sulfonyl) oxy) propanoate (5.46 g ,> 100%) as a red oil, which was directly applied.

- 93 038160 'll NMR (500 MHz, CDCI3, 27 ° C) 1.31 (3H, d), 2.96 (1H, pd), 3.75 (3H, s), 4.56 (1H, dd ), 4.69 (1H, dd).

Methyl- (S) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate

Methyl- (S) -2-methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate (4.60 g, 18.40 mmol) was added to a solution of (R) -1- (1H-indol-3-yl ) propan-2-amine (2.79 g, 16 mmol) and DIPEA (3.59 ml, 20.80 mmol) in 1,4 dioxane (42.1 ml) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The aqueous layer was extracted with EtOAc (50 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain methyl (S) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (3.71 g , 85%) as a pale yellow resin.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.11 (3H, d), 1.21-1.25 (3H, m), 2.72 (1H, ddd), 2.79 (1H, dd), 2.86 (1H, dd), 2.93 (2H, d), 3.13 (1H, q), 3.50 (3H, s), 7.08-7.15 (2H, m ), 7.20 (1H, ddd), 7.38 (1H, dt), 7.49-7.69 (1H, m), 8.23 (1H, s). mass / charge: ES + [M + H] + 275.

3-bromo-6-fluoro-2-methylbenzaldehyde

N-bromosuccinimide (2.99 g, 16.80 mmol) was added to 2-fluoro-6-methylbenzaldehyde (2.21 g, 16.0 mmol) in H ₂ SO ₄ (16.00 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water (150 ml). The precipitate was collected by filtration and dried to give 3-bromo-6-fluoro-2-methylbenzaldehyde (3.14 g, 90%) as a beige low melting solid. 'H NMR (500 MHz, CDCl3, 27 ° C) 2.70 (3H, s), 6.94 (1H, ddd), 7.74 (1H, dd), 10.46 (1H, s).

Methyl- (S) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3 , 4b] indol-2-yl) -2-methylpropanoate

Methyl- (S) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (549 mg, 2.0 mmol) and 3 bromo-6 α-fluoro-2-methylbenzaldehyde (456 mg, 2.10 mmol) was heated in toluene (9.0 ml) / acetic acid (1.0 ml) to 80 ° C overnight. After cooling, the volatiles were evaporated. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using MeOH followed by 1 M NH ₃ / MeOH to elute the product. The main filtrate was evaporated, then the crude product was purified by flash chromatography on silica, elution gradient from 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to give methyl- (S) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2methylphenyl) -3-methyl-1,3,4,9-tetrahydro -2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (421 mg, 44%) as a beige solid.

'H NMR (500 MHz, CDC13, 27 ° C) 0.85-0.89 (3H, m), 1.11 (3H, d), 2.10 (3H, s), 2.18 (1H, p), 2.36 (1H, ddd), 2.67-2.72 (1H, m), 2.95 (1H, dd), 3.10 (1H, ddd), 3.52-3.59 (1H, m), 3.64 (3H, s), 5.39 (1H, s), 6.89 (1H, t), 7.07-7.14 (2H, m), 7.19- 7.22 (1H, m), 7.22 (1H, s), 7.47-7.51 (1H, m), 7.54 (1H, dd). mass / charge: ES- [NH] - 471.

Example 57. (S) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Added 2 N. NaOH solution (1.19 ml, 2.37 mmol) to a solution of methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy ) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.300 g , 0.47 mmol) in THF (2.37 ml) / MeOH (1.19 ml) and the reaction mixture was stirred at room temperature for 4 h.

- 94 038160 the mixture was diluted with EtOAc (20 ml) and water (20 ml), then the pH was adjusted to -6 by adding 2N HCl. solution of HC1. The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined organics were dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in formic acid (2 ml) and heated to 40 ° C for 1 h. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length ) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (S) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) - 2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2methylpropanoic acid (0.147 g, 60%) as a beige solid ...

1H NMR (500 MHz, CDCl3, 27 ° C) 0.84 (3H, d), 1.17 (3H, d), 1.83-1.89 (4H, m), 1.92 (2H, dd ), 2.65 (2H, dd), 2.80 (1H, dd), 2.86 (2H, t), 3-3.1 (2H, m), 3.1-3.2 (1H, m), 3.55-3.65 (1H, m), 4.03 (2H, dq), 4.38 (1H, t), 4.48 (1H, t), 5.42 (1H, s ), 6.73 (1H, dd), 6.78-6.83 (1H, m), 6.83-6.89 (1H, m), 7.07 (1H, dd), 7.11 ( 1H, dd), 7.54 (1H, s), 8.00 (1H, s). 1 exchangeable was not observed, mass / charge: ES + [M + H] + 518.

Methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2methylphenyl) -6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate as a starting material was prepared as described below.

Methyl- (S) -3 (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate

To a cooled solution of (R) -1- (5-fluoro-1H-indol-3-yl) propan-2-amine (1.105 g, 5.75 mmol) and DIPEA (0.993 ml, 5.75 mmol) in dioxane ( 15 ml) methyl (S) -2-methyl-3 (((trifluoromethyl) sulfonyl) oxy) propanoate (1.44 g, 5.75 mmol) was added at 0 ° C. Allow the reaction mixture to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (50 ml). The organic phase was dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain methyl (S) -3 - (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate ( 1.520 g, 90%) as a pale yellow oil.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.13 (3H, d), 1.26-1.29 (3H, m), 2.67-2.85 (2H, m), 2 , 86-2.98 (3H, m), 3.14 (1H, h), 3.53 (3H, s), 6.95 (1H, td), 7.17-7.23 (2H, m ), 7.30 (1H, dd), 8.37 (1H, s). mass / charge: ES + [M + H] + 293.

Methyl- (S) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H -pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

Methyl- (S) -3 - (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (439 mg, 1.5 mmol) and 3-bromo-6-fluoro-2-methylbenzaldehyde (326 mg, 1.50 mmol) was heated in toluene (6.75 ml) / acetic acid (0.75 ml) to 110 ° C overnight. The volatiles were evaporated, then the residue was dissolved in DCM (25 ml) and washed with saturated NaHCO ₃ solution (25 ml). The organic matter was dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to give methyl- (S) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2methylphenyl) -6-fluoro-3-methyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (204 mg, 28%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3, 27 ° C) 0.87 (3H, d), 1.11 (3H, d), 2.10 (3H, s), 2.16 (1H, q), 2, 35 (1H, ddd), 2.63 (1H, d), 2.95 (1H, dd), 3.07 (1H, ddd), 3.52-3.59 (1H, m), 3.64 (3H, s), 5.37 (1H, s), 6.84 (1H, td), 6.90 (1H, t), 7.08-7.15 (2H, m), 7.20 ( 1H, s), 7.55 (1H, dd). mass / charge: ES + [M + H] + 491.

Methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2methylphenyl) -6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

- 95 038160

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (342 mg, 1.55 mmol) in toluene (6.18 ml) was added to a flask containing methyl- (S) -3 - ((1R, 3R ) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3-methyl1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (380 mg, 0.77 mmol), cesium carbonate (628 mg, 1.93 mmol) and Rockphos 3rd generation pre-catalyst (70.0 mg, 0.08 mmol). The reaction mixture was degassed, then heated to 105 ° C for 3 h. The reaction mixture was diluted with DCM (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The organic layer was dried over Na2SO4 and evaporated, then the crude product was purified by flash chromatography on silica, elution gradient from 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2 -methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (321 mg, 66%) in the form of a beige solid. Mass / charge: ES + [M + H] + 632.

Example 117 1H-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

(R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (200 mg, 0.33 mmol) was stirred in formic acid (2.0 ml) at 40 ° C for 1 h. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm in length) using water mixtures (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (R) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl ) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) 2-methylpropanoic acid (120 mg, 72%) as a colorless solid.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.10 (3H, d), 1.22 (3H, d), 1.80 (3H, s), 1.88 (2H, dq), 2.56 (1H, t), 2.71-2.90 (5H, m), 2.95 (1H, s), 2.99-3.07 (1H, m), 3.22-3, 32 (1H, m), 3.85 (1H, p), 4.06 (2H, t), 4.45 (1H, t), 4.55 (1H, t), 5.35 (1H, s ), 6.84 (1H, dd), 6.93 (1H, d), 7.08-7.17 (2H, m), 7.19-7.23 (1H, m), 7.38 ( 1H, s), 7.51 (1H, dd). (2 x exchangeable was not observed.) Mass / charge: ES + [M + H] + 500.

(R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid as a starting material was prepared as described below.

Methyl- (R) -2-methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate

Trifluoromethanesulfonic anhydride (7.48 ml, 44.44 mmol) was added to a solution of methyl (R) -3-hydroxy-2-methylpropanoate (5.00 g, 42.3 mmol) in DCM (128 ml) at 5 ° C. followed by the addition of 2,6-dimethylpyridine (5.42 ml, 46.6 mmol). The reaction mixture was stirred for 1 hour, then washed with 2N HCl. HCl solution (100 ml), dried over MgSO ₄ and evaporated to give methyl- (R) -2-methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate (11.64 g,> 100%) as red oil, which was used without additional purification.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.31 (3H, d), 2.91-3.03 (1H, m), 3.75 (3H, s), 4.56 (1H , dd), 4.69 (1H, dd).

Methyl- (R) -3 - (((R) -1- (1 N-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate

Methyl- (R) -2-methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate (10.46 g, 41.80 mmol) was added in DCM (20 ml) to a solution of (R) -1- (1H -indol-3-yl) propan-2-amine (6.62 g, 38.0 mmol) and DIPEA (8.21 ml, 47.5 mmol) in DCM (107 ml) at 5 ° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium chloride solution (50 ml), then dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to obtain methyl (R) -3 - (((R) -1- (1H-indol-3-yl) propan2-yl) amino) -2-methylpropanoate (8.45 g, 81 %) in the form of an orange liquid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.10 (3H, d), 1.12 (3H, d), 2.53-2.71 (2H, m), 2.74-2, 89 (2H, m), 2.94 (1H, dd), 3.05 (1H, h), 3.48 (3H, s), 7.04 (1H, d), 7.11 (1H, ddd ), 7.18 (1H, ddd), 7.35 (1H, dt), 7.53-7.64 (1H,

- 96 038160

m), 8.12 (1H, s). (1 x exchangeable was not observed); mass / charge: ES + [M + H] + 275.

Methyl-1H-3 - ((1 R, 3R) -1 - (3-bromo-6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3, 4b] indol-2-yl) -2-methylpropanoate

Methyl- (R) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (686 mg, 2.50 mmol) and 3-bromine -6-fluoro-2-methylbenzaldehyde (570 mg, 2.63 mmol) was heated in toluene (9.0 ml) / acetic acid (1.0 ml) to 90 ° C for 6 hours. After cooling, the reaction mixture was evaporated. The residue was dissolved in DCM (25 ml) and washed with saturated aqueous NaHCO ₃ solution (25 ml). The aqueous layer was extracted with DCM (25 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 30% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl- (R) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -3-methyl1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (795 mg, 67%) as a beige solid.

Ή NMR (500 MHz, CDCl ₃ , 27 ° C) 1.01-1.05 (3H, m), 1.09 (3H, d), 2.03 (3H, s), 2.57-2, 64 (3H, m), 2.692.75 (1H, m), 3.08-3.14 (1H, m), 3.52 (3H, s), 3.66-3.74 (1H, m) , 5.31 (1H, s), 6.90 (1H, t), 7.05-7.14 (2H, m), 7.18-7.22 (2H, m), 7.49 (1H , dd), 7.54 (1H, dd); mass / charge: ES + [M + H] + 473.

Methyl- (R) -3 - ((1 R, 3R) -1 - (3 - (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

XX hI '$ to θΛΑ ^Ξ

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (351 mg, 1.58 mmol) in toluene (5.0 ml) was added to a flask containing methyl- (R) -3 - ((1R, 3R ) -1- (3-bromo-6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (500 mg, 1.06 mmol), cesium carbonate (858 mg, 2.64 mmol) and Rockphos 3rd generation precatalyst (45.1 mg, 0.05 mmol) under nitrogen. The reaction mixture was degassed, then heated to 90 ° C for 4 h. After cooling, the reaction mixture was diluted with DCM (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The aqueous layer was extracted with DCM (25 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 40% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6- fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate (425 mg, 66%) as a beige solid substances.

Ή NMR (500 MHz, CDCl ₃ , 27 ° С) 1.03 (3H, d), 1.09 (3H, d), 1.43 (9H, s), 1.82 (3H, s), 1 , 85-1.97 (2H, m), 2.53-2.61 (1H, m), 2.61-2.68 (1H, m), 2.70 (1H, d), 3.12 (1H, ddd), 3.39 (2H, t), 3.49 (3H, s), 3.52-3.59 (3H, m), 3.64-3.73 (1H, m), 4.01 (2H, d), 4.36 (1H, s), 4.45 (1H, s), 5.27 (1H, s), 6.79 (1H, dd), 6.91 (1H , t), 7.01-7.12 (2H, m), 7.16-7.21 (1H, m), 7.23-7.26 (1H, m), 7.47-7.52 (1H, m). mass / charge: ES + [M + H] + 614.

H-3 - ((1 R, 3R) -1 - (3 - (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Added 2 N. NaOH solution (2.00 ml, 4.00 mmol) to a solution of methyl- (R) -3 - ((1H, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy ) -6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate (400 mg, 0.65 mmol) in THF (2.5 ml) / MeOH (2.5 ml) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (25 ml) and water (25 ml), then the pH was adjusted to ~ 5 by adding 2 n. HCl solution. The layers were separated and the aqueous layer was extracted with EtOAc (25 ml). The combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 30 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity in

- 97 038160 as eluents. Fractions containing the desired compound were evaporated to dryness to give (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6 -fluoro-2methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (225 mg, 58%) as colorless solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.13 (3H, d), 1.24 (3H, d), 1.41-1.47 (9H, m), 1.76 (3H, s), 1.88 (2H, d), 2.57 (1H, t), 2.75 (1H, s), 2.87 (2H, d), 3.29 (1H, d), 3, 39 (2H, s), 3.58 (2H, s), 3.82-3.96 (1H, m), 4.10 (2H, d), 4.38 (1H, s), 4.47 (1H, s), 5.39 (1H, s), 6.84 (1H, s), 6.95 (1H, s), 7.08-7.19 (2H, m), 7.23 ( 1H, d), 7.40 (1H, d), 7.50-7.57 (1H, m). (1 x exchangeable was not observed); mass / charge: ES + [M + H] + 600.

Example 121. (R) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

he

An aqueous solution of sodium hydroxide (2N, 0.45 ml, 0.90 mmol) was added to a solution of methyl- (R) -3 ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl ) -2-methylpropanoate (0.11 g, 0.18 mmol) in THF (0.54 ml) and MeOH (0.27 ml) and the reaction mixture was stirred at room temperature for 21 hours. Then the reaction mixture was diluted with water, acidified to pH 6 by adding aqueous HCl solution (2N) and extracted with ethyl acetate (2x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R) -3 - ((1R, 3R) -1- (3- (2 ((tert-butoxycarbonyl) (3-fluoropropyl) amino ) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (0.095 g, 85%) as an orange gum. This gum was dissolved in formic acid (1 ml) and stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by preparative SFC (Chiralpak IC, 5 μm, 21.2 mm in diameter, 250 mm in length, 75 ml / min, flow rate) eluting with isocratic (25% MeOH containing 0.2% NH4OH) in CO ₂ to give (R) -3 - ((1R, 3R) -6-fluoro- 1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4- B] indol-2-yl) -2-methylpropanoic acid (0.034 g, 42%) as a colorless solid.

1H NMR (300 MHz, DMSO-d6, 27 ° C) 0.88 (3H, d), 0.99 (3H, d), 1.63-1.95 (6H, m), 2.52-2 , 65 (4H, m), 2.77-2.85 (2H, m), 2.95 (1H, br dd), 3.84-4.00 (2H, m), 4.44 (2H, dt), 5.17 (1H, s), 6.77 (1H, td), 6.87-6.93 (1H, m), 6.93-7.01 (1H, m), 7.08 -7.15 (2H, m), 10.29 (1H, s). The multiplet corresponding to two hydrogen atoms is covered by a water peak; the other two peaks corresponding to the hydrogen atom were not observed, mass / charge: ES + [M + H] + 518.

Also (R) -3 - ((1S, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) amino) ethoxy) -2methylphenyl) -3-methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (0.015 g, 19%) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.88 (3H, d), 0.99 (3H, d), 1.63-1.95 (6H, m), 2.52 -2.65 (4H, m), 2.77-2.85 (2H, m), 2.95 (1H, br dd), 3.84-4.00 (2H, m), 4.44 ( 2H, dt), 5.17 (1H, s), 6.77 (1H, td), 6.87-6.93 (1H, m), 6.93-7.01 (1H, m), 7 08-7.15 (2H, m), 10.29 (1H, s). The multiplet corresponding to two hydrogen atoms is covered by a water peak; the other two peaks corresponding to the hydrogen atom were not observed, mass / charge: ES + [M + H] + 518.

Procedures used to prepare methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2R-pyrido [3,4b] indol-2-yl) -2-methylpropanoate starting material are described below.

Methyl- (R) -3 - (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate

A solution of crude methyl- (R) -2-methyl-3 - (((trifluoromethyl) sulfonyl) oxy) propanoate (0.456 g, 1.82 mmol) in DCM (1 ml) was added to a solution of (R) -1- (5 -fluoro-1H-indol-3-yl) propan-2-amine (0.35 g, 1.8 mmol) and DIPEA (0.32 ml, 1.8 mmol) in 1,4-dioxane (7.0 ml) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred under such conditions for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in hexane. The fractions containing the product were concentrated under reduced pressure to give methyl- (R) -3 (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2- methyl propanoate (0.33 g, 62%) as a pale 98 038 160 yellow oil.

Ή NMR (300 MHz, DMSO-d ₆ , 27 ° С) 0.96 (3H, d), 1.05 (3H, d), 2.53-3.03 (6H, m), 3.52 ( 3H, s), 6.88 (1H, td), 7.21 (1H, d), 7.24 (1H, dd), 7.31 (1H, dd), 10.92 (1H, br s) ... mass / charge: ES + [M + H] + 292.

Methyl- (R) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H -pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A solution of methyl- (R) -3 - (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (0.332 g, 1.14 mmol ) and 3-bromo-6-fluoro-2-methylbenzaldehyde (0.259 g, 1.19 mmol) in toluene (6.5 ml) and acetic acid (0.72 ml) were heated at 80 ° C for 24 hours. Temperature the reaction mixture was increased to 90 ° C and the reaction mixture was kept under such conditions for 24 hours. Then the temperature of the reaction mixture was increased to 100 ° C and the reaction mixture was kept under such conditions for 24 hours. The reaction mixture was then cooled, concentrated under reduced pressure and the resulting residue was dissolved in DCM and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient 0 to 30% EtOAc in hexane. The fractions containing the product were concentrated under reduced pressure to give methyl- (R) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3-methyl- 1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.170 g, 30%) as a pale yellow solid. Mass / charge: ES + [M + H] + 491.

Methyl-1H-3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A solution of tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (0.15 g, 0.69 mmol) in toluene (2.77 ml) was added to a flask containing methyl- (R) -3 - (( 1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indole-2 -yl) -2-methylpropanoate (0.17 g, 0.35 mmol), cesium carbonate (0.28 g, 0.87 mmol) and RockPhos 3rd generation precatalyst (0.03 g, 0.03 mmol) ... The resulting mixture was degassed and then heated at 100 ° C for 3 hours. Additional RockPhos 3rd generation precatalyst (64 mg) was added and the reaction mixture was kept under these conditions for another hour. Then allowed to cool the reaction mixture to room temperature, it was diluted with DCM and washed with saturated aqueous sodium chloride solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient 0 to 60% EtOAc in hexane. The fractions containing the product were concentrated under reduced pressure to give methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) - 6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol2-yl) -2-methylpropanoate (0.11 g , 52%) as a beige solid. Mass / charge: ES + [M + H] + 632.

Example 124. (S) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Added 2 M sodium hydroxide (0.020 ml, 0.04 mmol) to a solution of methyl- (S) -3 - ((1R, 3R) -1- (3- (2 ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3.4b] indol-2-yl) -2-methylpropanoate (0.007 g, 0.01 mmol ) in methanol (0.2 ml). The reaction mixture was stirred at room temperature overnight and then evaporated. The crude product was purified by preparative HPLC (Waters CSH C18 OBD column, 5 μ silica, 30 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents to give ( S) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropro-99 038160 pyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3 -methyl- 1,3,4,9-tetrahydro-2H-pyrido [3, 4-b] indol-2-yl) -2methylpropanoic acid (3.0 mg, 44%) as a dry film.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 0.91 (3H, d), 1.26 (3H, d), 1.53-2.07 (6H, m), 2.71-2, 87 (4H, m), 2.893.04 (3H, m), 3.29 (1H, d), 3.57-3.67 (1H, m), 3.95-4.05 (2H, m) , 5.54 (1H, s), 5.91 (1H, tt), 6.83 (1H, dd), 6.96 (1H, t), 7.10-7.17 (2H, m), 7.21-7.24 (1H, m), 7.40 (1H, s), 7.49-7.54 (1H, m). (2 able to exchange were not observed); mass / charge: ES + [M + H] + 518.

Methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl1,3 , 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate as starting material was prepared as described below.

Methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3 , 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

RockPhos 3rd generation precatalyst (0.018 g, 0.02 mmol) was added to the degassed suspension methyl- (S) -3 - ((1R, 3R) -1 - (3-bromo-6-fluoro-2-methylphenyl) - 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) -2-methylpropanoate (0.200 g, 0.42 mmol), 2 - ((tert-butyldimethylsilyl) hydroxy) ethan-1-ol (0.089 g, 0.51 mmol) and cesium carbonate (0.344 g, 1.06 mmol) in toluene (3 ml). The reaction mixture was heated to 90 ° C overnight and allowed to cool the reaction mixture. The reaction mixture was diluted with water (20 ml) and DCM (50 ml). The organic phase was separated and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 100% EtOAc in heptane to give crude methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - (( tert-butyldimethylsilyl) oxy) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.038 g, 17%). Mass / charge: ES + [M + H] + 569.

Methyl- (S) -3 - ((1R, 3R) -1 - (6-fluoro-2-methyl-3 - (2 - ((methylsulfonyl) oxy) ethoxy) phenyl) -3 -methyl1,3,4, 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

To a solution of methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -6-fluoro-2methylphenyl) -3-methyl-1,3 , 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.03 8 g, 0.07 mmol) in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (1 , 0 M in THF, 0.134 ml, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 hours and then evaporated to give a gum which was dissolved in dichloromethane (2 ml) and to which DIPEA (0.035 ml, 0.20 mmol) was added. Methanesulfonyl chloride (8.0 μl, 0.10 mmol) was added to this solution and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (5 ml), washed with water and the organic phase was evaporated to give methyl- ( S) -3 ((1 R, 3R) -1 - (6-fluoro-2-methyl-3 - (2 - ((methylsulfonyl) oxy) ethoxy) phenyl) -3 -methyl-1,3,4,9 -tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.028 g, 0.05 mmol). Mass / charge: ES + [M + H] + 569.

Methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl1,3 , 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

3,3-difluoro-1-aminopropane hydrochloride (8 mg, 0.06 mmol), methyl- (S) -3 - ((1R, 3R) -1- (6-fluoro-2methyl-3 - (2- ( (methylsulfonyl) oxy) ethoxy) phenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) -2-methylpropanoate (0.028 g, 0.05 mmol ), potassium carbonate (0.036 g, 0.26 mmol) and sodium iodide (0.016 g, 0.11 mmol) in acetonitrile (0.5 ml) were heated to 85 ° C under microwave irradiation for 4 h. The reaction mixture was separated between water (5 ml) and DCM (5 ml) and the organic phase was evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 100% EtOAc in heptane to give methyl- (S) -3 - ((1R, 3R) -1- (3- (2 - ((3 , 3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3, 4-b] indol2-yl) -2-methylpropanoate ( 7.0 mg, 25%) as a solid.

- 100 038160

1H NMR (500 MHz, CDC13, 27 ° C) 0.87 (3H, d), 1.11 (3H, d), 1.88 (3H, s), 1.93-2.04 (2H, m ), 2.21 (1H, h),

2.40 (1H, dd), 2.68 (1H, d), 2.82 (2H, t), 2.91-3.03 (3H, m), 3.10 (1H, ddd), 3 , 50-3.58 (1H, m), 3.63 (3H, s),

3.90-4.00 (2H, m), 5.34 (1H, s), 5.90 (1H, tt), 6.80 (1H, dd), 6.91 (1H, t), 7 03-7.13 (2H, m), 7.15-7.22 (1H, m),

7.42-7.54 (1H, m). (2 interchangeability was not observed); mass / charge: ES + [M + H] + 532.

Example 126. (S) -3 - ((1 R, 3R) -1 - (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3 methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (212 mg, 0.96 mmol) in toluene (3.20 ml) was added to a flask containing methyl- (S) -3 - ((1R, 3R ) -1- (2-chloro-5-fluoro-3-methylpyridin-4-yl) -3-methyl1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (275 mg, 0.64 mmol), cesium carbonate (416 mg, 1.28 mmol) and Rockphos 3rd generation pre-catalyst (29.0 mg, 0.03 mmol). The reaction mixture was degassed, then heated to 90 ° C for 4 h. After cooling, the reaction mixture was diluted with DCM (20 ml) and saturated aqueous sodium chloride solution (20 ml). The layers were separated and the aqueous layer was extracted with DCM (20 ml). The combined organics were evaporated. The crude product was dissolved in THF (2.5 ml) and MeOH (2.5 ml), then 2N hydrochloric acid was added. NaOH solution (2.5 ml) and the reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was diluted with EtOAc (20 ml) and water (20 ml) and the pH was adjusted to ~ 5 by adding 2N HCl. HCl solution. The layers were separated, then the aqueous layer was extracted with EtOAc (2x15 ml). The combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give (S) -3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5fluoro- 3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (350 mg), which was unrefined. The residue was dissolved in formic acid (2 ml) and heated to 40 ° C for 1 h. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters SunFire column, 5 μ silica, 19 mm in diameter, 100 mm in length ) using mixtures of water (containing 1% NH3) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3- methylpyridin-4-yl) -3-methyl1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (65.0 mg, 20%) in the form of a beige solid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 0.96 (3H, d), 1.19 (3H, d), 1.87 (3H, s), 1.90-2.05 (3H, m), 2.68-2.79 (2H, m), 2.88 (1H, dd), 3.04 (2H, t), 3.19 (1H, d), 3.24 (2H, s ), 3.61 (1H, d), 4.44 (2H, dt), 4.52 (1H, t), 4.574.69 (1H, m), 5.40 (1H, s), 7.07 -7.17 (2H, m), 7.21 (1H, d), 7.44-7.55 (1H, m), 7.84 (1H, s), 8.25 (1H, s), 8.34 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 501.

Methyl- (S) -3 - ((1R, 3R) -1- (2-chloro-5-fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H α-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate used as a starting material was prepared as described below.

2-Chloro-5-fluoro-3-methylisonicotinaldehyde

A solution of LDA (2 M, 3.85 ml, 7.70 mmol) was added to a cooled solution of 2-chloro-5-fluoro-3methylpyridine (1.02 g, 7.00 mmol) in THF (22.9 ml) at - 78 ° C. The reaction mixture was stirred for 30 min, then methyl formate (1.30 mL, 21.0 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched by the addition of 1N HCl. HCl solution (20 ml) and extracted with EtOAc (40 ml). The organic phase was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 20% EtOAc in heptane. The product containing fractions were evaporated to dryness to give 2-chloro-5-fluoro-3methylisonicotinaldehyde (754 mg, 62%) as a straw yellow liquid.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 2.65 (3H, s), 8.33 (1H, s), 10.51 (1H, s).

Methyl- (S) -3 - ((1R, 3R) -1- (2-chloro-5-fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate

- 101 038160

Methyl- (S) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (439 mg, 1.60 mmol) and 2-chloro -5-fluoro-3-methylisonicotinaldehyde (292 mg, 1.68 mmol) was heated in toluene (7.20 ml) / acetic acid (0.80 ml) to 90 ° C for 5 hours. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The layers were separated, then the organic phase was dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 30% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl (S) -3 - ((1R, 3R) -1- (2-chloro-5-fluoro-3-methylpyridin-4-yl) -3-methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (283 mg, 41%) as a beige solid.

Ή NMR (500 MHz, CDCl3, 27 ° С) 0.91 (3H, d), 1.11 (3H, d), 2.10 (3H, s), 2.27 (2H, ddd), 2, 72 (1H, d), 3.02 (1H, dd), 3.11 (1H, ddd), 3.53-3.60 (1H, m), 3.65 (3H, s), 5.37 (1H, s), 7.09-7.17 (2H, m), 7.24 (1H, dd), 7.30 (1H, s), 7.51 (1H, d), 8.20 ( 1H, s). mass / charge: ES + [M + H] + 430.

Example 127 (R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Jl JH ^H I 11 qu., ^Ξ (R) -3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5-fluoro- 3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (450 mg, 0, 75 mmol) was stirred in formic acid (4.0 ml) at 40 ° C for 1 h. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm long) using mixtures of water (containing 1% NH3) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (R) -3 - ((1R, 3R) -1- (5fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridine- 4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (302 mg, 81%) as colorless solid matter.

Ή NMR (500 MHz, CDCl ₃ , 27 ° C) 1.01 (3H, d), 1.12 (3H, d), 1.85 (3H, s), 1.87-1.98 (2H, m), 2.45-2.52 (1H, m), 2.57 (1H, ddd), 2.63 (1H, dd), 2.75 (1H, d), 2.81 (2H, t ), 2.89 (1H, ddd), 3.12 (1H, ddd), 3.17 (1H, ddd), 3.73 (1H, q), 4.23 (1H, ddd), 4.40 (1H, t), 4.50 (1H, t), 4.69 (1H, ddd), 5.25 (1H, s), 7.01-7.16 (2H, m), 7.20 ( 1H, dd), 7.41 (1H, s), 7.50 (1H, dd), 7.86 (1H, s). (2 x interchangeable were not observed); mass / charge: ES + [M + H] +501.

(R) -3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5-fluoro-3-methylpyridin-4-yl) - 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid as starting material was prepared as described below.

Methyl-1H-3 - ((1R, 3R) -1- (2-chloro-5-fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

Methyl- (R) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (741 mg, 2.7 mmol) and 2chlor-5 β-fluoro-3-methylisonicotinaldehyde (492 mg, 2.84 mmol) was heated in toluene (9.72 ml) / acetic acid (1.08 ml) to 90 ° C for 6 hours. After cooling, the reaction mixture was evaporated. The residue was dissolved in DCM (25 ml) and washed with saturated aqueous NaHCO ₃ solution (25 ml). The aqueous layer was extracted with DCM (25 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 30% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl- (R) -3 - ((1R, 3R) -1- (2-chloro-5-fluoro-3-methylpyridin4-yl) -3-methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (950 mg, 82%) as a beige solid.

Ή NMR (500 MHz, CDCl ₃ , 27 ° C) 1.04 (3H, d), 1.09 (3H, d), 2.01 (3H, s), 2.46-2.57 (1H, m), 2.62-2.70 (2H, m), 2.75 (1H, d), 3.11 (1H, ddd), 3.53 (3H, s), 3.68-3.78 (1H, m), 5.30 (1H, s), 7.08-7.18 (2H, m), 7.21-7.26 (1H, m), 7.46-7.52 (1H , m), 7.53 (1H, s), 8.15 (1H, s); mass / charge: ES + [M + H] + 430.

Methyl-1H-3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5-fluoro-3-me- 102 038160 tylpyridine-4 -yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (581 mg, 2.63 mmol) was added to the suspension methyl- (R) -3 - ((1R, 3R) -1- (2-chloro-5 -fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2R-pyrido [3,4b] indol-2-yl) -2-methylpropanoate (752 mg, 1, 75 mmol), cesium carbonate (1.42 g, 4.38 mmol) and Rockphos 3rd generation pre-catalyst (74.7 mg, 0.09 mmol) in degassed toluene (8.75 ml). The reaction mixture was warmed to 90 ° C and stirred for 4 h. After cooling, the reaction mixture was diluted with DCM (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The aqueous layer was extracted with DCM (25 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 40% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3fluoropropyl) amino) ethoxy) -5- fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) -2-methylpropanoate (571 mg, 53%) as a beige solid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.04 (3H, d), 1.08 (3H, d), 1.42 (9H, d), 1.82 (3H, s), 1, 84-2.00 (2H, m), 2.50-2.60 (1H, m), 2.60-2.77 (3H, m), 3.10 (1H, ddd), 3.30- 3.41 (2H, m), 3.51 (3H, s), 3.53-3.61 (2H, m), 3.653.73 (1H, m), 4.31-4.44 (3H, m), 4.46 (1H, t), 5.22 (1H, s), 7.10 (2H, dqt), 7.20 (1H, dd), 7.27-7.40 (1H, m ), 7.49 (1H, dd), 7.88 (1H, s); mass / charge: ES + [M + H] + 615.

1H-3 - ((1R, 3R) -1 - (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5-fluoro-3-methylpyridin-4-yl) -3- methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Added 2 N. NaOH solution (2.68 ml, 5.37 mmol) to a solution of methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy ) -5-fluoro-3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2R-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate ( 550 mg, 0.89 mmol) in THF (3.1 ml) / MeOH (3.1 ml). The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc (25 ml) and water (25 ml). The pH was adjusted to -5 by adding 2N HCl. HCl solution and the layers were separated. The aqueous layer was extracted with EtOAc (25 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was passed through a silica plug eluting with EtOAc. The filtrate was evaporated to give (R) -3 - ((1R, 3R) -1- (2 (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -5-fluoro-3-methylpyridine-4- yl) -3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (492 mg, 92%) as a beige solid. Mass / charge: ES + [M + H] + 601.

Example 143.

(S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Iodomethane (6.85 μL, 0.11 mmol) was added to a solution of (S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) -2 -methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2methylpropanoic acid (50 mg, 0.10 mmol) and DIPEA (51 , 9 μl, 0.30 mmol) in acetonitrile (0.95 ml). The reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (S) -3 - ((1R, 3R) -1- (6-fluoro-3- (2 ((3-fluoropropyl) (methyl) amino) ethoxy) - 2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2R-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (14.4 mg, 28%) in the form of a colorless solid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 0.90 (3H, d), 1.27 (3H, d), 1.70-1.90 (5H, m), 2.32 (3H, s), 2.57 (2H, t), 2.67-2.77 (1H, m), 2.77-2.82 (4H, m), 2.96 (1H, dd), 3.29 (1H, d), 3.55-3.68 (1H, m), 4.00 (2H, t), 4.42 (1H, t),

- 103 038160

4.51 (1H, t), 5.55 (1H, s), 6.83 (1H, dd), 6.95 (1H, t), 7.13 (2H, dtd), 7.22 (1H , dd), 7.46 (1H, s), 7.48-7.58 (1H,

m). (1 x exchangeable was not observed), mass / charge: ES + [M + H] + 514.

Example 145. (S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin4-yl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Methyl- (S) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (151 mg, 0.55 mmol) and 5-fluoro -2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde (300 mg, 50 wt%, 0.55 mmol) was heated in toluene (2.50 ml) / acetic acid ( 0.278 ml) to 90 ° C over 4 h. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 100% EtOAc.

The fractions containing the product were evaporated to dryness to give a yellow gum (300 mg). The residue was dissolved in THF (2 ml) and methanol (2 ml), then 2N hydrochloric acid was added. NaOH solution (2 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (20 ml) and water (20 ml). The pH was adjusted to ~ 5 by adding 2N HCl. HCl solution, then the layers were separated. The aqueous layer was extracted with EtOAc (20 ml), then the combined organic layers were dried over Na ₂ SO ₄ and evaporated to dryness. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (S) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (98 mg, 35%) as a colorless solid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 0.99 (3H, d), 1.23 (3H, d), 1.77-1.86 (2H, m), 1.87 (3H, d), 2.32 (3H, s), 2.59 (2H, t), 2.72-2.90 (6H, m), 3.21 (1H, d), 3.54-3.64 (1H, m), 4.36 (1H, ddd), 4.40 (1H, t), 4.43-4.48 (1H, m), 4.50 (1H, t), 5.43 ( 1H, s), 7.14 (2H, dtd), 7.24 (1H, d), 7.52 (2H, d), 7.90 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 515.

5-Fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde used as a starting material was prepared as described below.

2 - ((3-Fluoropropyl) (methyl) amino) ethan-1-ol

I

1-Fluoro-3-iodopropane (5.64 g, 30.0 mmol) was added to a suspension of 2- (methylamino) ethan-1-ol (2.65 ml, 33.0 mmol) and potassium carbonate (8.28 g , 60.0 mmol) in acetonitrile (88 ml). The reaction mixture was heated to 50 ° C for 2 hours, then cooled and stirred at room temperature overnight. The volatiles were evaporated, then the residue was partitioned between EtOAc (80 ml) and water (80 ml). The layers were separated and the aqueous layer was extracted with EtOAc (4 x 50 ml). The combined organics were dried over Na ₂ SO ₄ , filtered and evaporated to give 2 - ((3fluoropropyl) (methyl) amino) ethan-1-ol (3.95 g, 97%) as a colorless oil.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.88 (2H, ddd), 2.27 (3H, s), 2.51-2.62 (4H, m), 3.55-3, 65 (2H, m), 4.47 (1H, t), 4.56 (1H, t).

N- (2 - ((3-chloro-5-fluoropyridin-2-yl) oxy) ethyl) -3-fluoro-N-methylpropan-1-amine

Sodium hydride (0.308 g, 7.69 mmol) was added to a solution of 2 - ((3-fluoropropyl) (methyl) amino) ethan-1ol (1.040 g, 7.69 mmol) in THF (26.8 ml). After stirring for 10 min, 3-chloro-2,5difluoropyridine (1.00 g, 6.69 mmol) was added and stirring was continued for 1 h. The reaction mixture was quenched by adding water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organics were dried over MgSCO ₄ , filtered and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 100% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give N- (((3-chloro-5-fluoropyridin-2-yl) oxy) ethyl) -3-fluoro-N-methylpropan-1-amine (1.630 g, 92 %) in the form of a colorless liquid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.81-1.95 (2H, m), 2.36 (3H, s), 2.57-2.64 (2H, m), 2.83 (2H, t), 4.44 (2H, t), 4.47 (1H, t), 4.57 (1H, t), 7.46 (1H, dd), 7.90 (1H, d) ... mass / charge: ES + [M + H] + 265.

- 104 038160

3-Fluoro-N- (2 - ((5-fluoro-3-methylpyridin-2-yl) oxy) ethyl) -N-methylpropan-1-amine

ΛΧ ¹

2nd generation XPhos precatalyst (0.122 g, 0.16 mmol) and potassium carbonate (1.720 g, 12.47 mmol) were added to a solution of N- (2 - ((3-chloro-5-fluoropyridin-2-yl) oxy ) ethyl) -3-fluoro-N-methylpropan-1-amine (1.65 g, 6.23 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.436 ml, 3.12 mmol) in 1,4 dioxane (25.6 ml) / water (5.1 ml). The reaction mixture was degassed and heated to 90 ° C for 6 h. After cooling, the reaction mixture was diluted with EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (25 ml). The combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 20 to 100% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give 3-fluoro - ^ (2 - ((5-fluoro-3methylpyridin-2-yl) oxy) ethyl) -N-methylpropan-1-amine (1.50 g, 99 %) in the form of a light brown liquid.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.82-1.94 (2H, m), 2.19 (3H, t), 2.35 (3H, s), 2.58-2, 63 (2H, m), 2.81 (2H, t), 4.38 (2H, t), 4.47 (1H, t), 4.56 (1H, t), 7.15-7.19 (1H, m), 7.78-7.82 (1H, m). mass / charge: ES + [M + H] + 245.

5-Fluoro-2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3-methylisonicotinaldehyde

An LDA solution (2 M, 3.84 mL, 7.68 mmol) was added to an oven-dried flask containing 3-fluoro-N- (2 - ((5-fluoro-3-methylpyridin-2-yl) oxy) ethyl) -N-methylpropan-1-amine (1.5 g, 6.14 mmol) in THF (20.0 ml). The reaction mixture was stirred for 30 min, then methyl formate (0.946 mL, 15.4 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched by the addition of water (25 ml) and extracted with EtOAc (2 x 40 ml). The combined organics were dried over MgSCO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give 5fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde as a pale yellow liquid that was contaminated with unreacted starting material in the ratio 1: 1. Mass / charge: ES + [M + H] + 273.

Example 152 (R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin4-yl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

L। θ n I 11 qm. ^Ξ

A solution of formaldehyde (37 vol.%, 0.021 ml, 0.29 mmol) was added to a solution of (R) -3 - ((1R, 3R) -1- (5fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (90 mg , 0.18 mmol) in DCM (1.5 ml). After stirring for 5 min, sodium triacetoxyhydroborate (61.0 mg, 0.29 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 ml) and washed with saturated aqueous sodium chloride solution ( 10 ml). The layers were separated and the aqueous layer was extracted with DCM (2 x 10 ml). The combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (R) -3 ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) - 3-methylpyridin-4-yl) -3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (63.0 mg, 68% ) as a colorless solid.

1H NMR (500 MHz, CDC13, 27 ° C) 1.03 (3H, d), 1.13 (3H, d), 1.70-1.96 (5H, m), 2.32 (3H, s ), 2.46-2.55 (1H, m), 2.55-2.60 (1H, m), 2.60-2.65 (2H, m), 2.68 (2H, dt), 2.77 (1H, d), 2.96 (1H, ddd), 3.12-3.24 (1H, m), 3.64-3.79 (1H, m), 4.25 (1H, ddd), 4.37 (1H, t), 4.47 (1H, t), 4.64 (1H, dt), 5.25 (1H, s), 7.02-7.17 (2H, m ), 7.19 (1H, dd), 7.50 (1H, dd), 7.58 (1H, s), 7.86 (1H, s), 9.62 (1H, s); mass / charge: ES + [M + H] +515.

Example 155 (2R) -3 - [(1R, 3R) -6-fluoro-1- [5-fluoro-2- [2- [3-fluoropropyl (methyl) amino] ethoxy] -3-methyl-4pyridyl] -3-methyl-1,3,4,9-tetrahydropyrido [3,4-b] indol-2-yl] -2-methylpropanoic acid

- 105 038160 λα i hi i qAa ^ξ /

A 2 M sodium hydroxide solution (1.17 ml, 2.34 mmol) was added to a stirred solution of methyl (R) -3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2- ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl ) -2-methylpropanoate (426 mg, 0.47 mmol) in THF (4 ml) and MeOH (2 ml) at 21 ° C. The resulting mixture was stirred at 21 ° C for 16 hours. The mixture was concentrated under reduced pressure. Water (5 ml) and AcOH (1 ml) were added and the resulting mixture was extracted with DCM (3 x 15 ml). The combined organics were dried (using a phase separation cartridge) and concentrated under reduced pressure to give a crude product, which was sequentially purified by preparative HPLC (Puriflash C18, 15 μ silica, 35 g) using water mixtures (containing 0.1% formic acid) and MeCN with decreasing polarity as eluents, then by preparative HPLC (Waters CSH C18 OBD column, 5 μ silica, 30 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give (2R) -3 ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino ) ethoxy) -3-methylpyridin-4-yl) -3-methyl1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid (45.0 mg, 18%) as an off-white solid.

1H NMR (500 MHz, DMSO, 27 ° C) 0.94 (3H, d), 1.01 (3H, d), 1.69-1.86 (5H, m), 2.22 (3H, s ), 2.40-2.49 (4H, m), 2.56-2.71 (5H, m), 2.95 (1H, dd), 3.59-3.70 (1H, m), 4.25-4.31 (2H, m), 4.43 (2H, dt), 5.13 (1H, s), 6.83 (1H, td), 7.12-7.20 (2H, m), 8.00 (1H, s), 10.49 (1H, s); mass / charge: ES + [M + H] +533.

Procedures used to prepare methyl- (R) -3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -3 - methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) -2-methylpropanoate starting material are described below.

Methyl- (R) -3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridine-4 -yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

ΛΑ ί

F'yX О ^H I II qAa, ^Ξ

A solution of methyl- (R) -3 - (((R) -1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (200 mg, 0.68 mmol ) and 5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde (484 mg, 0.89 mmol) in toluene (3 ml) and acetic acid (0.33 ml) was heated at 95 ° C for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 ml) and washed with saturated aqueous NaHCO ₃ solution (25 ml). The aqueous phase was extracted with EtOAc (50 ml) and the combined organics were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was partially purified by flash chromatography on silica eluting with EtOAc. The fractions containing the desired product were evaporated to dryness to obtain methyl- ( ^Λ ) -3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2 (2 - ((3-fluoropropyl) (methyl ) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate ( 426 mg,> 100%) as a yellow gum. It was taken to the next stage without additional purification.

Example 156.

Preparation 3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3- methyl-1,3,4,9-tetrahydro-2Н-pyrido [3,4-b] indol-2-yl) propanoic acid λ-ν

A F OH

Added 2 N. NaOH solution (0.563 ml, 1.13 mmol) to a solution of methyl-3 - ((1R, 3R) -6-fluoro-1- (5-fluoro2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy ) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) propanoate (120 mg, 0.23 mmol) in THF (1.0 ml) / MeOH (1.0 ml). The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc (20 ml) and water (20 ml). The pH was adjusted to ~ 5 by adding 2N HCl. HCl solution and the layers were separated. Waters

The 106,038,160 layer was extracted with EtOAc (2 x 10 ml), then the combined organics were dried over Na ₂ SO4 and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 20% MeOH in DCM. The fractions containing the product were evaporated to dryness to give 3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) - 3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol2-yl) propanoic acid (82 mg, 70%) as a beige solid substances.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.10 (3H, d), 1.88 (3H, s), 1.89-1.93 (2H, m), 2.10-2 , 38 (2H, m), 2.43 (3H, s), 2.66 (2H, d), 2.76 (2H, s), 2.81-2.93 (2H, m), 2, 98-3.07 (1H, m), 3.11 (1H, d), 3.63 (1H, s), 4.22-4.36 (1H, m), 4.36-4.41 ( 1H, m), 4.47 (1H, s), 4.57-4.69 (1H, m), 5.29 (1H, s), 6.83 (1H, t), 7.11 (2H , t), 7.81 (1H, s), 11.71 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 519.

Procedures used to prepare methyl-3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridine-4- yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) propanoate starting material are described below.

Methyl- (R) -3 - ((1 - (5-fluoro-1 N-indol-3-yl) propan-2-yl) amino) propanoate

F '- < ^{λ -} χ'> o—

Methyl acrylate (95 μL, 1.05 mmol) was added to a solution of (R) -1- (5-fluoro-1H-indol-3-yl) propan-2amine (192 mg, 1.0 mmol) in MeOH (0.40 ml). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were evaporated, then the crude product was purified by flash chromatography on silica, elution gradient from 0 to 10% MeOH in DCM. The fractions containing the product were evaporated to dryness to give methyl (R) -3 - ((1- (5-fluoro1H-indol-3-yl) propan-2-yl) amino) propanoate (270 mg, 97%) in the form of a pale yellow liquid.

L NMR (500 MHz, CDCl3, 27 ° C) 1.10 (3H, d), 2.36-2.53 (2H, m), 2.70-2.80 (2H, m), 2.80 -2.90 (1H, m), 2.91-3.06 (2H, m), 3.57 (3H, s), 6.93 (1H, td), 7.09 (1H, d), 7.23 (1H, dd), 7.25-7.30 (1H, m), 8.04 (1H, s). (x exchangeable was not observed) mass / charge: ES + [M + H] + 279.

Methyl-3 - ((1 R, 3R) -6-fluoro-1 - (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3 -methylpyridin-4yl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate

Methyl- (R) -3 - ((1- (5-fluoro-1H-indol-3-yl) propan-2-yl) amino) propanoate (139 mg, 0.50 mmol) and 5fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde (65% by weight, 209 mg, 0.50 mmol) was heated to 90 ° C in toluene (2.25 ml) / acetic acid (0 , 25 ml) overnight. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organics were dried over Na2SO4 and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 micron silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give methyl-3 - ((1R, 3R) -6-fluoro-1- (5-fluoro-2- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) propanoate (134 mg, 50%) as pale yellow resin.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.09 (3H, d), 1.74-1.87 (2H, m), 1.88 (3H, s), 2.30 (3H, s), 2.30-2.40 (2H, m), 2.53 (2H, t), 2.64 (1H, d), 2.67-2.73 (1H, m), 2.73 -2.77 (2H, m), 2.91 (1H, dt), 3.08 (1H, ddd), 3.56 (3H, s), 3.59-3.67 (1H, m), 4.33 (2H, t), 4.39 (1H, t), 4.49 (1H, t), 5.27 (1H, s), 6.84 (1H, td), 7.09 (1H , dd), 7.12 (1H, dd), 7.51 (1H, s), 7.85 (1H, s). mass / charge: ES + [M + H] + 533.

Example 157. Preparation of 3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3methylpyridin-4-yl) -3-methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid

he

Added 2 N. NaOH solution (0.729 ml, 1.46 mmol) to a solution of methyl-3 - ((1R, 3R) -1- (5-fluoro-2- (2 ((3-fluoropropyl) (methyl) amino) ethoxy) -3 -methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) propanoate (150 mg, 0.29 mmol) in THF (1 , 0 ml) / MeOH (1.0 ml). The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc (20 ml) and water (20 ml). The pH was adjusted to ~ 5 by adding 2N HCl. HCl solution and the layers were separated. Ex water layer

- 107 038160 traced with EtOAc (2 x 10 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient from 0 to 20% MeOH in DCM. The fractions containing the product were evaporated to dryness to give 3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3methylpyridine-4- yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid (128 mg, 88%) as a beige solid.

1H NMR (500 MHz, CDCls, 27 ° C) 1.14 (3H, d), 1.81-1.95 (5H, m), 2.18 (1H, dt), 2.35 (3H, s ), 2.43 (1H, ddd), 2.63-2.74 (4H, m), 2.77 (1H, d), 2.87 (1H, dt), 3.00 (1H, ddd) , 3.19 (1H, ddd), 3.65 (1H, p), 4.26 (1H, ddd), 4.40 (1H, t), 4.49 (1H, t), 4.75 ( 1H, dt), 5.31 (1H, s), 7.09-7.16 (2H, m), 7.23 (1H, dd), 7.43 (1H, s), 7.497.53 (1H , m), 7.89 (1H, s). (2 x exchangeable not observed) mass / charge: ES + [M + H] + 501.

Procedures used to prepare methyl-3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indole-2yl) propanoate starting material are described below.

Methyl- (R) -3 - ((1- (1 N-indol-3-yl) propan-2-yl) amino) propanoate

Methyl acrylate (0.284 ml, 3.15 mmol) was added to a solution of (R) -1- (1H-indol-3-ul) propan-2-amine (523 mg, 3.00 mmol) in MeOH (0.92 ml) ... The reaction mixture was stirred at room temperature for 2 hours. The volatiles were evaporated, then the crude product was purified by flash chromatography on silica, elution gradient from 0 to 10% MeOH in DCM. The product containing fractions were evaporated to dryness to give methyl (R) -3 - ((1- (1H-indol-3yl) propan-2-yl) amino) propanoate (755 mg, 97%) as a pale yellow liquid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.12 (3H, d), 2.34-2.53 (2H, m), 2.68-2.91 (3H, m), 2.96 (1H, dt), 3.04 (1H, h), 3.55 (3H, s), 7.05 (1H, d), 7.11 (1H, ddd), 7.19 (1H, ddd) , 7.36 (1H, dt), 7.59-7.66 (1H, m), 8.02 (1H, s). (I x exchangeable was not observed) mass / charge: ES + [M + H] + 261.

Methyl 3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate

Methyl (R) -3 - ((1- (1H-indol-3-yl) propan-2-yl) amino) propanoate (156 mg, 0.60 mmol) and 5-fluoro-2- (2 (( 3-fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde (65% by weight, 251 mg, 0.60 mmol) was heated in toluene (4.50 ml) / acetic acid (0.50 ml) to 90 ° From during the night. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO3 solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 μ silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give methyl-3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3methylpyridine -4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate (164 mg, 53%) as a beige gum.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.09 (3H, d), 1.72-1.86 (2H, m), 1.88 (3H, s), 2.29 (3H , s), 2.30-2.40 (2H, m), 2.53 (2H, t), 2.63-2.73 (2H, m), 2.74 (2H, td), 2, 92 (1H, dt), 3.11 (1H, ddd), 3.56 (3H, s), 3.59-3.67 (1H, m), 4.32 (2H, t), 4.39 (1H, t), 4.48 (1H, t), 5.28 (1H, s), 7.00-7.15 (2H, m), 7.15-7.21 (1H, m), 7.49 (1H, dd), 7.55 (1H, s), 7.84 (1H, s); mass / charge: ES + [M + H] +514.

Examples 158 and 159. Preparation of 3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3methylpyridin-4-yl) -3-methyl -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) butanoic acid

Ethyl 3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) butanoate (216 mg, 0.75 mmol) and 5-fluoro-2- (2- ( (3fluoropropyl) (methyl) amino) ethoxy) -3-methylisonicotinaldehyde (314 mg, 0.75 mmol) was heated in toluene (3.375 ml) / acetic acid (0.375 ml) to 100 ° C overnight. After cooling, the volatiles were evaporated. The residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organic

108 038160 substances were dried over Na ₂ SO4 and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 10% MeOH in EtOAc. The pure fractions were evaporated to dryness to give a pale yellow oil (~ 250 mg) that was contaminated with unreacted starting material. The residue was dissolved in THF (1 ml) and MeOH (1 ml), then 2N hydrochloric acid was added. NaOH solution (1 ml). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc (10 ml) and water (10 ml). The pH of the aqueous layer was adjusted to 5 by adding 2N HCl. HCl solution and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 ml), then the combined organics were dried over Na ₂ SO4 and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 5 micron silica, 19 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH3) and MeCN with decreasing polarity as eluents. The fractions containing the required compound were evaporated to dryness to give two isomers, (3R) 3 - ((1 R, 3R) -1 - (5-fluoro-2- (2 - ((3-fluoropropyl) (methyl) amino ) ethoxy) -3 -methylpyridin-4-yl) -3 -methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) butanoic acid and (3S) -3- ((1R, 3R) -1- (5-fluoro-2- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3 -methyl-1,3,4, 9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) butanoic acid.

Example 158; isomer 1: 15.0 mg, 4% (as colorless solid).

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.21 (3H, d), 1.25 (3H, d), 1.82 (3H, s), 1.85-1.93 (2H , m), 2.26 (1H, dd), 2.33 (3H, s), 2.57-2.63 (2H, m), 2.67 (1H, d), 2.73-2, 82 (2H, m), 2.86 (1H, ddd), 3.12-3.19 (2H, m), 3.843.92 (1H, m), 4.27-4.36 (1H, m) , 4.39 (1H, t), 4.43-4.54 (2H, m), 5.73 (1H, s), 7.01-7.16 (2H, m), 7.16-7 , 25 (1H, m), 7.42-7.55 (1H, m), 7.65 (1H, s), 7.88 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 515.

Example 159; isomer 2: 35.0 mg, 9% (as colorless solid).

1H NMR (500 MHz, CDCl3, 27 ° C) 1.17 (3H, d), 1.19 (3H, d), 1.79-1.91 (2H, m), 1.92 (3H, s ), 2.12 (1H, dd), 2.37 (3H, s), 2.63-2.79 (4H, m), 2.81-2.91 (2H, m), 3.05- 3.14 (1H, m), 3.26 (1H, d), 3.83 (1H, dq), 4.324.41 (3H, m), 4.47 (1H, q), 5.68 (1H , s), 7.10 (2H, tdt), 7.20 (1H, dd), 7.48 (1H, dd), 7.73 (1H, s), 7.86 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 515.

The procedures used to prepare ethyl 3 - (((R) -1- (1H-indol-3-yl) propan-2yl) amino) butanoate starting material are described below.

Ethyl 3 - (((R) -1- (1 N-indol-3-yl) propan-2-yl) amino) butanoate

o (R) -1- (1H-indol-3-yl) propan-2-amine (0.871 g, 5 mmol) and ethyl (E) -but-2-enoate (0.777 ml, 6.25 mmol) were stirred in MeOH (2.50 ml) at 50 ° C for 1 h, then additionally heated under reflux and continued stirring overnight. After cooling, the volatiles were evaporated. The crude product was purified by flash chromatography on silica, elution gradient 25% to 100% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give ethyl 3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) butanoate (1.310 g, 91%) as pale yellow resin, which is a mixture of diastereoisomers 1: 1.

1H NMR (500 MHz, CDCl ₃ , 27 ° C) 0.99-1.27 (9H, m), 2.18 (0.5H, dd), 2.30 (0.5H, dd), 2, 41 (1H, ddd), 2.75 (1H, dddd), 2.81-2.94 (1H, m), 3.12 (1H, hd), 3.25 (1H, dq), 4.11 (2H, p), 7.04 (1H, dd), 7.11 (1H, ddt), 7.18 (1H, tt), 7.35 (1H, d), 7.52-7.70 ( 1H, m), 8.02 (1H, s). (1 x exchangeable was not observed) mass / charge: ES + [M + H] + 289.

Example 160. (R) -3 - ((1 R, 3R) -6-fluoro-1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2methylphenyl) - 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

F

Added 2 M sodium hydroxide (1 ml, 2.00 mmol) to a stirred solution of methyl- (R) -3 ((1 R, 3R) -6-fluoro-1 - (6-fluoro-3 - (2 - (( 3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3 -methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate ( 87 mg, 0.16 mmol) in THF (2 ml) and MeOH (1 ml). The resulting mixture was stirred at 21 ° C for 16 hours. The mixture was concentrated under reduced pressure, then water (5 ml) and AcOH (1 ml) were added and the aqueous mixture was extracted with DCM (4x15 ml). The combined organics were dried (using a phase separation cartridge) and concentrated under reduced pressure to give the crude product as a yellow gum, which was purified by preparative HPLC (Waters CSH C18 OBD column, 5 μ silica, 30 mm diameter, 100 mm in length) using mixtures of water (containing

- 109 038160 (0.1% formic acid) and MeCN with decreasing polarity as eluents. Fractions containing the desired compound were evaporated under reduced pressure, redissolved in 1 M ammonia in MeOH (1 ml) and concentrated under reduced pressure to give (R) -3 - ((1R, 3R) -6fluoro-1 - (6- fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro2H-pyrido [3,4-b] indole- 2-yl) -2-methylpropanoic acid (32.0 mg, 38%) as a pale yellow solid.

¹ H NMR (500 MHz, DMSO, 27 ° C) 0.99 (3H, d), 1.07 (3H, d), 1.72-1.95 (5H, m), 2.27 (3H, s), 2.30-2.38 (1H, m), 2.51 (2H, t), 2.64-2.72 (1H, m), 2.73 (2H, t), 3.02 (1H, dd), 3.23 (3H, s), 3.64-3.73 (1H, m), 4.03 (2H, ddt), 4.49 (2H, dt), 5.24 ( 1H, s), 6.86 (1H, td), 6.97-7.14 (2H, m), 7.14-7.25 (2H, m), 10.40 (1H, s); mass / charge: ES + [M + H] + 532.

Procedures used to prepare methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) -2-methylpropanoate starting material are described below.

Methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2methylphenyl) -6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

3rd generation RockPhos catalyst (31.2 mg, 0.04 mmol) was added to the degassed mixture of methyl- (R) -3 - ((1 R, 3R) -1 - (3-bromo-6-fluoro-2- methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4b] indol-2-yl) -2-methylpropanoate (181 mg, 0.37 mmol), tert -butyl- (3-fluoropropyl) (2hydroxyethyl) carbamate (163 mg, 0.74 mmol) and cesium carbonate (360 mg, 1.11 mmol) in toluene (2 ml) at 21 ° C. The resulting mixture was heated at 90 ° C for 6 hours. Allow the mixture to cool to room temperature and dilute it with EtOAc (25 ml) and water (25 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organics were dried (using a phase separation cartridge) and concentrated to give the crude product as a brown gum, which was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) - 6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2methylpropanoate (108 mg, 46 %) in the form of a pale yellow foam.

¹ H NMR (500 MHz, CDCl3, 27 ° C) 1.02 (3H, d), 1.09 (3H, d), 1.40-1.48 (9H, m), 1.81 (3H, s), 1.84-1.94 (2H, m), 2.52-2.67 (4H, m), 3.04-3.12 (1H, m), 3.35-3.46 ( 2H, m), 3.50 (3H, s), 3.52-3.59 (2H, m), 3.64-3.72 (1H, m), 4.03 (2H, s), 4 , 41 (2H, d), 5.26 (1H, s), 6.73-6.86 (2H, m), 6.91 (1H, t), 7.04-7.13 (2H, m ), 7.23 (1H, s); ES + [M + H] + 632.

Methyl-1H-3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) 3-Methyl -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A solution of methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro2-methylphenyl) -6-fluoro -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (100 mg, 0.16 mmol) in formic acid (610 μl ) was stirred at 40 ° C for 1 h. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in DCM (25 ml) and washed with saturated aqueous NaHCO ₃ solution (25 ml). The aqueous layer was extracted with DCM (25 ml) and the combined organics were evaporated to -10 ml. To this solution was added a 37% w / w aqueous solution. formaldehyde (23.55 μL, 0.24 mmol) followed by the addition of sodium triacetoxyborohydride (51.8 mg, 0.24 mmol). The resulting mixture was stirred at 21 ° C for 1 h. The reaction mixture was diluted with DCM (10 ml) and washed with saturated aqueous NaHCO3 solution (20 ml). The aqueous layer was extracted with DCM (20 ml) and the combined organics were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was taken directly to the next step.

Example 161. Obtaining (R) -3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3methylpyridin-4-yl) -3-methyl-1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

- 110 038160

Lithium hydroxide monohydrate (9.0 mg, 0.22 mmol) was added to a solution of methyl- (R) -3 - ((1R, 3R) -1- (2 (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2Hpyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.011 g, 0.020 mmol ) in tetrahydrofuran (0.2 ml), methanol (0.2 ml) and water (0.2 ml). The resulting mixture was stirred at room temperature for 5 h and then neutralized with aqueous hydrochloric acid (1N; 0.21 ml, 0.21 mmol). The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 70% MeOH in DCM, to give (R) -3 - ((1R, 3R) -1 - (2- (2 - ((3-fluoropropyl) ( methyl) amino) ethoxy) -3 -methylpyridin-4-yl) -3 -methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid ( 7.6 mg, 71%) as a pale yellow solid. H NMR (500 MHz, DMSO-06, 27 ° C) 1.03 (3H, d), 1.05 (3H, d), 1.72-1.88 (2H, m), 2.14-2 , 33 (6H, m), 2.55-2.63 (5H, m), 2.75 (2H, br t), 2.83 (1H, br dd), 4.29-4.40 (2H , m), 4.49 (2H, dt), 4.98 (1H, br s), 6.40 (1H, br d), 6.94-6.99 (1H, m), 7.00- 7.05 (1H, m), 7.22 (1H, d), 7.43 (1H, d), 7.82 (1H, br d), 10.39 (1H, br s), 11.93 -12.45 (1H, br s). (Two peaks corresponding to a hydrogen atom were not observed) mass / charge: ES + [M + H] + 497.

Procedures used to prepare methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3, 4-b] indol2-yl) -2-methylpropanoate starting material are described below.

Preparation of methyl- (R) -3 - ((1 R, 3R) -1 - (2-chloro-3-methylpyridin-4-yl) -3 -methyl-1,3,4,9-tetrahydro-2Нpyrido [3 , 4-b] indol-2-yl) -2-methylpropanoate ci n p / = Ts GL ''

A mixture of methyl- (R) -3 - (((R) -1- (1H-indol-3-yl) propan-2-yl) amino) -2-methylpropanoate (0.85 g, 3.1 mmol), 2-chloro-3-methylisonicotinaldehyde (0.50 g, 3.2 mmol) in toluene (10 ml) and acetic acid (1.0 ml) was stirred at 90 ° C for 8 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 40% ethyl acetate in hexanes, to give methyl- (R) -3 - ((1R, 3R) -1- (2-chloro-3-methylpyridine- 4-yl) -3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.75 g, 59%) as pale yellow foam.

1H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.03 (6H, d), 2.33 (3H, br s), 2.40-2.48 (1H, m), 2.56 -2.80 (3H, m), 2.81-2.93 (1H, m), 3.35-3.48 (1H, m), 3.52 (3H, s), 4.98 (1H , s), 6.82-7.09 (3H, m), 7.13-7.30 (1H, m), 7.44 (1H, d), 8.15 (1H, d), 10, 34 (1H, s). mass / charge: ES + [M + H] + 412.

Preparation of methyl-1H-3 - ((1R, 3R) -1 - (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -3 methylpyridin-4-yl) -3-methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A mixture of methyl- (R) -3 - ((1 R, 3R) -1 - (2-chloro-3-methylpyridin-4-yl) -3 -methyl-1,3,4,9-tetrahydro-2Hpyrido [3 , 4-b] indol-2-yl) -2-methylpropanoate (0.30 g, 0.73 mmol), tert-butyl (3-fluoropropyl) (2hydroxyethyl) carbamate (0.209 g, 0.95 mmol), RockPhos 3rd generation pre-catalyst (0.031 g, 0.04 mmol) and cesium carbonate (0.593 g, 1.82 mmol) were evacuated and filled with nitrogen (3x). Toluene (3.5 ml) was added and the mixture was evacuated again and backfilled with nitrogen (2x). The resulting suspension was stirred at 90 ° C for 24 h, allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, gradient elution from 0 to 40% ethyl acetate in hexanes, to give the crude product, which was further purified by SFC (Chialpak IB column, 250 mm long, 21.2 mm in diameter, 5 μm, 75 ml / min, flow rate) eluting with 10% (0.2% NH4OH methanol) in CO2 for 10 min to give methyl- (R) -3 - ((1R, 3R) -1- ( 2- (2- 111 038160 ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [ 3,4-b] indol-2-yl) -2-methylpropanoate (0.041 g, 9%) as a pale amber foam.

¹ H NMR (500 MHz, DMSO-d6, 27 ° C) 0.97-1.10 (6H, m), 1.30-1.47 (9H, m), 1.81-1.97 (2H , m), 2.19 (3H, br s), 2.54-2.66 (3H, m), 2.68-2.79 (1H, br m), 2.84 (1H, br d) , 3.35-3.44 (3H, m), 3.45-3.75 (2H, m), 3.51 (3H, s), 4.24-4.34 (1H, m), 4 , 34-4.47 (1H, m), 4.46 (2H, dt), 4.93 (1H, br s), 6.45 (1H, br s), 6.93-6.99 (1H , m), 6.99 7.04 (1H, m), 7.21 (1H, d), 7.43 (1H, d), 7.84 (1H, br d), 10.33 (1H, br s). mass / charge: ES + [M + H] + 597.

Preparation of methyl- (R) -3 - ((1 R, 3R) -1 - (2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3 methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A solution of methyl- (R) -3 - ((1R, 3R) -1 - (2- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -3 methylpyridin-4-yl) -3- methyl 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (0.04 g, 0.07 mmol) in formic acid (1 ml, 26.07 mmol) was left to stand at room temperature for 18 h and then concentrated under reduced pressure. The residue was increased in basicity with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% MeOH in DCM, to give methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((3fluoropropyl ) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3, 4-b] indol-2yl) -2-methylpropanoate (0.030 g , 90%) in the form of a transparent film.

1H NMR (500 MHz, DMSO-d ₆ , 27 ° C) 0.97-1.10 (6H, m), 1.74-1.86 (2H, m), 2.08-2.29 (3H , m), 2.57-2.64 (2H, m), 2.69 (2H, t), 2.71-2.78 (1H, m), 2.85 (1H, br dd), 2 , 90 (2H, t), 3.39-3.47 (1H, m), 3.51 (3H, s), 4.254.34 (2H, m), 4.50 (2H, dt), 4, 91 (1H, s), 6.37-6.52 (1H, m), 6.93-6.98 (1H, m), 6.99-7.05 (1H, m), 7.21 ( 1H, d), 7.42 (1H, d), 7.84 (1H, br d), 10.34 (1H, s). (Two peaks corresponding to a hydrogen atom were not observed); mass / charge: ES + [M + H] + 497.

Preparation of methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -3-methylpyridin-4yl) -3-methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

A solution of formaldehyde in water (37 wt%; 7.8 μL, 0.10 mmol) was added to a stirred solution of methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((3 -fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl-1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate ( 26 mg, 0.05 mmol) in dichloromethane (1 ml). Then sodium triacetoxyborohydride (22 mg, 0.10 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours and then treated with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 10% MeOH in DCM, to give methyl- (R) -3 - ((1R, 3R) -1- (2- (2 - ((3 -fluoropropyl) (methyl) amino) ethoxy) -3methylpyridin-4-yl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2 α-methylpropanoate (14 mg, 52%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ , 27 ° C) 0.98-1.07 (6H, m), 1.74-1.88 (2H, m), 2.18 (3H, br s ), 2.28 (3H, s), 2.56-2.68 (3H, m), 2.68-2.78 (3H, m), 2.85 (1H, br dd), 3.39 -3.47 (1H, m), 3.51 (3H, s), 4.29-4.40 (2H, m), 4.49 (2H, dt), 4.92 (1H, br s) , 6.45 (1H, brd), 6.93-6.98 (1H, m), 6.99-7.04 (1H, m), 7.21 (1H, d), 7.42 (1H , d), 7.84 (1H, br d), 10.32 (1H, s). (Two peaks corresponding to a hydrogen atom were not observed); mass / charge: ES + [M + H] + 511.

Example 162. Preparation of 1H-3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2methylphenyl) -6-fluoro-3-methyl -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid

Methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3methyl -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (115 mg, 0.21 mmol) by dissolving 112 038160 in THF (0, 8 ml) / MeOH (0.8 ml) and treated with a solution of lithium hydroxide monohydrate (88 mg, 2.1 mmol) in water (0.8 ml). The reaction mixture was stirred at room temperature for 4.5 hours and then concentrated under reduced pressure. The resulting residue was carefully neutralized with aqueous HCl (1N) to pH 7 and the resulting mixture was extracted with EtOAc (2x). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative SFC (Chiralpak IC column, 5 μm, 21 mm in diameter, 250 mm in length, 75 ml / min, flow rate) eluting with 20% (0.2% NH4OH in MeOH) in CO ₂ to give (R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3 difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -6-fluoro-3-methyl - 1,3,4,9-tetrahydro-2R-pyrido [3,4b] indol-2-yl) -2-methylpropanoic acid (41 mg, 37%) as a beige dry film.

1H NMR (500 MHz, DMSO-d6, 27 ° C) 0.91 (3H, d), 0.99 (3H, d), 1.63-2.04 (5H, m), 2.17-2 , 33 (1H, m), 2.51-2.57 (2H, m), 2.62 (br 1H, d), 2.67 (2H, t), 2.72-2.89 (2H, m), 2.92-3.00 (1H, m), 3.53-3.70 (1H, m), 3.783.93 (1H, m), 3.93-4.04 (1H, m) , 5.16 (1H, s), 6.07 (1H, tt), 6.78 (1H, td), 6.87-6.98 (1H, m), 6.99-7.07 (1H , m), 7.07-7.23 (2H, m), 10.34 (1H, s). (Two peaks corresponding to a hydrogen atom were not observed); mass / charge: ES + [M + H] + 536.

Procedures used to prepare methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) - 6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) -2-methylpropanoate starting material are described below.

Preparation of methyl- (R) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2-hydroxyethoxy) -2-methylphenyl) -3-methyl1,3,4,9- tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate one

Methyl- (R) -3 - ((1R, 3R) -1- (3-bromo-6-fluoro-2-methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2R -pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (330 mg, 0.67 mmol), cesium carbonate (547 mg, 1.68 mmol), and 2 ((tert-butyldimethylsilyl) oxy ) ethan-1-ol (178 mg, 1.01 mmol) was suspended in toluene (3.5 ml). The reaction flask was then evacuated and backfilled with nitrogen (3x) before adding RockPhos 3rd generation precatalyst (30 mg, 0.03 mmol). The reaction flask was evacuated again and backfilled with nitrogen (3x) before heating at 90 ° C for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM (25 ml) and washed with saturated aqueous sodium chloride solution (25 ml). The aqueous layer was extracted with DCM (25 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in THF (3.5 ml) and treated with TBAF (1.0 M in THF; 2 ml). After 30 min, the reaction mixture was diluted with EtOAc (25 ml), washed with saturated aqueous sodium chloride solution (25 ml) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 80% EtOAc in hexanes. The fractions containing the product were concentrated under reduced pressure to give methyl- (R) -3 - ((1R, 3R) -6fluoro-1 - (6-fluoro-3 - (2-hydroxyethoxy) -2-methylphenyl) -3 - methyl 1,3,4,9-tetrahydro-2R-pyrido [3, 4-b] indol2-yl) -2-methylpropanoate (130 mg, 39%) as a brown solid.

¹ H NMR (500 MHz, DMSO-d6, 27 ° C) 0.91 (3H, d), 0.98 (3H, d), 1.55-1.91 (3H, m), 2.42- 2.65 (4H, m), 2.85-2.98 (1H, m), 3.41 (3H, s), 3.57-3.71 (3H, m), 3.77-3, 99 (2H, m), 4.76 (1H, t), 5.11 (1H, s), 6.72-6.83 (1H, m), 6.89-7.06 (2H, m) , 7.07-, 19 (2H, m), 10.33 (1H, s). mass / charge: ES + [M + H] + 473.

Preparation of methyl- (R) -3- (1R, 3R) -6-fluoro-1- (6-fluoro-2-methyl-3- (2 - ((methylsulfonyl) oxy) ethoxy) phenyl) -3-methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate o II

Methanesulfonyl chloride (0.022 ml, 0.28 mmol) was added to a solution of methyl- (R) -3 - ((1R, 3R) -6-fluoro1 - (6-fluoro-3 - (2-hydroxyethoxy) -2-methylphenyl) - 3-methyl- 1,3,4,9-tetrahydro-2H-pyrido [3, 4-b] indol-2-yl) 2-methylpropanoate (121 mg, 0.26 mmol), DIPEA (0.056 ml, 0, 32 mmol) and DCM (2.5 ml). The reaction mixture was stirred at room temperature for 20 min and then diluted with DCM (10 ml) and washed with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude methyl- (R) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-2-methyl-3- (2 - ((methylsulfonyl) oxy) ethoxy) phenyl) -3- 113 038160 methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (141 mg, 100%) as a yellow foam. Mass / charge: ES + [M + H] + 551.

Preparation of methyl- (R) -3 - ((1 R, 3R) -1 - (3- (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) 6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate

Methyl- (R) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-2-methyl-3- (2 - ((methylsulfonyl) oxy) ethoxy) phenyl) -3methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoate (141 mg, 0.26 mmol), 3,3-difluoropropan-1-amine hydrochloride (67 mg, 0.51 mmol), potassium carbonate (106 mg, 0.77 mmol) and potassium iodide (42.5 mg, 0.26 mmol) were suspended in acetonitrile (2.5 ml) and heated at 80 ° C for 17 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous sodium chloride solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica, elution gradient from 0 to 20% MeOH in DCM. The fractions containing the product were concentrated under reduced pressure to give methyl- (R) -3 - ((1R, 3R) -1- (3- (2 - ((3,3 difluoropropyl) amino) ethoxy) -6-fluoro-2 -methylphenyl) -6-fluoro-3-methyl-1,3,4,9-tetrahydro-2R-pyrido [3,4b] indol-2-yl) -2-methylpropanoate (119 mg, 85%) as beige foam. Mass / charge: ES + [M + H] + 550.

Example 163. Preparation of 3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl (methyl) amino) ethoxy) -2methylphenyl) -3-methyl-1,3,4 , 9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid

A solution of NaOH (0.82 ml, 1.65 mmol) was added to a solution of methyl-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) propanoate (170 mg, 0.33 mmol) in THF (1.24 ml) / MeOH (1.24 ml). The reaction mixture was stirred at room temperature for 2 hours, then neutralized by the addition of 2N HCl. HCl solution. The volatiles were evaporated, then the crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5 μ silica, 30 mm diameter, 100 mm long) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to give 3 ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoic acid (145 mg, 88%) as a colorless solid.

1H NMR (500 MHz, CDCl3, 27 ° C) 1.23 (3H, d), 1.85 (2H, ddt), 1.87 (3H, s), 2.16 (1H, d), 2, 32 (3H, s), 2.48-2.56 (1H, m), 2.58 (2H, t), 2.66-2.88 (3H, m), 2.89-2.96 ( 2H, m), 3.27 (1H, ddd), 3.76 (1H, p), 4.03 (2H, dp), 4.42 (1H, t), 4.52 (1H, t), 5.40 (1H, s), 6.83 (1H, dd), 6.94 (1H, t), 7.09-7.19 (2H, m), 7.22 (1H, dd), 7 , 38 (1H, s), 7.51 (1H, dd). (1 x Exchangeable Not Observed); mass / charge: ES + [M + H] + 500.

Procedures used to prepare methyl-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate starting material are described below.

2- (3-bromo-6-fluoro-2-methylphenyl) -1,3-dioxolane

F - Br o - <\ H / °

3-bromo-6-fluoro-2-methylbenzaldehyde (4.8 g, 22.12 mmol) was added to ethane-1,2-diol (4.12 g, 66.35 mmol) and 4-methylbenzenesulfonic acid (0.381 g , 2.21 mmol) in toluene (100 ml). The resulting mixture was stirred at 100 ° С for 16 h. The reaction mixture was poured into saturated NaHCO ₃ solution (50 ml), extracted with EtOAc (2 x 50 ml), then the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated with obtaining a yellow gum, which was purified by flash chromatography on silica, elution gradient from 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 2- (3-bromo-6-fluoro-2-methylphenyl) 1,3-dioxolane (5.00 g, 87%) as a colorless oil.

1H NMR (300 MHz, CDCl3, 27 ° C) 2.50 (3H, s), 3.94-4.14 (2H, m), 4.10-4.30 (2H, m), 6.16 (1H, s), 6.746.87 (1H, m), 7.47-7.58 (1H, m).

- 114 038160

Tert-Butyl- (2- (3- (1,3-dioxolan-2-yl) -4-fluoro-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate

F — Oh ^? '

O- / '</ °

Tert-butyl- (3-fluoropropyl) (2-hydroxyethyl) carbamate (5.08 g, 23.0 mmol) was added to 2- (3-bromo-6fluoro-2-methylphenyl) -1,3-dioxolane (5, 00 g, 19.2 mmol), Cs ₂ CO ₃ (18.72 g, 57.45 mmol) and Rockphos 3rd generation pre-catalyst (0.801 g, 0.96 mmol) in toluene (12 mL) under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 16 hours. The solvent was removed under reduced pressure, then the reaction mixture was diluted with EtOAc (50 ml) and washed sequentially with saturated aqueous NaHCO ₃ solution (2 x 20 ml), water (20 ml) and saturated aqueous sodium chloride solution (20 ml). The organic layer was dried over Na ₂ SO _4, filtered and evaporated. The crude product was purified by flash chromatography on C18-flash with a gradient elution of 0-80% MeCN in water. Pure fractions were evaporated to dryness to obtain tert-butyl- (2- (3- (1,3-dioxolan-2-yl) -4-fluoro-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate (4.80 g, 62%) as a yellow resin.

¹ H NMR (300 MHz, CDCl ₃ , 27 ° C) 1.45 (9H, s), 1.85-2.11 (2H, m), 2.29 (3H, s), 3.46 (2H , t), 3.57-3.64 (2H, m), 3.94-4.09 (4H, m), 4.17-4.29 (2H, m), 4.40 (1H, t ), 4.55 (1H, t), 6.15 (1H, s), 6.70-6.90 (2H, m). mass / charge (ES +), [M-tBu] + = 346.

Tert-butyl- (2- (4-fluoro-3-formyl-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate

--y o F

I— ¹

N— 'F— ^f

O

4-Methylbenzenesulfonic acid (0.244 g, 1.42 mmol) was added to tert-butyl- (2- (3- (1,3-dioxolan-2-yl) -4-fluoro-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate (5.70 g, 14.2 mmol) in acetone (80 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO3 solution (50 ml), extracted with EtOAc (2 x 50 ml), then the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give yellow resin which was purified by flash chromatography on silica, gradient elution 0 to 20% EtOAc in petroleum ether. The fractions containing the product were evaporated to dryness to give tert-butyl- (2- (4-fluoro-3-formyl-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate (3.40 g, 67%) as yellow resin that hardened on standing.

¹ H NMR (400 MHz, CDCl ₃ , 27 ° C) 1.47 (9H, s), 1.86-2.10 (2H, m), 2.50 (3H, s), 3.48 (2H , t), 3.60-3.74 (2H, m), 3.99-4.15 (2H, m), 4.44 (1H, t), 4.55 (1H, t), 6, 81-7.16 (2H, m), 10.51 (1H, s). mass / charge (ES +), [NBos] = 258.

Methyl-3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2methylphenyl) -3-methyl-1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate

Methyl (R) -3 - ((1- (1H-indol-3-yl) propan-2-yl) amino) propanoate (260 mg, 1.0 mmol) and tert-butyl- (2 (4-fluoro -3-formyl-2-methylphenoxy) ethyl) (3-fluoropropyl) carbamate (357 mg, 1.00 mmol) was heated in toluene (3.60 ml) / acetic acid (0.40 ml) to 100 ° C for 6 h. After cooling, the volatiles were evaporated and the residue was taken up in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography on silica, elution gradient 0 to 40% EtOAc in heptane. The fractions containing the product were evaporated to dryness to give methyl-3 - ((1R, 3R) -1- (3- (2 ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2 α-methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate (301 mg, 50%) as a beige solid. Mass / charge: ES + [M + H] + 600.

Methyl-3 - ((1R, 3R) -1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl- 115 038160

1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate

omethyl-3 - ((1R, 3R) -1- (3- (2 - ((tert-butoxycarbonyl) (3-fluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3-methyl-1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate (280 mg, 0.47 mmol) was stirred in formic acid (2.33 ml) at 40 ° C for 1 hour. The volatiles were evaporated, then the residue was dissolved in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (10 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated to a volume of ~ 10 ml. To this solution was added 37% formaldehyde solution (71.9 mg, 0.70 mmol) followed by sodium triacetoxyborohydride (97 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM (10 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (20 ml), then the combined organics were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5 μ silica, 30 mm in diameter, 100 mm in length) using mixtures of water (containing 1% NH ₃ ) and MeCN with decreasing polarity as eluents. The fractions containing the desired compound were evaporated to dryness to obtain methyl-3 - ((1R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2 -methylphenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) propanoate (180 mg, 75%) as a beige solid.

¹ H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.00 (3H, d), 1.72 (2H, ddd), 1.78 (3H, s), 2.11-2.19 (2H , m), 2.19 (3H, s), 2.44 (2H, t), 2.59 (1H, d), 2.61-2.68 (3H, m), 2.79 (1H, dt), 3.02 (1H, ddd), 3.44 (3H, s), 3.49-3.56 (1H, m), 3.87 (2H, tt), 4.30 (1H, t ), 4.39 (1H, t), 5.24 (1H, s), 6.68 (1H, dd), 6.80 (1H, t), 6.91-7.00 (2H, m) , 7.00-7.07 (1H, m), 7.23 (1H, s), 7.38 (1H, dd). mass / charge: ES + [M + H] + 514.

Examples 16-56, 58-116, 118-120, 122-123, 125, 128-142, 144, 146-151 and 153-154 (Table G below) were prepared using methods similar to those described above.

Table G

Example Structure Name 1H NMR LCMS [M + H] + 16 <4% "P" --- Z ___/ T τι 3-Fluoro-A- (2- (3 ((1H, 3I) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl ) about pan-1-amine H NMR (300 MHz, DMSO-d ₆ 27 ° C) 1.11 (3H, d), 1.59 - 1.92 (3H, t), 2.54 - 2.71 (4H, t), 2 , 82 (2H, brt), 2.91 3.05 (1H, t), 3.07-3.20 (Br, t), 3.57 (IH, dq), 3.94 (2H, brt) , 4.47 (2H, dt), 4.97 (B, s), 6.74 (B, br s), 6.79 - 6.89 (2H, t), 6.95 -7.02 ( 1H, t), 7.04-7.11 (1H, t), 7.25 (B, t), 7.30 (IH, d), 7.45 (B, d), 10.83 (B , S). 464 17 3-Fluoro-C- (2- (4methyl-3- ((1A, 3A) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl) pro pan-1-amine L NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.07 (ЗН, d), 1.52 - 1.83 (ЗН, t), 2.34 (ЗН, s), 2.52 2 , 59 (2H, t), 2.63 (1H, br dd), 2.69 - 2.83 (3H, t), 2.99 (W, dq), 3.28 3.37 (W, t ), 3.47 (W, dq), 3.82 (2H, t), 4.43 (2H, dt), 5.09 (IH, s), 6.22 (W, br s), 6, 78 (Sh, dd), 6.95 - 7.02 (IH, t), 7.02 - 7.08 (IH, t), 7.12 (lH, d), 7.22-7.29 ( W, t), 7.45 (W, d), 10.57 478

- 116 038160

(1H, s). eighteen ll T / Z --- 'll ya XJ) 3-Fluoro-A- (2- (3methyl-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy ) ethyl) propan-1-amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.11 (ЗН, d), 1.64 - 1.88 (ЗН, br), 2.23 (ЗН, s), 2.53 2.70 (4H, br), 2.81 (2H, t), 2.89 - 3.06 (1H, br), 3.07 - 3.23 (1H, br), 3.55 (1H, dq), 3.92 (2H, t), 4.47 (2H, dt), 4.92 (1H, S), 6.54 - 6.60 (1H, t), 6.60 - 6.64 (1H, t), 6.66 -6.71 (1H, t), 6.957.02 (1H, t), 7.03-7.11 (1H, t), 7.27-7.33 (1H , t), 7.44 (B, d), 10.80 (1H, s). 478 19 Z - / LL X T, 3-Fluoro-M- (2- (2methyl-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy ) ethyl) propan-1-amine L NMR (300 MHz, DMSO-d ₆ 27 ° C) 1.11 (3H, d), 1.61 - 1.90 (3H, t), 2.13 (3H, s), 2.552.72 (4H , t), 2.86 (2H, t), 2.92 - 3.07 (1H, t), 3.09 - 3.24 (1H, t), 3.54 (1H, dq), 3, 90 (2H, t), 4.49 (2H, dt), 4.95 (1H, s), 6.63 (1H, d), 6.91 (1H, S), 6.94-7.01 (Sh, t), 7.02-7.10 (2H, t), 7.29 (1H, d), 7.44 (1H, d), 10.77 (1H, s). 478 twenty C-b vvO ¹ 3-Fluoro-M- (2- (2methyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy ) ethyl) propan-1-amine L NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.07 (ЗН, d), 1.65 - 1.96 (ЗН, t), 2.29 (ЗН, s), 2.56 2 , 86 (4H, t), 2.91 (2H, t), 2.90 - 3.10 (1H, t), 3.28 -3.37 (1H, t), 3.37 - 3.57 (1H, t), 4.00 (2H, t), 4.52 (2H, dt), 5.15 (1H, s), 6.29 (1H, brd), 6.9O (1H, d) , 6.94-7.09 (3H, m), 7.20-7.28 (1H, m), 7.44 (1H, d), 10.53 (1H, s). 478 21 ll ZE / Z --- 'LL x A M- (2- (4-ethyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl ) -3 -fluoropropane- L NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.07 (3H, d), 1.15 (3H, t), 1.61 - 1.78 (3H, m), 2.52 2 , 56 (2H, m), 2.63 - 2.85 (6H, m), 2.90-3.10 (1H, m), 2.90-3.10 (lH, m), 3.39 - 3.58 (1H, m), 3.81 (2H, t), 4.42 (2H, dt), 5.16 (1H, s), 6.14 (1H, br 492

- 117 038160

1-amine s), 6.84 (IH, dd), 6.96 7.02 (1H, br), 7.02 - 7.08 (1H, br), 7.17 (lH, d), 7.24 - 7.28 (1H, br), 7.46 (IH, d), 10.61 (IH, s). 22 I ^^ NH ίΎ ° S A Η 1 A QUA ^f M- (2- (4-chloro-3 ((1H, 3Y) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl ) -3-fluoropropane 1-amine Ή NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (ЗН, d), 1.60 - 1.77 (ЗН, br), 2.58 - 2.77 (ЗН, br), 2.83 (lH, dd), 2.92-3.10 (1H, br), 3.31 -3.41 (1H, br), 3.51 (IH, brdq), 3.83 (2H, 1), 4.41 (2H, dt), 5.32 (IH, s), 6.30 (1H, d), 6.94 (IH, dd), 6.96 7.03 (1H, br) , 7.03 - 7.09 (1H, br), 7.21 - 7.29 (1H, br), 7.42 (IH, d), 7.47 (IH, d), 10.62 (IH , s). (The multiplet corresponding to two hydrogen atoms is overlapped by DMSO). 498 23 Z - / uк ty Q_Q 4- (2 - ((3Fluoropropyl) amino) ethoxy) -2 ((1H, 3Ya) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) benzonitrile 'H NMR (300 MHz, Methanol ^ 4.27 ° C) 1.08 (3H, d), 1.59 -1.91 (2H, br), 2.51-2.70 (3H, br), 2.81 (2H, t), 2.80-2.96 (1H, H), 3.04 (IH, dd), 3.27 - 3.38 (1H, overlapped br), 3.40 3, 52 (1H, s), 3.95 (2H, t), 4.35 (2H, dt), 5.11 (IH, s), 6.79 (IH, d), 6.85 - 7.00 (3H, m), 7.08 -7.16 (1H, m), 7.27 7.42 (IH, m), 7.60 (IH, d). (2 interchangeable were not observed). 489 24 ^zz SNE 4- T1 y --- Z / I P 3-Fluoro-M- (2- (2φτορ-3 - ((1Λ, 3Λ) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) propan-1-amine Ή NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.66 - 1.95 (3H, n), 2.55 - 2.80 (4H, br), 2.92 (2H, t), 2.91-3.01 (1H, s), 3.17-3.32 (1H, s), 3.53 (IH, dq), 4.09 (2H, t), 4.52 (2H, dt), 5.32 (IH, S), 6.18-6.26 (1H, ny), 6.89- 7.17 (4H, ny), 7.20 - 7.30 (1H, s), 7.46 (IH, d), 10.69 (1H, S). 482 25 M- (2- (2-chloro-3- ((1Я, ЗЯ) -3methyl-2- (2,2,2- ^: H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.67 - 1.96 (3H, 498

- 118 038160

il X / Ζ --- <u- X / b iz, X) trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl) -3-fluoropropan1-amine br), 2.64 (IH, d), 2.72 (2H, t), 2.83 (IH, brdd), 2.90 - 3.08 (3H, m), 3.33 - 3.42 (lH, m), 3.51 (IH, dq), 4.02-4.19 (2H, m), 4.53 (2H, dt), 5.41 (IH, s), 6.40 ( IH, dd), 6.94 7.17 (4H, m), 7.20-7.26 (IH, m), 7.46 (IH, d), 10.59 (IH, s). 26 IL I / IL LnP ~ ^{/ Q} M 3-Fluoro - \ '- (2- (4methoxy-2methyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole- 1yl) phenoxy) ethyl) propan-1-amine 'H NMR (500 MHz, CDC1 _3, 27 ° C) 1,17 (3H, d ), 1,78 - 1,84 (IH, m), 1,86 - 1,89 (4H, m), 2 , 70 (IH, d), 2.76 (2H, t), 2.84 -2.99 (3H, m), 3.12 (IH, dt), 3.24 (IH, ddd), 3, 66 - 3.74 (IH, m), 3.84 (3H, s), 3.92 -4.01 (2H, m), 4.44 (IH, t), 4.53 (IH, t) , 5.73 (IH, s), 6.76 (IH, d), 6.85 (IH, d), 7.05 7.11 (2H, m), 7.15-7.19 (IH, m), 7.24 (IH, s), 7.48 (IH, dt). (1 exchangeable was not observed). 508 27 0> V yK) -Π 3-Fluoro - \ '- (2- (3fluoro-4-methoxy5 - ((lR, 3R) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenoxy) ethyl) propan-1-amine ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.11 (3H, d), 1.55 - 1.81 (3H, br), 2.56 - 2.82 (4H, br) , 2.86 - 3.08 (1H, br), 3.35 -3.25 (1H, br), 3.51 (1H, dq), 3.80 (2H, t), 3.87 (3H , s), 4.41 (2H, dt), 5.32 (IH, s), 5.90 (1H, dd), 6.91 (lH, dd), 6.967.03 (IH, m), 7 , 03 -7.10 (IH, m), 7.23-7.29 (IH, m), 7.46 (IH, d), 10.64 (IH, s). (The multiplet corresponding to two hydrogen atoms is overlapped by DMSO). 512 28 F ^ \ _NH A ALL ^f 3-Fluoro - \ '- (2- (2fluoro-4-methoxy5 - ((lR, 3R) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenoxy) ethyl) propan-1-amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.51 - 1.78 (3H, br), 2.41-2.48 (2H, br) , 2.54 - 2.69 (3H, br), 2.77 - 3.05 (2H, br), 3.33 3.55 (2H, br), 3.63 - 3.81 (2H, br ), 3.84 (3H, s), 4.39 (2H, dt), 5.32 (1H, s), 6.44 (IH, d), 6.92 7.00 (1H, br), 7.00 - 7.06 512

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(1H, br), 7.07 (IH, d), 7.19-7.26 (lH, m), 7.44 (IH, d), 10.47 (IH, s). 29 AN -L / --- Z __ / I -NS # - (2- (2,5difluoro-4methoxy-3 ((1L, ZL) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy ) ethyl) -3-fluoropropane 1-amine Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.18 (3H, d), 1.84 (2H, dddd), 2.64 (IH, ddd), 2.76 (2H, t), 2 , 95 (2H, dd), 2.97 - 3.05 (IH, m), 3.11 (IH, ddd), 3.25 (IH, dq), 3.60 - 3.68 (IH, m ), 3.69 (3H, d), 4.01 (2H, td), 4.44 (IH, t), 4.54 (IH, t), 5.40 (IH, s), 6.76 (IH, dd), 7.05 7.14 (2H, m), 7.18-7.22 (IH, m), 7.49-7.52 (IH, m), 7.63 (IH, s). (1 exchangeable was not observed) 530 thirty | A ^ NH R .0 L Η \ d d ^ b ΑχΧτ # - (2- (3,4difluoro-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl ) -3-fluoropropane 1-amine A NMR (500 MHz, CDC1 _3, 27 ° C) 1,17 (ZN, d), 1,82 (2H, dddd), 2,58 (IH, ddd), 2,72 ( 2H, 1), 2 , 87 (2H, t), 2.88-3.01 (2H, br), 3.25 (IH, dd), 3.42 - 3.53 (1H, br), 3.83 (2H, t ), 4.41 (lH, t), 4.51 (IH, t), 5.29 (IH, s), 6.30 (IH, dt), 6.64 (IH, ddd), 7.12 (lH, td), 7.14-7.21 (IH, m), 7.25 (IH, dd), 7.49-7.58 (IH, m), 7.87 (IH, s). (1 exchangeable was not observed) 500 31 Sd \ H ^ # - (2- (2,5difluoro-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl ) -3-fluoropropane 1-amine 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.19 (3H, d), 1.92 (2H, dddd), 2.59 (IH, ddd), 2.85 (2H, t), 2.91 (IH, dd), 2.96 (1H, dd), 3.06 (2H, td), 3.27 (IH, dq), 3.47 - 3.52 (1H, br), 4 , 11 (2H, td), 4.51 (lH, t), 4.60 (lH, t), 5.31 (IH, s), 6.32 (IH, ddd), 6.62 (IH, dd), 7.12 (IH, td), 7.15-7.20 (lH, m), 7.25-7.30 (IH, m), 7.53 (IH, d), 7.88 (IH, s). (1 exchangeable was not observed) 500 32 3-Fluoro - \ '- (2 (2,4,5-trifluoro-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) - 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.18 (3H, d), 1.86 (2H, dddd), 2.65 (IH, ddd), 2.79 (2H, t), 2.86 - 3.02 (ZN, w), 3.08 518

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Q D 'ZI -η -π Ohm * Ήg Π / y - 1 -Π 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) phenoxy) ethyl) propan-1-amine (IH, ddd), 3.29 (IH, dq), 3.59 (lH, d), 4.01 -4.11 (2H, pt), 4.47 (1H, 1), 4.56 ( IH, t), 5.38 (IH, s), 6.83 (IH, dt), 7.11 (1H, td), 7.13 - 7.19 (1H, br), 7.21-7 , 25 (IH, m), 7.49-7.54 (IH, m), 7.55 (IH, s). (1 exchangeable was not observed) 33 ll τ / Ζ --- 'LL AS 3-Fluoro - \ '- (2- (4fluoro-2 -methyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) propan-1-amine L NMR (500 MHz, CDCl ₃ , 27 ° C) 1.17 (3H, d), 1.74 - 1.96 (5H, br), 2.66-2.81 (3H, br), 2, 85 -3.04 (3H, br), 3.133.31 (2H, br), 3.66-3.77 (1H, br), 3.98 (2H, ddt), 4.43 (IH, t) , 4.52 (IH, t), 5.46 (IH, s), 6.82 (1H, dd), 6.92 (IH, t), 7.06 7.15 (2H, br), 7 , 16-7.23 (1H, br), 7.38 (IH, s), 7.46-7.56 (1H, br). (1 exchangeable was not observed). 496 34 Ll r / Ζ --- ^f LL C s g UC> ¹ e) 3-Fluoro-M- (2 - ((6 ((1 £, 3I) -3-methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridine -2yl) oxy) ethyl) pr opan-1-amine 'H NMR (500 MHz, DMSO-d ₆ , 27 ° C) 1.19 (3H, d), 1.62 - 1.78 (2H, br), 2.52 - 2.62 (3H, br) , 2.63 - 2.67 (1H, br), 2.72 - 2.83 (2H, br), 3.00 3.13 (1H, br), 3.25-3.35 (2H, br ), 3.54 - 3.69 (1H, br), 4.21 - 4.32 (2H, br), 4.46 (2H, dt), 4.96 (1H, s), 6.67 ( IH, d), 6.92 6.96 (1H, br), 7.00 (1H, d), 7.03-7.08 (1H, br), 7.30 (IH, d), 7, 41 (1H, d), 7.67 (IH, t), 10.67 (IH, s) 465 35 A “/ \ ^{z =} \ V / M CHA -L / --- Z __ / t P 3-Fluoro-M- (2 - ((2 ((1X, ZL) -3-methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl) pyridine -4yl) oxy) ethyl) pr opan-1-amine L NMR (500 MHz, DMSO-d ₆ , 27 ° C) 1.18 (3H, d), 1.69 - 1.81 (2H, br), l, 86 (lH, brs), 2.542.66 ( 4H, br), 2.86 (2H, t), 2.99-3.11 (1H, br), 3.23-3.30 (1H, br), 3.57 - 3.67 (1H, br), 4.05 (2H, brt), 4.47 (2H, dt), 4.99 (IH, s), 6.90 (IH, dd), 6.92 - 6.96 (IH, m ), 6.98 (IH, brd), 7.00-7.04 (IH, m), 7.30 (IH, d), 7.40 (IH, d), 8.33 (IH, 465

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d), 10.67 (1H, s) 36 u. I / Z --- ^f u- 3-Fluoro-M- (2 - ((6metho xi-5 ((1Λ, ЗΛ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1 yl) pyridin-3yl) oxy) ethyl) pr opan-1-amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (ЗН, d), 1.62 - 1.77 (ЗН, br), 2.52 - 2.64 (ЗН, br) , 2.70 - 2.80 (3H, br), 2.99 (W, brdq) 3.14 - 3.28 (W, w) 3.51 (lH, dq), 3.87 (2H, t ), 3.91 (3H, s), 4.41 (2H, dt), 5.26 (1H, s), 6.52 (1H, d), 6.94 7.02 (1H, br), 7.02 - 7.09 (W, br), 7.21 -7.26 (1H, br), 7.46 (1H, d), 7.81 (W, d), 10.59 (1H, s). 495 37 u. T / Z --- 'u- Ό 3-Fluoro-M- (2 - ((6methyl-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl ) pyridin-3yl) oxy) ethyl) pr opan-1-amine Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.15 (3H, d), 1.74 - 1.91 (2H, br), 2.60 - 2.69 (4H, br), 2, 73 (2H, t), 2.85 - 3.00 (4H, br), 3.23 (1H, dq), 3.37 3.44 (1H, br), 3.89 (2H, tt), 4.43 (1H, t), 4.52 (1H, t), 5.06 (1H, s), 6.70 (1H, d), 7.11-7.21 (2H, m), 7 , 29 (1H, d), 7.55 (1H, d), 7.92 (1H, d), 8.57 (1H, s). (1 exchangeable was not observed). 479 38 ex ^ZI ox? “Π / y - Z -π 3-Fluoro-M- (2 - ((4methyl-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl ) pyridin-3yl) oxy) ethyl) pr opan-1-amine 'H NMR (500 MHz, CDCl3, 27 ° C) 1.16 (3H, d), 1.87 (1H, ddd), 1.92 (B, ddd), 2.19 (3H, s), 2 , 63-2.71 (1H, br), 2.84 (2H, t), 2.95-3.08 (4H, br), 3.20 (1H, dt), 3.48 3.57 ( 1H, br), 4.10-4.22 (2H, br), 4.49 (1H, t), 4.58 (1H, t), 5.05 (1H, s), 7.10-7 , 19 (2H, m), 7.23-7.25 (1H, m), 7.53 (2H, d), 7.84 (1H, s), 8.17 (1H, s). (1 exchangeable was not observed). 479 39 DN \ H 1 ί _F θ-ΑΑ f 3-Fluoro-M- (2 - ((5φτορ-4 - ((1Λ, 3Λ) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) pyridin-2yl) oxy) ethyl) pr opan-1-amine ^: H NMR (500 MHz, CDCI3, 27 ° C) 1.20 (3H, d), 1.83 (2H, dddd), 2.54 (B, ddd), 2.66 - 2.80 (3H, br), 2.83 - 2.99 (3H, br), 3.19-3.36 (2H, t), 4.27 (2H, td), 4.42 (1H, t), 4.52 (1H, t), 5.25 (1H, S), 6.25 (1H, d), 7.14 (Sh, ddd), 7.19 (1H, ddd), 7.28 (1H, dt) , 7.54 483

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(W, d), 7.98 (IH, d), 8.13 (IH, s). (1 exchangeable was not observed) 40 ll X / Z --- 'LL X T; O ~ “O ^{- / O} X) Al- (3fluoropropyl) -A2 (4-methoxy-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenyl ) ethane 1,2-diamine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (ZH, d), 1.61 - 1.74 (ZH, br), 2.44 - 2.49 (br, 2 H ), 2.53 - 2.64 (2H, br), 2.71 -3.01 (4H, br), 3.343.44 (2H, br), 3.76 (3H, s), 4.42 ( 2H, dt), 4.96 (W, t), 5.34 (IH, S), 6.03 (W, d) 6.45 (IH, dd), 6.86 (IH, d), 6 , 93 - 6.99 (W, br), 6.99 - 7.06 (1H, br), 7.18 - 7.26 (1H, br), 7.43 (IH, d), 10.52 (1H, d). (One peak corresponding to a hydrogen atom was not observed, overlapped by DMSO) 493 41 Ll X / Z --- <LL Vt ^{_ /} ° hz A1- (3fluoropropyl) -A2 (6-methoxy-5 ((1DZA) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridin-3yl ) ethane-1,2diamine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (ЗН, d), 1.58 - 1.78 (ЗН, br), 2.54 - 2.64 (ЗН, br) , 2.70 - 2.78 (1H, br), 2.85 - 3.04 (3H, br), 3.24 3.35 (1H, overlapped n), 3.41 - 3.57 (IH, t), 3.84 (3H, s), 4.43 (2H, dt), 5.10 (lH, t), 5.24 (Sh, s), 6.43 (IH, d), 6, 91-6.99 (1H, br), 6.99 -7.06 (1H, br), 7.187.27 (1H, br), 7.38 (1H, d), 7.45 (IH, d) , 10.58 (W, s). (Two peaks corresponding to the hydrogen atom were not observed, overlapped by DMSO) 494 42 Z - / LL Gu / A1- (3fluoropropyl) -A2 (5-methoxy-4 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridine -2yl) ethane-1,2- ^: H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.11 (3H, d), 1.58 (IH, brd), 1.60 - 1.82 (2H, m), 2.52 - 2.74 (6H, m), 2.84 3.05 (IH, m), 3.07 - 3.21 (2H, m), 3.26 - 3.39 (IH, overlapped m), 3 , 49 (IH, dq), 3.81 (3H, s), 4.44 (2H, dt), 5.25 (IH, s), 5.83 (IH, s), 6.00 (IH, t), 6.95-7.01 (lH, m), 494

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diamine 7.01-7.09 (1H, br), 7.22-7.28 (1H, br), 7.45 (1H, d), 7.79 (IH, s), 10.61 (s, 1 H). 43 u. T / Z --- 'LL Ts T, # 1- (3- fluoropropyl) - # 2 (5-methoxy-6- ((1 ^, 3 ^) - 3 -methyl2- (2,2,2trifluoroethyl) - 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridine-2yl) ethane-1,2diamine ⁴ H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.15 (3H, d), 1.23 - 1.42 (1H, br), 1.55 - 1.68 (2H, br) , 2.35 - 2.44 (4H, br), 2.52 - 2.58 (1H, br), 2.65 (1H, dd), 2.89 - 3.07 (3H, br), 3 , 48 (IH, dq), 3.77 (3H, s), 4.08 - 4.20 (1H, br), 4.40 (2H, dt), 5.40 (1H, s), 5, 86 (IH, t), 6.40 (1H, d), 6.92 - 7.03 (2H, br), 7.18-7.25 (1H, br), 7.30 (B, d) , 7.39 (IH, d), 10.32 (IH, s). 494 44 O V / W 4% AND 3 - ((1H, 3Y) -1- (2chlor-5- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2 -yl) 2,2 difluoropropane-1ol 1H NMR (500 MHz, CDC13, 27 ° C) 1.18 (3H, d), 1.78 - 1.89 (2H, br), 2.69 (IH, ddd), 2.74 (2H, t ), 2.78 - 2.87 (1H, br), 2.89 (2H, ddd), 3.12 3.26 (2H, br), 3.60 (1H, ddd), 3.66 - 3 , 74 (1H, br), 3.74-3.81 (1H, br), 3.88 - 3.98 (2H, br), 4.44 (1H, t), 4.53 (IH, t ), 5.34 (1H, S), 6.79 - 6.87 (2H, br), 7.09 - 7.17 (2H, br), 7.22 (IH, dt), 7.35 ( IH, d), 7.42 (IH, S), 7.51-7.57 (W, br). (2 interchangeable were not observed). 510 45 ⁿ JL ΐ ^ CA ⁰ 2,2-Difluoro-3 ((1H, 3Y) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3 , 4b] indol-2yl) propan-1-ol H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.18 (3H, d), 1.78 - 2.00 (5H, br), 2.70 - 2.89 (4H, br), 2, 98 (2H, tq), 3.13 -3.24 (2H, br), 3.53 - 3.64 (2H, t), 3.75 - 3.85 (1H, t), 4.02 ( 2H, t), 4.46 (IH, t), 4.55 (W, t), 5.34 (IH, S), 6.84 (W, dd), 6.94 (IH, t), 7.07-7.15 (2H, t), 7.17-7.23 (1H, t), 7.29 (1H, s), 7.50 (IH, dd). (2 interchangeable were not observed). 508 46 2,2-Difluoro-3 ((1Λ, 3Λ) -6-φτορ1- (5- (2 - ((3fluoropropyl) amy ⁴ H NMR (500 MHz, CDCl3, 27 ° C) 1.20 (3H, d), 1.79-1.91 (2H, t), 2.59 (IH, ddd), 2.75 (2H, 524

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Od C '4 a O /----' Z / but) ethoxy) -2methoxyphenyl) 3-methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2yl) propan-1-ol 1), 2.84-3.01 (4H, br), 3.12-3.23 (1H, br), 3.63 - 3.73 (2H, br), 3.78 (1H, q) , 3.86 - 3.97 (5H, br), 4.44 (lH, t), 4.54 (lH, t), 5.34 (IH, S), 6.64 (1H, d), 6.81-6.92 (3H, m), 7.10-7.17 (2H, m), 7.67 (IH, s). (2 interchangeable were not observed). 47 L “ ^{o /} ν AA A z / 2,2-Difluoro-3 ((1Λ, 3Λ) -1- (5 (((R) -1 - ((3fluoropropyl) amino) propan-2yl) oxy) -2methoxyphenyl) 3-methyl-1,3, 4.9 tetrahydro-2Hpyrido [3.4b] indol-2yl) propan-1-ol 'H NMR (DMS0-d6, 300 MHz) 1.00 -1.13 (6H, br), 1.52 - 1.70 (2H, br), 2.38 - 2.46 (4H, t), 2.53 - 2.79 (4H, t), 2.98 3.17 (1H, t), 3.65-3.82 (5H, t), 4.06- 4.19 (1H, t) , 4.31 (lH, t), 4.47 (lH, t), 5.21 (IH, br s), 5.35 (IH, s), 6.11 (1H, d), 6.86 (IH, dd), 6.91 7.08 (3H, t), 7.21 (1H, d), 7.44 (IH, d), 10.56 (IH, s). (NH not observed) 520 48 ^ | Aa _nh к. Ί Ύ XX Η 1 I ___ / ^Ν ^ - '''' Α '''' Χ '-''' ^ 0 Η ODCHA ^f П 'r ^% 2,2-Difluoro-3 ((1Λ, 3Λ) -1- (5 ((0-1 - ((3fluoropropyl) amino) propan-2yl) oxy) -2methoxyphenyl) 3-methyl-1,3,4, 9tetrahydro-2Hpyrido [3,4b] indol-2yl) propan-1-ol 'H NMR (DMSO-d6, 400 MHz) 1.05 - 1.08 (6H, t), 1.59 - 1.69 (2H, t), 2.42-2.51 (4H, t), 2.52 - 2.77 (4H, t), 3.03 3.20 (1H, t), 3.68-3.91 (5H, t), 4.11 -4.24 (1H, t) , 4.34 (1H, 1), 4.46 (1H, 1), 5.23 (1H, 1), 5.36 (IH, s), 6.12 (IH, d), 6.86 ( IH, dd), 6.93 - 7.08 (3H, t), 7.22 (lH, d), 7.45 (IH, d), 10.58 (1H, s). (ΝΗ did not observe) 520 49 / z / - 'o ........ AF, ) - ^ 2 - I Αχ 2,2-Difluoro-3 ((1Λ, 3Λ) -1- (5 (0-2 - ((3fluoropropyl) amino) propoxy) -2methoxyphenyl) 3-methyl-1,3,4,9tetrahydro-2Нpyrido [3 , 4b] indol-2yl) propan-1-ol 1H NMR (Methanol-b4, 300 MHz) 1.16 (3H, d), 1.31 (3H, d), 1.83 -2.08 (2H, t), 2.63 (IH, dd), 2.73-2.91 (2H, t), 2.94-3.31 (3H, t), 3.403.58 (2H, t), 3.69-3.98 (6H, t), 4, 04 (IH, dd), 4.39 (1H, 1), 4.55 (ΙΗ, Ι), 5.49 (IH, s), 6.47 (IH, d), 6.93 (IH, dd ), 6.98 7.12 (3H, m), 7.24 (IH, d), 7.47 (IH, d), 8.54 (IH, s). (INION not observed) 520 50 2,2-Difluoro-3- IH NMR (Methanol-b4, 520

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Q / ^ZI o H.> O / - 'I / P ((1L, ZL) -1- (5 ((^) - 2 - ((3fluoropropyl) amino) propoxy) -2methoxyphenyl) 3-methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indole- 2yl) propan-1-ol 300 MHz) 1.16 (3H, d), 1.31 (3H, d), 1.86-2.10 (2H, m), 2.63 (IH, dd), 2.68-2.91 (2H, m), 2.97 - 3.32 (3H, m), 3.39 3.57 (2H, m), 3.70 - 3.96 (6H, m), 4.05 (IH, dd), 4.39 (IH, t), 4.55 (IH, t), 5.49 (IH, s), 6.47 (IH, d), 6.93 (IH, dd), 6, 99 7.12 (3H, m), 7.25 (IH, d), 7.47 (IH, d), 8.53 (IH, s). (INION not observed) 51 sh t / Z --- ^f LL Ah Μ- (2- (3 - ((1Λ, 3Λ) 2- (2,2difluoroethyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1-yl) 2,4difluorophenoxy) ethyl) -3fluoropropane-1amine Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.17 (3H, d), 1.82 - 1.94 (2H, m), 2.64 (IH, ddd), 2.72 2.83 (3H, m), 2.97-3.00 (2H, m), 3.02-3.12 (2H, m), 3.48-3.56 (IH, m), 4.06-4 , 11 (2H, m), 4.52 (2H, dt), 5.30 (IH, s), 5.67 (IH, tdd), 6.80 (IH, td), 6.92 (IH, td), 7.08 7.15 (2H, m), 7.22-7.25 (IH, m), 7.50-7.54 (2H, m). (1 exchangeable was not observed). 482 52 ⁿ Α Ϊ AaX> 3-Fluoro - \ '- (2- (3 ((1Λ, 3Λ) -2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1-yl ) -4methoxyphenoxy) ethyl) propane-1amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.55 0.68 (2H, br), 0.90 - 1.02 (2H, br), 1.05 (3H, dd), 1.56 - 1.76 (2H, br), 1.84 (IH, br s), 2.52-2.64 (4H, br), 2.67 - 2.78 (2H, br), 2 , 85 (IH, dd), 3.06 (IH, dd), 3.47 - 3.60 (1H, br), 3.78 - 3.81 (2H, br), 3.85 (3H, s ), 4.42 (2H, dt), 5.35 (IH, s), 6.38 (IH, d), 6.83 (IH, dd), 6.88 -7.08 (3H, m) , 7.21 (IH, dd), 7.42 (IH, d), 10.27 (IH, s). 484 53 (5) -3 - ((1H, 3I) -1 (5- (2 - ((3fluoropropyl) amino) ethoxy) -2methoxyphenyl) 3-methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropane Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.13 (3H, d), 1.25 (3H, d), 1.72 1.89 (2H, m), 2.57 - 2.69 (2H, m), 2.71 (2H, t), 2.80 - 2.88 (4H, m), 2.97 (IH, s), 3.56 (IH, ddd), 3.80 ( 3H, s), 3.87 (2H, t), 4.42 (lH, t), 4.51 (lH, t), 5.59 (IH, s), 6.35 (IH, s), 498

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i am acid 6.82 (IH, dd), 6.85 (1H, d), 7.17 (lH, td), 7.197.24 (IH, m), 7.27 - 7.36 (IH, m), 7 , 56 (IH, d), 7.89 (IH, s). (2 interchangeable not observed) 54 ll / I i - 'o z -' ^{o =} ^ o Xz 'k. (5) -3 - ((1 ^) - 1 (6-chloro-2-fluoro3- (2 - ((3- fluoropropyl) amino) ethoxy) phenyl) -3 -methyl- 1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid L NMR (500 MHz, CDCl ₃ , 27 ° C) 1.01 (3H, d), 1.28 (3H, d), 1.85 (2H, dq), 2.14 (IH, br s), 2.69 - 2.86 (4H, m), 2.88 -3.03 (3H, m), 3.15 (IH, d), 3.66 (IH, q), 4.01 4.09 (2H, m), 4.43 (IH, t), 4.52 (IH, t), 5.62 (IH, s), 6.93 (lH, t), 7.107.18 (3H, m) , 7.24 (IH, d), 7.50-7.56 (IH, m), 7.73 (IH, s). (2 interchangeable not observed) 520 55 IL / i with X '- ° / (/ kXX (5) -3 - ((1Λ, 3Λ) -1 (6-fluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3 , 4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCl3, 27 ° C) 0.86 (3H, d), 1.20 (3H, d), 1.82 1.97 (5H, br), 2.68 - 2.80 (3H, br), 2.83 (3H, 1), 2.94 - 3.07 (2H, br), 3.21 (IH, dd), 3.42 (2H, s), 3.54 - 3.65 (1H, br), 4.02 (IH, q), 4.40 (1H, 1), 4.50 (IH, t), 5.47 (IH, s), 6.18 (IH , s), 6.77 (IH, dd), 6.89 (1H, 1), 7.09 (2H, td), 7.14-7.22 (1H, br), 7.48-7, 52 (IH, m), 7.82 (IH, s). 500 56 u. T / Z --- ^f u- AA 3-Fluoro-A- (2 - ((5methoxy-6- ((1 ^, 3 ^) - 3-methylg ^ DDtrifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) pyridin-2yl) oxy) ethyl) pr opan-1-amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.15 (3H, d), 1.55 - 1.68 (2H, m), 2.38 (2H, t), 2.54 2.61 (3H, m), 2.64-2.73 (lH, m), 2.98-3.11 (IH, m), 3.43-3.56 (IH, m), 3, 85 (3H, s), 3.88 (2H, dt), 3.92 - 4.00 (IH, m), 4.39 (2H, dt), 5.45 (IH, s), 6.72 (IH, d), 6.92 7.00 (2H, m), 7.18-7.25 (IH, m), 7.38-7.44 (IH, d), 7.55 (IH, d), 10.37 (IH, s). (1 exchangeable was not observed) 495

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58 C $) - s - ((1ASYa) -1 (2,6-difluoro-3- (2 ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3,4b ] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.06 (3H, d), 1.28 (3H, d), 1.76 1.89 (2H, br), 2.51 (1H, s), 2.65 - 2.79 (4H, br), 2.85 (1H, 1), 2.91 - 3.02 (3H, br), 3.59 - 3.68 (1H, br) , 4.04 (2H, 1), 4.47 (2H, dt), 5.45 (IH, s), 6.76 (IH, t), 6.87 - 6.94 (1H, br), 7.13 (2H, dtd), 7.26 (IH, d), 7.52 (1H, d), 8.26 (IH, s). (2 interchangeable were not observed.) 504 59 X- ^F An ^g * he (5) -3 - ((1Λ, 3Λ) -1 (2,6-difluoro-3- (2 ((3fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3methyl-1,3,4,9tetrahydro -2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCl3, 27 ° C) 1.06 (3H, d), 1.29 (3H, d), 1.77 1.91 (2H, br), 2.65 (1H, dd ), 2.71-3.01 (8H, br), 3.58 - 3.67 (1H, br), 4.04 (2H, t), 4.47 (2H, dt), 5.44 ( IH, S), 6.72 - 6.79 (1H, br), 6.86 - 6.95 (2H, br), 7.13-7.2 (2H, br), 8.45 (IH, s). (2 interchangeable were not observed.) 522 60 ss / ^ζτ λ ki Ζ / 3 - ((1Λ, 3Λ) -1- (2,6difluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -8-fluoro-3methyl-1,3,4,9tetrahydro-2Нpyrido [3 , 4b] indol-2-yl) 2,2 difluoropropane-1ol Ή NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (3H, d), 1.67 - 1.85 (3H, t), 2.55 - 2.71 (4H, t), 2.79-2.89 (3H, t), 3.17 (IH, q), 3.34 - 3.53 (2H, t), 3.56 - 3.76 (1H, t), 4, 02 (2H, t), 4.47 (2H, dt), 5.24 - 5.32 (2H, t), 6.81-6.98 (3H, t), 7.16 (IH, brtd) , 7.25 (lH, d), 11.13 (IH, s). 530 61 % k \ / ^ΖΙ h xb 1Ί 3 - ((1Λ, 3Λ) -1- (2,6difluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -7-fluoro-3 methyl-1,3,4,9tetrahydro-2Hpyrido [ 3,4b] indol-2-yl) 2,2 difluoropropane-1ol ^: H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.08 (3H, d), 1.67 - 1.88 (3H, t), 2.53 - 2.68 (4H, t) , 2.80-2.89 (3H, t), 3.16 (IH, q), 3.37-3.51 (2H, t), 3.55 - 3.74 (1H, t), 4 , 02 (2H, t), 4.48 (2H, dt), 5.23 (IH, s), 5.26 (lH, t), 6.81 (IH, ddd), 6.91-7, 00 (2H, t), 7.17 (IH, td), 7.39 (IH, dd), 10.71 (IH, s). 530

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62 jCX m ζι -π 4 / -n 3 - ((1D 3 ^) - 1- (2,6difluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -5-fluoro-3methyl-1,3,4,9tetrahydro-2Hpyrido [3 , 4b] indol-2-yl) 2,2 difluoropropan-1 ol 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.64 - 1.84 (2H, br), 1.79 (IH, S), 2.55 2.77 (4H, br), 2.83 (2H, 1), 2.99 (lH, dd), 3.16 (lH, q), 3.33 -3.51 (2H, br), 3 , 64 (IH, brdd), 4.01 (2H, 1), 4.46 (2H, dt), 5.21-5.28 (2H, br), 6.68 (lH, ddd), 6, 90-7.04 (3H, br), 7.16 (lH, td), 10.91 (IH, d). 530 63 I ^^ NH A \ ⁿ JL T Guka ^f 3 - ((1H, 3Y) -1- (2,6 difluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3,6-dimethyl1,3,4,9tetrahydro-2Hpyrido [3,4b ] indol-2-yl) 2,2 difluoropropane-1ol 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.08 (ЗН, d), 1.66 - 1.86 (ЗН, br), 2.36 (ЗН, s), 2.54 2.68 (4H, br), 2.79 - 2.88 (3H, br), 3.06 - 3.24 (1H, br), 3.36-3.51 (2H, br), 3, 56 - 3.74 (1H, br), 4.02 (2H, t), 4.47 (2H, dt), 5.22 (IH, br s), 5.26 (1H, t), 6, 83 (IH, dd), 6.90 6.97 (1H, br), 7.07 (1H, d), 7.11-7.21 (2H, br), 10.43 (IH, S). 526 64 I ^^ NH A ^H JL i ATl l ^ ^0H XykA 3 - ((1Н, ЗЯ) -1- (3,5 difluoro-2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3methyl-1,3,4,9tetrahydro-2Npyrido [ 3,4b] indol-2-yl) 2,2 difluoropropane-1ol H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.19 (3H, d), 1.80 - 1.94 (2H, br), 2.67 (IH, ddd), 2.80 (2H, t), 2.82 - 2.90 (1H, br), 2.96 -3.09 (3H, br), 3.17 - 3.29 (1H, br), 3.64 (1H, h) , 3.70 - 3.87 (2H, br), 4.41 (IH, ddd), 4.444.53 (2H, br), 4.56 (1H, t), 5.34 (IH, S), 7.12 (1H, td), 7.16 (lH, td), 7.24 (lH, dd), 7.52 (lH, d), 7.63 (IH, s), 7.79 (IH , s). (2 interchangeable were not observed.) 513 65 xzx / ^ZI XA -n 3 - ((1H, 3Ya) -1- (3,5difluoro-2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -6-fluoro3-methyl-1,3,4, 9tetrahydro-2Hpyrido [3.4b] indol-2-yl) 2,2 difluoropropan-1 ol H NMR (500 MHz, CDCl3, 27 ° C) 1.19 (3H, d), 1.82 - 1.94 (2H, br), 2.62 (IH, dd), 2.78 - 2.90 (3H, br), 2.96 - 3.05 (3H, br), 3.18 -3.30 (1H, br), 3.63 (lH, q), 3.71-3.85 (2H , br), 4.42 (IH, ddd), 4.45 - 4.60 (3H, br), 5.33 (IH, s), 6.90 (lH, td), 7.16 (2H, dd), 7.57 (IH, s), 7.80 (IH, s). (2 531

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no interchangeable ones have been observed.) 66 / I i— 'o \ Z / O U- "D Xx 3 - ((LR, 3 ^) - 1- (3,5difluoro-2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3,6dimethyl-1,3,4,9tetrahydro -2Нpyrido [3,4b] indol-2-yl) 2,2 difluoropropane-1ol L NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.08 (3H, d), 1.70 - 1.89 (2H, br), 2.35 (3H, s), 2.52 2 , 68 (2H, br), 2.74 (2H, br s), 2.91 -3.06 (2H, br), 3.09 - 3.24 (1H, br), 3.34 -3, 67 (5H, br), 4.31 4.39 (2H, br), 4.50 (2H, dt), 5.22 - 5.33 (2H, br), 6.84 (IH, dd), 7.08 (1H, d), 7.20 (IH, s), 7.93 (IH, s), 10.48 (IH, s). 527 67 A \ n JI I / ^N ^ r- ^X ^ 'N'<g- ^X ^ OH ryKA ^f 3 - ((1H, ZYa) -1- (3,5 difluoro-2- (2 - ((3fluoropropyl) (meth yl) amino) ethoxy) pyridin-4-yl) 6-fluoro-3 -methyl1, 3.4 , 9tetrahydro-2Hpyrido [3.4b] indol-2-yl) 2,2 difluoropropan-1 ol L NMR (300 MHz, DMSO-D, 27 ° C) 1.08 (3H, d), 1.61 - 1.87 (2H, br), 2.21 (3H, s), 2.41 2, 46 (2H, br), 2.53 - 2.64 (2H, br), 2.70 (2H, t), 2.84 (IH, dd), 3.04 - 3.26 (1H, br) , 3.33 -3.71 (3H, br), 4.29 - 4.45 (4H, br), 5.27 (2H, s), 6.85 (1H, td), 7.05-7 , 31 (2H, br), 7.94 (IH, s), 10.75 (1H, s). 545 68 Q ^zz SNE A z / Π 3 - ((1Λ, 3Λ) -1- (2 (difluoromethyl) 3- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3,4b] indole -2-yl) 2,2 difluoropropane-1ol Ή NMR (400 MHz, DMSO-d6) 1.04 (3H, d), 1.03 (IH, d) 1.74 - 1.84 (2H, br), 2.53 - 2.64 (1H, br), 2.64 - 2.74 (3H, br), 2.82-2.90 (3H, br), 3.14 (lH, q), 3.38 - 3.55 (1H, br) , 3.55 - 3.76 (2H, br), 4.08 - (2H, t), 4.45 (1H, t), 4.57 (lH, t), 5.21 (IH, s) , 5.36 (lH, t), 6.51 (IH, s), 6.95-7.10 (2H, m), 7.24-7.31 (2H, m), 7.42 (IH , d), 7.44 - 7.80 (IH, m), 10.41 (IH, s) (1 exchangeable proton was not observed.) 526 69 Ll L yX, tvO ιζ, X. Xj 2- (2 - ((3Fluoropropyl) amino) ethoxy) -6 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1- L NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (ZN, d), 1.69 -1.91 (ZN, br), 2.61-2.72 (ZN, br), 2.89 - 3.06 (4H, br), 3.39 -3.61 (2H, br), 4.18 (2H, t), 4.51 (2H, dt), 5.17 (IH, s), 6.76 (IH, d), 6.94 - 7.08 (2H, m), 7.18 - 7.24 (2H, m), 7.45 (IH, 489

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sludge) benzonitrile d), 7.52 (1H, 1), 10.52 (IH, s). 70 ll I / Z --- 'LL it, Α- / Λ / ^IZ \ / ° Xa (4- (2 - ((3Fluoropropyl) amino) ethoxy) -2 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenyl) methano l 1H NMR (400 MHz MeOH-d4, 27 ° C) 1.15 (3H, d), 1.77 - 1.95 (2H, br), 2.74 (2H, 1), 2.82 2.95 (3H, br), 2.99-3.18 (2H, br), 3.23 (2H, q), 3.94-4.07 (2H, br), 4.40 (lH, t), 4.52 (IH, 1), 5.11 (IH, dd), 5.29 (IH, dd), 6.49 (IH, d), 6.61 (1H, d), 6.94-7 , 07 (2H, br), 7.05-7.14 (1H, br), 7.23-7.33 (2H, br), 7.58 (1H, ddd) (3 exchangeable protons were not observed .) 494 71 Ll I / Z --- 'LL AS / ^xz \ 3-Fluoro - \ '- (2- (4 (methoxymethyl) 3 - ((1H, 3I) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenoxy) ethyl) propan-1-amine Ή NMR (DMSO-d ₆ , 400 MHz, 27 ° C) 1.07 (3H, d), 1.62 - 1.80 (2H, br), 2.55 (2H, 1), 2.64 ( 1H, dd), 2.75 (2H, t), 2.85 (IH, dd), 2.94-3.11 (1H, pt), 3.33 (3H, s), 3.35 3, 51 (2H, br), 3.85 (2H, 1), 4.38 (1H, 1), 4.45 4.56 (2H, br), 4.70 (1H, d), 5.17 ( IH, S), 6.34 (IH, s), 6.88 (IH, dd), 6.94 - 7.09 (2H, br), 7.22 - 7.29 (1H, br), 7 , 36 (1H, d), 7.45 (lH, d), 10.51 (IH, s) (1 exchangeable proton was not observed.) 508 72 Qxy CAQ '4-> Tl -П у --- z \ / T NS 3.3.3-Trifluoro - \ (2- (4-methoxy-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenoxy) ethyl) propan-1-amine Ή NMR (DMSO-d ₆ , 400 MHz, 27 ° C) 1.08 (3H, d), 2.23 - 2.40 (2H, br), 2.53-2.61 (2H, t), 2.62 - 2.69 (2H, t), 2.69 2.81 (3H, t), 2.87-3.03 (1H, t), 3.38 - 3.53 (1H, t) , 3.78 (2H, 1), 3.82 (3H, s), 5.36 (IH, s), 6.15 (IH, d), 6.82 - 6.90 (1H, t), 6.93 - 7.08 (3H, t), 7.22 (IH, d), 7.44 (1H, d), 10.57 (IH, s) (1 exchangeable proton was not observed.) 530

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73 / ^Zi Ή '4-g-l y --- Ζ __ / I p 3-Fluoro-M- (2- (3φτορ-5 - ((1Λ, 3Λ) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) propan-1-amine 'H NMR (500 MHz, CDC1 _3, 27 ° C) 1,16 (ZN, d), 1,84 - 1,87 (2H, br), 2.50 - 2.56 (1H, br), 2 , 73 - 2.85 (3H, br), 2.89 3.04 (3H, br), 3.13 -3.35 (2H, br), 3.98 (2H, t), 4.47 ( IH, t), 4.56 (IH, t), 4.90 (IH, S), 6.52 (1H, ddd), 6.63 - 6.69 (2H, br), 7.11-7 , 16 (1H, br), 7.19 (IH, dd), 7.28 - 7.33 (1H, br), 7.53 (IH, d), 7.86 (IH, d). (1 exchangeable proton was not observed) 482 74 T ¹ h) 3-Fluoro - \ '- (2- (2φτορ-5 - ((1Λ, 3Λ) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) propan-1-amine 'H NMR (500 MHz, CDCl3, 27 ° C) 1.15 (3H, d), 1.86 - 1.89 (2H, br), 2.54 - 2.58 (1H, br), 2, 80 (2H, t), 2.85 (IH, dd), 2.91 -2.97 (1H, br), 2.97 -3.01 (2H, br), 3.183.27 (1H, br) , 3.30 -3.36 (1H, br), 4.07 (2H, t), 4.48 (IH, t), 4.57 (IH, t), 4.90 (IH, S), 6.74 (1H, ddd), 6.97 (IH, dd), 7.04 (IH, dd), 7.13 (IH, ddd), 7.19 (IH, ddd), 7.277.32 (1H , br), 7.53 (1H, d), 7.66 (IH, s). (1 exchangeable proton was not observed.) 482 75 GT y \ i 4/4 ^ FROM Μ- (2- (3 - ((1Λ, 3Λ) 1,3-dimethyl-2 (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl) -3-fluoropropane 1-amine ⁴ H NMR (500 MHz, CDCl3, 27 ° C) 1.15 (3H, d), 1.74 (3H, s), 1.80 1.97 (2H, br), 2.48 - 2.67 (2H, br), 2.80 (2H, t), 2.97 (2H, dd), 3.06 - 3.25 (2H, br), 3.27 - 3.35 (1H, br), 4.01 (2H, t), 4.53 (2H, dt), 6.72 - 6.76 (1H, br), 6.91 (2H, br s), 7.127.18 (2H, m), 7.22 (IH, ddd), 7.39 (IH, dt), 7.49 7.53 (IH, m), 7.98 (IH, s). (1 exchangeable was not observed.) 478

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76 Q ZI -P He Π # - (2- (2,4difluoro-3- ((1L, ZL) -2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) phenoxy) ethyl) -3-fluoropropan1-amine 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 0.43 0.55 (2H, br), 0.92 - 1.04 (2H, br), 1.15 (3H, d), 1, 81 - 1.94 (2H, br), 2.65 (1H, ddd), 2.72 (1H, dd), 2.79 (2H, t), 2.98 (2H, dd), 3.09 (1H, ddd), 3.17 (lH, dd), 3.71 -3.79 (B, br), 4.03 - 4.09 (2H, br), 4.52 (2H, dt), 5.35 (1H, s), 6.77 (1H, td), 6.89 (lH, td), 7.07- 7.14 (2H, br), 7.20-7.23 (1H, br), 7.45 (1H, S), 7.48 - 7.55 (1H, m). (1 exchangeable was not observed.) 490 77 ex -Π # - (2- (2,4 difluoro-3 ((1Λ, 3Λ) -3methyl-2 - ((1 (methylsulfonyl) cyclopropyl) methyl) -2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) -3-fluoropropan1-amine L NMR (500 MHz, CDCI3, 27 ° C) 0.56 0.66 (1H, br), 0.87 - 0.93 (1H, br), 1.11 (3H, d), 1.39 - 1.48 (2H, br), 1.80 - 1.94 (2H, br), 2.67 2.84 (4H, br), 2.98 (2H, S), 3.08 -3.17 (4H, br), 3.18-3.28 (1H, br), 3.81 - 3.90 (1H, br), 4.09 (2H, d), 4.51 (2H, dt), 5.14 (1H, s), 6.82 (1H, t), 6.92 - 6.99 (1H, m), 7.07 7.15 (2H, m), 7.19-7.23 (1H, m), 7.47-7.53 (1H, m), 7.58 (1H, s). (1 exchangeable was not observed.) 550 78 Ll_ I / Ζ --- 'UЧ / t ο "к. XJ # - (2- (4-chloro-2φτορ-3 - ((1Λ, 3Λ) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) -3-fluoropropan1-amine L NMR (500 MHz, DMSO-d ₆ , 27 ° C) 1.12 (3H, d), 1.67 - 1.84 (3H, t), 2.62 (2H, brt), 2.64 2 , 70 (1H, t), 2.80 - 2.87 (2H, t), 2.87 - 2.98 (1H, t), 2.99 - 3.06 (1H, t), 3.49 - 3.60 (2H, t), 4.00 - 4.07 (2H, t), 4.46 (2H, dt), 5.45 (1H, s), 6.93 6.98 (1H, t), 6.99 - 7.03 (1H, t), 7.19 (lH, d), 7.21- 7.30 (2H, t), 7.41 (1H, d), 10.54 (1H, s). 516

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79 Oh qX -L y --- Z __ / I NS NC-CAdimethyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenoxy) ethyl) -3-fluoropropane 1- amine 'H NMR (500 MHz, DMSO, 27 ° C) 1.12 (3H, d), 1.63 - 1.87 (6H, br), 2.36 - 2.45 (3H, br), 2, 59 (1H, t), 2.64 - 2.82 (4H, br), 2.93 (1H, t), 3.02 3.11 (1H, br), 3.32-3.43 (1H , m), 3.55 - 3.65 (1H, m), 3.83 - 4.07 (2H, m), 4.36 - 4.59 (2H, m), 5.24 - 5.40 (1H, m), 6.83 (1H, s), 6.84 - 7.09 (3H, m), 7.16 (lH, t), 7.37 (lH, d), 10.05 - 10.2 (1H, m). (1 exchangeable was not observed.) 492 80 0> \ yX -П / --- Z __ / I T | 3-Fluoro-M- (2- (2fluoro-4-methyl-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole -1yl) phenoxy) ethyl) propan-1-amine ¹ H NMR (600 MHz, DMSO-d ₆ , 27 ° C) 1.13 (3H, d), 1.75 -1.91 (6H, br), 2.70 (3H, dd), 2.83 (lH, qd), 2.91 (2H, brt), 3.05 (1H, qdd), 3.48 (1H, brqd), 3.56 - 3.65 (1H, m), 4.01- 4.13 (2H, m), 4.52 (2H, td), 5.37 (1H, s), 6.84 (1H, brd), 6.95 (1H, ddd), 7.00 (1H , ddd), 7.04 (1H, dd), 7.19 (1H, d), 7.41 (1H, d), 10.43 (1H, s) 496 81 I ^^ NH .о L ^{ГТ \ н} JL ΐ ЛГТ ^ ^ОН гуАА ^f 2,2-Difluoro-3 ((1Λ, 3Λ) -1- (2fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -6methoxyphenyl) 3-methyl-1,3,4,9tetrahydro-2Нpyrido [ 3,4b] indol-2yl) propan-1-ol 'H NMR (300 MHz, DMSO4, 27 ° C) 1.06 (3H, d), 1.59 - 1.82 (3H, m), 2.53 - 2.68 (4H, m), 2, 76 (2H, brt), 2.852.96 (lH, m), 3.00-3.14 (1H, m), 3.22-3.39 (1H, m), 3.51 (1H, sxt) , 3.56 3.74 (1H, m), 3.78 (3H, s), 3.85 - 3.99 (2H, m), 4.44 (2H, dt), 5.17 (1H, t), 5.35 (1H, s), 6.81 (1H, dd), 6.95 (2H, queen doublet), 7.10 (lH, t), 7.15 7.20 (1H, m ), 7.38 (1H, d), 10.40 (1H, s) 524 82 ll T / Z --- 'LL A ^{/ O} X) Μ- (2- (3 - ((1Λ, 3Λ) 2- (2,2difluoroethyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1-yl) -2fluoro-4methoxyphenoxy) 'H NMR (300 MHz, DMSO-i7 ₆ , 27 ° C) 1.09 (3H, d), 1.61 - 1.83 (3H, m), 2.54 - 2.73 (4H, m) , 2.76 (2H, t), 2.84 (1H, dd), 3.04 (1H, qd), 3.34 3.43 (1H, m), 3.81 (3H, s), 3 , 85 - 3.98 (2H, m), 4.43 (2H, dt), 5.33 (1H, 494

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ethyl) -3fluoropropane-1amine s), 5.64-6.10 (1H, br), 6.83 (IH, dd), 6.90-7.03 (2H, br), 7.10 (lH, t), 7.16 -7.22 (1H, br), 7.36 - 7.42 (1H, br), 10.49 (IH, s). 83 Η 1 ΐ 3-Φτορ-Μ- (2- (2φτορ-3 - ((1Λ, 3Λ) 2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indole-1- yl) -4methoxyphenoxy) ethyl) propane-1amine ^X H NMR (300 MHz, DMSO4, 27 ° C) 0.36 0.52 (2H, br), 0.78 - 0.95 (2H, br), 1.05 (3H, d), 1.62 - 1.83 (3H, br), 2.54 -2.71 (4H, br), 2.77 (2H, 1), 2.92 (IH, brddd), 3.06 (IH, dd), 3.54 - 3.67 (1H, br), 3.78 (3H, s), 3.84 4.01 (2H, br), 4.44 (2H, dt), 5.35 (IH, s ), 6.81 (IH, dd), 6.89 - 6.99 (2H, br), 7.09 (lH, t), 7.157.18 (1H, dd), 7.35-7.40 ( IH, m), 10.34 (IH, s) 502 84 0χ (XX Π 3-Fluoro-A- (2- (2φτορ-3 - ((1Λ, 3Λ) 2 - ((3fluorooxetane-3yl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indole-1 -yl) -4methoxyphenoxy) ethyl) propane-1amine ^X H NMR (300 MHz, DMS0-4.27 ° C) 1.07 (ZH, d), 1.60 -1.81 (ZH, br), 2.53 - 2.62 (ZH, br), 2.71 - 2.90 (4H, br), 3.08 - 3.29 (1H, br), 3.37 3.49 (1H, br), 3.78 (3H, S), 3.86 - 3.99 (2H, br), 4.20 (IH, dd), 4.33 - 4.56 (5H, br), 5.36 (IH, s), 6.83 (IH, dd), 6.95 (2H, doublet queen), 7.10 (1H, t), 7.15-7.20 (1H, t), 7.36-7.42 (IH, m), 10.42 (IH , s). 518 85 Km Ά “Π 3 - ((1Λ, 3Λ) -1- (2chloro-6-fluoro-3 (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) 2,2 difluoropropane-1ol Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.16 (3H, d), 1.85 - 1.97 (2H, m), 2.70 (IH, d), 2.74 - 2, 84 (IH, m), 2.86 (2H, t), 2.98 - 3.07 (2H, m), 3.17 (IH, ddd), 3.26 (IH, dt), 3.55 - 3.66 (2H, m), 3.76 - 3.86 (IH, m), 4.09 (2H, tt), 4.47 (IH, t), 4.56 (IH, t), 5.50 (IH, s), 6.85 (IH, dd), 6.91 (lH, t), 7.027.13 (lH, m), 7.14-7.20 (IH, m), 7 , 20-7.27 (IH, m), 7.48-7.52 (IH, m), 7.69 (IH, s). (2 interchangeable were not observed). 528

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86 n 1 1 / y ^ D. ^f F 2,2-Difluoro-3 ((1L, ZL) -6-fluoro1- (2-fluoro-3- (2 ((3fluoropropyl) amino) ethoxy) -6methoxyphenyl) 3-methyl-1,3,4,9tetrahydro -2Нpyrido [3,4b] indol-2yl) propan-1-ol 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.16 (3H, d), 1.80 - 1.92 (2H, br), 2.58 - 2.65 (1H, br), 2 , 78 (2H, t), 2.81-2.92 (1H, br), 2.95 (2H, 1), 3.09 (IH, ddd), 3.18-3.27 (1H, br ), 3.35 - 3.55 (2H, br), 3.61 -3.81 (6H, t), 4.06 (2H, 1), 4.50 (2H, dt), 5.33 ( IH, s), 6.64 (IH, dd), 6.83 (IH, td), 6.97 (IH, t), 7.08 (1H, dd), 7.13 (lH, dd), 7.49 (IH, s). 542 87 y ^ NH AC \ Η 1 A.N £ ^ Xa 3 - ((1DZYA) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2yl) propane nitrile l Ή NMR (DMSO-d ₆ , 300 MHz, 27 ° C) 1.04 (3H, d), 1.88 - 1.95 (5H, t), 2.32 - 2.46 (1H, t), 2.52 - 2.65 (2H, t), 2.65 2.83 (2H, t), 2.83 - 2.92 (2H, t), 3.05- 3.15 (3H, t) , 3.63 (IH, s), 3.97 4.14 (2H, t), 4.41 (1H, t), 4.56 (IH, t), 5.26 (1H, S), 6 , 89 - 7.05 (3H, t), 7.06 - 7.23 (2H, t), 7.42 (IH, d), 10.34 (IH, s). (1 exchangeable proton was not observed.) 467 88 Οχ ν / χχ Φ π “Π i --- 2 __ / X -π A1- (2,4-difluoro3 - ((1H, 3H) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenyl) -N2- (3fluoropropyl) ethane -1,2-diamine 'H NMR (500 MHz, CDCl3, 27 ° C) 1.18 (3H, d), 1.80 - 1.85 (2H, t), 2.62 - 2.65 (1H, t), 2, 72 - 2.77 (2H, t), 2.87 (2H, t), 2.95 - 3.04 (1H, t), 3.08-3.21 (3H, t), 3.22 - 3.27 (1H, t), 3.58 3.67 (1H, t), 4.46 (1H, t), 4.56 (IH, t), 5.35 (1H, s), 6, 61-6.64 (1H, t), 6.73-6.81 (1H, t), 7.07-7.15 (2H, t), 7.23 (2H, d), 7.44 - 7.54 (2H, t). (1 exchangeable proton was not observed.) 499 89 Z ^ NH JMH L Λ X ^H A Ϊ ^ CC4 ^H F 3 - ((1Н, ЗЯ) -1- (2,6 difluoro-3 - ((2 - ((3fluoropropyl) amino) ethyl) amino) phenyl) -6-fluoro-3methyl-1,3,4,9tetrahydro -2Hpyrido [3,4b] indol-2-yl) - ^X H NMR (500 MHz, CDCl3, 27 ° C) 1.16 (3H, d), 1.92 - 2.03 (2H, t), 2.55-2.64 (1H, t), 2, 81 - 2.94 (5H, t), 3.05 (1H, dd), 3.15 -3.38 (4H, t), 3.54-3.64 (1H, t), 3.68 - 3.78 (2H, t), 4.38 4.55 (3H, t), 5.23 (1H, 529

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2.2- difluoropropane-1 - 0L s), 6.60 (IH, td), 6.74 6.85 (2H, br), 7.08-7.16 (2H, br), 7.93 (IH, s). (1 interchangeable not watched.) 90 u_ I / Z ---- 'LL. AT M- (2-fluoro-4methoxy-3 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) fsnyl) - \ '2- (3fluoropropyl) ethane -1,2-diamine ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (3H, d), 1.62 - 1.80 (3H, br), 2.53 - 2.67 (5H, br) , 2.87 - 3.05 (4H, br), 3.36 - 3.52 (2H, br), 3.73 (3H, s), 4.44 (2H, dt), 4.67 4, 73 (1H, br), 5.40 (1H, s), 6.67 (IH, t), 6.76 (1H, d), 6.95 (2H, quint), 7.16-7.20 (IH, br), 7.36-7.40 (1H, t), 10.44 (IH, S). 511 91 Cn V / Tl · ’Tn n / - Z __ / I Π M1- (2-fluoro-4metho xi-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) phenyl) - M2- (3 fluoropropyl) ethane -1,2-diamine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.49 - 1.70 (3H, t), 2.37 (2H, t), 2.42 2.47 (2H, t), 2.54 - 3.02 (5H, t), 3.36 - 3.49 (2H, t), 3.78 (3H, s), 4.39 (2H, dt), 4.69 - 4.75 (1H, t), 5.31 (IH, s), 6.14 (IH, d), 6.91 - 7.05 (3H, t), 7.20 - 7.24 (1H, t), 7.43 (IH, d), 10.44 (1H, S). 511 92 q ^ZI 047 TA -L / --- Z __ / I Π 3-Fluoro-M- (2 - ((3fgor-2 - ((15, 3Y) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole- 1 yl) pyridin-4yl) oxy) ethyl) pr opan-1-amine ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (3H, d), 1.70 - 1.88 (2H, t), 1.88 - 2.05 (1H, t) , 2.53 - 2.72 (4H, t), 2.94 (2H, t), 2.97-3.15 (1H, t), 3.47-3.71 (2H, t), 4 , 19 (2H, quinn), 4.51 (2H, dt), 5.37 (IH, s), 6.93 - 7.00 (1H, t), 7.00 -7.06 (1H, t ), 7.177.26 (2H, t), 7.43 (1H, d), 8.07 (IH, d), 10.58 (IH, s). 483 93 о ^ZI 0Ό T ° t П M- (2 - ((3-chloro-2 ((1 £, 3I) -3-methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl) pyridin-4yl) oxy) ethyl) -3 - ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.11 (3H, d), 1.68 - 1.96 (3H, t), 2.60 - 2.74 (3H, t) , 2.80 - 3.08 (4H, t), 3.33 - 3.39 (1H, t), 3.56 (1H, br dd), 4.29 - 4.64 (4H, t), 5.38 (IH, s), 6.42 (IH, d), 6.96 - 7.02 (1H, t), 7.03-7.10 (1H, t), 517

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fluoropropane-1- amine 7.21-7.26 (1H, br), 7.47 (IH, d), 7.93 (IH, d), 10.61 (IH, s). 94 ll I / Z --- 'u- D / b vHD iz _k Al - (3-fluoro-2 ((1 ^, 3 ^) - 3-methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridin-4yl) -A2- (3fluoropropyl) ethane -1,2-diamine L NMR (300 MHz, DMSO4, 27 ° C) 1.10 (3H, d), 1.68 - 1.94 (3H, br), 2.54 - 2.76 (6H, br), 2.93 - 3.15 (1H, br), 3.21 (2H, q), 3.45 - 3.63 (1H, br), 3.67 - 3.79 (1H, br), 4.51 (2H , dt), 5.29 (1H, s), 6.43 (IH, brtd), 6.66 (IH, dd), 6.92 - 6.98 (1H, br), 6.98 - 7, 05 (1H, br), 7.18-7.24 (1H, br), 7.39 - 7.45 (1H, br), 7.77 (1H, d), 10.57 (IH, S) ... 482 95 ll I / Z --- 'LL ¹ A1- (3fluoropropyl) -A2 (3-methyl-2 ((1 ^, 3 ^) - 3 -methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl ) pyridine-4yl) ethane-1,2diamine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.08 (3H, d), 1.67 - 1.85 (2H, br), 1.93 (3H, s), 2.57 2.76 (5H, br), 2.85 (1H, dd), 2.95 - 3.12 (IH, br), 3.19 (2H, q), 3.35-3.51 (1H, br), 3.59 - 3.69 (1H, br), 4.49 (2H, dt), 5.14 (IH, s), 5.61 (IH, brt), 6.50 (IH, d ), 6.96 (2H, doublet queen), 7.17 - 7.22 (1H, br), 7.38 - 7.43 (1H, br), 7.93 (IH, d), 10.32 (IH, s). (NH dialkyl was not observed.) 478 96 Ck = / X ^{z =} \ T | 2,2-Difluoro-3 ((IX, 3 ^) 4- (4- (2 ((3fluoropropyl) amino) ethoxy) -3methylpyridin-2 yl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3 , 4b] indol-2yl) propan-1-ol L NMR (500 MHz, CDCl ₃ , 27 ° C) 1.18 (3H, d), 1.85 - 1.96 (2H, br), 2.22 (3H, s), 2.68 (1H, d), 2.76 - 2.89 (3H, br), 3.08 (2H, t), 3.11 -3.25 (2H, br), 3.58 (IH, q), 3.75 - 3.85 (2H, br), 4.14 (2H, t), 4.55 (2H, dt), 5.23 (IH, S), 6.74 (1H, d), 7.06- 7.12 (2H, m), 7.19 (IH, dd), 7.45-7.55 (2H, m), 8.29 (IH, d). (2 interchangeable were not observed.) 491

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97 / \ ^{z =} \ V / M h-χ P 2,2-Difluoro-3 ((15.3 ^) - 1- (3fluoro-4- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-2-yl) -3methyl-1,3,4, 9tetrahydro-2Hpyrido [3,4b] indol-2yl) propan-1-ol 'H NMR (300 MHz, DMSO4, 27 ° C) 1.07 (3H, d), 1.70 - 1.96 (2H, br), 2.52 - 2.72 (3H, br), 2, 75 (2H, t), 3.02 (2H, br 1), 3.08 - 3.23 (1H, br), 3.51-3.80 (3H, br), 4.22 (2H, brt ), 4.51 (2H, dt), 5.33 (IH, t), 5.38 (IH, s), 6.91-6.98 (lH, m), 6.98 -7, O4 ( 1H, m), 7.157.23 (2H, m), 7.41 (IH, d), 8.07 (IH, d), 10.55 (IH, s). (NH amine was not observed.) 495 98 ll z / Z --- 'll oz at M- (2 - ((2 - ((1X, ZL) 2- (2,2 difluoroethyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1-yl) -3fluoropyridin-4yl) hydroxy) ethyl) -3 fluoropropane-1amine Ή NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.09 (3H, d), 1.70 - 1.94 (3H, br), 2.53 - 2.78 (5H, br), 2.94 (2H, t), 3.06 - 3.25 (1H, br), 3.41-3.59 (1H, br), 4.19 (2H, t), 4.51 (2H, dt), 5.37 (IH, s), 6.05 (IH, tt), 6.92 - 6.99 (1H, br), 6.99 - 7.07 (1H, br), 7.17 -7.25 (2H, br), 7.42 (IH, d), 8.07 (1H, d), 10.55 (B, S). 465 99 (ΆμΗ a; \ _f ^н X ^F I ^F Afi V θΑΧχ ^v 3-Fluoro-Y- (2 - ((3fgor-2 - ((15, 3Y) 2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indole-1 yl) pyridin-4yl) oxy) ethyl) pr opan-1-amine 'H NMR (300 MHz, DMSO4, 27 ° C) 0.55 0.78 (2H, t), 0.83 -1.05 (2H, t), 1.08 (3H, d), 1.70 - 1.89 (2H, t), 1.90 - 2.07 (1H, t), 2.52 2.75 (5H, t), 2.94 (2H, t), 3.08-3, 22 (1H, t), 3.58 -3.70 (1H, t), 4.19 (2H, t), 4.51 (2H, dt), 5.49 (IH, S), 6.90 - 7.04 (2H, t), 7.16-7.22 (2H, t), 7.41 (B, d), 8.07 (IH, d), 10.50 (IH, s). 473 100 ρ'ΆΐΗ AA L Of 1 N jL ^F I ^F ^ XXq, 3-Fluoro-Y- (2 - ((3fluoro-2 - ((1 ^, 3 ^) 2 - ((3fluorooxetane-3yl) methyl) -3methyl-2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl) pyridin-4yl) oxy) ethyl) pr opan-1-amine ^: H NMR (300 MHz, DMSO4, 27 ° C) 1.13 (3H, d), 1.71 - 1.94 (3H, t), 2.53 - 2.72 (4H, t), 2, 83 (IH, dd), 2.93 (2H, t), 3.20 - 3.37 (1H, t), 3.44 -3.59 (1H, t), 4.18 (2H, t) , 4.41 -4.70 (6H, t), 5.43 (Sh, s), 6.92 6.99 (1H, t), 6.99 - 7.05 (1H, t), 7, 16-7.23 (2H, t), 7.39-7.45 (1H, t), 8.05 (IH, d), 10.54 (1H, 489

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S). 101 IL I / Z --- <LL 44 Z = / \ - / ^IZ A 3-Fluoro-M- (2 - ((5 ((1H, 3Y) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1 yl) pyridine -3yl) oxy) ethyl) pr opan-1-amine 'H NMR (500 MHz, CDC1 _3, 27 ° C) 1,17 (ZN, d), 1,79 - 1,97 (2H, br), 2.54 (III, dd), 2,75 - 2 , 88 (ZN, br), 2.95 - 3.03 (ZN, br), 3.20 - 3.36 (2H, br), 4.00-4.11 (2H, br), 4.48 (1H, 1), 4.57 (1H, 1), 4.99 (IH, S), 7.12-7.17 (2H, br), 7.20 (IH, ddd), 7.30 7 , 34 (B, br), 7.54 (1H, d), 7.92 (IH, S), 8.14 (IH, d), 8.22 (IH, d). (1 exchangeable proton was not observed.) 465 102 [A ^ nh 4 ° \ H 1 ί _F DDA ^F 3-Fluoro-M- (2 - ((4 ((lR, 3R) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) pyridin-2yl) oxy) ethyl) pr opan-1-amine ^X H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.18 (3H, d), 1.81-1.94 (2H, m), 2.54 (W, dd), 2.71-2 , 82 (3H, m), 2.91 -3.02 (3H, br), 3.16-3.23 (IH, br), 3.24 - 3.30 (1H, t), 4.33 - 4.42 (2H, t), 4.47 (1H, 1), 4.56 (1H, 1), 4.93 (1H, s), 6.48-6.62 (1H, t), 7.00 (B, dd), 7.15 (1H, ddd), 7.20 - 7.25 (1H, t), 7.32 - 7.36 (1H, t), 7.54 (IH, d), 7.81 (IH, s), 8.09 (B, dd). (1 exchangeable proton was not observed.) 465 103 Q. ^ZI I / -n 2,2-Difluoro-3 ((1R, 3R) -1- (2- (2 ((3fluoropropyl) amino) ethoxy) -3methylpyridin-4 yl) -3 -methyl- 1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2yl) propan-1-ol ^X H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.17 (3H, d), 1.85 - 1.97 (2H, t), 2.30 (3H, s), 2.67 (1H , dd), 2.75 - 2.88 (3H, t), 2.98 - 3.08 (3H, t), 3.12 - 3.24 (1H, t), 3.57 3.66 ( Sh, t), 3.72 (2H, 1), 4.44 (2H, td), 4.55 (2H, dt), 5.08 (IH, s), 6.49 (IH, d), 7.11 -7.19 (2H, t), 7.21 -7.25 (1H, t), 7.54 (IH, d), 7.66 (IH, S), 7.82 (IH, d). (2 interchangeable were not observed.) 491

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104 Oh COQ P 3 - ((1L, ZL) -1- (3chloro-2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3, 4b] indol-2-yl) 2,2 difluoropropan-1 ol 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.00 (3H, d), 1.64 - 1.82 (3H, br), 2.48 - 2.67 (4H, br) , 2.78 - 2.90 (3H, br), 3.03-3.17 (1H, br), 3.283.37 (1H, t), 3.38-3.71 (2H, t), 4 , 31 (2H, td), 4.44 (2H, dt), 5.14-5.24 (1H, t), 5.27 (IH, s), 6.39 (Sh, d), 6, 88 - 6.94 (1H, t), 6.94- 7.01 (1H, t), 7.14 (lH, d), 7.39 (IH, d), 7.84 (IH, d) , 10.47 (IH, s). 511 105 0> \ Ohm * g T | 3-Fluoro-M- (2 - ((5mstil-6 - ((15.3 /?) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indole- 1yl) pyridin-2yl) oxy) ethyl) pr opan-1-amine 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.19 (3H, d), 1.79-1.91 (2H, t), 2.13 (3H, s), 2.64 (1H , ddd), 2.75 (2H, t), 2.86 2.91 (2H, t), 2.95-3.05 (1H, t), 3.10 (IH, ddd), 3.15 -3.25 (1H, t), 3.54 -3.66 (1H, t), 4.174.24 (1H, t), 4.26 - 4.32 (1H, t), 4.51 (2H , dt), 5.13 (B, s), 6.63 (1H, d), 7.07-7.15 (2H, t), 7.24 (IH, dt), 7.36 (1H, d), 7.49-7.53 (1H, t), 7.87 (IH, s). (1 exchangeable was not observed.) 479 106 Oy OOO 'U uv __ / I t 3-Fluoro-M- (2 - ((3methyl-4 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyridin-2yl) oxy) ethyl) pr opan-1-amine Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.14 (3H, d), 1.82 - 1.96 (2H, t), 2.28 (3H, s), 2.55 - 2, 67 (1H, t), 2.84 (2H, t), 2.93 (2H, ddt), 2.99 3.05 (2H, t), 3.13 -3.28 (1H, t), 3.37 - 3.43 (2H, t), 4.34 - 4.45 (2H, t), 4.47 (W, t), 4.57 (IH, t), 5.08 (W, s), 6.38 (1H, d), 7.11 (lH, td), 7.15 (lH, td), 7.21 -7.29 (1H, t), 7.53 (IH, d ), 7.70 (IH, d), 8.44 (IH, s). 479

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107 LL. I / Z --- ^f uAt ChChe A) # - (2 - ((3,5 difluoro-4 ((17?, 3R) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4- B] indol-1yl) pyridin-2yl) oxy) ethyl) -3fluoropropane-1amine 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.20 (3H, d), 1.87 (2H, dddd), 2.65 (1H, ddd), 2.80 (2H, 1), 2.95 (1H, dt), 2.99 - 3.09 (3H, br), 3.31 (1H, dq), 3.55 (1H, h), 4.43 (2H, ddd), 4 , 47 (1H, t), 4.56 (lH, t), 5.37 (1H, s), 7.12 (lH, ddd), 7.14-7.19 (1H, m), 7, 24-7.28 (1H, m), 7.50-7.55 (1H, m), 7.67 (1H, s), 7.77 (1H, s). (1 exchangeable was not observed). 501 108 I ^^ NH ЛХ X ^н X Ϊ ΧΥι V / ukA ^ν # - (2 - ((3,5 difluoro-4 ((1Λ, 3Λ) -2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1 yl) pyridine-2yl) oxy) ethyl) -3 fluoropropane-1amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.45 0.59 (2H, br), 0.79 - 0.96 (2H, br), 1.01 (3H, d), 1.60 - 1.78 (3H, br), 2.45 - 2.69 (4H, br), 2.75 2.85 (3H, br), 3.03 (1H, dd), 3.42 - 3.53 (1H, br), 4.26 (2H, t), 4.40 (2H, dt), 5.26 (1H, s), 6.85 6.92 (1H, br), 6 , 92 - 6.99 (1H, br), 7.11 -7.16 (1H, br), 7.36 (1H, d), 7.88 (1H, s), 10.56 (1H, s ). 491 109 / ^ΖΙ λ AA 7 γ τι # - (2 - ((3,5 difluoro-4 ((1Λ, 3Λ) -6-φτορ2 - ((1fluorocyclopropyl) methyl) -3methyl-2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) pyridin-2yl) oxy) ethyl) -3fluoropropane-1amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.44 0.60 (2H, br), 0.78 - 0.95 (2H, br), 1.00 (3H, d), 1.69 (3H, dsxt), 2.45 2.69 (4H, br), 2.73 - 2.84 (3H, br), 3.02 (1H, dd), 3.39 - 3.53 (1H, t), 4.26 (2H, t), 4.40 (2H, dt), 5.26 (1H, s), 6.78 (1H, td), 7.08-7.16 ( 2H, t), 7.89 (1H, s), 10.68 (1H, s). 509 BUT cx =, I / -Π 2,2-Difluoro-3 ((1Λ, 3Λ) -1- (5fluoro-2 - (2 - ((3fluoropropyl) amino) ethoxy) -3methylpyridin-4 yl) -3 -methyl- 1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2yl) propan-1-ol Ή NMR (500 MHz, CDCI3, 27 ° C) 1.17 (3H, d), 1.84 (2H, dddd), 1.93 (3H, s), 2.66 - 2.76 (2H, t ), 2.77 (2H, t), 2.96 (2H, qdd), 3.11 -3.24 (2H, t), 3.51 -3.69 (2H, t), 3.72 - 3.82 (1H, t), 4.32 (1H, ddd), 4.38 4.48 (2H, t), 4.54 (1H, t), 5.33 (1H, S), 7, 07 7.16 (2H, t), 7.18-7.24 509

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(1H, br), 7.43 (IH, s), 7.48 - 7.54 (IH, br), 7.88 (IH, s). (2 interchangeable were not observed). 111 I ^^ NH, N. L ΓΥ 1 H 1 I / LAA ^f 3 - ((1Н, ЗЯ) -1- (3chloro-5-fluoro-2 (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3methyl-1,3,4,9tetrahydro-2Нpyrido [3,4b] indol-2-yl) 2,2 difluoropropane-1ol 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.14 (3H, d), 1.78 - 1.95 (2H, t), 2.54 (IH, d), 2.66 - 2 , 73 (1H, t), 2.72 - 2.79 (1H, t), 2.81 (2H, t), 2.92 (IH, s), 3.01 (2H, t), 3, 16 (IH, ddd), 3.25 (IH, dt), 3.61-3.70 (1H, t), 3.71-3.80 (1H, t), 4.34 4.50 (3H , t), 4.55 (1H, t), 5.49 (IH, s), 7.10 (2H, tdd), 7.18 (lH, dd), 7.51 (IH, dd), 7 , 76-7.83 (IH, m), 7.95 (IH, s). (1 exchangeable was not observed.) 529 112 Qw XX __ / I NS 3-Fluoro-M (2 - ((6metho xi-5 ((1Λ, 3Λ) -3methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) pyridazin-3 yl) oxy) ethyl) pr opan-1-amine 'H NMR (500 MHz, CDCl3, 27 ° C) 1.23 (3H, d), 1.76 - 1.92 (2H, t), 2.56 (IH, dd), 2.67 - 2, 84 (3H, t), 2.95 (3N, pt), 3.15-3.40 (2H, t), 4.20 (3N, s), 4.31-4.49 (3N, t) , 4.52 (lH, t), 5.18 (IH, s), 6.49 (IH, s), 7.13 (lH, td), 7.19 (lH, td), 7.30 - 7.35 (1H, t), 7.52 (IH, d), 8.59 (IH, s). (1 exchangeable was not observed). 496 113 Y ^ nh (Y ³ \ hi A ^F YrX θ-ΥΑ ^f 3-Fluoro-M (2 - ((6 ((1 £, 3I) -3-methyl2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyrimidine) 4yl) oxy) ethyl) pr opan-1-amine ^X H NMR (400 MHz, DMSO-d ₆ , 27 ° C) 1.24 (3H, d), 1.68 - 1.86 (2H, t), 1.95 (IH, S), 2.52 2.67 (4H, t), 2.87 (2H, t), 3.02 - 3.27 (2H, t), 3.59 - 3.75 (1H, t), 4.30 - 4, 47 (3H, t), 4.54 (1H, t), 5.02 (IH, s), 6.88 (1H, s), 6.92-7.01 (1H, t), 7.02 -7.11 (1H, t), 7.35 (IH, d), 7.42 (IH, d), 8.76 (IH, d), 10.77 (1H, S). 466

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114 | A \ nH CC λ Η I Ϊ _F ^F Ν Λ / ψ guKL ^f 3-Φτορ - # - (2 - ((5methyl-b-DDZL) 3-methyl-2- (2,2,2trifluoroethyl) 2,3,4,9tetrahydro-1Hpyrido [3,4b] indol-1yl) pyrimidine- 4yl) oxy) ethyl) pr opan-1-amine ¹ H NMR (400 MHz, DMSO-d ₆ , 27 ° C) 1.11 (3H, d), 1.69 - 1.87 (2H, br), 1.92-2.15 (4H, br) , 2.59-2.71 (3H, t), 2.75 - 2.85 (1H, br), 2.90 (2H, 1), 3.00 -3.16 (1H, br), 3 , 47 - 3.69 (2H, br), 4.33 - 4.48 (3H, br), 4.56 (1H, 1), 5.21 (IH, s), 6.92 7.07 ( 2H, br), 7.18-7.26 (1H, br), 7.40 - 7.47 (1H, br), 8.51 (B, s), 10.50 (IH, s) 480 115 [A \ _NH rV \ H 1 1 ^F ___H nAA ^f 2,2-Difluoro-3 ((15.3 ^) - 1- (6- (2 ((3fluoropropyl) amino) ethoxy) -5methylpyrimidin-4-yl) -3-methyl l1,3,4,9tetrahydro- 2Hpyrido [3,4b] indol-2yl) propan-1-ol ^X H NMR (400 MHz, DMSO-d ₆ , 27 ° C) 1.10 (3H, d), 1.69 - 1.87 (2H, br), 2.09 (3H, s), 2.55 2.86 (5H, br), 2.90 (2H, 1), 3.10 -3.23 (1H, br), 3.46-3.71 (3H, br), 4.37 (2H, 1), 4.44 (1H, 1), 4.55 (lH, t), 5.12 (IH, s), 5.37 (1H, 1), 6.92 - 7.06 (2H, br ), 7.21 (B, d), 7.43 (lH, d), 8.51 (IH, s), 10.46 (IH, s). (1 exchangeable proton was not observed.) 492 116 CV_ Ohm M о / - ^f z / T | 3 - ((15.35) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indole- 2yl) propanoic acid 1H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.02 (3 H, d), 1.66 - 1.89 (5H, br), 1.96 - 2.17 (1H, br) , 2.18-2.32 (1H, br), 2.53-2.70 (4H, br), 2.71 2.93 (3H, br), 2.94 - 3.05 (1H, br ), 3.55 - 3.66 (1H, br), 3.86 - 4.06 (2H, br), 4.38 (IH, t), 4.54 (1H, 1), 5.22 ( IH, S), 6.87-7.11 (4H, br), 7.13 -7.25 (1H, br), 7.34-7.44 (1H, br), 10.26 (IH, s). (2 exchangeable protons were not observed.) 486 118 cv Oyj Poison z / T 2,2-Difluoro-3 ((15.35) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3 ,4- ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.04 (3H, d), 1.78 (3H, s), 1.90 - 2.10 (2H, br), 2.63 (IH, brd), 2.77-3.05 (6H, br), 3.65 -3.76 (1H, br), 4.24 - 4.36 (1H, br), 4.37 - 4 , 58 (3H, br), 5.22 (IH, s), 6.89 - 7.04 (4H, 522

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B] indole-2yl) propanoic acid br), 7.15-7.21 (1H, br), 7.35 - 7.43 (1H, br), 10.32 (IH, s). (Three peaks corresponding to a hydrogen atom were not observed, at least one multiplet was overlapped by a water peak.) 119 ζΐ -η A / T / NS 3 - ((1Λ, 3Λ) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indole- 2-yl) 2,2 dimethylpropanoic acid 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 0.87 (3H, S), 1.19 (3H, d), 1.23 (3H, s), 1.82 - 2.03 (3H , br), 2.67 - 2.81 (5H, br), 2.85 (2H, 1), 2.98 (IH, d), 3.13 (IH, s), 3.25 (1H, d), 3.61 (IH, s), 4.12 (IH, ddd), 4.28 (IH, s), 4.45 (1H, 1), 4.55 (1H, 1), 5, 38 (IH, s), 6.82 (1H, dd), 6.95 (1H, 1), 7.07 7.15 (2H, br), 7.16-7.21 (1H, br), 7.30 (IH, s), 7.48-7.53 (1H, br). (2 interchangeable not observed) 514 120 xx / ^ZI AND SC) Ή Ζ / P 1 - (((1H, 3Y) -1- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indole -2yl) methyl) cyclobutan-1carboxylic acid 1H NMR (500 MHz, CDC13) 1.25 (d, 3H), 1.70 (br, 2H), 1.76 (s, 3H), 1.86 (br, 2H), 1.932.05 (br, 2H), 2.10-2.30 (br, 2H), 2.57 (br, 1H), 2.72 (d, 1H), 2.76 (d, 1H), 3.01 (br, 1H ), 3.06 (d, 1H), 3.16 (br, 2H), 3.21 (br, 1H), 3.63 (br, 1H), 4.15 (dt, 2H), 4.49 (dt, 2H), 5.36 (s, 1H), 6.79 (dd, 1H), 6.93 (br, 1H), 7.11 (br, 2H), 7.19 (d, 1H) , 7.49 (d, 1H), 7.63 (s, 1H), 8.26 (s, 1H). (1 exchangeable was not observed). 526 122 and. / I / - '9' - ° / \ * - ^-W ”X) (5) -3 - ((1Λ, 3Λ) -3ethyl-1- (6-fluoro3- (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) 1,3,4,9tetrahydro-2Hpyrido [3,4b ] indol-2-yl) -2methylpropanoic acid ⁴ H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.77 (3H, d), 0.90 (3H, t), 1.19 - 1.34 (IH, m), 1.65 1.93 (6H, m), 2.14-2.31 (2H, m), 2.69-3.09 (8H, m), 3.16 (IH, brd), 3.95-4, 09 (2H, m), 4.47 (2H, dt), 5.27 (IH, s), 6.90 7.08 (4H, m), 7.14-7.19 (IH, m), 7.38 - 7.43 (IH, m), 8.45 (IH, br s), 10.29 514

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(1H, s). 123 sx A Π (Λ) -3 - ((1Λ, 3Λ) -1 (3- (2 - ((3,3 difluoropropyl) a mino) ethoxy) -6fluoro-2methylphenyl) -3methyl-1,3,4,9tetrahydro-2Hpyrido [3 ,4- B] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.06 (3H, d), 1.20 (3H, d), 1.80 (3H, s), 2.06 (2H, ddt), 2.49 - 2.63 (1H, br), 2.62 - 2.74 (1H, br), 2.77 2.86 (2H, br), 2.89 (2H, t), 3.03 (2H, t), 3.173.29 (1H, m), 3.84 (1H, p), 4.06 (2H, s), 5.35 (1H, s), 5.88 (1H, t) , 6.79 (1H, dd), 6.90 (1H, d), 7.05- 7.14 (2H, m), 7.18 (1H, tt), 7.50 (1H, dd), 7.62 (1H, s). (2 interchangeable were not observed). 518 125 I ^^ NH jOO \ ⁿ 1 z II, ΑΎι AX ' ^0H bow ¹ (5) -3 - ((1Λ, 3Λ) -1 (2 (difluoromethyl) 6-fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro- 2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 1H NMR (500 MHz, CDCI3, 27 ° C) 0.94 (3H, d), 1.18 (3H, d), 1.92 (2H, ddt), 2.79 (2H, dd), 2, 86 (3H, t), 3.00-3.12 (3H, m), 3.31 (1H, d), 3.62 (1H, q), 4.14 (2H, ddt), 4.50 (1H, t), 4.60 (1H, t), 5.53 (1H, s), 6.95 (lH, dd), 7.05-7.25 (4H, m), 7.20 ( 1H, dd), 7.41 (lH, t), 7.51 (1H, s). (2 interchangeable were not observed). 536 128 I ^^ NH XX \ CI ^ X ^^ CI 0 ^ F and 1 II A Am aA ° ^h lAL ¹ (5) -3 - ((1Λ, 3Λ) -1 (2,6-dichloro-3- (2 ((3fluoropropyl) amino) ethoxy) phenyl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3 , 4b] indol-2-yl) -2methylpropanoic acid Ή NMR (300 MHz, MeOH-d ₄ , 27 ° C) 0.82 0.94 (ЗН, br), 1.12 - 1.24 (ЗН, br), 1.83 - 2.34 (ЗН, br), 2.40 - 2.64 (1H, br), 2.73 (1H, brd), 2.91 3.10 (3H, m), 3.11 -3.28 (3H, br), 3.65 - 3.79 (1H, br), 4.11-4.31 (2H, br), 4.39 (1H, dt), 4.56 (1H, dt), 5.82 (0, 5H, s), 5.89 (0.5H, S), 6.92 - 7.02 (2H, t), 7.06- 7.19 (2H, t), 7.20 - 7.26 ( 0.5H, t), 7.37 - 7.42 (1H, t), 7.47 (0.5H, d). (One peak corresponding to a hydrogen atom was not observed.) 536

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129 ¥ o ¥ ° ^h F Isomer 1 isolated as trimic acid salt 3 - ((1DZYA) -1- (2,6dichloro-3 - (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b ] indol-2-yl) -2methylpropanoic acid ¹ H NMR (600 MHz, MeOH-d ₄ , 27 ° C) 0.99 1.09 (3H, br), 1.17 - 1.28 (3H, br), 1.94 - 2.16 (2H , br), 2.34 - 2.59 (1H, br), 2.60 - 2.63 (0.4H, br), 2.66-2.81 (1.6H, br), 2.82 - 3.28 (5H, br), 3.32 - 3.47 (1H, br), 3.85 3.95 (1H, br), 4.24 - 4.63 (4H, t), 5, 80 - 5.85 (0.6H, t), 5.94 - 5.99 (0.4H, t), 6.73 - 6.79 (1H, t), 7.06 (IH, brd), 7.10-7.21 (2H, t), 7.23 - 7.28 (0.4H, t), 7.46 7.52 (0.6H, t), 8.53 (3H, br s ). (Three peaks corresponding to the hydrogen atom and signals corresponding to the OH formic acid were not observed.) 554 130 Γχ ° S h ^ i ¥ ^ci 8 ^{F OH} F Isomer 2 isolated as a salt of trimic acid 3 - ((1Λ, 3Λ) -1- (2,6dichloro-3 - (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -6-fluoro-3methyl-1,3,4,9tetrahydro-2Нpyrido [3 , 4b] indol-2-yl) -2methylpropanoic acid ¹ H NMR (600 MHz, MeOH-d ₄ , 27 ° C) 0.81 0.94 (ZH, br), 1.12-1.19 (ZH, br), 1.90 - 2.34 (ZH , br), 2.37 - 2.46 (0.4H, br), 2.47 - 2.57 (0.6H, br), 2.65 - 2.72 (1H, br), 3.03 (lH, td), 3.08 -3.17 (2H, br), 3.22 - 3.28 (1H, br), 3.32 - 3.39 (2H, br), 3.40 - 3 , 51 (1H, br), 3.653.76 (1H, br), 4.22 - 4.32 (1H, t), 4.37 (IH, br s), 4.40 - 4.46 (0, 6H, br), 4.47 - 4.52 (0.6H, br), 4.53 - 4.56 (0.4H, br), 4.61 - 4.64 (0.4H, t), 5.80 (0.6H, br s), 5.86 (0.4H, s), 6.74 (IH, brt), 7.02-7.06 (2H, br), 7.08 -7 , 19 (2H, t), 7.227.25 (0.4H, br), 7.43 7.52 (0.6H, br), 8.52 (2H, br s). (Three peaks corresponding to the hydrogen atom and signals corresponding to the OH formic acid were not observed.) 554

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131 Cx I: I Ζ / NS 3 - ((1L, ZL) -1- (2chlor-6-fluoro-3 (2 - ((3fluoropropyl) amino) ethoxy) phenyl ) -3-methyl1,3,4,9- tetrahydro-2Hpyrido [3.4b] indol-2-yl) 2,2dimethylpropanoic acid 'H NMR (500 MHz, DMSO, 27 ° C) 0.83 (3H, S), 0.88 (3H, s), 1.06 (3H, d), 1.85 (2H, d), 2 , 24 (IH, d), 2.75 (2H, S), 2.87 -3.07 (5H, br), 3.12 (2H, d), 4.06 - 4.23 (3H, br ), 4.49 - 4.55 (1H, br), 4.56 - 4.63 (1H, br), 5.40 (IH, S), 6.95 - 7.05 (2H, br), 7.12 (IH, s), 7.197.24 (2H, br), 7.44 (1H, d), 10.43 (IH, s). 534 132 Ι ^^ ΝΗ L iX L О V n 1 and __ _n # LAA ¹ (X) -3 - ((1H, ZYa) -1 (2- (2 - ((3fluoropropyl) amino) ethoxy) -3methylpyridin-4 yl) -3 -methyl1, 3,4,9tetrahydro-2Hpyrido [3, 4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCl ₃ , 27 ° C) 1.04 (3H, d), 1.16 (3H, d), 1.92 (2H, ddt), 2.24 (3H, s), 2.44 - 2.63 (2H, br), 2.67 (IH, dd), 2.85 - 2.92 (3H, br), 3.00 (IH, d), 3.05 (2H, s), 3.52 (IH, q), 4.38 - 4.47 (3H, br), 4.55 (IH, t), 5.15 (IH, s), 6.49 (IH, S ), 7.09- 7.18 (2H, br), 7.24 (IH, d), 7.53 (IH, d), 7.72 (IH, d), 8.40 (IH, s) ... (2 interchangeable not observed) 483 133 / I with X '- ° ° \ / (X) -3 - ((1H, ZYa) -1 (3-chloro-5 -fluoro2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3methyl-1,3,4 , 9tetrahydro-2Hpyrido [3,4- B] indol-2-yl) -2methylpropanoic acid NMR (500 MHz, CDCl3, 27 ° C) 1.03 (3H, d), 1.23 (3H, d), 1.83 1.98 (2H, br), 2.40 (1H, s) , 2.66 - 2.76 (2H, br), 2.87 (2H, 1), 2.89 - 2.96 (1H, br), 3.02- 3.16 (3H, br), 3 , 56 - 3.66 (2H, br), 4.43.4.54 (3H, u), 4.58 (IH, t), 5.58 (IH, s), 7.13 (lH, dd), 7.16 (lH, td), 7.24 (IH, d), 7.53 (IH, d), 7.82 (IH, s), 7.85 (IH, s). (1 exchangeable was not observed.) 521 134 / m with X '—o / \ / OXZ? (S) -3 - ((R) -I- (6fluoro-3 - (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) 3,3-dimethyl1,3,4,9tetrahydro-2Hpyrido [3,4 - B] indol-2-yl) -2methylpropane NMR (500 MHz, CDCl3, 27 ° C) 0.87 (3H, d), 1.19-1.28 (4H, m), 1.31-1.41 (IH, m), 1.50 (3H, s), 1.77 (3H, s), 1.79 - 1.90 (2H, m), 2.78 (3H, q), 2.85 (IH, d), 2.87 2 , 97 (IH, m), 3.01 (IH, ddd), 3.05 - 3.14 (2H, m), 3.95 - 4.05 (2H, m), 4.49 (2H, dt ), 5.56 (IH, s), 514

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i am acid 6.85 (IH, dd), 7.00 (1H, 1), 7.10 - 7.18 (2H, br), 7.23 (IH, dd), 7.33 (1H, S), 7 , 47 - 7.52 (1H, br). (1 exchangeable was not observed.) 135 u_ / - 'about A ^w IZ, X. (5) -3 - ((1L, ZL) -1- (6-fluoro-3 - ((2 - ((3fluoropropyl) amino) ethyl) amino) 2-methylphenyl) 3-methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2 methylpropanoic acid 'H NMR (300 MHz, MeOH-d ₄ 27 ° C) 0.91 (3H, d), 1D8 (3H, brd), 1.69 - 2.02 (3H, br), 2.04 - 2, 25 (2H, br), 2.83 3.14 (3H, t), 3.16-3.25 (2H, t), 3.26-3.39 (4H, t, obsc), 3.53 (2H, 1), 3.80 - 4.06 (1H, t), 4.56 (2H, dt), 5.82 (IH, br s), 6.85 (IH, dd), 6.97 -7.12 (3H, m), 7.44 (IH, d), 7.46 (lH, d). Four peaks corresponding to a hydrogen atom were not observed. 499 136 O- zi -П '/ X O /----' z / T (5) -3 - ((1Λ, 3Λ) -1 (6-fluoro-3 - ((2 - ((3fluoropropyl) amino) ethyl) (methyl) a mino) -2methylphenyl) -3methyl-1,3, 4.9 tetrahydro-2Hpyrido [3.4b] indol-2-yl) -2methylpropanoic acid 'H NMR (300 MHz, MeOH-d ₄ , 27 ° C) 0.81 (3H, d), 1.15 (3H, d), 1.83-2.01 (3H, m), 2.05 (3H, s), 2.45 (IH, brdd), 2.55 (3H, s), 2.62 - 2.74 (IH, m), 2.87 - 3.26 (8H, m), 3.74 (IH, br qdd), 4.44 (2H, dt), 5.45 (IH, s), 6.92 - 7.06 (3H, m), 7.13-7.28 (2H , m), 7.37-7.45 (IH, m). (Three peaks corresponding to the hydrogen atom were not observed.) 513 137 γΥ X F 0.5 equivalents of formic acid salt (5) -3 - ((LR, 35) -3 (difluoromethyl) 1- (6-fluoro-3- (2 ((3fluoropropyl) amino) ethoxy) -2methylphenyl) 1,3,4,9tetrahydro-2Hpyrido [ 3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.72 (3H, d), 1.63 - 1.93 (5H, br), 2.00- 2.14 (1H, br) , 2.41-2.46 (1H, br), 2.63 (2H, t), 2.80 - 2.97 (5H, br), 3.60 - 3.72 (2H, br), 3 , 86 - 4.05 (3H, br), 4.44 (2H, dt), 5.64 (IH, s), 6.24 (IH, td), 6.90 - 7.02 (4H, br ), 7.14-7.20 (1H, br), 7.38-7.44 (1H, br), 8.18 (0.5H, s), 10.41 (1H, s). (OH formic acid was not observed.) 536

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138 % - > kn χχ m (5) -3 - ((1Λ, 35) -1 (2-chloro-6-fluoro3- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 (difluoromethyl) 1,3,4,9tetrahydro- 2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.80 (3H, d), 1.76 - 1.93 (2H, br), 2.33 - 2.48 (2H, br) , 2.80 (2H, brt), 2.902.96 (2H, br), 2.98 - 3.06 (2H, br), 3.56 - 3.72 (1H, br), 4.09-4 , 18 (2H, br), 4.51 (2H, dt), 5.75 (1H, s), 6.20 (IH, brtd), 6.907.25 (6H, br), 7.41-7, 46 (IH, br), 10.57 (IH, s). (Two peaks corresponding to the hydrogen atom were not observed.) 556 139 η A π (5) -3 - ((1 ^, 35) -1 (3-chloro-5 -fluoro- 2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3 (difluoromethyl) - 1,3,4,9- tetrahydro-2Hpyrido [3.4b] indol-2-yl) -2methylpropanoic acid ^X H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.83 (3H, d), 1.66 - 1.88 (2H, n), 2.35 - 2.48 (3H, br) , 2.68 (2H, t), 2.85 - 3.00 (4H, n), 3.58 - 3.71 (1H, n), 4.36 (2H, t), 4.50 (2H , dt), 5.74 (Sh, s), 6.24 (IH, td), 6.93 - 7.07 (2H, m), 7.17-7.21 (1H, u), 7, 46 (IH, d), 8.07 (IH, s), 10.68 (B, s). (Two peaks corresponding to the hydrogen atom were not observed.) 557 140 Ck / ^ΖΙ Ή v / yk ή ί) = Ο> —ζ / / ¹ ο / - τι (5) -3 - ((1 ^, 35) -1 (6-fluoro-3- (2 - ((3fluoropropyl) amino) ethoxy) -2methylphenyl) -3 (trifluoromethyl) 1,3,4,9tetrahydro- 2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid ^: H NMR (500 MHz, CDCl ₃ , 27 ° C) 0.67 (3H, d), 1.86 (3H, s), 1.89 2.02 (2H, n), 2.74 (1H, dd), 2.93 (2H, t), 3.12 (4H, dd), 3.27 - 3.40 (IH, m), 3.96-4.12 (2H, m), 4.12 -4.25 (2H, m), 4.39 (IH, t), 4.48 (IH, t), 5.74 (IH, s), 6.73 (IH, dd), 6.88 ( lH, t), 7.02-7.11 (2H, m), 7.12-7.20 (IH, m), 7.40 (IH, s), 7.45 (2H, dd). (1 exchangeable was not observed). 554

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141 O \ Dord ⁴ F (S) -3 - ((lR, 35) -1 (2-chloro-6-fluoro3- (2 - ((3fluoropropyl) amino) ethoxy) phenyl) -3 (trifluoromethyl) 1,3,4,9tetrahydro- 2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDC1 _3, 27 ° C) 0,80 0,93 (6H, br), 1.88 - 2.02 (2H, br), 2,69 (IH, s) , 2, 86 - 2.99 (2H, br), 3.03 - 3.26 (5H, br), 3.27 3.37 (1H, br), 4.05 (1H, s), 4.13 (2H , s), 4.384.51 (1H, br), 4.51-4.60 (1H, br), 4.70 (2H, s), 5.87 (IH, S), 6.72-6, 80 (2H, br), 7.10 (2H, td), 7.17 (IH, dd), 7.45-7.54 (1H, br), 7.70 (IH, s). 574 142 YO z / -n (5) -3 - ((1H, 35) -1 (3-chloro-5 -fluoro2- (2 - ((3fluoropropyl) amino) ethoxy) pyridin-4-yl) -3 (trifluoromethyl) 1,3 , 4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDCI3, 27 ° C) 0.92 (3H, d), 1.96 (2H, d), 2.34 (IH, d), 2.59 (IH, s), 2 , 95 (2H, s), 3.16 (4H, d), 3.45 (B, S), 4.01 (IH, s), 4.41 (2H, s), 4.50 (IH, S), 4.58 (IH, S), 5.82 (IH, s), 6.55 - 6.66 (2H, br), 7.10 (2H, dq), 7.18 (IH, d ), 7.49 (IH, d), 7.61 (IH, s), 7.98 (IH, s). 575 144 Q ζζ -η Xp z / Π (5) -3 - ((15.35) -1 (2,6-difluoro-3- (2 ((3- fluoropropyl) (methyl) amino) ethoxy) phenyl) -3 -methyl1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 0.83 (3H, d), 1.00 - 1.06 (3H, br), 1.65 - 1.84 (2H, br) , 2.15-2.28 (4H, br), 2.44 (2H, t), 2.57 (IH, brdd), 2.68 (2H, t), 2.77 - 2.97 (2H , br), 4.05 (2H, t), 4.44 (2H, dt), 5.15 (1H, s), 6.90-7.02 (3H, br), 7.11-7, 22 (2H, br), 7.35 - 7.43 (1H, br), 10.56 (IH, s). (One peak corresponding to a hydrogen atom is overlapped by a peak for water; two peaks corresponding to a hydrogen atom were not observed.) 518

- 151 038160

146 D ^ 2X Ή z ^z \) - \ / ° / - \ o / ---- '' X / (S) -3 - ((lR, 3R) -6φτορ-1- (6-φτορ3- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) 3-methyl-1,3, 4.9 tetrahydro-2Hpyrido [3.4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDC1 _3, 27 ° C) 0,89 (ZN, d), 1,25 (ZN, d), 1,82 (2H, dd), 1,86 - 1,93 (ZN , br), 2.32 (3H, s), 2.54 2.62 (2H, br), 2.63 - 2.86 (5H, br), 2.89 (IH, dd), 3.23 (IH, d), 3.54 - 3.65 (1H, t), 4.01 (2H, t), 4.41 (ΙΗ, Ι), 4.51 (lH, t), 5.51 ( IH, s), 6.76-6.91 (2H, m), 6.94 (lH, t), 7.07-7.19 (2H, m), 7.52 (IH, s). 532 147 ^ ¥ ^^ ZX -η vH) '-SP / / - \ o / -' ^x X / (5) -3 - ((1Λ, 3Λ) -1 (6-fluoro-3 - ((2 - ((3fluoropropyl) (meth yl) amino) ethyl) (methyl) amino) -2methylphenyl) -3 methyl-1 , 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (300 MHz, MeOH-d ₄ 27 ° C) 0.84 (3H, d), 1D5 -1.25 (3H, m), 1.75 - 2.08 (6H, m), 2, 40 (3H, s), 2.54 - 2.58 (3H, m), 2.58 - 2.66 (IH, m), 2.66 - 2.80 (5H, m), 2.95 - 3.23 (4H, m), 3.68 -3.81 (IH, m), 4.40 (2H, dt), 5.06 (IH, s), 5.53 (IH, br s), 6.94-7.06 (3H, m), 7.13-7.28 (2H, m), 7.33-7.51 (IH, m). (NH indole was not observed.) 527 148 K. Π. λ Ας 0> n | r 11 ___H ^ yKJx ¹ (5) -3 - ((1Λ, 3Λ) -1 (2 (difluoromethyl) 6-fluoro-3 - (2 - ((3fluoropropyl) (meth yl) amino) ethoxy) phenyl) -3 -methyl1,3,4 , 9tetrahydro-2Hpyrido [3.4b] indol-2-yl) -2methylpropanoic acid ^: H NMR (500 MHz, CDC1 _3, 27 ° C) 0,93 (ZN, d), 1,21 (ZN, d), 1,85 1,98 (2H, br), 2.37 (SH, S), 2.63 (2H, S), 2.73 2.81 (3H, br), 2.88 (2H, s), 3.17 (IH, s), 3.33 3.41 (1H , br), 3.58-3.67 (1H, br), 4.17 (2H, s), 4.54 (2H, dt), 5.60 (1H, s), 6.93-7, 01 (1H, br), 7.06-7.15 (4H, br), 7.18 - 7.22 (IH, br), 7.39 (1H, s), 7.50 - 7.53 ( IH, t). (1 exchangeable was not observed) 550 149 ίΎ Ί F ^^^ A о ^ f h I 11 __H r ¥¥> r ^{F λ} 'F (5) -3 - ((1 ^, 35) -1 (6-fluoro-3- (2 - ((3fluoropropyl) (meth yl) amino) ethoxy) -2-methylphenyl) 3 (trifluoromethyl) 1,3, 4.9 tetrahydro-2Hpyrido [3.4- 'H NMR (500 MHz, CDCl3, 27 ° C) 0.79 (3H, d), 1.88 - 1.95 (2H, t), 1.98 - 2.06 (1H, t), 2, 34 - 2.41 (4H, t), 2.642.69 (2H, t), 2.80 - 2.89 (4H, t), 3.13 (lH, d), 3.22 (IH, dd) , 3.29 - 3.4 (2H, t), 4.00-4.16 (3H, t), 4.45 (2H, dt), 5.78 568

- 152 038160

B] indol-2-yl) -2methylpropanoic acid (IH, s), 6.81 (IH, dd), 6.93 (lH, t), 7.07-7.13 (2H, m), 7.17-7.19 (IH, m), 7.33 (IH, s), 7.45 7.49 (IH, m). (1 exchangeable was not observed) 150 O w / / G Q-z - Q y - 'o with ± y) (5) -3 - ((1Ya, ZYa) -1 (6-fluoro-3- (2 - ((3fluoropropyl) (meth yl- d3) amino) ethoxy) -2-methylphenyl) 3-methyl-1,3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid Ή NMR (500 MHz, CDC1 _3, 27 ° C) 0,90 (ZN, d), 1,25 (ZN, d), 1,70 1,96 (5H, br), 2.56 (2H, t ), 2.70 - 2.82 (5H, br), 2.90 (IH, dd), 3.20 - 3.32 (1H, br), 3.56 - 3.67 (1H, br), 3.99 (2H, t), 4.42 (IH, t), 4.52 (IH, t), 5.53 (IH, s), 6.83 (IH, dd), 6.94 (lH , t), 7.06-7.18 (2H, m), 7.22 (IH, dd), 7.46 (IH, s), 7.51 (IH, dd). 517 151 GuG O I 1 II / uKA ¹ (Λ) -3 - ((1Λ, 3Λ) -1 (6-fluoro-3- (2 - ((3fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) 3-methyl-1,3,4 , 9tetrahydro-2Hpyrido [3.4b] indol-2-yl) -2methylpropanoic acid Ή NMR (500 MHz, CDC1 ₃ , 27 ° C) 1.09 (3H, d), 1.21 (3H, d), 1.75 1.90 (5H, m), 2.32 (3H, s ), 2.53-2.61 (3H, m), 2.68 (IH, s), 2.81 (4H, td), 3.20-3.31 (IH, m), 3.84 ( IH, p), 4.02 (2H, ddq), 4.41 (lH, t), 4.51 (IH, t), 5.34 (IH, s), 6.82 (IH, dd), 6.92 (IH, t), 7.07-7.16 (2H, m), 7.17-7.22 (lH, m), 7.41 (IH, s), 7.50 (IH, dd). 514 153 ^aГ / ζζ λ '..... V q o>-' □ -e - σ -Π O (Λ) -3 - ((1Λ, 3Λ) -1 (5-fluoro-2- (2 - ((3fluoropropyl) (meth yld3) aMHH0) 3T0Kcn) -3- methylpyridin-4 yl) -3 -methyl- 1, 3,4,9tetrahydro-2Hpyrido [3,4b] indol-2-yl) -2methylpropanoic acid 'H NMR (500 MHz, CDC1 _3, 27 ° C) 1,04 (ZN, d), 1,15 (3H, d), 1,781,94 (5H, m), 2,46 - 2,56 (IH , m), 2.56 - 2.73 (4H, m), 2.78 (IH, d), 3.01 (IH, ddd), 3.20 (IH, ddd), 3.70 (2H, q), 4.26 (IH, ddd), 4.39 (IH, t), 4.49 (IH, t), 4.66 - 4.77 (IH, m), 5.26 (IH, s ), 7.12 (2H, dtd), 7.22 (IH, dd), 7.51 (2H, dd), 7.89 (IH, s). 518 154 / ^ΖΖ Ή Oh) Π # - (2- (2,4 difluoro-3 ((1Λ, 3Λ) -2 - ((3fluorooxetane-3yl) methyl) -3methyl-2,3,4,9tetrahydro-1Нpyrido [3,4- B] indol-1yl) phenoxy) ethyl) -3-phτορ-Νmethylpropane-1amine 'H NMR (300 MHz, DMSO-d ₆ , 27 ° C) 1.10 (3H, d), 1.66 - 1.84 (2H, m), 2.21 (3H, s), 2.45 (2H, t), 2.58 (IH, dd), 2.67 (2H, t), 2.70 - 2.86 (2H, m), 3.15 -3.30 (IH, m), 3.33 - 3.42 (IH, m), 4.05 (2H, t), 4.22 - 4.58 (6H, m), 5.26 (IH, s), 6.90-7, 02 (3H, m), 7.11-7.22 (2H, m), 7.40 (IH, d), 10.59 (IH, s). 520

The foregoing description of illustrative embodiments is intended only to familiarize other specialists in the art with the description created by the authors of the present invention, its principles and its practical application, so that others in the art can easily adapt and apply this description in its many forms as they may be best suited to the needs of a particular application. This description and its specific examples illustrating embodiments of this description are for illustrative purposes only. Therefore, this description is not limited to the illustrative embodiments described herein, and may be modified in various ways. In addition, it should be understood that various features of this specification, which for clarity are described in the context of separate embodiments, can also be combined to form a single embodiment. Conversely, various features of this disclosure, which for brevity are described in the context of one embodiment, can also be combined to form sub-combinations thereof.

Claims (10)

CLAIM 1. Compound of formula (IJ) R ¹ / = E / —N ^f 4 \ n v // N / - \ Г ^Me / N-Me Me OH (I) where E is CH or N; R ¹ is CH2F or CHF2; R ¹⁵ is H or F and R ²⁰ represents H or Me; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (IJ) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹⁵ is H. 3. A compound of formula (IJ) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein E is N. 4. A compound of formula (IJ), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R ¹ is CH ₂ F. 5. A compound of formula (IJ) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of (S) -3 - ((1 R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3 -methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2- methylpropanoic acid; (R) -3 - ((1 R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3 -methyl-1,3, 4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (R) -3 - ((1 R, 3R) -6-fluoro-1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) amino) ethoxy) -2-methylphenyl) -3 -methyl1, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (R) -3 - ((1R, 3R) -1 - (3 - (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3 -methyl-1,3 , 4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (S) -3 - ((1 R, 3R) -1 - (3 - (2 - ((3,3-difluoropropyl) amino) ethoxy) -6-fluoro-2-methylphenyl) -3 -methyl-1, 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (S) -3 - ((1 R, 3R) -1 - (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl- 1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (R) -3 - ((1 R, 3R) -1 - (5-fluoro-2- (2 - ((3-fluoropropyl) amino) ethoxy) -3-methylpyridin-4-yl) -3-methyl- 1,3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (S) -3 - ((1R, 3R) -6-fluoro-1- (6-fluoro-3- (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3methyl- 1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (S) -3 - ((1 R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) (methyl-b3) amino) ethoxy) -2-methylphenyl) -3 -methyl1 , 3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid; (R) -3 - ((1 R, 3R) -1 - (6-fluoro-3 - (2 - ((3-fluoropropyl) (methyl) amino) ethoxy) -2-methylphenyl) -3-methyl-1 , 3,4,9tetrahydro-2H-pyrido [3,4-b] indol-2-yl) -2-methylpropanoic acid and (R) -3 - ((1 R, 3R) -1 - (5-fluoro- 2- (2 - ((3-fluoropropyl) (methyl-b3) amino) ethoxy) -3-methylpyridin-4-yl) -3 methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4 -B] indol-2-yl) -2-methylpropanoic acid. 6. The compound of formula (IJ) according to claim 1, which is (R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3fluoropropyl) amino) ethoxy) -3- methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) -2-methylpropanoic acid or a pharmaceutically acceptable salt thereof. 7. A compound of formula (IJ) according to claim 1, which is (R) -3 - ((1R, 3R) -1- (5-fluoro-2- (2 - ((3fluoropropyl) amino) ethoxy) -3- methylpyridin-4-yl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indol-2yl) -2-methylpropanoic acid - 154 038160 8. A pharmaceutical composition containing a compound of formula (IJ) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in the prevention or treatment of cancer in a warm-blooded animal. 9. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the prevention or treatment of cancer in a warm-blooded animal. 10. Use according to claim 9, wherein the cancer is breast cancer or gynecological cancer.