Thiophene and thiazole derivatives as WIP1 inhibitors

Abstract

The present invention relates to compounds of formula (I) and salts, stereoisomer, tautomer, or N-oxide thereof that are useful as modulator or inhibitor of Wip1 (PPM1D) phosphatase. The present invention further relates to the compound of formula (I) for use as a medicament and to a pharmaceutical composition comprising said compounds.

Description

[0001] THIOPHENE AND THIAZOLE DERIVATIVES AS WIP1 INHIBITORS

[0002] Filed of invention

[0003] The present invention relates to compounds of formula (I) and salts, stereoisomer, tautomer, or N-oxide thereof that are useful as modulator or inhibitor of Wipl (PPM1D) phosphatase. The present invention further relates to the compound of formula (I) for use as a medicament and to a pharmaceutical composition comprising said compounds.

[0004] Background of the Invention

[0005] The wild-type p53-induced phosphatase 1 (Wipl; also referred to as serine / threonine phosphatase PPM1D, protein phosphatase 2C delta (PP2C <T), PPMID, or IDDGIP) is a negative regulator of the tumor suppressor p53 and is overexpressed in several human (solid) tumors. The Wipl gene (also known as PPMID gene) is located at 17q23. The expression of this gene is induced in a p53-dependent manner in response to various environmental threats, and plays an important role in homeostatic down-regulation of various stress response, cell cycle regulation, DNA damage repair and tumor cell metabolism. At present, Wipl has particularly been found to be amplified and overexpressed in various (human) tumors and is currently considered to be an oncogene.

[0006] Wipl is a member of the PP2C family of Ser / Thr protein phosphatase that are dependent on Mg2+or Mn2+for their catalytic activity and can be induced by various DNA damaging treatments including ionizing or UV irradiation in a P53 dependent manner (Fiscel la et al. PNAS 94, 6048-6053 (1997)). Upon its induction, Wipl acts upon multiple effectors of the DNA damage response pathway to dephosphorylate and consequently inactivate them. Among its reported substrates are UNG2 (Lu et al., Molecular Cell 15, 621-634 (2004)), MDM2 (Lu et al., Cancer Cell 12, 342-354 (2008)), MDMX (Xinna et al., Journal of Biological Chemistry 281, 24847-24862 (2009)), ATM (Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)), yH2AX (Cha et al., Cancer Research 70, 4112-4122 (2010)), p38MAPK (Bulavin et al., Nature Genetics 36, 343-350 (2004)), Chk2 (Fujimoto et al., Cell Death and Differentiation 13, 1170-1180 (2006)), KPNA2 (P. Wang et al, .J. Cell. Biochem. (2019)), Chkl and p53(Lu et al., Genes and Development 19, 1162-1174 ( 2005)).

[0007] In cellular studies, overexpression of Wipl in E1A transduced rat embryonic fibroblasts was sufficient to induce transformation foci (Nannenga et al., Molecular Carcinogenesis 45, 594-604 (2006)). Conversely, murine embryonic fibroblasts homozygous for Wipl deletion showed significantly reduced tumor growth when co-transfected with the transforming oncogenes HRAS and E1A, HRAS and ErbB2, or HRAS and Myc (Bulavin et.aL, Nature Genetics 36, 343-350 (2004)). Wipl- / - mice also demonstrated tumor-resistance to both induced tumor models, using infection with MMTV driven ErbB2 or HRAS, as well as a decreased incidence of spontaneous leukemias and sarcomas. Similarly, Wipl- / - mice were relatively resistant to Ep-Myc induced lymphomas (Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)).

[0008] Overexpression of Wipl is reported to result in delay or suppression of base-excision repair by inhibition of UNG2 and P53. Similarly, its overexpression suppresses DNA double- strand-break repair by inhibition of the ATM response, inhibiting repair by both homologous recombination and non-homologous end joining. Conversely, silencing or knockout of Wipl has been reported to elevate the activity of multiple stress response pathways, resulting in elevated levels of phospho-p38, phospho-p53(S15), p53 response genes p21 / Waf, pl6INKAA, and ARF (Bulavin et al., Nature Genetics 36, 343-350 (2004)), and elevated y H2AX and DNA damage-associated nuclear foci (Moon et al., Journal of Biological Chemistry 285, 12935-1294 7 (2010)). Further, it is reported that Wipl overexpression predicts poor prognosis in esophageal squamous cell carcinoma ESCC (K. Li, Y. Liu et al., Pathol. Oncol. Res.: POR (2018)).

[0009] Amplified or overexpressed Wipl has also been proposed to promote tumorigenesis in multiple cancers by suppressing the regulatory activity of a host of its tumor suppressor substrates. Amplification of the Wipl / PPMID gene locus on 17q23 has been reported in breast cancer (Li et al., Nature Genetics 31, 133-134 (2002)), ovarian clear cell carcinoma (Hirasawa et al., Clinical Cancer Research 9, 1995-2004 (2003)), neuroblastoma (Saito-Ohara et al., Journal of Experimental Medicine 203, 2793-2799 (2003)), and pancreatic adenocarcinoma (Loukopoulos et al., Cancer Science 98, 392-400 (2007)). Moreover, elevated expression of Wipl is reported in medulloblastomas (Castellino et al., Journal of Neuro-Oncology 86, 245-256 (2008)) and gastric carcinomas (Fuku et al., Pathology International 57, 566-571 (2007)). In several of these tumors, gene amplification has been confirmed to correlate with elevated protein expression.

[0010] Wenhong et al. reviews the role of Wipl in cancer (Wenhong et al. Biomed. Pharmacother., 125, 1-10 (2020)). It is inter alia disclosed that Wipl gene mutation exists in colon cancer, which lead to the persistent suppression of p53 and the occurrence of tumors (P. Kleiblova et al., J. Cell Biol., 201 (4), 511-521 (2013)). In addition, Wipl mutations were associated with hematological diseases such as myelodysplastic syndrome, leukemia and lymphoma (M. Xie et al., Nat. Med., 20 (12), 1472-1478 (2014)), observed in a 3-year-old patient with glioblastoma multiforme (A. J. Dodgshun et al., Cancer Genet., 209 (1-2) 53-56 (2016)), and mutant genes in thyroid cancer were identified by Next Generation Gene Sequencing, wherein mutations were found in genes including Wipl (B. Pekova et al., Endocr. Connect., 796-805 (2019)). Furthermore, Wipl can be expressed in lung cancer tissues and can also mediate the regulation of amyloid protein-binding protein 2 APPBP2 on lung cancer tissues as an intermediate molecule of pathway. Gong et al. observed an ectopic expression of APPBP2, Wipl and SPOP in human NSCLC tissues (H. Gong et al., EBioMedicine, 44 138- 149 (2019)). Furthermore, it was observed that the expression of Wipl in nasopharyngeal carcinoma, in hepatocellular carcinoma, and in human renal cell carcinoma is significantly higher than that in normal tissues (G.G. Sun et al., Pathol. Oncol. Res.: POR, 21 (2) 283-291 (2015); G.B. Li et al., PLoS One, 8 (3) e60775 (2013); and S. Liu et al., PLoS One, 9 (10) ell0218 (2014)). It is also assumed that Wipl is a target molecule for bladder cancer treatment (W. Wang et al., Braz. J. Med. Biol. Res., 47 (12) 1044-1049 (2014)). As a final oncogenic example, it was found that the expression of Wipl in prostate cancer is significantly higher than that in benign prostatic hyperplasia BPH control group (L. Jiao et al., Anticancer Res., 34 (6) 2919-2925 (2014)).

[0011] In addition, mutations in Wipl are associated with multiple myeloma (Mouhieddine et al., Nat Commun., 11(1) (2020)). Wang et al. discloses that Wipl also has an important roles in cervical cancer (Oncol Res., 22(4) 225-233 (2014) and Zhang at al. report that Wipl regulates the proliferation and invasion of nasopharyngeal carcinoma (Tumour Biol., 35(8) 7651-7 (2014)). Further, Wipl is associated with osteosarcoma, Ewing's sarcoma (He et al., Eur Rev Med Pharmacol Sci., 25(1) 78-85 (2021), Long et al., J Cell Biochem., 120(4) 5652- 566 (2019)), Wilm’s tumor (Saliba et al., Pediatr Dev Pathol., 23(2) 167-171 (2020)), mesothelioma (Yu et al., Aging (Albany NY), 13(17) 21294-21308 (2021)), and melanoma (Wu et al., Br J Cancer, 118(4) 495-508 (2018)).

[0012] Further to the above-outlined connections of Wipl and potential indications, Wipl is associated with the treatment of amyotrophic lateral sclerosis (CN109876143A) and individual allergic asthma (CN105727295A), as well as with the regulation of the adipogenic differentiation capacity of mesenchymal stem cells (MSCs) (CN111118046A).

[0013] Based on the above, inhibition of Wipl by small molecule inhibitors was investigated (JP2021138671A2, JP2018024645A2) and found to provide suitable selectivity (WC2012 / 149102). However, the known in the art small molecule inhibitors are either not potent enough or do not provide satisfying pharmacokinetic properties, e.g. regarding the metabolic stability, in particular the half-life.

[0014] In view of the above, compounds modulating or inhibiting Wipl are useful for treating one or more diseases such as cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases.

[0015] Of particular relevance is the treatment of cancer and pre-cancerous syndromes. Cancers may be in the form of solid tumors such as sarcomas, carcinomas, and lymphomas or in the form of liquid tumors, e.g. leukemia.

[0016] Compounds modulating or inhibiting Wipl are particularly useful for the treatment of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan- Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer (e.g. inflammatory breast cancer, triple negative breast cancer (TNBC), and HER2+ breast cancer), brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor. Relevant blood cancers include leukemia, lymphoma and multiple myeloma. Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). Of particular relevance is AML. Relevant brain cancers include glioblastoma, oligodendroglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblastoma. Relevant lung cancers include small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC. The most relevant liver cancer is hepatocellular carcinoma (HCC). Compounds modulating or inhibiting Wipl may be especially useful in the treatment of amyotrophic lateral sclerosis, Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte- Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor.

[0017] Objects and Summary of the Invention

[0018] It is therefore an object of the present invention to provide compounds, which modulate Wipl. It is another object of the present invention to provide compounds, which inhibit Wipl.

[0019] It is another object of the present invention to provide compounds, which exhibit a high activity regarding the modulation or inhibition of Wipl, especially within the cell. It is another object of the present invention to provide compounds with a high metabolic stability, in particular a long half-life. It is another object of the present invention to provide compounds with a satisfying activity regarding the modulation or inhibition of Wipl, while at the same time exhibiting a long half-life.

[0020] It is another object of the present invention to provide compounds, which are suitable for use as a medicament. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of one or more diseases, which are linked to Wipl, e.g. its overexpression, genomic amplification, gain of function mutations, and / or fusions / translocations. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of one or more disease selected from cancer, pre-cancerous syndromes, autoimmune conditions, neurological disease, and viral disease. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of cancer, in particular in the treatment of solid or liquid tumors. In particular, it is an object of the present invention to provide compounds, which are suitable for the treatment of cancer, especially the treatment of Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte-Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of autoimmune conditions such as asthma, in particular of individual allergic asthma. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of neurological diseases such as amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, or autism. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of viral diseases.

[0021] At least one of the above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceutical compositions comprising the same, and by the medical uses thereof.

[0022] The inventors of the present invention inter alia surprisingly found that the compounds of formula (I) as defined herein inhibit Wipl. Further, the compounds of the present invention exhibit a long half-life. Accordingly, the compounds of formula (I) can be used as a medicament, in particular for the treatment of one or more diseases selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte- Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

[0023] In a first aspect, the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer, or N-oxide thereof, wherein

[0024] X1is CH or N;

[0025] L1is CH2, CHCH3, CHCF3, or S(=O)2;

[0026] L2is CH2, CH2CH2, CHOH, CHOCH3or absent;

[0027] R1is H, C1-C4-al kyl, C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx;

[0028] R2is 5- to 10-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;

[0029] R3is H, C!-C2-alkyl, or CH2C(=O)OH;

[0030] R4is H, C1-C2-al kyl, 3- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz;

[0031] R5is H or C1-C2-al kyl; and wherein

[0032] Rxis halogen, CN, OH, S(=O)2CH3, S(=O)(=NH)CH3, NHC(=O)CH3, NH2, Cj-C^alkyl, C C4-alkoxy, C1-C4- ha loa I ky I , or Cj-C / j-hydroxyalkyl;

[0033] RYis halogen, CN, C1-C4-alkyl, Cj-C alkoxy, C^C^hal oa I kyl , Cj-C / j-haloalkoxy, or Cj-C4- hydroxyalkyl;

[0034] Rzis halogen, CN, OH, C1-C4-alkyl, C1-C4- ha loa I ky I , C1-C4-haloalkoxy, or CJ-C J- hydroxyal kyl; or two Rzattached to the same atom form a C1_C3-alkylene chain. with the proviso that at least one of the following conditions is met:

[0035] R1is

[0036] (i) a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; or

[0037] (ii) a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx;

[0038] R4is

[0039] (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or

[0040] (ii) a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0041] (iii) a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0042] (iv) a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0043] L2is CHOH or CH0CH3.

[0044] In the following, preferred embodiments of the compound of formula (I) are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments.

[0045] In a preferred embodiment Al of the first aspect, the proviso applies that at least one of the following conditions is met:

[0046] R1is 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0047] Rxis F, CF3, or CH3; or

[0048] R4is

[0049] (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or

[0050] (ii) a 4-membered saturated carbocyclyl; wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0051] (iii) a 4- to 6-membered saturated heterocyclyl, or 5- to 7-membered saturated carbobicyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; wherein

[0052] Rzis F, CF3, or CH3; or two Rzattached to the same atom form a C3-alkylene chain; or

[0053] L2and R4together form wherein the dotted line marks the connection to the remainder of the molecule.

[0054] In a preferred embodiment A2 of the first aspect, the proviso applies that at least one of the following conditions is met: R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; or

[0055] L2and R4together form wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0056] In a preferred embodiment A3 of the first aspect, the proviso applies that at least one of the following conditions is met:

[0057] R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; or

[0058] L2and R4together form: wherein the dotted line marks the connection to the remainder of the molecule.

[0059] In a preferred embodiment A4 of the first aspect,

[0060] R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; and

[0061] L2and R4together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0062] In a preferred embodiment A5 of the first aspect,

[0063] X1is N.

[0064] In a preferred embodiment A6 of the first aspect,

[0065] X1is CH.

[0066] In a preferred embodiment A7 of the first aspect,

[0067] L1is CH2; and / or

[0068] L2is CH2.

[0069] In a preferred embodiment A8 of the first aspect,

[0070] R5is H.

[0071] In a preferred embodiment A9 of the first aspect,

[0072] R3is H.

[0073] In a preferred embodiment A10 of the first aspect,

[0074] R2is any one of wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0075] In a preferred embodiment All of the first aspect, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridin-3-ylamino) pro pan -2 -yl)th iophene -2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -5-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-4-ylamino) propan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-ch loro-2- methyl pyrid in -3-yl) ami no) methyl) -N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (pyrid azin -3 -y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl) -l-oxo-l-(pyri midin -5- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch loro -2 -methyl pyrid in -3- yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(4,4-difluorocyclohexyl) -l-oxopropan -2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- (4,4-difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino) propan-2-yl)thiophene-2- carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rim id in -5-y lam i no) pro pan -2-yl) th iazole-5-carboxam ide, (S) -2 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl)-l-oxo-l-(pyridazin-4- y la mino) propan -2-yl) th iazole-5-carboxam ide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((l R, 2S)-l-cyc I open tyl-3- (eye Io propyl a mino)-l -hydroxy-3 -oxopropan- 2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((S)-3- (4,4-difluorocyclohexyl)-l-(((lr,3S)-3-hydroxycyclobutyl)amino)-l -oxopropan -2- y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S) -3- (4,4-difluorocyclohexyl)-l-(((lr,3S)-3-hydroxy-3- methylcyclobutyl) ami no) -1 -oxopropan -2- y I) th iophene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(pyridazin-4-y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol-4-yl)amino)-l-oxopropan-

[0076] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrazin-2-ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-l, 2, 4-triazol-

[0077] 3-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloropyridin-3- yl)amino)methyl)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2- y I) th iophene-2 -carboxamide, (S) -N-(3-cyclopentyl-l-((l -methyl -lH-pyrazol-4-yl)amino)-l- oxopropan-2-yl)-5-(((5-(difluoromethyl)-2-methylpyridin-3-yl)amino)methyl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxo-3-((R) -tetra hydrofuran -2-yl) propan -2-yl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxo-3-((S) -tetra hydrofuran -2-yl) propan -2-yl)thiophene-2- carboxamide, (S) -N-(3-(l, 3-dioxan-2-yl) -l-((l-methyl- lH-pyrazol -4-yl) amino) -1- oxopropa n-2-y I) -5-(((5-chloro-2-methy I py rid in-3-yl)a mino) methyl) th iophene-2- carboxamide, (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2- yl)-5-(((2,5-dimethylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide, and (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-(isoxazol-4-ylamino)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide.

[0078] In a second aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to the first aspect and optionally a pharmaceutically acceptable carrier or excipient.

[0079] In a third aspect, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in medicine.

[0080] In a fourth aspect, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre- cancerous syndromes, and neurological diseases. In particular, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of cancer.

[0081] In a fifth aspect, the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

[0082] Detailed Description

[0083] Before describing in detail exemplary embodiments of the present invention, definitions important for understanding the present invention are given.

[0084] The term “compound(s) of the present invention" is to be understood as equivalent to the term "compound(s) according to the invention", and also covers a salt, stereoisomer, tautomer or N-oxide thereof.

[0085] The compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities. The present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof.

[0086] Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.

[0087] Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are replaced by Cj-^-alkyl, Cj-C4- hyd roxya I ky I, Cj-^-alkoxy, Cj-^-alkoxy- Cj-Cj-al kyl, hydroxy-Cj-^-alkoxy-Cj-^-alkyl, phenyl or benzyl. Examples of substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetra butylammonium, 2- hydroxyethylammonium, 2 -(2 -hydroxyethoxy) ethyl -ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.

[0088] Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of Cj-^-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p- toluenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisulfonate. They can be formed by reacting compounds according to the invention that have a basic functionality with an acid of the corresponding anion.

[0089] Depending on the substitution pattern, the compounds according to the invention may have one or more centres of chirality, including axial chirality. The invention provides both, pure enantiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures. Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis / trans isomers or E / Z isomers) and mixtures thereof. E / Z- isomers may be present with respect to, e.g., an alkene, carbonnitrogen double-bond or amide group.

[0090] Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like. Furthermore, the core structure comprising the 6-membered ring that contains the =0 substituent principally allows for keto-enol-tautomerization.

[0091] The term "N-oxide" includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to a N-oxide moiety.

[0092] The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.

[0093] The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.

[0094] When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents. When neither the term “unsubstituted” nor “substituted” is explicitly mentioned concerning a moiety, said moiety is to be considered as unsubstituted.

[0095] The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0096] The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine. The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n - propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl,

[0097] 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethyl propyl,

[0098] 1.2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1 ,2-d imethy I buty 1 , 1 ,3-d imethyl butyl , 2,2-dimethylbutyl, 2,3-dimethylbutyl,

[0099] 3.3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-tri methyl propyl, 1,2,2-trimethylpropyl, 1- ethyl-l-methylpropyl, and l-ethyl-2-methylpropyl.

[0100] The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, frequently 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from Cj-C4- ha loa I ky I , more preferably from C1-C3- h a I oa I ky I or CJ-CJ- ha loa I ky I , in particular from Cj-Cj-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-f I uoroethyl, 2,2-d if I uoroethyl, 2,2,2-trif luoroethyl, pentafluoroethyl, and the like.

[0101] The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert. -butyloxy, and the like.

[0102] The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include Cj-haloalkoxy, in particular Cj-fluoroalkoxy, such as trifluoromethoxy and the like.

[0103] The term “hydroxyalkyl” as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy grou ps, in particular with 1 hydroxy group. Preferably, the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule. Examples of an hydroxyalkyl group are hydroxymethyl, hydroxyethyl, n-hydroxypropyl, 2-hydroxypropyl, n-hydroxybutyl, 2- hydroxybutyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are preferred, in particular hydroxymethyl and hydroxyethyl.

[0104] The term “carbocyclic” or “carbocyclyl” includes, unless otherwise indicated, in general a

[0105] 3- to 9-membered, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7- membered, more preferably a 5- or 6-membered monocyclic ring comprising 3 to 9, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled. The term “carbocylce” or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings.

[0106] The term “cycloalkyl” as used herein denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0107] The term "carbobicyclic" or “carbobicyclyl” includes in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms. The carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled. Preferably, the term “aromatic” in connection with the carbobicyclic ring means that both rings of the bicyclic moiety are aromatic, so that, e.g., 8 n electrons are present in case of a 10-membered aromatic carbobicyclic ring. The term “carbobicyclic” or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloalkenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as norbornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bicyclo[3.3.3]undecane), norbornene, naphthalene and the like. Preferably, the carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naphthalene.

[0108] The term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in particular 6-membered monocyclic ring. The heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled. The heterocycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. In a preferred embodiment, the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. Examples of aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”. The saturated or partially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The skilled person is aware that S, SO or SO2is to be understood as follows:

[0109] Further, a skilled person is aware that resonance structures of the oxidized forms may be possible. Saturated heterocycles include, unless otherwise indicated, in general 3- to 9- membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered monocyclic rings comprising 3 to 9, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.

[0110] The term “heterobicyclic” or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings. The heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled. In principal, for being “aromatic”, it is sufficient if one of the two rings of the bicyclic moieties is aromatic, while the other is non-aromatic. However, it is preferred in connection with the term “aromatic” that both rings of the bicyclic moiety are aromatic, so that, e.g., 8 n electrons are present in case of a 9- or 10-membered aromatic heterobicyclic ring. The heterobicycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, 0 and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. Examples of heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1 ,8 - na phthyridyl , pteridyl, pyrido[3,2-d] pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like. Preferred heterobicycles according to the invention are aromatic heterobicycles such as benzodiazole, benzothiazole, quinoline, and iso-quinoline.

[0111] The term "hetaryl" or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, where S-atoms as ring members may be present as S, SO or SO2. Examples of 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5- pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-,

[0112] 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isoth iazolyl , pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-i midazolyl, oxadiazolyl, e.g. 2- or

[0113] 5- [l,3,4]oxadiazolyl, 4- or 5-(l,2,3-oxadiazol)yl, 3- or 5-(l,2,4-oxadiazol)yl, 2- or 5-(l,3,4- thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(l,3,4-thiadiazol)yl, 4- or 5-(l,2,3-thiadiazol)yl, 3- or 5- (l,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or 3H-l,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-l,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl. Unless otherwise indicated, the term “hetaryl” further covers “aromatic heterobicycles” as defined above.

[0114] The term “aryl” or “aromatic carbocyclyl” preferably includes 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. Unless otherwise indicated, the term “aryl” further covers “aromatic carbobicycles” as defined above. As used herein, the terms “carbocyclylmethyl” and “heterocyclylmethyl” refer to the corresponding groups, which are bonded to the remainder of the molecule via a (%-alkyl group. Preferred examples include benzyl (i.e. phenylmethyl), cyclohexylmethyl, pyridinylmethyl, and piperidinomethyl.

[0115] As used herein, the term “alkylene chain” refers to a linking straight-chain or branched alkylene group having usually from 1 to 4 carbon atoms, e.g. 1, 2, 3, or 4 carbon atoms. The alkylene group bridges a certain group to the remainder of the molecule. Preferred alkylene groups include methylene (CH2), ethylene (CH2CH2), propylene (CH2CH2CH2) and the like. A skilled person understands that, if it is referred, e.g., to CH2that the carbon atom being tetravalent has two valences left for forming a bridge (-CH2-). Similarly, when it is referred, e.g., to CH2CH2, each carbon atom has one valence left for forming a bridge (-CH2CH2-). Furthermore, when it is referred, e.g., to CH2CH2CH2, each terminal carbon atom has one valence left for forming a bridge (-CH2CH2CH2-).

[0116] The term “cyclic” moiety can refer to any cyclic groups, which are present in the compounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocycle.

[0117] As used in the specification and the claims, the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates otherwise.

[0118] The terms “about” and “approximately” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ± 10%, preferably ± 5%, more preferably ± 2%.

[0119] It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group, which preferably consists of these embodiments only.

[0120] The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.

[0121] The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be understood as “treatment and / or prophylaxis” or “treating and / or preventing”.

[0122] The term “half-life” as used herein denotes the time it takes for a substance from its maximum concentration (Cmax) to half of its maximum concentration in e.g. the blood plasma and is typically abbreviated by t1 / 2. The half-life can be indicated as the elimination half-life, which is the time required to produce a 50% reduction in blood or plasma concentration.

[0123] In the following, preferred embodiments of the substituents in the above formula (I) are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments.

[0124] Furthermore, it is to be understood that the preferences in each case also apply to the salts, stereoisomers, tautomers, and N-oxides of the compounds of the invention.

[0125] As indicated above, the present invention relates in a first aspect to a compound of formula (I) wherein

[0126] X1is CH or N, and the remaining substituents are as defined above.

[0127] Accordingly, the compound of formula (I) may therefore be a compound of formula (la) or (lb) as shown below:

[0128] In connection with the compounds according to formula (la) and (lb), it is to be understood that the substituents R1, R2, R3, R4, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents are provided further below.

[0129] In a preferred embodiment, the compound of formula (I) is a compound of formula (la). In another preferred embodiment, the compound of formula (I) is a compound of formula (lb).

[0130] In connection with the compound of formula (I), as well as in connection with the compounds of formulae (la) and (lb), the following provisos apply.

[0131] In a preferred embodiment, the proviso applies that at least one of the following conditions is met:

[0132] R1is (i) a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; or

[0133] (ii) a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0134] Rxis F, CF3, or CH3; or

[0135] R4is (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or

[0136] (ii) a 4-membered saturated carbocyclyl; wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0137] (iii) a 4- to 6-membered saturated heterocyclyl, or 5- to 7-membered saturated carbobicyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0138] (iv) a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz; wherein

[0139] Rzis F, CF3, or CH3; or two Rzattached to the same atom form a C3-alkylene chain; or

[0140] L2and R4together form wherein the dotted line marks the connection to the remainder of the molecule.

[0141] In a preferred embodiment, the proviso applies that at least one of the following conditions is met:

[0142] R1is a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0143] Rxis F, CF3, or CH3; or

[0144] R4is

[0145] (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or (ii) a 4-membered saturated carbocyclyl; wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0146] (iii) a 4- to 6-membered saturated heterocyclyl, or 5- to 7-membered saturated carbobicyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; wherein

[0147] Rzis F, CF3, or CH3; or two Rzattached to the same atom form a C3-alkylene chain; or

[0148] L2and R4together form wherein the dotted line marks the connection to the remainder of the molecule.

[0149] In a preferred embodiment, the proviso applies that at least one of the following conditions is met: wherein the dotted line in each case marks the connection to the remainder of the molecule; or

[0150] L2and R4together form wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0151] In a preferred embodiment, the proviso applies that at least one of the following conditions is met: R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; or

[0152] L2and R4together form: wherein the dotted line marks the connection to the remainder of the molecule.

[0153] In a preferred embodiment, the proviso applies that at least one of the following conditions is met: R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; or

[0154] L2and R4together form: wherein the dotted line marks the connection to the remainder of the molecule.

[0155] The provisos according to the invention are further il lustrated in the following compounds of formulae (Ic), (Id), (le), (If), (Ig), (Ih), and (li). In one embodiment, the compound of formula (I) is selected from the group of compounds of formulae (Ic), (Id), (le), (If), (Ig), (Ih), and (li).

[0156] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ic) wherein

[0157] R1Ais a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0158] In a preferred embodiment,

[0159] Rxis halogen, CN, OH, NH2, C1-C4-alkyl, Cj-C alkoxy, Cj-C^i- haloa I ky I, or Cj-C4- hydroxyalkyl, preferably halogen, C^C^al kyl or Cj-C^i- ha loa I kyl , and in particular F, CF3, or CH3.

[0160] In one preferred embodiment,

[0161] R1Ais a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0162] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0163] In one preferred embodiment,

[0164] R1Ais a 5- or 6-membered aromatic heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0165] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0166] In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0167] In a preferred embodiment,

[0168] R1Ais wherein the dotted line in each case marks the connection to the remainder of the molecule. In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0169] In a preferred embodiment,

[0170] R1Ais wherein the dotted line in each case marks the connection to the remainder of the molecule; and

[0171] L2and R4together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0172] In connection with the compounds according to formula (Ic), it is to be understood that the substituents X1, R2, R3, R4, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rxare provided further below.

[0173] In a preferred embodiment, the compound of formula (I) is a compound of formula (Id) wherein

[0174] R1Bis a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0175] In a preferred embodiment,

[0176] Rxis halogen, CN, OH, NH2, C1-C4-alkyl, Cj-C alkoxy, Cj-C4- haloa I ky I, or Cj-C4- hydroxyalkyl, preferably halogen, Cj-C4-al kyl or Cj-C4- ha loa I kyl , and in particular F, CF3, or CH3.

[0177] In one preferred embodiment,

[0178] R1Bis a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0179] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0180] In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0181] In connection with the compounds according to formula (Id), it is to be understood that the substituents X1, R2, R3, R4, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rxare provided further below.

[0182] In a preferred embodiment, the compound of formula (I) is a compound of formula (le) wherein

[0183] R4Ais cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz.

[0184] In a preferred embodiment,

[0185] R4Ais cyclohexyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz, wherein

[0186] Rzis halogen, OH, C1-C4-a I ky I , or C1-C4- ha loa I ky I ; or two Rzattached to the same atom form a C Cg-alkylene chain, preferably F, CH3, or CF3.

[0187] In a preferred embodiment,

[0188] R4Ais cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz, wherein

[0189] Rzis halogen, OH, C1-C4-al kyl, or C1-C4- ha loa I ky I ; or two Rzattached to the same atom form a C1_C3-alkylene chain, preferably F, CH3, or CF3.

[0190] In a preferred embodiment, wherein the dotted line marks the connection to the remainder of the molecule. In connection with the compounds according to formula (le), it is to be understood that the substituents X1, R1, R2, R3, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rzare provided further below.

[0191] In a preferred embodiment, the compound of formula (I) is a compound of formula (If) wherein

[0192] R4Bis a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0193] In a preferred embodiment,

[0194] R4Bis a 3- to 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0195] In a preferred embodiment,

[0196] Rzis halogen, C1-C4-al kyl, or C1-C4-haloal ky; or two Rzattached to the same atom form a C Cs-alkylene chain; preferably halogen or C1-C4-alkyl; or two Rzattached to the same atom form a C Cg-alkylene chain.

[0197] In a preferred embodiment,

[0198] R4Bis a 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz, wherein

[0199] Rzis C1-C4-al kyl or two Rzattached to the same atom form a C Cg-alkylene chain.

[0200] In a preferred embodiment,

[0201] R4B , preferably wherein the dotted line marks the connection to the remainder of the molecule.

[0202] In connection with the compounds according to formula (If), it is to be understood that the substituents X1, R1, R2, R3, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rzare provided further below.

[0203] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ig) wherein R4Cis a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0204] In a preferred embodiment,

[0205] R4Cis a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0206] In a preferred embodiment,

[0207] R4Cis a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one oxygen heteroatoms, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0208] In a preferred embodiment,

[0209] Rzis halogen, C1-C4-al kyl, or C1-C4-haloal ky; or two Rzattached to the same atom form a C Cs-alkylene chain; preferably halogen or C1-C4-al kyl; or two Rzattached to the same atom form a C^Cg-alkylene chain.

[0210] In a preferred embodiment, wherein the dotted line marks the connection to the remainder of the molecule.

[0211] In connection with the compounds according to formula (Ig), it is to be understood that the substituents X1, R1, R2, R3, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rzare provided further below.

[0212] In a preferred embodiment, the com ound of formula (I) is a compound of formula (I h) wherein

[0213] R4Dis a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0214] In a preferred embodiment,

[0215] R4Dis a 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz. In a preferred embodiment,

[0216] R4Dis O; wherein the dotted line marks the connection to the remainder of the molecule.

[0217] In connection with the compounds according to formula (Ih), it is to be understood that the substituents X1, R1, R2, R3, R5, L1, and L2are as defined above in formula (I). Further preferred embodiments regarding these substituents and Rzare provided further below.

[0218] In a preferred embodiment, the compound of formula (I) is a compound of formula (li) wherein

[0219] RAis H or CH3.

[0220] In connection with the compounds according to formula (li), it is to be understood that the substituents X1, R1, R2, R3, R4, R5, and L1are as defined above in formula (I). Further preferred embodiments regarding these substituents are provided further below.

[0221] In connection with the compound of formula (I), as well as in connection with the compounds of formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), and (li) , the following preferred embodiments regarding the remaining substituents X1, R1, R2, R3, R4, R5, L1, and L2are relevant. The skilled person will understand that in the event that the compounds of formulae (la), (lb), (Ic), (Id), (le), (If) , (Ig), (Ih), and (li) do not comprise one of the substituents X1, R1, R4, or L2, that the respective below preferred embodiments regarding these substituents are not relevant, but only the preferred embodiments regarding substituents, which are present in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), or (li).

[0222] In a preferred embodiment,

[0223] R1is C1-C4-al kyl, Cj-^-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0224] In this connection, Rxis preferably halogen, CN, OH, NH2, C1-C4-alkyl, Cj-Cj-alkoxy, C1-C4-haloalkyl, or Cj-C^hydroxyalkyl, more preferably halogen, OH, C1-C4-alkyl or Cj-C^ haloalkyl, and in particular F, OH, CF3, CH3, or OCH3.

[0225] In another preferred embodiment, R1is C1-C4-alkyl or 3- to 10-membered saturated or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0226] In another preferred embodiment,

[0227] R1is 3- to 10-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0228] In yet another preferred embodiment,

[0229] R1is

[0230] (i) a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; or

[0231] (ii) a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0232] In a preferred embodiment,

[0233] R1is a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0234] In this connection, Rxis preferably halogen, CN, OH, NH2, C1-C4-a I ky I , Cj-C alkoxy, C1-C4-haloalkyl, or Cj-C / j-hydroxyalkyl, more preferably halogen, C^C^alkyl or Cj-C4- haloalkyl, and in particular F, CF3, or CH3.

[0235] In one more preferred embodiment,

[0236] R1is a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0237] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0238] In another more preferred embodiment,

[0239] R1is a 5- or 6-membered aromatic heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0240] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0241] In another more preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0242] In another more preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0243] In another preferred embodiment,

[0244] R1is wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0245] In an especially preferred embodiment,

[0246] R1is wherein the dotted line in each case marks the connection to the remainder of the molecule; and

[0247] L2and R4together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0248] In a preferred embodiment,

[0249] R1is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx.

[0250] In this connection, Rxis preferably halogen, CN, OH, NH2, C1-C4-alkyl, Cj-C alkoxy, C1-C4-haloalkyl, or Cj-C / j-hydroxyalkyl, more preferably halogen, C1-C4-alkyl or Cj-C4- haloalkyl, and in particular F, CF3, or CH3.

[0251] In another preferred embodiment,

[0252] R1is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx; wherein

[0253] Rxis halogen, OH, C1-C4-alkyl, C1-C4- ha loa I ky I, preferably F, CF3, or CH3.

[0254] In a more preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0255] In a further preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0256] In one more preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0257] In another more preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0258] In a particularly preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule; and

[0259] L2and R4together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0260] In a preferred embodiment,

[0261] R4is C1-C2-alkyl, 3- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0262] In this connection, Rzis preferably halogen, OH, Cj-^-alkyl, or C1-C4- ha loa I ky I ; or two Rzattached to the same atom form a C Cg-alkylene chain, more preferably F, OH, CH3, or CF3; or two Rzattached to the same atom form a C1_C3-alkylene chain.

[0263] In one preferred embodiment,

[0264] R4is Cj-02-alkyl.

[0265] In another preferred embodiment,

[0266] R4is 3- to 6-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0267] In a preferred embodiment, R4I S (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or

[0268] (ii) a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0269] (iii) a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or

[0270] (iv) a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0271] In one preferred embodiment,

[0272] R4is cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz.

[0273] In this connection, Rzis preferably halogen, C1-C4-al kyl, or Cj-C4- haloa I ky I ; or two Rzattached to the same atom form a C1_C3-alkylene chain, more preferably F, CH3, or CF3.

[0274] In one more preferred embodiment,

[0275] R4is cyclohexyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz, wherein

[0276] Rzis halogen, C1-C4-al kyl, or C1-C4-haloal kyl; or two Rzattached to the same atom form a C1_C3-alkylene chain, preferably F, CH3, or CF3.

[0277] In another more preferred embodiment,

[0278] R4is cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz, wherein

[0279] Rzis halogen, C1-C4-al kyl, or C1-C4-haloal kyl; or two Rzattached to the same atom form a C1_C3-alkylene chain, preferably F, CH3, or CF3.

[0280] In a particularly preferred embodiment, wherein the dotted line marks the connection to the remainder of the molecule.

[0281] In another preferred embodiment,

[0282] R4is a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz. In this connection, Rzis preferably halogen, C1-C4-al kyl, or Cj-C4- haloa I ky I ; or two Rzattached to the same atom form a C Cg-alkylene chain, more preferably halogen or Cj-C4- al kyl; or two Rzattached to the same atom form a C Cg-alkylene chain, and in particular F or CH3; or two Rzattached to the same atom form a C1_C3-alkylene chain.

[0283] In one more preferred embodiment,

[0284] R4is a 3- to 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0285] In a particularly preferred embodiment,

[0286] R4 , preferably wherein the dotted line marks the connection to the remainder of the molecule.

[0287] In another more preferred embodiment,

[0288] R4is a 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz, wherein

[0289] Rzis halogen or C1-C4-al kyl; or two Rzattached to the same atom form a C1_C3-alkylene chain, preferably C1-C4-al kyl or two Rzattached to the same atom form a CrC3- alkylene chain.

[0290] In another preferred embodiment,

[0291] R4is a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0292] In this connection, Rzis preferably halogen, C1-C4-alkyl, or Cj-C4- ha loa I ky; or two Rzattached to the same atom form a C Cg-alkylene chain; more preferably halogen or Cj-C4- alkyl; or two Rzattached to the same atom form a C Cg-alkylene chain.

[0293] In a more preferred embodiment,

[0294] R4is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0295] In an even more preferred embodiment,

[0296] R4is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one oxygen heteroatom, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0297] In a particularly preferred embodiment, R4is wherein the dotted line marks the connection to the remainder of the molecule.

[0298] In a preferred embodiment,

[0299] R4is a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0300] In a more preferred embodiment,

[0301] R4is a 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0302] In a particularly preferred embodiment, wherein the dotted line marks the connection to the remainder of the molecule.

[0303] In a preferred embodiment,

[0304] R4is 3- to 10-membered, preferably 4-to 6-membered, saturated carbocyclyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz.

[0305] In a particularly preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0306] In one preferred embodiment,

[0307] X1is N.

[0308] In another preferred embodiment,

[0309] X1is CH.

[0310] In a preferred embodiment,

[0311] L1is CH2, CHCH3, or CHCF3, preferably CH2.

[0312] In a preferred embodiment,

[0313] L2is CH2, CHOH, or CHOCH3.

[0314] In one more preferred embodiment,

[0315] L2is CH2.

[0316] In another more preferred embodiment,

[0317] L2is CHOH or CHOCH3.

[0318] In a preferred embodiment,

[0319] L1is CH2; and / or

[0320] L2is CH2. In a more preferred embodiment,

[0321] L1is CH2; and

[0322] L2is CH2.

[0323] In a preferred embodiment,

[0324] R2is a 5- to 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY.

[0325] In this connection, RYis preferably halogen, C1-C4-alkyl, C^-Cs- hal oa I ky I , Cj-^-haloalkoxy, or Cj-C hydroxyalkyl.

[0326] In a more preferred embodiment,

[0327] R2is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY.

[0328] In an even more preferred embodiment,

[0329] R2is any one of wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0330] In a particularly preferred embodiment,

[0331] R2is wherein the dotted line in each case marks the connection to the remainder of the molecule.

[0332] In another particularly preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule

[0333] In a preferred embodiment,

[0334] R3is H or CH2C(=O)OH.

[0335] In a particularly preferred embodiment,

[0336] R3is H.

[0337] In a preferred embodiment,

[0338] R5is H or methyl.

[0339] In a particularly preferred embodiment,

[0340] R5is H.

[0341] In a preferred embodiment,

[0342] R2is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;

[0343] R3is H or CH2C(=O)OH; and

[0344] R5is H or methyl; wherein

[0345] RYis halogen, C1-C4-alkyl, C1-C3- ha loa I ky I , Cj-C^-haloalkoxy, or Cj-C^-hydroxyalkyl, preferably halogen.

[0346] In a preferred embodiment,

[0347] L1is CH2, CHCH3, or CHCF3, preferably CH2;

[0348] L2is CH2, CHOH, or CH0CH3, preferably CH2;

[0349] R2is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;

[0350] R3is H or CH2C(=0)0H; and

[0351] R5is H or methyl; wherein

[0352] RYis halogen, C1-C4-alkyl, C1-C3- ha loa I ky I , Cj-^-haloalkoxy, or Cj-^-hydroxyalkyl, preferably halogen.

[0353] In a preferred embodiment,

[0354] R2is wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0355] R3is H or CH2C(=O)OH; and

[0356] R5is H or methyl.

[0357] In a preferred embodiment,

[0358] L1is CH2, CHCH3, or CHCF3;

[0359] L2is CH2, CHOH, or CHOCH3;

[0360] R2is wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0361] R3is H or CH2C(=O)OH; and

[0362] R5is H or methyl.

[0363] In a preferred embodiment,

[0364] L1is CH2;

[0365] L2is CH2;

[0366] R2is wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0367] R3is H; and

[0368] R5is H.

[0369] In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0370] R3is H or CH2C(=O)OH; and

[0371] R5is H or methyl.

[0372] In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0373] R3is H or CH2C(=O)OH; and

[0374] R5is H or methyl.

[0375] In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule;

[0376] R3is H; and

[0377] R5is H.

[0378] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-N-(5-chloro-2-methylpyridin-3-yl)-N-((5-((3-cyclopentyl-l- (cyc lop ropy lam i no) -1 -oxopropan -2-yl) carbamoyl) th io phen -2 -y I) methyl) glycine, 5-(l-((5- chloro-2-methylpyridin-3-yl)amino)ethyl)-N-((S)-3-cyclopentyl-l-(cyclopropylamino) -l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, 5-(l-((5-chloro-2-methylpyridin-3-yl)amino) - 2,2,2-trifluoroethyl)-N-((S)-3-cyclopentyl-l-(cyclopropylamino) -l-oxopropan-2- y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((1R,2S) - 1 -eye Io pentyl -3- (cyclopropylami no) -l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(4,4-dimethyl-l-oxo-l-((pyridin-3- y I methyl)amino) pen tan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin- 3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-((pyridin-3-ylmethyl)amino)propan-2- y I) th iophene-2 -carboxamide, ( S)-N-(l-(benzyl amino) -1 -oxo -3 -(tetra hydro -2H-pyran-4- y I) pro pan -2-yl) -5- (((5-ch loro-2- methy I pyrid in -3-yl) ami no) methyl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino) -l-oxo-3- (tetra hyd ro-2 H - py ra n -4-y I) propan -2 -y I) th iophene-2 -carboxamide, ( S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(l-oxo-l-((pyridin-3-ylmethyl)amino) -3-(tetrahydro- 2H-py ran -4-y I) pro pan -2 -y I) th io phene-2 -carboxamide, (S) -5- (((5-ch loro-2- methyl pyridin -3- yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(3,3-difluorocyclobutyl) -l-oxopropan -2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l- (cyc lop ropy lam i no) -3-(l -methy I eye I op ropy I) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino) -3-(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl) -l-oxo-l-((pyridin -3- y I methy l)amino) propan -2-yl) th iophene-2-carboxam ide, (S) -5- (((5-ch loro-2- methyl pyridin - 3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl)-l-((2-methoxyethyl)amino) -l-oxopropan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-ch loro-2- methyl pyrid in -3-yl) ami no) methyl) -N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide, (S) -5- (((5-ch loro-2- methyl pyrid in-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -((pyrid in -4-yl methyl) ami no) pro pan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-

[0379] 2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-((pyridin -2- y I methyl)amino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methyl yridin-

[0380] 3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-((pyrimidin-5-ylmethyl)amino)pro an-2- y I) th io hene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo-1 -(pyrid in -4-y lam i no) pro pan -2-yl) th io hene-2-carboxam ide, (S)-N-(l- ((lH-pyrazol-4-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxamide, (S) -5 -(((5 -ch loro -2 -methyl pyrid in -3- y I) a min o) methyl) -N-(3 -eye I o pentyl- 1-oxo- 1-((1- (trifluoro methyl) -IH-pyrazo 1-4- yl) ami no) pro pan -2-yl) th io hene-2-carboxam ide, (S)-5-(((5-chloro-2-methyl yridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((5-methyl-l, 3, 4-thiadiazol-2-yl)amino)-l-oxopropan-

[0381] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methyl yridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo-1 -(th iazol-2-y lam i no) ropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5-methylisoxazol -3- y I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methyl yridin-

[0382] 3-yl)amino)methyl)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-3-yl)amino)-l-oxopropan-2- y I) th io hene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-(isoxazol-3-ylamino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-N-(l- ((1,3, 4-th iadiazol -2-yl) ami no) -3-cyclopenty 1-1 -oxopropan -2-yl) -5- (((5-ch loro-2- methy I pyrid in -3-yl)amino) methyl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5-methylthiazol-2-yl)amino)-l- oxop ropa n -2 -y I) th io hene-2 -carboxamide, (S)-N-(l-((lH-pyrazol-5-yl)amino)-3- cyclopenty I -1 -oxopropa n -2-yl) -5- (((5-chloro-2-methy I pyrid in -3-yl)amino) methyl) th iophene-

[0383] 2 -carboxamide, (S)-5-(((5-chloro-2-methyl yridin-3-yl)amino) methyl) -N-(3 -eye Io pentyl -1- ((l-methyl-lH-pyrazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-imidazol-4- y I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methyl yridin-

[0384] 3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-((5-(trifluoromethyl) -4H-1, 2, 4-triazol-3- yl)amino)propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methyl yridin-3- yl)amino)methyl)-N-(3-cyclo entyl-l-((3-methylpyridin-4-yl)amino)-l-oxopropan-2- y I) th io hene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((l- methyl- IH-indol -5-yl) a mino)-l-oxopropan-2-yl)thiophene-2- carboxamide, (S)-N-(l-((lH-benzo[d]imidazol-5-yl)amino)-3-cyclo entyl-l-oxo ro an-2- yl)-5-(((5-chloro-2-methyl yridin-3-yl)amino)methyl)thiophene-2-carboxamide, (S)-N-(l- ((lH-indazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxamide, (S) -5 -(((5 -ch loro -2 -methyl pyrid in -3- yl)a min o) methyl) -N-(3 -eye I opentyl-l-((l-m ethyl -lH-benzo[d]imidazo I -5 -yl) amino) -1- oxop ropa n -2 -y I) th io hene-2 -carboxamide, (S)-N-(l-((lH-indol-5-yl)amino) -3-cyclopenty I - 1 -oxopropan -2-yl) -5- (((5-ch loro-2- methyl pyrid in -3-yl) ami no) methyl) th iophene-2- carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- (cyc lo ropy lam i no) -1 -oxopropan -2-yl) th iazole-5-carboxam ide, (S)-N-(3- (bicyclo[l.l.l]pentan-l-yl)-l-(cyclopropylamino)-l-oxopropan-2-yl)-5-(((5-chloro-2- methy I pyrid in -3-yl)amino) methyl) th iophene-2-carboxam ide, 5-(((5-chloro-2-methyl yridin- 3-yl)amino) methyl) -N-((S)-3-(4,4-difluorocyclohexyl)-l-(((lr,3S) -3- hydroxycyclobuty I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5 -(((5-ch loro-2- methyl pyridin-3-yl)amino) methyl) -N-((S) -3 -(4, 4-difluorocyc I oh exyl)-l-(((lr,3S) -3 -hydroxys’ methylcyclobutyl) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro- 2-methylpyridin-3-yl)amino) methyl) -N-(4-cyclohexyl-l-(cyclopropylamino)-l-oxobutan-2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- (4,4-difluorocyclohexyl)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene- 2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((S)-l-

[0385] (cyclopropy lam i no) -3-((ls,4R) -4- hydroxycyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((S)-l-

[0386] (cyclopropy lam i no) -3-((lr,4S) -4- hydroxycyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S)-2-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-4-ylamino) propan- 2 -y I) th iazole-5 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-2- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5- y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4-ylamino)propan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid in-3-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl)-l-oxo-l-(pyri midin -5- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3- (4, 4-difluorocyc I oh exyl)- 1-oxo- l-(pyridazin-4-ylami no) propan-2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- 1 - (py ridazi n -3 -y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridin-2- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-2-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(3-(4,4-difluorocyclohexyl)-l-oxo-l-(pyrimidin-5-ylamino)propan-2- y I) th iazole-5 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino)propan-2-yl)thiazole-5-carboxamide, (S)- 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin -2- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol-4-yl)amino)-l-oxopropan-

[0387] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrazin-2-ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-l, 2, 4-triazol-

[0388] 3-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(3,3-dimethylcyclobutyl)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(l-(cyclopropylamino)-l-oxo-3-(spiro[3.3]heptan-2-yl)propan-2- y I) th iophene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l- (cyclopropylami no) -1 -oxo-3- (spiro [3.3] heptan -2-yl) propan-2-yl)thiazole-5-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-((l-methyl-lH-pyrazol-4- y I) ami no) -1 -oxo-3- (spiro [3.3] heptan -2-yl) propan -2-yl) th iophene-2-carboxam ide, (S)-2- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(l-((l -methyl -lH-pyrazol-4-yl)amino)-l- oxo-3 - (s pi ro [3.3] h epta n -2 -y I) pro pan -2 -y I) th iazole-5 -carboxamide, (S) -5 -(((5 -ch I oro-2- methyl pyridin-3-yl)amino) methyl) -N-(l-oxo-l-(pyridazin-4-ylamino)-3-(spiro[3.3] heptan -2- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)-N-(l-oxo-l-(pyridazin-4-ylamino)-3-(spiro[3.3]heptan-2-yl) propan-2- y I) th iazo I e-5 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-3- ((S)-cyclohex-3-en-l-yl)-l-(cyclopropylamino)-l-oxopropan-2-yl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-3-((R) -cyclohex-3- en -1-y I) -l-(cyclopropy la mino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro- 2-methylpyridin-3-yl)amino) methyl) -N-((lS,2S)-l-cyclopentyl-3-(cyclopropylamino) -l- hyd roxy-3 -oxo pro pa n -2 -y I) th io phene-2 -carboxamide, 5- (((5-ch loro-2- methyl pyridin -3- yl)a min o) methyl) -N-((l R, 2S) - 1-cyc I open tyl-3- (eye Io propyl a mino) -l -meth oxy-3 -oxo pro pan-

[0389] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloropyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(py rid in -3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5- chloropyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l -methyl -lH-pyrazol-4-yl)amino)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, (S) -5- (((5-ch loropyridin-3-yl)amino) methyl) -N- (3 -eye I open tyl-l-oxo-1- (py rim id in -5 -ylami no) pro pa n-2-y I) thiophene -2 -carboxamide, 5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -l-oxo-3-((ls,3R)-

[0390] 3-(trifluoromethyl)cyclobutyl)propan-2-yl)thiophene-2-carboxamide, 5 - (((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -l-oxo-3-((lr,3S) -3- (trifluoromethyl)cyclobutyl)propan-2-y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino) -3-(6,6-difluorospiro[3.3] heptan-

[0391] 2 -y I) - 1 -oxop ropa n -2 -y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)-N-(l-(cyclopropylamino)-l-oxo-3-(spiro[2.3] hexan-5-yl)propan-2- y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l- (cyclopropy lam i no) -3-((ls,4R)-4-fluorocyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-l-

[0392] (cyclopropylamino)-3-((lr,4S)-4-fluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-l-

[0393] (cyclopropy lam i no) -3-((S)-4-fluorocyclohex-3-en-l-y I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-l-

[0394] (cyclopropy lam i no) -3-((R)-4-fluorocyclohex-3-en-l-y I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- ((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-cyclopentyl-l-((5- (difluoromethyl) -l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- ((3-f luoro- 1 -methy I -IH-pyrazol -4-yl) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-cyclopentyl-l-((3- (difluoromethyl) -l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide, (S) -5- (((5-ch loro-2- methyl pyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1- ((l-methyl-lH-l,2,3-triazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5- (((4-chloropyridin-2-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4- y I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2-methylpyridin-

[0395] 3-yl)amino) methyl) -N-(3-(cyclopent-3-en-l-yl)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, (S) -5- (((5-ch loropyridin-3-yl)amino) methyl) -N- (3- (cyclopent-3-en -1 -yl)-l-((l -methyl -IH-pyrazol -4-yl) ami no) -1 -oxopropan -2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- (cyclopent-3-en-l-yl)-l-(cyclopropylamino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloropyridin-3-yl)amino) methyl) -N-(3-(cyclopent-3-en-l-yl)-l-

[0396] (cyclopropy lam i no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S) -N-(3-cyclopentyl-l- ((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((5-(difluoromethyl) -2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide, (S) -N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((5-(difluoromethyl) pyridin-3- yl)amino) methyl)thiophene-2-carboxamide, 5-(((5-chloro-2-methyl pyridin-3- yl) ami no) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol -4-yl) ami no) -1 -oxo-3- ((S)-tetrahydro-2H- py ra n -2 -y I) p ropa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl) ami no) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol -4-yl) ami no) -1 -oxo-3- ((R)-tetrahydro-2H- py ra n -2 -y I) p ropa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S)-1- (eye Io propyl a mino)-l-oxo-3-((S) -tetrahydro-2H-pyran-2- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S)-1- (eye Io propyl a mino)-l-oxo-3-((R) -tetra hydro-2H-pyran-2- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl) ami no) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol -4-yl) ami no) -1 -oxo-3- ((R)-tetrahydro-2H- py ra n -3 -y I) p ropa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl) ami no) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol -4-yl) ami no) -1 -oxo-3- ((S)-tetrahydro-2H- py ra n -3 -y I) p ropa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S)-1- (eye Io propyl a mino)-l-oxo-3-((R) -tetra hydro-2H-pyran-3- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S)-1- (eye Io propyl a mino)-l-oxo-3-((S) -tetrahydro-2H-pyran-3- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl) am i no) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol -4-yl) ami no) -1 -oxo-3- ((R)- tetra hyd rofu ra n -2 -y I) pro pa n -2 -y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-

[0397] 3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxo-3-((S)- tetra hyd rofu ra n -2 -y I) pro pa n -2 -y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin- 3 -yl) ami n o) m ethyl) -N-((S) - l-(cyc Io propylamino) -1-oxo -3 -((R) -tetrahydrofuran -2- y I) p ro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S) -1- (eye Io propyl a mino)-l-oxo-3-((S) -tetrahydrofuran -2 -yl) pro pan-

[0398] 2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-3- ((ls,4R)-4-methoxycyclohexyl)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l-oxopropan-2- y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l- (cyclopropy lam i no) -3-((lr,4S) -4- methoxycyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-3-((lr,4S)-4- methoxycyclohexyl)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l-oxopropan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloropyridin-3-yl)(methyl)amino) methyl) -N-(3 -cyclopentyl -1-((1- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -N-(5- chloropyridin-3-yl)-N-((5-((3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino) -l- oxop ropa n -2 -y I) ca r ba moy I) th io phen -2 -y I) methyl) glycine, (S) -5-(((5-chloro-2-methylpyridin-

[0399] 3-yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(l,3-dioxan -2-yl) -1-oxopropan -2- y I) th iophene-2 -carboxamide, (S) -N-(3 -(1,3 -dioxan-2 -yl) -l-((l- methyl -IH-pyrazo 1-4- yl) ami no)- 1 -oxopropan -2-yl) -5- (((5-ch loro-2- methyl py rid in -3-yl)a mi no) methyl) th iophene- 2 -carboxamide, (S) -N-(3-(l, 3 -dioxan-2 -yl) -1- ((1- methyl -IH-pyrazo I -4-yl) ami no) -1- oxopropan-2-yl)-5-(((5-chloropyridin-3-yl)amino) methyl)thiophene-2-carboxamide, (S)-5- (((5-ch loro-2- methy I pyrid in -3-y I) am i no) methy I) - N - (3 - (5,5 -d if I uoro-1 ,3-d ioxan -2-y I) -1 - ((1 - methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5- chloropyridin-3-yl)amino) methyl) -N-(3-(5,5-difluoro-l,3-dioxan -2-yl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxo pro pan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxo-3-(3- (trifluoromethyl)cyclobutyl) propan-2-y I) th io phene-2 -carboxamide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l-oxo-3- ((ls,3R) -3- (trifluoromethy I) cyclobutyl) pro pan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro- 2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l-oxo-3- ((lr,3S)-3-(trifluoromethyl)cyclobutyl)propan-2-yl)thiophene-2-carboxamide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(6,6-difluorospiro[3.3] heptan -2-yl) -1-((1- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, 5-(((5-chloro- 2-methylpyridin-3-yl)amino) methyl) -N-((S)-3-((ls,4R)-4-fluorocyclohexyl) -l-((l-methyl- lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-((lr,4S)-4-fluorocyclohexyl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxo pro pan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -3-((lR,3R) -3- f I uorocyclopenty I) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -3-((lR,3S) -3- fl uorocyclopenty I) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -3-((lS,3S) -3- fl uorocyclopenty I) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-(cyclopropylamino) -3-((lS,3R) -3- fl uorocyclopenty I) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-((lR,3R)-3-fluorocyclopentyl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-((lR,3S)-3-fluorocyclopentyl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-((lS,3S)-3-fluorocyclopentyl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-((lS,3R)-3-fluorocyclopentyl) -l-((l-methyl-lH- py razol-4-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S) -3-((S)-5,5-difluorotetrahyd ro-2H-pyran-2-yl) -1- ((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, 5-(((5- ch loro-2-methyl pyrid in-3-yl)amino) methyl) -N-((S) -3- ((R)-5,5-difluorotetrahydro-2H- pyran- 2-yl)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((2,5- d i methy I pyrid in -3-yl) ami no) methyl) th iophene-2-carboxam ide, and (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-(isoxazol-4-ylamino) -l-oxopropan-2- y I) th iophene-2 -carboxamide.

[0400] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl- 1 -oxo-1 -(pyrid in -3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch loro-2- methyl pyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino) propan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(pyridazin-4-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-

[0401] 4-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-3-ylamino) propan-

[0402] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- (4,4-difluorocyclohexyl)-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l- (cyclopropylamino)-3-(4,4-difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-(4,4-difluorocyclohexyl) -1-oxo- 1 - (py rid azin -4-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -2 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyri midin -5-ylamino) propan-

[0403] 2 -y I) th iazole-5 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- (4,4-difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino)propan-2-yl)thiazole-5-carboxamide,

[0404] 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lR,2S)-l-cyclopentyl -3- (cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-(4,4-difluorocyclohexyl)-l-(((lr,3S) -3- hyd roxycyclobuty I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-3-(4,4-difluorocyclohexyl)-l-(((lr,3S)-3-hydroxy-

[0405] 3- methylcyclobutyl) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-2-(((5-chloro- 2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin -4- y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4-ylamino)propan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- ((2-methyl-2H-l,2,3-triazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrazin-2- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-l, 2, 4-triazol-3-yl)amino)-l-oxopropan- 2 -y I) th io phene-2 -carboxamide, (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)- 1 -oxopropan -2-yl) -5- (((2,5-dimethy I pyrid in -3-yl) a mino) methyl) th iophene-2-carboxam ide, and (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-(isoxazol -4- y la mino)-l -oxopropan -2-yl) th iophene-2-carboxam ide.

[0406] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((lR,2S)-l- cyclopentyl-3-(cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino)-3-(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)- 1 -oxo pro pa n -2 -y I) th io phene-2 -carboxamide; 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S) -3- (4, 4-difluorocyc I oh exyl)-l-(((lr,3S) -3 -hydroxycyclo butyl) ami no)- 1 -oxo pro pa n -2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a mino) methyl) -N-((S) -3- (4, 4-difluorocyc I oh exyl)-l-(((lr,3S) -3 -hydroxy-3 - methylcyclobutyl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch I oro-2- methyl pyridin-3-yl)amino) methyl) -N-(3 -eye I open tyl-l-oxo-l-(pyridazin -4-yl amino) propan-

[0407] 2 -y I) th io phene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(pyridazin-4-y la mino) propan -2-yl) th iazole-5-carboxam ide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-2-(((5-chloro-2-methylpyridin-3- yl)a mino) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyrimidin -5 -y la mi no) propan -2 -yl)thiazole-5- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -4-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridin-3-ylamino) propan -2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- (4,4-difluorocyclohexyl)-l-oxo-l-(pyrimidin-5-ylamino) propan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino) propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-cyclopentyl-l-oxo-l-(pyridazin-

[0408] 3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol-4-yl)amino)-l-oxopropan-

[0409] 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrazin-2-ylamino) propan-2-yl)thiophene-2-carboxamide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-l, 2, 4-triazol-

[0410] 3-y l)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((2,5-dimethylpyridin-3- yl)amino) methyl)thiophene-2-carboxamide, and (S)-5-(((5-chloro-2-methylpyridin-3- y I) a mino) methyl) -N-(3 -eye I o pentyl- l-(isoxazol-4-yl a mino) -1-oxo pro pan -2 -y I) th io phene -2- carboxamide.

[0411] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lR,2S) -l- cyclopentyl-3-(cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino) -3-(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)- 1 -oxo pro pa n -2 -y I) th io phene-2 -carboxamide; 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((S) -3- (4, 4-difluorocyc I oh exyl)-l-(((lr,3S) -3 -hydroxycyclo butyl) ami no) -

[0412] 1 -oxo pro pa n -2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridazin-4-ylami no) propan -2 -yl)thiop he ne -2- carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid azin -4-y lam i no) pro pan -2-yl) th iazole-5-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyri midin -5-ylamino) propan-

[0413] 2 -y I) th io phene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty I -1 -oxo- l-(py rim id in -5-ylamino) propan -2-yl) th iazole-5-carboxam ide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridin-3-ylamino) pro pan -2 -yl)th iophene -2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-! -oxo-1 -(pyrim id in -5-ylamino) pro pan -2-yl)thiophene-2-carboxam ide, (S) -5 - (((5 -ch I o ro-2 - m ethy I py rid i n -3 -y I) a m i n o) methy I) - N - (3 - (4,4-d if I uo rocyc I oh exy I) - 1 -oxo- 1 - (pyridazin-4-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-3-ylamino) propan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -((2- methy 1-2 H-l, 2, 3-triazol-4-yl)ami no) -1 -oxopropan -2-yl) th iophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (pyrazin-2-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-l H-l, 2, 4-triazol-3- y I) ami no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-N-(3-cyclopentyl-l-((l-methyl- lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((2,5-dimethylpyridin-3- yl)amino) methyl)thiophene-2-carboxamide, and (S)-5-(((5-chloro-2-methylpyridin-3- y I) a mino) methyl) -N-(3 -eye I o pentyl- l-(isoxazol-4-yl a mino) -1-oxo pro pan -2 -y I) th io phene -2- carboxamide.

[0414] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-

[0415] 1-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-N-(l-((lH-indazol-5-yl)amino)-3- cyclopenty 1-1 -oxopropan -2-yl) -5- (((5-chloro-2-methy I py rid in -3-yl)a mino) methy I) th iophene-

[0416] 2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -2-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-4-ylamino) propan- 2 -y I) th iazole-5 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2-carboxamide, (S) -2- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5- y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4-ylamino)propan-2-yl)thiophene-2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid in-3-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl) -l-oxo-l-(pyri midin -5- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3- (4, 4-difluorocyc I oh exyl)- 1-oxo- l-(pyridazin-4-ylami no) propan-2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- 1 - (py ridazi n -3 -y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridin-2- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol-4-yl)amino)-l-oxopropan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrazin-2-ylamino) propan-2-yl)thiophene-2-carboxamide, (S)-N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)-5-(((2,5- dimethylpyridin-3-yl)amino) methyl)thiophene-2-carboxamide, and (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-(isoxazol-4-ylamino) -l-oxopropan -2- y I) th iophene-2 -carboxamide. In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-

[0417] 1-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-N-(l-((lH-indazol-5-yl)amino)-3- cyclopenty 1-1 -oxopropan -2-y I) -5- (((5-chloro-2-methy I py rid in -3-yl)a mino) methyl) th iophene-

[0418] 2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -2-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-4-ylamino) propan- 2 -y I) th iazole-5 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2-carboxamide, (S) -2- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5- y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridin-3-ylamino) pro pan -2 -yl)th iophene -2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l -oxo-1 -(pyrim id in-5-ylami no) pro pan -2-yl)thiophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-(4,4-difluorocyclohexyl) -1-oxo- 1 -(py rid azin -4-y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridazin-3-ylamino) propan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(py rid in -2-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol- 4-y l)amino)-l -oxopropan -2-y I) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrazin-2-ylamino) propan -2- y I) th iophene-2 -carboxamide, (S) -N-(3-cyclopentyl-l-((l -methyl -lH-pyrazol-4-yl)amino)-l- oxopropan-2-yl)-5-(((2,5-dimethylpyridin-3-yl)amino) methyl)thiophene-2-carboxamide, and (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(3-cyclopentyl-l-(isoxazol -4- y la mino)-l -oxopropan -2-y I) th iophene-2-carboxam ide.

[0419] In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-

[0420] 1-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridazin-4- ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3- yl)a mino) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridazin-4-ylami no) propan -2 -yl)thiazole-5- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(pyrim id in -5-y lam i no) pro pan -2-y I) th iophene-2-carboxam ide, (S) -2-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyri midin -5-ylamino) propan-

[0421] 2-y I) th iazole-5 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyridin-3-ylamino) propan-2-yl)thiophene-2-carboxamide, (S) -5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-(4,4-difluorocyclohexyl) -l-oxo-l- (pyrimidin-5-ylamino) propan-2-yl)thiophene-2-carboxamide, (S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl) -l-oxo-l-(pyridazin -4- ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(3 -eye I o pentyl- 1-oxo- 1 - (py rid azin -3 -ylami no) propan -2 -y I) th iop he ne -2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- ((2-methyl-2H-l,2,3-triazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(3-cyclopentyl-l-oxo-l-(pyrazin-2- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S) -N- (3-cyclope ntyl-l-((l- methyl- IH- pyrazol -4-yl)a mino) -1-oxopropan -2-yl) -5-(((2,5-di methyl pyridin -3- yl)amino) methyl)thiophene-2-carboxamide, and (S) -5 -(((5 -ch loro -2 -methyl pyridin -3- y I) a mino) methyl) -N-(3 -eye I o pentyl- l-(isoxazol-4-yl a mino) -1-oxo pro pan -2 -y I) th io phene -2- carboxamide.

[0422] In another preferred embodiment, the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloropyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino) -1-oxopropan -2-yl) -5-(((5- (difluoromethyl)-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide, 5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol-4-yl)amino) -l- oxo-3 - ((R) -tetra hyd rof u ra n -2 -y I) p ropan -2 -y I) th io phene -2 -carboxamide, 5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l-oxo-3- ((S) -tetra hyd rof u ra n -2 -y I) propan -2 -y I) th iophene-2 -carboxamide, (S) -N-(3-(l,3-dioxan-2- yl)-l-((l- methyl -IH-pyrazol -4-yl) ami no) -1-oxopropan -2-yl) -5- (((5 -ch loro-2- methyl pyridin- 3-y l)a mino) methyl) th iophene-2-carboxam ide, (S) -N-(3-cyclopentyl -l-((l-methyl-l IH- pyrazol -4-yl) a mino) -1-oxopropan -2-yl) -5 -(((2,5 -di methyl pyridin -3- yl)amino) methyl)thiophene-2-carboxamide, and (S) -5 -(((5 -ch loro -2 -methyl pyridin -3- y I) a mino) methyl) -N-(3 -eye I o pentyl- l-(isoxazol-4-yl a mino) -1-oxo pro pan -2 -y I) th io phene -2- carboxamide.

[0423] Description of pharmaceutical compositions according to the present invention

[0424] As indicated above, the invention relates in a second aspect to a pharmaceutical composition comprising a pharmaceutically effective amount of the above-outlined compounds and optionally a pharmaceutically acceptable carrier or excipient.

[0425] A pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application. Preferred non - parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred. Preferred parenteral routes include but, are not limited to, one or more of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal and epidural administrations. Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes. Particularly preferred is intratumoral administration. The compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.

[0426] A pharmaceutical composition of the present invention may also be designated as formulation or dosage form. A compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.

[0427] Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration. In general, the inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form. A “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, releasemodifying materials, carrier materials, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.

[0428] The term “pharmaceutically acceptable carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrolidone, crosspovidone and the like. Preferably, the compounds of the present invention are administered in a pharmaceutical composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co- glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody.

[0429] The pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and / or aromatic substances and the like which do not deleteriously react with the active compound. It is to be understood that the term “pharmaceutically acceptable carrier” also covers an antibody that delivers the compound of formula (I).

[0430] If liquid dosage forms are considered for the present invention, these can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners / flavoring agents.

[0431] For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Particularly preferred dosage forms are injectable preparations of a compound of formula (I). Thus, sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and / or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium. Preferred applications for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration.

[0432] Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.

[0433] For administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0434] Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I).

[0435] A solid dosage form may comprise a film coating. For example, the inventive dosage form may be in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.

[0436] The dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and / or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories.

[0437] The phrase “effective amount” means an amount of compound (i.e. compound of formula (I)) that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition. The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective amount (also known as effective dosage) is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg / day, preferably about 0.7 to about 2500 mg / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

[0438] Furthermore, the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof. A prodrug is any compound, which is converted under physiological conditions or by solvolysis to any of the compounds of the invention. A prodrug may be inactive prior to administration but may be converted to an active compound of the invention in vivo.

[0439] Indications, for which the compounds of the present invention may be used

[0440] As indicated above, the above-outlined compounds or an above-outlined pharmaceutical composition are suitable for use in medicine.

[0441] In particular, the compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease associated with Wipl. In this connection, it is to be understood that the compounds according to the present invention or the pharmaceutical composition according to the present invention are capable to modulate or inhibit Wipl.

[0442] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre-cancerous syndromes, and neurological diseases.

[0443] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syndromes. In this connection, it is to be understood that cancers may be in the form of solid tumors such as sarcomas, carcinomas, and lymphomas or in the form of liquid tumors, e.g. leukemia.

[0444] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan - Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

[0445] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of breast cancer, preferably selected from the group consisting of inflammatory breast cancer, triple negative breast cancer (TNBC), and HER2+ breast cancer.

[0446] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of blood cancers, preferably selected from the group consisting of leukemia, lymphoma and multiple myeloma. Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). Of particular relevance is AML.

[0447] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of brain cancers, preferably selected from the group consisting of glioma, glioblastoma, oligodendroglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblastoma.

[0448] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of lung cancers, preferably selected from the group consisting of small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC.

[0449] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of liver cancer, preferably hepatocellular carcinoma (HCC).

[0450] In a preferred embodiment, compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma and glioma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte-Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor.

[0451] It is to be understood that in connection with the medical uses of the invention it can be preferred that the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer.

[0452] Combination therapy may be achieved by use of a single pharmaceutical composition that includes both agents, or by administering two distinct compositions at the same time, wherein one composition includes a compound of the present invention, and the other includes the second agent(s).

[0453] The two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks. In embodiments where the other agents are applied separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agents would still be able to exert an advantageously combined effect on the patient. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. In some embodiments, the compound of the present invention is administered prior to administration of the distinct cancer treatment. In other embodiments, the distinct cancer treatment is administered prior to administration of the compound of the present invention.

[0454] The present invention is further illustrated by the following examples.

[0455] Examples

[0456] The following abbreviations are used hereinafter.

[0457]

[0458] The compounds of the present invention were prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. ChemDraw 20 was used to generate the IUPAC name. Analytical data of compounds made according to the following examples are shown in Table 1.

[0459] Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications. Unless otherwise specified, all temperatures are expressed in ° C and all reactions are conducted at r.t..

[0460] Methods and analytical data:

[0461] NMR is recorded on Bruker Avance or Bruker Advance II - Ultrashield 400 spectrometers. Chemical shifts (3) are reported in ppm relative to the residual solvent signal (3 = 2.5 ppm for NMR in DMSO-o / ). NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets), td (triplet of doublets), qd (quartet of doublets), br (broad), hex (hextet).

[0462] HPLC methods:

[0463] Method Al: Apparatus: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320 nm, PDA: 210-320 nm, MSD: Agilent G6135B ESI, pos / neg 100- 1000, ELSD G7102A: Evap 40 ° C, Neb 50 ° C, gasflow 1.6 ml / min, Column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 25 ° C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2min= 98% B, t2.7min= 98% B, Post time: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH=9.5), Eluent B: MeCN.

[0464] Method A2: Apparatus: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320 nm, PDA: 210-320 nm, MSD: Agilent G6135B ESI, pos / neg 100- 1000, ELSD G7102A: Evap 40 ° C, Neb 40 ° C, gasflow 1.6 ml / min, Column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 40 ° C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2min= 98% B, t2.7min= 98% B, Post time: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in MeCN.

[0465] Method A3: Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: gaspressure 40 psi, drift tube temp: 50 ° C; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 25

[0466] C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2.0miri= 98% B, t27mjn= 98% B, Posttime: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH=9.5), Eluent B: MeCN.

[0467] Method A4: Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: gaspressure 40 psi, drift tube temp: 50 ° C; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 40

[0468] C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2.0miri= 98% B, t2 7min= 98% B, Posttime: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in MeCN.

[0469] Method A5: Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, MS: QDA ESI, pos / neg 100-800; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 25 ° C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2 0min= 98% B, t2 7min= 98% B, Posttime: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH=9.5), Eluent B: MeCN.

[0470] Method A6: Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, MS: QDA ESI, pos / neg 100-800; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 40 ° C, Flow: 0.6 mL / min, Gradient: t0= 5% B, t2 0min= 98% B, t2 7min= 98% B, Posttime: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in MeCN.

[0471] Purification methods by reversed phase chromatography:

[0472] Method Bl: Instrument type: Reveleris™ prep MPLC; Column: Waters XSelect CSH C18 (145x25 mm, 10 ); Flow: 40 mL / min; Column temp: r.t.; Eluent A: 10 mM ammonium bicarbonate in water pH = 9.0); Eluent B: 99% MeCN + 1% 10 mM ammonium bicarbonate in water; detection by UV and / or ELSD. Appropriate fractions were combined and lyophilised.

[0473] Method B2: Instrument type: Reveleris™ prep MPLC; Column: Dr. Maisch Reprosil C18 150x25 mm, 10 ); Flow: 40 mL / min; Column temp: r.t.; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% (v / v) formic acid in MeCN; detection UV : 220, 254, 340 nm, ELSD. Appropriate fractions were combined and lyophilised.

[0474] Method B3: MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; column: Waters XSelect (C18, 100x30 mm, 10pm); flow: 55 ml / min prep pump; column temp: r.t.; eluent A: 10 mM ammonium bicarbonate in water pH=9.5, eluent B: 100% MeCN; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 - 800; fraction collection based on MS and DAD.

[0475] Method B4: MS instrument type: Agilent Technologies G6120AA Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Waters XSelect CSH (C18, 100x30 mm, lOp); Flow: 55 ml / min; Column temp: r.t.; Eluent A: 0.1% formic acid in water; Eluent B: 100% MeCN; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100 - 1000; fraction collection based on MS and DAD

[0476] Purification methods by SFC:

[0477] Method Cl: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml / min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in EtOH; Isocratic method: 30% B; Detection: UV 210 nm; Timed fraction collection.

[0478] Method C2: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 PDA Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 35 ° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in EtOH; Isocratic method: 50% B; Detection: PDA (210-400 nm); Fraction collection based on PDA TIC.

[0479] Method C3: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i -Cel lu lose-5 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml / min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 10% B; Detection: UV 210 nm; Timed fraction collection.

[0480] Method C4: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 PDA Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Chiral pak IC for SFC (250x20 mm, 5 pm); Column temp: 35 ° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Linear gradient: T=0 min 35% B, T=6 min 50% B; Detection: PDA (210-400 nm); Timed fraction collection.

[0481] Method C5: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Amylose-1 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml / min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 5% B; Detection: UV 215 nm; Timed fraction collection.

[0482] Method C6: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux Amylose-1 (250x21mm, 5pm); Column temp: 35° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Linear gradient: t=0 min 35% B, t=5 min 50% B; t=15 min 50% B; Detection: PDA (210-400 nm); Timed fraction collection. Method C7: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Diacel Phenomenex Lux i -Cel I u lose-5 (250x21mm, 5pm); Column temp: 35° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 50% B for 9 min; Detection: PDA (210-400 nm); Timed fraction collection.

[0483] Method C8: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i -Cel lu lose-5 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml / min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 5% B; Detection: UV 210 nm; Timed fraction collection.

[0484] Method C9: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 40° C; Flow: 100 ml / min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 15 % B; Detection: UV 210 nm; Timed fraction collection.

[0485] Method CIO: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux i-Amylose-3 (250x21mm, 5pm); Column temp: 35° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Linear gradient: t=0 min 40% B, t=5.5 min 50% B; t=7.5 min 50% B; Detection: PDA (210- 400 nm); Fraction collection based on PDA TIC.

[0486] Method CH: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux i-Amylose-3 (250x21mm, 5pm); Column temp: 35° C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Ethanol; Linear gradient: t=0 min 10% B, t=20 min 50% B; Detection: PDA (210-400 nm); Timed fraction collection.

[0487] Synthetic procedures intermediates:

[0488] General Procedure Al

[0489] BocHN

[0490] Step 1 To an argon-sparged solution of (R)-2-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine (1.0 equiv.) in anhydrous THF (0.3 M) at -78 ° C was added 2.5 M n-BuLi in hexanes (1.2 equiv.) over a period of 2 min at -78 ° C. The reaction mixture was stirred for 15 min. Then, a solution of a bromide (1.25 equiv.) in anhydrous THF (0.3 M) was added and the reaction was stirred at -78 ° C for 15 min. The reaction mixture was brought to r.t. and stirred for an additional 2h. The reaction mixture was poured into a mixture of water / brine (1:1) and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-5%) affording the dihydropyrazine intermediate.

[0491] Step 2 The dihydropyrazine intermediate (1.0 equiv.) was dissolved in MeCN (0.2 M) to which was added 0.1 M TFA (3 equiv.) and the reaction was stirred at r.t. for 14h. The reaction was concentrated in vacuo. To the concentrate was added a saturated aqueous solution of NaHCO3(3 mL) and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting amine intermediate was used as such in the next step.

[0492] Step 3 The amine intermediate (1.0 equiv.) was dissolved in DCM (0.05 M) and TEA (2.0 equiv.) and di-tert-butyl dicarbonate (1.0 equiv.) were added. The reaction mixture was stirred at r.t. for 14h. The reaction mixture was concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) affording the Boc-protected intermediate.

[0493] Step 4 To a solution of Boc-protected intermediate (1.0 equiv.) in MeOH (0.5 M) was added a 2.5 M aqueous solution of NaOH (5 equiv.) at r.t.. The reaction was stirred at r.t. for 14-72h after which the reaction was acidified with a 4 M aqueous solution of HCI . The product was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo affording the intermediate Boc-protected amino acid which was used as such.

[0494] General Procedure A2:

[0495] Step 1a,

[0496] Step la To a solution of Boc-protected amino acid (1 equiv.) in DCM (0.15-0.4 M) was added TEA (2 equiv.) and HATU (1.2 equiv.). After stirring at r.t. for 10 min amine (1.2 equiv.) was added and stirring was continued at r.t. for 2-20h. The reaction mixture was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%).

[0497] Step lb To (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (1 equiv.) and amine (1.2 equiv.) was added anhydrous pyridine (0.39 M) and the resulting solution was cooled with a cooling bath to -12 ° C. Phosphorus oxychloride (1.7 equiv.) was added and after 30 min the temperature was raised to 0 ° C. The temperature was allowed to reach r.t. overnight. To the reaction mixture was added water (1.9 M), filtered and purified by reversed phase chromatography according to Method Bl.

[0498] Step lc A solution of the carboxylic acid (1 equiv.), TEA (1.2-3 equiv.) and HATU (1.0-1.2 equiv.) in DCM (0.1-0.2 M) was stirred at r.t. for 10 min before amine (1.0-1.2 equiv.) was added and stirring was continued for 2-20h. To the reaction mixture was added an aqueous saturated solution of NaHCO3and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to obtain the corresponding amide.

[0499] Step 2 The Boc-protected amino acid was dissolved in DCM (0.02-0.1 M) and a solution of 4 M HCI in dioxane (15-20 equiv.) was added. After stirring at r.t. for l-24h the reaction mixture was concentrated in vacuo o afford the HCI salt intermediate.

[0500] Intermediate 1: 5-(l-((5-chloro-2-methylpyridin-3-yl)amino)ethyl)thiophene-2-carboxylic acid

[0501] 5-Chloro-2-methylpyridin-3-amine (84 mg, 0.59 mmol), molsieves (4 A) and 5- acetylthiophene-2-carboxylic acid (100 mg, 0.588 mmol) were mixed (solvent free) and the mixture was heated in a closed vial for 3h at 150 ° C. The melt was allowed to reach r.t. and anhydrous THF (2.5 mL) was added. Under an inert atmosphere, the closed reaction vial was heated for 5 min at reflux and was then allowed to reach r.t.. The turbid solution was filtered to give a clear filtrate to which sodium borohydride (22.2 mg, 0.588 mmol) was added in portions. The reaction mixture was stirred for 2h at 60 ° C and was diluted with 2 mL water / MeOH / formic acid (1:2:1) The resulting solution was purified by reversed phase chromatography according to Method B2 to afford 2. 5-(l-((5-chloro-2-methylpyridin-3- yl)amino)ethyl)thiophene-2-carboxylic acid (37 mg, 0.13 mmol, 21% yield) as a white solid.

[0502] Intermediate 2: 5-(l-((5-chloro-2-methylpyridin-3-yl)amino)-2,2,2- trifluoroethyl)thiophene-2-carboxylic acid

[0503] 5-Chloro-2-methylpyridin-3-amine (28.6 mg, 0.201 mmol), molsieves (4 A) and 5-(2,2,2- trifluoroacetyl)thiophene-2-carboxylic acid (50 mg, 0.22 mmol) were mixed (solvent free) and the mixture was heated in a closed vial for 2h at 150 ° C. The melt was allowed to reach r.t. and anhydrous THF (2.5 mL) was added. Under an inert atmosphere, the closed reaction vial was heated for 5 min at reflux and was then allowed to reach r.t.. The turbid solution was filtered to give a clear filtrate to which sodium borohydride (8.44 mg, 0.223 mmol) was added in portions. The reaction mixture was stirred for 2h at 60 ° C and was diluted with 2 mL water / MeOH / formic acid (1:2:1). The resulting solution was purified by reversed phase chromatography according to Method B2. 5-(l-((5-chloro-2-methylpyridin- 3-yl)amino)-2,2,2-trifluoroethyl)thiophene-2-carboxylic acid (16 mg, 0.046 mmol, 20% yield) was obtained as a beige solid, which was used as such.

[0504] Intermediate 3: 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid

[0505] A solution of 5-formylthiophene-2-carboxylic acid (1.41 g, 9.04 mmol) and 3-amino-5- chloropicoline (1.29 g, 9.05 mmol) in MeOH (20 mL) was stirred at 50 ° C overnight. The reaction mixture was concentrated in vacuo and redissolved in anhydrous THF (20 mL) to which was added sodium borohydride (0.34 g, 9.04 mmol). The reaction mixture was stirred at 50 ° C and after 2h the temperature was raised to 60 ° C. Additional sodium borohydride (0.095 g, 2.5 mmol) was added and the mixture was stirred overnight. After cooling the reaction mixture to r.t. it was quenched with a saturated aqueous solution of Na HCO3to which was added EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc after which the aqueous layer was acidified with a 4 M aqueous solution HCI until pH 4 was reached. The obtained suspension was filtered and the resulting residue was dried in vacuo o afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2- carboxylic acid (1.47 g, 5.22 mmol, 57% yield) as an off-white solid.

[0506] Intermediate 4: 2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid

[0507] A suspension of 5-chloro-2-methylpyridin-3-amine (45.4 mg, 0.32 mmol), 2-formylthiazole- 5-carboxylic acid (50 mg, 0.32 mmol) and acetic acid (18.2 pL, 0.32 mmol) in DCM (2.7 mL) was stirred at r.t. for 3h. The reaction mixture was concentrated in vacuo and redissolved in DCM (2.7 mL) to which was added acetic acid (18.2 pL, 0.32 mmol). The mixture was stirred at r.t. overnight. The reaction mixture was concentrated in vacuo, redissolved in MeOH (2.7 mL) and purged with nitrogen for 10 min. To the resulting mixture was added 10% palladium on activated carbon (67.7 mg, 0.03 mmol). Then the reaction mixture was purged with hydrogen for 10 min and left to stir under a hydrogen atmosphere at r.t. for 5h. The reaction mixture was filtered over Celite® and the residue was washed with MeOH and water. The resulting filtrate was concentrated in vacuo to obtain 2-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)thiazole-5-carboxylic acid (88 mg, 0.30 mmol, 95% yield) as a light-yellow solid.

[0508] Intermediate 5: (S)-2-(5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2- ca rboxam id o) -3 -eye Io pentyl propanoic acid

[0509] To a solution of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (1.24 g, 4.39 mmol) and TEA (1.8 mL, 13 mmol) in DCM (29 mL) was added HATU (2.00 g, 5.26 mmol). After stirring at r.t. for 5 min methyl (S)-2-amino-3-cyclopentylpropanoate hydrochloride (1.00 g, 4.82 mmol) was added and stirring was continued for 2h. A saturated aqueous solution of NaHCO3was added to the reaction mixture and the resulting mixture was extracted with DCM. The combined organic layers were concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (5-100%) to afford methyl (S)-2-(5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)thiophene-2-carboxamido)-3-cyclopentylpropanoate (1.80 g, 4.03 mmol, 91% yield) as a light-yellow gum.

[0510] To a solution of methyl (S)-2-(5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)thiophene-2-carboxamido)-3-cyclopentylpropanoate (1.80 g, 4.13 mmol) in MeOH (20 mL) and water (10 mL) was added lithium hydroxide monohydrate (1.73 g, 41.3 mmol). After stirring at r.t. for 4h the reaction mixture was concentrated in vacuo and partitioned into a saturated aqueous solution of NaHCO3and EtOAc. The layers were separated and the organic layer was subsequently washed with a saturated aqueous solution of NaHCO3. The combined aqueous layers were acidified until pH 4 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo obtain (S) -2-(5-(((5-chloro-2- methy I py rid in -3-yl)amino) methyl) th io p he ne-2 -carboxamide) -3 -cycl ope nty I propanoic acid (1.35 g, 3.16 mmol, 77% yield) as a white solid.

[0511] Intermediate 6: (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide

[0512] To an ice-cold solution of b-cyclopentyl-L-alanine (3.25 g, 20.7 mmol) in a 2 M aqueous solution of NaOH (31 mL, 62 mmol) was added dropwise benzyl chloroformate (3.5 mL, 25 mmol) and the reaction mixture was stirred at 0 ° C for Ih. The obtained emulsion was extracted with Et2O. The aqueous layer was acidified with a 2 M aqueous solution of HCI until ~ pH 4 and was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S) - 2-(((benzyloxy)carbonyl)amino) -3-cyclopentylpropanoic acid (5.66 g, 19.4 mmol, 94% yield) as a transparent oil. The crude material was used without further purification.

[0513] To a solution of (S)-2-(((benzyloxy)carbonyl)amino) -3-cyclopentylpropanoic acid (3.24 g, 11.1 mmol) in anhydrous DMF (56 mL) was added TEA (1.9 mL, 13 mmol) and HATU (4.23 g, 11.1 mmol). After stirring at r.t. for Ih cyclopropylamine (642 mg, 11.2 mmol) was added and stirring was continued for 4h. A saturated aqueous solution of NaHCO3was added to the reaction mixture and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (1-100%) to afford benzyl (S) -(3-cyclopentyl-l- (cyclopropylamino)-l-oxopropan-2-yl)carbamate (3.54 g, 10.6 mmol, 94% yield) as an off- white solid.

[0514] A clear solution of benzyl (S) -(3-cyclopentyl-l-(cyclopropylamino) -l-oxopropan-2- yl)carbamate (3.54 g, 10.7 mmol) in a mixture of EtOH (36 ml_) / THF (36 mL) was purged with nitrogen gas for 20 min. After adding 10% palladium on activated carbon (2.28 g, 1.07 mmol) hydrogen gas was bubbled through the mixture for 10 min and the mixture was stirred at r.t. for 18h. The reaction mixture was filtered and the filtrate was concentrated in vacuo le obtain (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide (1.88 g, 9.20 mmol, 86% yield) as a clear gum.

[0515] Intermediate 7: (S)-2-((tert-butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl) propanoic acid

[0516] To a colorless solution of (2S) -2-amino-3-(4,4-difluorocyclohexyl) propanoic acid HCI (500 mg, 2.05 mmol) in water (6 mL) and dioxane (4 mL) was subsequently added NaHCO3(302 mg, 3.59 mmol) and d i - tert- b u ty I dicarbonate (672 mg, 3.08 mmol). The reaction mixture was stirred overnight at r.t. and was then diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The aqueous layer was acidified until pH 1 with a 2 M aqueous solution of HCI and extracted with EtOAc . The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl)propanoic acid (525 mg, 1.71 mmol, 83% yield) as a colorless oil.

[0517] Intermediate 8: (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide hydrochloride

[0518] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (2.53 g, 9.83 mmol) and cyclopropylamine (0.72 mL, 10 mmol). (S)-2-amino-3-cyclopentyl-N- cyclopropylpropanamide hydrochloride (1.35 g, 5.52 mmol, 56% yield over two steps) was obtained as a white solid. The crude material was used without further purification.

[0519] Intermediate 9: (S) -2 -a min o-3 -eye I open ty I - N - (1 -methyl -IH-pyrazo I -4-yl) propan amide hydrochloride

[0520] Title compound was prepared according to General Procedure A2,a with (S)-2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (200 mg, 0.78 mmol) and 1-methyl-lH- pyrazol-4-amine (0.07 mL, 0.78 mmol). (S) -2-amino-3-cyclopentyl-N-(l-methyl-lH-pyrazol- 4-yl)propanamide hydrochloride (301 mg, 0.78 mmol, quant, yield) was obtained as a white solid.

[0521] Intermediate 10: (S)-2-amino-3-cyclopentyl-N-(pyridazin-4-yl)propanamide hydrochloride Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.39 mmol) and pyridazin -4- amine (38.8 mg, 0.41 mmol). (S) -2-amino-3-cyclopentyl-N-(pyridazin-4-yl) propanamide hydrochloride was obtained as a white solid in 77% yield over two steps and was used as such.

[0522] Intermediate 11: (S)-2-amino-3-cyclopentyl-N-(pyrimidin-5-yl)propanamide hydrochloride

[0523] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.39 mmol) and pyrimidin -5- amine (38.8 mg, 0.41 mmol). (S) -2-amino-3-cyclopentyl-N-(pyrimidin-5-yl) propanamide hydrochloride was obtained as a white solid in 52% yield over two steps and was used as such.

[0524] Intermediate 12: (S) -2 -a mino-3-(bicyclo [1.1.1] pen tan -1-y I) -N -cyclop ropy I propana m ide hydrochloride

[0525] Title compound was prepared according to General Procedure A2,a with (2S) -3- {bicyclo[l.l.l]pentan-l-yl}-2-{[(tert-butoxy)carbonyl]amino}propanoic acid (50 mg, 0.20 mmol) and cyclopropylamine (16.0 pL, 0.235 mmol) to afford (S) -2-amino-3- (bicyclo[l.l.l] pentan-l-yl)-N-cyclopropylpropanamide hydrochloride (43.9 mg, 0.168 mmol, 86% yield over two steps) as a colorless oil.

[0526] Intermediate 13: (S)-2-amino-3-(4,4-difluorocyclohexyl)-N-((lr,3S) -3- hydroxycyclobutyl) propanamide hydrochloride

[0527] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl) propanoic acid (61.2 mg, 0.199 mmol) and (lr,3r)-3-aminocyclobutan-l-ol (20.0 mg, 0.230 mmol) to afford (S) -2-amino-3-(4,4- difluorocyclohexyl)-N-((lr,3S)-3-hydroxycyclobutyl) propanamide hydrochloride (60.6 mg, 0.190 mmol, 95% yield over two steps) as a white solid.

[0528] Intermediate 14: (S)-2-amino-3-(4,4-difluorocyclohexyl)-N-((lr,3S) -3-hydroxy-3- m ethyl cyclobutyl) pro pan am ide hydrochloride

[0529] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl)propanoic acid (50 mg, 0.16 mmol) and trans-3-hydroxy-3-methylcyclobutylamine hydrochloride (30 mg, 0.22 mmol) to afford (S) -2- amino-3-(4,4-difluorocyclohexyl)-N-((lr,3S)-3-hydroxy-3-methylcyclobutyl)propanamide hydrochloride (78 mg, 0.23 mmol, quant, yield over two steps) as a solid.

[0530] Intermediate 15: (S)-2-amino-3-cyclopentyl-N-(pyrimidin-4-yl)propanamide hydrochloride

[0531] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 4- aminopyrimidine (44.4 mg, 0.466 mmol). Step 1 was performed in DMF instead of DCM and purification was performed by reversed phase chromatography according to Method B3. (S)-2-Amino-3-cyclopentyl-N-(pyrimidin-4-yl)propanamide hydrochloride (46.2 mg, 0.171 mmol, 44% yield over two steps) was isolated as a solid.

[0532] Intermediate 16: (S)-2-amino-3-cyclopentyl-N-(pyridin-3-yl)propanamide hydrochloride

[0533] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 3- aminopyridine (43.9 mg, 0.466 mmol). Step 1 was performed in DMF instead of DCM and purification was performed by reversed phase chromatography according to Method B3. (S)-2-Amino-3-cyclopentyl-N-(pyridin-3-yl)propanamide hydrochloride (88.5 mg, 0.285 mmol, 73% yield over two steps) was isolated as a solid.

[0534] Intermediate 17: (S)-2-amino-3-cyclopentyl-N-(pyridazin-3-yl)propanamide hydrochloride

[0535] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 3- aminopyridazine (44.4 mg, 0.466 mmol). Step 1 was performed in DMF instead of DCM and purification was performed by reversed phase chromatography according to Method B3. (S)-2-Amino-3-cyclopentyl-N-(pyridazin-3-yl)propanamide hydrochloride (64.4 mg, 0.173 mmol, 45% yield over two steps) was isolated as a solid. Intermediate 18: (S)-2-amino-3-cyclopentyl-N-(pyridin-2-yl)propanamide hydrochloride

[0536] The title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 2- aminopyridine (43.9 mg, 0.466 mmol). Step 1 was performed in DMF instead of DCM and purification was performed by reversed phase chromatography according to Method B3. (S)-2-Amino-3-cyclopentyl-N-(pyridin-2-yl)propanamide hydrochloride (23.7 mg, 0.066 mmol, 17% yield over two steps) was isolated as a solid.

[0537] Intermediate 19: (S)-2-amino-3-cyclopentyl-N-(pyrimidin-2-yl)propanamide hydrochloride

[0538] Title compound was prepared according to General Procedure A2,b with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 2- aminopyrimidine (44.4 mg, 0.466 mmol) to afford (S)-2-amino-3-cyclopentyl-N-(pyrimidin- 2-yl)propanamide hydrochloride (20.6 mg, 0.066 mmol, 16% yield over two steps) as a solid.

[0539] Intermediate 20: (S)-2-amino-3-cyclopentyl-N-(2-methyl-2H-l,2,3-triazol-4- yl)propanamide hydrochloride

[0540] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 2-methyl- 2H-l,2,3-triazol-4-amine (45.8 mg, 0.466 mmol). Step 1 was performed in DMF instead of DCM and purification was performed by reversed phase chromatography according to Method B3. (S)-2-Amino-3-cyclopentyl-N-(2-methyl-2H-l,2,3-triazol -4-yl) propan amide hydrochloride (54.0 mg, 0.175 mmol, 45% yield over two steps) was isolated as a solid.

[0541] Intermediate 21: (S)-2-amino-3-cyclopentyl-N-(pyrazin-2-yl)propanamide hydrochloride

[0542] Title compound was prepared according to General Procedure A2,b with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (101 mg, 0.392 mmol) and aminopyrazine (44.8 mg, 0.471 mmol) to afford (S)-2-amino-3-cyclopentyl-N-(pyrazin-2- yl)propanamide hydrochloride

[0543] (17.0 mg, 0.045 mmol, 12% yield over two steps) as an off white solid. Intermediate 22: (S)-2-amino-3-cyclopentyl-N-(l-methyl-lH-l,2,4-triazol-3- yl)propanamide hydrochloride

[0544] Title compound was prepared according to General Procedure A2,b with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.389 mmol) and 1-methyl- lH-[l,2,4]triazol-3-ylamine (45.8 mg, 0.466 mmol) to afford (S) -2-amino-3-cyclopentyl-N- (l-methyl-lH-l,2,4-triazol-3-yl)propanamide hydrochloride (32.2 mg, 0.079 mmol, 20% yield over two steps) as a yellow transparent solid.

[0545] Intermediate 23: (S)-2-amino-4-cyclohexyl-N-cyclopropylbutanamide hydrochloride

[0546] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-4-cyclohexylbutanoic acid (219 mg, 0.77 mmol) and cyclopropylamine (55.8 pL, 0.81 mmol). (S) -2-amino-4-cyclohexyl-N-cyclopropylbutanamide hydrochloride was obtained as a white solid in quant, yield and was used as such.

[0547] Intermediate 24: (S) -2 -ami no-3 -(4, 4-difluorocyclo hexyl) -N-(l- methyl -IH-pyrazo 1-4- yl)propanamide hydrochloride

[0548] Title compound was prepared according to General Procedure A2,a with (S) -2-((tert- butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl)propanoic acid (153 mg, 0.498 mmol) and l-methyl-lH-pyrazol-4-amine (0.051 mL, 0.60 mmol). In step 1, the reaction mixture was concentrated in vacuo and the concentrate was dissolved in DMSO to be purified by reversed phase chromatography according to Method Bl. (S)-2-amino-3-(4,4- difluorocyclohexyl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (133 mg, 0.413 mmol, 81% yield over two steps) was obtained as a white solid which was used as such.

[0549] Intermediate 25: (S) -2 -ami n o-3- (4, 4-difluorocyclohexyl)-N-(pyridazin -4-yl) propan amide hydrochloride

[0550] Title compound was prepared according to General Procedure A2,a with (S)-2-((tert- butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl)propanoic acid (154 mg, 0.501 mmol) and 4-aminopyridazine (57.2 mg, 0.601 mmol). In step 1, anhydrous DMF (20 vol%) was added to the reaction mixture and purification was performed by reversed phase chromatography according to Method Bl. (S) -2-amino-3-(4,4-difluorocyclohexyl) -N-(pyridazin-4- yl) propanamide hydrochloride (151 mg, 0.471 mmol, 74% yield over two steps) was obtained as an off-white solid, which was used as such.

[0551] Intermediate 26: (S)-2-amino-3-(4,4-difluorocyclohexyl)-N-(pyrimidin-5-yl) propanamide hydrochloride

[0552] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(4,4-difluorocyclohexyl) propanoic acid (50 mg, 0.16 mmol) and pyrimidin-5-amine (18.6 mg, 0.195 mmol). In step 1, anhydrous DMF (25 vol%) was added. (S) -2 -ami no-3 -(4, 4-difluorocyc Io hexyl) -N-(pyri mid in -5 -yl) pro panamide hydrochloride (55.7 mg, 0.159 mmol, 92% yield over two steps) was obtained as a white solid, which was used as such.

[0553] Intermediate 27: (S)-2-amino-N -cyclopropyl -3- (3, 3 -di methylcyclo butyl) propanam ide hydrochloride

[0554] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-(3,3-dimethylcyclobutyl) propanoic acid (40.0 mg, 0.15 mmol) and cyclopropylamine (12.5 pL, 0.18 mmol). (S) -2-amino-N-cyclopropyl-3-(3,3- dimethylcyclobutyl)propanamide hydrochloride (34.0 mg, 0.14 mmol, 71% yield over two steps) was obtained as an oil.

[0555] Intermediate 28: (S) -2 -a mino-3-cyclopentyl-N-(l -methyl -IH-pyrazol -4-yl) propanam ide

[0556] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(spiro[3.3]heptan-2-yl) propanoic acid (133 mg, 0.47 mmol) and 1 - methyl-lH-pyrazol-4-amine (47.9 mg, 0.49 mmol). (S)-2-amino-N-(l-methyl-lH-pyrazol-4- yl)-3-(spiro[3.3]heptan-2-yl) propanamide hydrochloride (154 mg, 0.47 mmol, quant, yield) was obtained as a white solid and was used as such.

[0557] Intermediate 29: (S) -2 -a mino-N -cyclopropyl -3- (spiro [3.3] hepta n -2-yl) propanam ide hydrochloride

[0558] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-(spiro[3.3]heptan-2-yl)propanoic acid (133 mg, 0.47 mmol) and cyclopropylamine (34.1 pL, 0.49 mmol). (S) -2-amino-N-cyclopropyl-3-(spiro[3.3]heptan-2- yl)propanamide hydrochloride (120 mg, 0.46 mmol, 97% yield over two steps) was obtained as a clear oil and was used as such.

[0559] Intermediate 30: (S) -2 -a mino-N-(pyridazin -4-yl) -3- (spiro [3.3] hepta n -2-yl) propana m ide hydrochloride

[0560] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(spiro[3.3]heptan-2-yl)propanoic acid (133 mg, 0.47 mmol) and pyridazin-4-amine (46.9 mg, 0.49 mmol). (S)-2-amino-N-(pyridazin-4-yl)-3-

[0561] (spiro[3.3]heptan-2-yl)propanamide hydrochloride (245 mg, 0.47 mmol, quant, yield) was obtained as a turbid oil and was used as such.

[0562] Intermediates 31 and 32: Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- hydroxycyclohexyl)propanoate and methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4- hydroxycyclohexyl)propanoate

[0563] To a nitrogen purged solution of methyl (tert-butoxycarbonyl)-L-tyrosinate (10.0 g, 33.9 mmol) in MeOH (200 m L) was added rhodium on carbon (5%) (2.79 g, 1.35 mmol). The reaction mixture was purged with hydrogen and was stirred under hydrogen atmosphere (9 bar) at 65 ° C for 72h. The reaction mixture was cooled to r.t., filtered over Celite® and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (5-50%) to afford the two diastereomers which were separated by SFC according to Method C3 to afford methyl (S) -2-((tert- butoxycarbonyl)amino)-3-((ls,4R)-4-hydroxycyclohexyl)propanoate (2.04 g, 6.77 mmol, 33% yield) and methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4- hydroxycyclohexyl)propanoate (1.33 g, 4.41 mmol, 22% yield).

[0564] Intermediate 33: (S)-2-amino-N -cyclopropyl -3- ((ls,4R)-4-hydroxycyclohexyl)propanam ide hydrochloride To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- hydroxycyclohexyl)propanoate (200 mg, 0.66 mmol) in MeOH (3.0 mL) was added a 2.5 M aqueous solution of NaOH (2.66 mL, 6.64 mmol). After stirring at r.t. for 18h the reaction mixture was acidified with a 6 M aqueous solution of HCI and the resulting mixture was extracted with DCM. The combined organic layers were concentrated in vacuo o afford (S)- 2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4-hydroxycyclohexyl)propanoic acid (159 mg, 0.55 mmol, 83% yield) which was used as such.

[0565] Subsequent reaction steps were performed according to General Procedure A2,c with (S) - 2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4-hydroxycyclohexyl)propanoic acid (159 mg, 0.55 mmol) and cyclopropylamine (40.3 pL, 0.58 mmol). (S) -2-amino-N-cyclopropyl-3- ((ls,4R)-4-hydroxycyclohexyl)propanamide hydrochloride (141 mg, 0.54 mmol, 98% yield over two steps) was obtained as a brown solid and was used as such.

[0566] Intermediate 34: (S)-2-amino-N -cyclopropyl -3- ((lr,4S) -4- hydroxycyclohexyl)propanam ide hydrochloride

[0567] Title intermediate was prepared using the same procedure as for the preparation of intermediate 35 (S)-2-ami no- N -cyclopropyl -3- ((1 s, 4 R) -4- hydroxycyclo hexyl) pro pa nam ide starting from methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4- hydroxycyclohexyl)propanoate (200 mg, 0.664 mmol) affording (S)-2-amino-N-cyclopropyl- 3-((lr,4S)-4-hydroxycyclohexyl)propanamide hydrochloride (84 mg, 0.27 mmol, 41% yield over 3 steps) as a brown solid and was used as such.

[0568] Intermediate 35: (2S,3R)-2-amino-3-cyclopentyl-N -cyclopropyl -3- hydroxy pro pa nam ide hydrochloride

[0569] Step 1 An argon-sparged solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.97 mL, 5.4 mmol) in anhydrous THF (6 mL) was cooled to -78° C. Next, 2.5 M n-BuLi in hexanes (2.4 mL, 6.0 mmol) was added over 10 min and the solution was stirred at -78 ° C. After 15 min a solution of cyclopentanecarbaldehyde (0.87 mL, 8.1 mmol) in anhydrous THF (3 mL) was added over 15 min. The reaction mixture was stirred at -78 ° C for 30 min and the temperature was raised to r.t. and stirring was continued for 2h. The reaction mixture was quenched in a mixture of water / brine (1:1, 20 mL) and the water layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-50%) to afford (S)-cyclopentyl((2S,5R)-5-isopropyl-3,6- dimethoxy-2,5-dihydropyrazin-2-yl)methanol (232 mg, 0.822 mmol, 15% yield) as the first eluting isomer and (R)-cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-

[0570] 2-yl)methanol (1.02 g, 3.61 mmol, 67% yield) as the second eluting isomer. Both isomers were used as such.

[0571] Step 2 (R)-cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl)methanol (520 mg, 1.84 mmol) was dissolved in MeCN (6 mL). Next, a 0.1 M aqueous solution of TFA (55 mL, 5.5 mmol) was added and the reaction mixture was stirred at r.t. for 17h. The reaction mixture was concentrated in vacuo and to the resulting concentrate was added a saturated aqueous solution of sodium hydrogen carbonate (5 mL) and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude methyl (2S,3R)-2-amino-3- cyclopentyl-3-hydroxypropanoate (508 mg, crude) was used as such in the subsequent Boc protection step without purification.

[0572] Step 3 Crude methyl (2S,3R)-2-amino-3-cyclopentyl-3-hydroxypropanoate (508 mg, crude) was dissolved in MeCN (38 mL) and di-tert-butyl dicarbonate (592 mg, 2.72 mmol) and TEA (0.75 mL, 5.4 mmol) were added and the mixture was stirred at r.t. for 17h. The reaction mixture was concentrated in vacuo and the resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to afford methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3-hydroxypropanoate (157 mg, 0.546 mmol, 30% yield over 2 steps).

[0573] Step 4 Methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- hydroxypropanoate (157 mg, 0.546 mmol) was dissolved in a mixture of THF / water (2:1, 4 mL) and lithium hydroxide monohydrate (115 mg, 2.73 mmol) was added and the mixture was stirred at r.t. for 4h. The reaction mixture was diluted with water (5 mL) and a 1 M aqueous solution of HCI (5.5 mL, 5.5 mmol) was added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo o afford (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- hydroxypropanoic acid (154 mg, 0.535 mmol, 98% yield) as a colorless clear oily residue, which was used as such.

[0574] Step 5 To a solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- hydroxypropanoic acid (50 mg, 0.18 mmol) and cyclopropylamine (14 pL, 0.20 mmol) in DCM (2 mL) was added TEA (38 pL, 0.27 mmol) and HATU (77 mg, 0.20 mmol) and the resulting suspension was stirred at r.t. for 17h. To the reaction mixture was added a saturated aqueous solution of NaHCO3. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were concentrated in vacuo and the resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to afford tert-butyl ((lR,2S)-l-cyclopentyl-3-(cyclopropylamino)- l-hydroxy-3-oxopropan-2-yl)carbamate (38 mg, 0.12 mmol, 66% yield) as a colorless sticky resin-like residue, which was used as such.

[0575] Step 6 To a solution of tert-butyl ((lR,2S)-l-cyclopentyl-3-(cyclopropylamino)-l-hydroxy-

[0576] 3-oxopropan-2-yl)carbamate (38 mg, 0.12 mmol) in DCM (2 mL) was added 4 M HCI in dioxane (0.46 mL, 1.83 mmol). The solution was stirred for 17h at r.t. and was concentrated in vacuo o give (2S,3R)-2-amino-3-cyclopentyl-N-cyclopropyl-3-hydroxypropanamide hydrochloride (29 mg, 0.12 mmol, 96% yield) as a white solid.

[0577] Intermediate 36: (2S,3R)-2-amino-3-cyclopentyl-N -cyclopropyl -3- methoxypropanam ide hydrochloride

[0578] Step 1 (R)-cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- y I) methanol cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl)methanol (201 mg, 0.712 mmol) was dissolved in anhydrous THF (5 mL). Next, sodium hydride (28.5 mg, 0.712 mmol) was added portion-wise and the reaction mixture was stirrred for 10 min at ambient temperature. Next, methyliodide (0.443 ml, 7.12 mmol) was added and the reaction mixture was stirred 18h. Reaction was quenched by adding an aqueous solution of saturated NH4CI. The reaction mixture was extracted with EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with Heptane:EtOAc (0-100%) to afford (2S,5R)-2- ((R)-cyclopentyl(methoxy)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (134 mg, 0.452 mmol, 55 %) as a colorless clear oil.

[0579] Step 2 (2S, 5 R) -2- ((R) -eye Io pentyl (meth oxy) methyl ) -5 -isop ropy 1-3, 6-di meth oxy-2,5 - dihydropyrazine (166 mg, 0.560 mmol) was dissolved in MeCN (3 mL). Next, 0.1 M aqueous TFA (16.8 ml, 1.68 mmol) was added and the reaction mixture was stirred at r.t. for 18h. The reaction mixture was concentrated in vacuo and to the resulting concentrate was added a saturated aqueous solution of NaHCO3(5 mL) and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude methyl (2S,3R)-2-amino-3-cyclopentyl-3-methoxypropanoate was used as such in the subsequent step.

[0580] Step 3 Crude methyl (2S,3R)-2-amino-3-cyclopentyl-3-methoxypropanoate (146 mg, 0.725 mmol) was dissolved in MeCN (6 mL) and di-tert-butyl dicarbonate (158 mg, 0.725 mmol) and TEA (0.20 ml, 1.4 mmol) were added, and the mixture was stirred at r.t. for 18h. The reaction mixture was concentrated in vacuo and the resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to afford methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3-methoxypropanoate (143 mg, 0.474 mmol, 47% yield over 2 steps).

[0581] Step 4 Methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- methoxypropanoate (143 mg, 0.474 mmol) was dissolved in a mixture of THF / water (2:1, 6 mL) and lithium hydroxide monohydrate (100 mg, 2.37 mmol) was added and the mixture was stirred at r.t. for 4h. The reaction mixture was diluted with water (5 mL) and a 1 M aqueous solution of potassium bisulfate (4.74 mL, 4.74 mmol) was added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over sodium sulfaat, filtered and concentrated in vacuo o afford (2S,3R)-2-((tert- butoxycarbonyl)amino)-3-cyclopentyl-3-methoxypropanoic acid (136 mg, 0.473 mmol, quant, yield) which was used as such.

[0582] Step 5 To a solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- methoxypropanoic acid (68 mg, 0.237 mmol) and cyclopropylamine (0.018 ml, 0.26 mmol) in DCM (2 mL) was added TEA (0.049 ml, 0.36 mmol) and HATU (99 mg, 0.26 mmol) and the resulting suspension was stirred at r.t. for 17h. To the reaction mixture was added a saturated aqueous solution of NaHCO3(3 mL). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were concentrated in vacuo and the concentrate was purified by column chromatography on silica eluting with Heptane:EtOAc (0-100%) to afford tert-butyl ((lR,2S)-l-cyclopentyl-3-(cyclopropylamino)- l-methoxy-3-oxopropan-2-yl)carbamate (51 mg, 0.16 mmol, 66 % yield) which was used as such.

[0583] Step 6 To a solution of tert-butyl tert-butyl ((lR,2S)-l-cyclopentyl-3-(cyclopropylamino)- l-methoxy-3-oxopropan-2-yl)carbamate (51 mg, 0.16 mmol) in DCM (2 mL) was added 4 M HCI in dioxane (0.60 ml, 2.3 mmol)and. The solution was stirred for 4 h at r.t. and was concentrated in vacuo o give (2S,3R)-2-amino-3-cyclopentyl-N-cyclopropyl-3- methoxypropanamide hydrochloride (61 mg, 0.16 mmol, quant, yield) which was used as such.

[0584] Intermediate 37: (S) -2- ((tert- butoxycarbonyl) a mi no) -3- (spiro [3.3] hepta n -2-yl) propanoic acid

[0585] Title intermediate was prepared according to General Procedure Al with (R)-2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (500 mg, 2.71 mmol), 2.5 M n-BuLi in hexanes (1.30 mL, 3.26 mmol) and 2-(bromomethyl)spiro[3.3]heptane (641 mg, 3.39 mmol). In step 2, a 1 M aqueous solution of HCI (5 equiv.) was used instead of TFA. (S)-2-((tert- butoxycarbonyl)amino)-3-(spiro[3.3]heptan-2-yl)propanoic acid (560 mg, 1.46 mmol, 53% yield over four steps) was isolated as a white solid.

[0586] Intermediate 38: (S) -2- ((tert- butoxycarbonyl) a mi no) -3- (3, 3 -di methylcyclo butyl) propanoic acid

[0587] Title intermediate was prepared according to General Procedure Al with (R) -2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (350 mg, 1.9 mmol), 2.5 M n-BuLi in hexanes (0.9 mL, 2.3 mmol) and 3-(bromomethyl)-l,l-dimethylcyclobutane (505 mg, 2.85 mmol). In step 4, lithium hydroxide (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF / water (2:1, 0.2 M). (S)-2-((tert-butoxycarbonyl)amino)-3-(3,3- dimethylcyclobutyl)propanoic acid (262 mg, 0.97 mmol, 50% yield over four steps) was isolated as a transparent gum.

[0588] Intermediate 39: (2S) -2- ((tert- butoxycarbonyl) ami no) -3- (cyclohex-3-en-l-y I) propanoic acid

[0589] A solution of methyl (S)-2-((tert-butoxycarbonyl)amino) - hydroxycyclohexyl) propanoate (100 mg, 0.332 mmol) in a mixture of anhydrous DMF (0.8 mL) and carbon tetrachloride (0.2 mL) was degassed with nitrogen before triphenylphosphine (218 mg, 0.830 mmol) was added. Subsequently, potassium fluoride (38.6 mg, 0.664 mmol) was added and the reaction mixture was stirred at r.t. under a nitrogen atmosphere for 1.5h. To the reaction mixture was added EtOAc and brine. The layers were separated and the water layer was extracted with EtOAc. The combined organ ic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-50%) affording the methyl (2S)-2-((tert-butoxycarbonyl)amino) -3- (cyclohex-3-en-l-yl) propanoate (45 mg, 0.16 mmol, 47% yield).

[0590] To a solution of methyl (2S) -2-((tert-butoxycarbonyl)amino) -3-(cyclohex-3-en-l- yl) propanoate (45 mg, 0.16 mmol) in THF (0.5 mL) was added a solution of lithium hydroxide monohydrate (33.3 mg, 0.794 mmol) in water (0.25 mL) and the mixture was stirred at r.t. for 3h. Subsequently, a 1 M aqueous solution of HCI (until pH 2) and DCM were added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo o afford (2S)-2-((tert-butoxycarbonyl)amino)-3-(cyclohex-3-en-l-yl)propanoic acid (52.6 mg, 0.159 mmol, quant, yield) as a transparent gum.

[0591] Intermediate 40: (2S)-2-ami no-3- (eye Io hex-3 - en - 1-y I) -N -cyclopropyl pro pa nam ide hydrochloride

[0592] The title compound was prepared according to General Procedure A2,a with (2S) -2-((tert- butoxycarbonyl)amino)-3-(cyclohex-3-en-l-yl) propanoic acid (52.6 mg, 0.159 mmol) and cyclopropylamine (13.0 pL, 0.191 mmol) to afford (2S)-2-amino-3-(cyclohex-3-en-l-yl)-N- cyclopropylpropanamide hydrochloride (25.8 mg, 0.083 mmol, 52% yield over two steps) as a white solid.

[0593] Intermediate 41: 5-(((4-chloropyridin-2-yl)amino) methyl)thiophene-2-carboxylic acid A mixture of 4-chloro-2-fluoropyridine (122 mg, 0.930 mmol) and 5- (aminomethyl)thiophene-2-carboxylic acid hydrochloride (120 mg, 0.620 mmol) in DMSO (1.0 mL) was stirred at 80 ° C for 4 h and at 110 ° C for 37 h. After cooling the reaction mixture to r.t., the suspension was dissolved in water (0.5 mL) and DMSO (1.0 mL), filtered and purified by reversed phase chromatography according to Method B4 to afford 5-(((4- chloropyridin-2-yl)amino)methyl)thiophene-2-carboxylic acid (31 mg, 0.12 mmol, 18% yield) as a light yellow solid.

[0594] Intermediate 42: 5-(((5-chloropyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid

[0595] To a solution of 5-formylthiophene-2-carboxylic acid (1.22 g, 7.78 mmol) and 3-amino-5- chloropyridine (1.0 g, 7.8 mmol) in absolute EtOH (39 mL) was added titanium(IV)isopropoxide (2.3 mL, 7.8 mmol) in one portion. After stirring at r.t. for 18h, sodium borohydride (677 mg, 17.9 mmol) was added to the reaction mixture in portions and stirring was continued at r.t. for Ih. Then the reaction mixture was quenched with a saturated aqueous solution of NH4CI and further diluted with water and EtOAc. The layers were separated and the aqueous layer was filtered under gravity. The resulting filtrate was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and co-evaporated with toluene, / -PrOH and MeOH. The residue was triturated with DIPE, filtered and dried in vacuo o afford 5-(((5-chloropyridin-3- yl)amino)methyl)thiophene-2-carboxylic acid (1.55 g, 5.77 mmol, 74% yield) as a beige solid.

[0596] Intermediate 43: (S)-2-((tert-butoxycarbonyl)amino)-3-(3- (trif I uoro methyl) cyclobutyl) propanoic acid

[0597] Title compound was prepared according to General Procedure Al with (R)-2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (700 mg, 3.80 mmol) and l-(bromomethyl)-3- (trifluoromethyl)cyclobutane (1.03 g, 4.75 mmol). In step 2, a 1 M aqueous solution of HCI (7 equiv.) was used instead of TFA and the organic layer was used as such without concentrating in the subsequent step. In step 4, lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH and the reaction was performed in a mixture of THF / water (2:1, 0.2 M).

[0598] (S) -2 -((tert- butoxycarbonyl) ami no) -3- (3- (trifluoro methyl) eye Io butyl) propanoic acid (677 mg, 1.96 mmol, 51% yield over four steps) was isolated as a colorless oil.

[0599] Intermediate 44: (S)-2-((tert-butoxycarbonyl)amino)-3-(6,6-difluorospiro[3.3]heptan-2- yl)propanoic acid

[0600] Title compound was prepared according to General Procedure Al with (R) -2-isopropyl-

[0601] 3,6-dimethoxy-2,5-dihydropyrazine (550 mg, 2.99 mmol) and 6-(bromomethyl) -2,2- difluorospiro[3.3]heptane (1.00 g, 4.48 mmol). In step 2, after concentration the mixture was co-evaporated with toluene and DCM and extraction was performed with DCM instead of EtOAc. In step 4, lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH and the reaction was performed in a mixture of THF / water (2:1, 0.2 M). (S) -2-((tert- butoxycarbonyl)amino)-3-(6,6-difluorospiro[3.3]heptan-2-yl)propanoic acid (438 mg, 1.20 mmol, 40% yield over four steps) was isolated as a a colorless oil.

[0602] Intermediate 45: (S) -2- ((tert- butoxycarbonyl) a mi no) -3- (spiro [2.3] hexan -5-yl) propanoic acid

[0603] Title compound was prepared according to General Procedure Al with (R) -2-isopropyl-

[0604] 3,6-dimethoxy-2,5-dihydropyrazine (700 mg, 3.80 mmol) and 5-

[0605] (bromomethyl)spiro[2.3]hexane (998 mg, 5.70 mmol). In step 4, lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF / water (2:1, 0.2 M). (S) -2-((tert-butoxycarbonyl)amino) -3-(spiro[2.3]hexan- 5-yl)propanoic acid (516 mg, 1.72 mmol, 45% yield over four steps) was isolated as a colorless oil.

[0606] Intermediate 46: (2S) -2- ((tert- butoxycarbonyl) ami no) -3- (tetra hydro -2 H- pyran -3- yl) propanoic acid

[0607] Title compound was prepared according to General Procedure Al with (R) -2-isopropyl-

[0608] 3,6-di meth oxy-2,5 -di hydropyrazine (R) -2 - iso propyl -3,6 -di met hoxy-2,5 -di hydropyrazine (800 mg, 4.34 mmol and 3-(bromomethyl)tetrahydro-2H-pyran (972 mg, 5.43 mmol). In step 4, lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH and the reaction was performed in a mixture of TH F / water (2:1, 0.08 M). Upon completion of the reaction, the aqueous layer was extracted with EtOAc instead of DCM and the resulting concentrate was purified by reversed phase chromatography according to Method B2 to afford (2S)-2-((tert- butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-3-yl)propanoic acid (153 mg, 0.560 mmol, 13% yield over four steps) as a colorless oil.

[0609] Intermediate 47: methyl (2S) -2-((tert-butoxycarbonyl)amino) -3-(4-fluorocyclohex-3-en-l- yl) propanoate

[0610] Step 1 To a nitrogen purged solution of methyl (tert-butoxycarbonyl)-L-tyrosinate (10.0 g, 33.9 mmol) in MeOH (200 mL) was added rhodium on carbon (5%) (2.8 g, 1.4 mmol). The reaction mixture was purged with hydrogen and was stirred under hydrogen atmosphere (5.5 bar) at 60 ° C for 72 h . Then, the reaction mixture was cooled to r.t., filtered and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica affording methyl (S)-2-((tert-butoxycarbonyl)amino)- 3-(4- hydroxycyclohexyl)propanoate (6.6 g, 22 mmol, 66% yield) as a white crystalline solid.

[0611] Step 2 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- hydroxycyclohexyl)propanoate (11.4 g, 37.9 mmol) in DCM (350 mL) was added 3-oxo-H5- benzo[d] [1,2] iodaoxole-1 , 1, 1 (3 H) -triy I triacetate (19.3 g, 45.5 mmol). After stirring at r.t. for 18 h, the reaction mixture was diluted with water and DCM and filtered. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-40%) affording methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- oxocyclohexyl)propanoate (10.1 g 33.8 mmol, 89% yield) as a colorless oil.

[0612] Step 3 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- oxocyclohexyl)propanoate (10.1 g, 33.7 mmol) in DCM (130 mL) at 0 ° C was added a 50% solution of Deoxo-Fluor® in THF (29.3 mL, 67.5 mmol) in DCM (130 mL), followed by addition of EtOH (394 pL, 6.75 mmol). The reaction mixture was stirred at r.t. for 23h. Additional 50% solution of Deoxo-Fluor® in THF (3.2 mL, 8.4 mmol) was added and stirring was continued at r.t. for Ih. The mixture was cooled in an ice bath and quenched with a saturated aqueous solution of NaHCO3. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-25%) and subsequently by SFC according to Method C5 to afford methyl (2S)-2-((tert- butoxycarbonyl)amino)-3-(4-fluorocyclohex-3-en-l-yl)propanoate (2.5 g, 8.3 mmol, 24% yield) as a colorless oil.

[0613] Intermediate 48: (S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohexyl)propanoic acid

[0614] Step 1 To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohex- 3-en-l-yl)propanoate (100 mg, 0.332 mmol) in MeOH (3.0 mL) was added Evonik NOBLYST® P1126 5% Pd. The mixture was purged with hydrogen for 2 min and left to stir under a hydrogen atmosphere at r.t. for 4h to obtain a first batch. To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohex-3-en-l-yl)propanoate (100 mg, 0.33 mmol) was added MeOH (3.0 mL) and Evonik NOBLYST® P1109 5% Pd. The mixture was purged with hydrogen for 2 min and left to stir under a hydrogen atmosphere at r.t. for 4h to obtain a second batch. The above two batches were combined, filtered and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-25%) and co-evaporated with DCM to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohexyl)propanoate (159 mg, 0.524 mmol, 79% yield) as a clear oil.

[0615] Step 2 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorocyclohexyl)propanoate (80 mg, 0.26 mmol) in THF (7.0 mL) and water (3.5 mL) was added lithium hydroxide monohydrate (55.3 mg, 1.32 mmol). After stirring at r.t. for 18h, the reaction mixture was acidified to pH~l with a 4 M aqueous solution of HCI and extracted with DCM. The combined organic layers were concentrated in vacuo affording (S)-2-((tert- butoxycarbonyl)amino)-3-(4-fluorocyclohexyl)propanoic acid (76 mg, 2.6 mmol, quant, yield) as a clear oil.

[0616] Intermediate 49: (2S) -2 -((tert-butoxycar bo nyl)a min o) -3 -(4-fluorocyc Io hex -3 -en-1- yl)propanoic acid

[0617] To a clear solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohex-3- en-l-yl)propanoate (250 mg, 0.830 mmol) in MeOH (1.7 mL) was added a 2.5 M aqueous solution of NaOH (1.7 mL, 4.3 mmol). After stirring at r.t. for 3h, the reaction mixture was acidified with a 4 M aqueous solution of HCI and extracted with DCM. The combined organic layers were concentrated in vacuo to obtain (2S)-2-((tert-butoxycarbonyl)amino)-3- (4-fluorocyclohex-3-en-l-yl)propanoic acid (256 mg, 0.739 mmol, 89% yield) as a clear oil.

[0618] Intermediate 50: (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-3-en-l-yl)propanoic acid

[0619] Title compound was prepared according to General Procedure Al with (R) -2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (921 mg, 5.00 mmol) and cyclopent-3-en-l-ylmethyl 4- methylbenzenesulfonate (1.26 g, 5.00 mmol). In step 4, only 0.37 mmol of the boc-protected intermediate was used out of 1.27 mmol, lithium hydroxide (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF / water (2:1, 0.2 M) to afford (S) - 2-((tert-butoxycarbonyl)amino)-3-(cyclopent-3-en-l-yl)propanoic acid (95 mg, 0.37 mmol, 25% yield over four steps) as a clear oil.

[0620] Intermediate 51: (2S) -2- ((tert- butoxycarbonyl) ami no) -3- (tetra hydro -2 H- pyran -2- yl)propanoic acid

[0621] Title compound was prepared according to General Procedure Al with (R) -2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (800 mg, 4.34 mmol) and 2-(bromomethyl)tetrahydro- 2H-pyran (972 mg, 5.43 mmol). In step 4, lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH and the reaction was performed in a mixture of THF / water (2:1, 0.08 M). Upon completion of the reaction, the aqueous layer was extracted with EtOAc instead of DCM. (2S)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid (47 mg, 0.17 mmol, 4% yield over four steps) was isolated as a colorless oil.

[0622] Intermediate 52: (S)-2-amino-3-cyclopentyl-N-(pyrimidin-5-yl)propanamide hydrochloride

[0623] The title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (3.0 g, 12 mmol) and pyrimidin-5-amine (1.2 g, 13 mmol). After concentration in step 2, mixture was suspended in DCM, filtered, washed with Et2O and dried to afford (S)-2-amino-3-cyclopentyl-N-(pyrimidin-5- yl)propanamide hydrochloride (1.72 g, 5.79 mmol, 49% yield over two steps) as a white solid.

[0624] Intermediate 53: (S) -2-amino-N -cyclopropyl -3- (3-(trifluoromethyl)cyclobuty I) propanam ide hydrochloride

[0625] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(3-(trifluoromethyl)cyclobutyl)propanoic acid (212 mg, 0.616 mmol) and cyclopropylamine (51.0 pL, 0.740 mmol). Step 1 was performed in DMF instead of DCM. The reaction mixture was diluted with MeCN and purified by reversed phase chromatography according to Method B3 to afford (S)-2-amino-N-cyclopropyl-3-(3- (trifluoromethyl)cyclobutyl)propanamide hydrochloride (134 mg, 0.381 mmol, 61% yield over two steps) as a light yellow oil.

[0626] Intermediate 54: (S) -2-amino-N -cyclopropyl -3- (6,6-difluorospiro [3.3] heptan -2- yl)propanamide hydrochloride

[0627] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(6,6-difluorospiro[3.3]heptan-2-yl)propanoic acid (152 mg, 0.416 mmol) and cyclopropylamine (35.0 pL, 0.500 mmol) to afford (S)-2-amino-N-cyclopropyl-3- (6,6-d if I u o ros pi ro [3.3] he pta n -2 -y I) p ropa n a m ide hydrochloride (102 mg, 0.288 mmol, 69% yield over two steps) as a colourless oil.

[0628] Intermediate 55: (S) -2-amino-N -cyclopropyl -3- (spiro [2.3] hexan -5-yl) propanam ide

[0629] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(spiro[2.3]hexan-5-yl)propanoic acid (121 mg, 0.406 mmol) and cyclopropylamine (34.0 pL, 0.487 mmol). In step 1, no purification was performed after extraction. In step 2, only 0.15 mmol of the boc-protected intermediate was used and TFA (15 equiv.) was used instead of a 4 M solution of HCI in dioxane. The reaction mixture was concentrated in vacuo and partitioned between water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The aqueous layer was then basified with solid NaHCO3and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo o afford (S) -2-amino-N-cyclopropyl-3- (spiro[2.3] hexan-5-yl)propanamide (25.1 mg, 0.120 mmol, 78% yield over two steps) as a colourless oil.

[0630] Intermediate 56: (S) -2-amino-N -cyclopropyl -3- (4-fluorocyclohexyl) propanam ide hydrochloride

[0631] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(4-fluorocyclohexyl)propanoic acid (76.0 mg, 0.264 mmol) and cyclopropylamine (18.3 pL, 0.264 mmol). Step 1 was performed with DIPEA (3 equiv.) instead of TEA. (S)-2-amino-N-cyclopropyl-3-(4-fluorocyclohexyl)propanamide hydrochloride (48.5 mg, 0.116 mmol, 43% yield over two steps) was obtained as an colourless oil.

[0632] Intermediate 57: (2S) -2-amino-N -eye Io propyl -3- (4-fluorocyclohex-3-en-l-yl) propanam ide hydrochloride

[0633] Title compound was prepared according to General Procedure A2,c with (2S) -2-((tert- butoxycarbonyl)amino)-3-(4-fluorocyclohex-3-en-l-yl) propanoic acid (238 mg, 0.830 mmol) and cyclopropylamine (70 pL, 1.0 mmol) to afford (2S)-2-amino-N-cyclopropyl-3-(4- fluorocyclohex-3-en-l-yl)propanamide hydrochloride (195 mg, 0.720 mmol, 87% yield over two steps) as a white solid. Intermediate 58: (S)-2-amino-3-cyclopentyl-N-(l-(difluoromethyl)-lH-pyrazol-4- yl)propanamide hydrochloride

[0634] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (150 mg, 0.583 mmol) and 1- (difluoromethyl)-lH-pyrazol-4-amine (78.0 mg, 0.583 mmol). In step 1, the reaction mixture was concentrated in vacuo and purified by reversed phase chromatography according to Method B3. (S)-2-amino-3-cyclopentyl-N-(l-(difluoromethyl)-lH-pyrazol-4-yl)propanamide hydrochloride (140 mg, 0.375 mmol, 64% yield over two steps) was obtained as a brown oil.

[0635] In ter mediate 59: (S)-2-amino-3-cyclopentyl-N-(5-(difluoromethyl)-l -methyl -IH-pyrazol- 4-yl)propanamide hydrochloride

[0636] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (70.0 mg, 0.272 mmol) and 5-

[0637] (difluoromethyl)-l-methyl-lH-pyrazol-4-amine hydrochloride (50.0 mg, 0.272 mmol). In step

[0638] 1, the reaction mixture was concentrated in vacuo and purified by reversed phase chromatography according to Method B3. (S)-2-amino-3-cyclopentyl-N-(5-(difluoromethyl)- l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (67.7 mg, 0.175 mmol, 64% yield over two steps) was obtained as a yellow oil.

[0639] Intermediate 60: (S)-2-amino-3-cyclopentyl-N-(3-fluoro-l- methyl -IH-pyrazol -4- yl)propanamide hydrochloride

[0640] Title compound was prepared according to General Procedure A2,c with (S) -2-((tertbutoxycarbonyl)amino)-3-cyclopentylpropanoic acid (110 mg, 0.427 mmol) and 3-fluoro-l- methyl-lH-pyrazol-4-amine (50.0 mg, 0.434 mmol). In step 1, the reaction mixture was concentrated in vacuo and purified by reversed phase chromatography according to Method B3. (S)-2-amino-3-cyclopentyl-N-(3-fluoro-l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (91.3 mg, 0.294 mmol, 68% yield over two steps) was obtained as a light brown solid. Intermediate 61: (S)-2-amino-3-cyclopentyl-N-(3-(difluoromethyl)-l -methyl -IH-pyrazol- 4-yl)propanamide hydrochloride

[0641] Title compound was prepared according to General Procedure A2,c with (S) -2-((tertbutoxycarbonyl)amino)-3-cyclopentylpropanoic acid (95.5 mg, 0.371 mmol) and 3-

[0642] (difluoromethyl)-l-methyl-lH-pyrazol-4-amine (55.0 mg, 0.374 mmol). In step 1, DMF was used instead of DCM and the reaction mixture was purified by reversed phase chromatography according to Method B3. (S)-2-amino-3-cyclopentyl-N-(3-(difluoromethyl)- l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (82.1 mg, 0.284 mmol, 77% yield over two steps) was obtained as a yellow solid.

[0643] Intermediate 62: (S) -2-amino-3-cyclopenty I- N-(l- methyl -1H- 1,2, 3 -triazol -4- yl)propanamide hydrochloride

[0644] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (104 mg, 0.404 mmol) and 1-methyl- lH-l,2,3-triazol-4-amine (39.6 mg, 0.404 mmol). In step 1, DMF was used instead of DCM and the reaction mixture was purified by reversed phase chromatography according to Method B3. (S) -2 -ami n o-3 -eye I o pe n tyl-N-(l-m ethyl- 1H-1, 2, 3 -triazol -4-yl) propan amide hydrochloride (107 mg, 0.304 mmol, 75% yield over two steps) was obtained as a light yellow solid.

[0645] In ter mediate 63: (S)-2-amino-3-(cyclopent-3-en-l-yl)-N-(l-methyl-lH-pyrazol-4- yl)propanamide

[0646] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(cyclopent-3-en-l-yl)propanoic acid (47.4 mg, 0.186 mmol) and 1- methyl-lH-pyrazol-4-amine (18.9 mg, 0.195 mmol). In step 2, TFA (189 equiv.) was used instead of 4 M HCI in dioxane. The reaction mixture was concentrated in vacuo and partitioned between water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The aqueous layer was then basified with solid NaHCO3and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo o afford (S)-2-amino-3-(cyclopent-3-en-l-yl)-N-(l-methyl-lH- pyrazol-4-yl)propanamide (29.0 mg, 0.124 mmol, 66% yield over two steps) as a oil. Intermediate 64: (S)-2-amino-3-(cyclopent-3-en- 1-yl) -N -eye Io propyl propanam ide

[0647] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-(cyclopent-3-en-l-yl)propanoic acid (47.4 mg, 0.186 mmol) and cyclopropylamine (13.5 pL, 0.195 mmol). In step 2, TFA (275 equiv.) was used instead of 4 M HCI in dioxane. The reaction mixture was concentrated in vacuo and partitioned between water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The aqueous layer was then basified with solid NaHCO3and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-amino-3-(cyclopent-3-en-l-yl)-N-cyclopropylpropanamide (14 mg, 0.074 mmol, 39% yield over two steps) as a milky white oil.

[0648] Intermediate 65: (2S) -2 -a min o-N-(l- methyl- IH-pyrazo I -4-yl) -3 -(tetra hydro -2 H- pyran -2- yl) pro panamide 2,2,2-trifluoroacetate

[0649] Title compound was prepared according to General Procedure A2,a with (2S) -2-((tert- butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid (23 mg, 0.084 mmol) and l-methyl-lH-pyrazol-4-amine (11 pL, 0.13 mmol). In step 2, TFA (58 equiv.) was used instead of 4 M HCI in dioxane. (2S)-2-amino-N-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro- 2H-pyran-2-yl) propanamide 2,2,2-trifluoroacetate (23 mg, 0.063 mmol, 80% yield over two steps) was obtained as a beige solid and was used as such.

[0650] Intermediate 66: (2S) -2 -a mi no- N -eye Io propyl -3 -(tetra hydro -2 H- pyran -2-yl) propanam ide 2,2,2-trifluoroacetate

[0651] Title compound was prepared according to General Procedure A2,a with (2S) -2-((tert- butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid (23 mg, 0.084 mmol) and cyclopropylamine (8.8 pL, 0.13 mmol). In step 2, TFA (58 equiv.) was used instead of 4 M HCI in dioxane. (2S)-2-amino-N-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl) propanamide 2,2,2-trifluoroacetate (20 mg, 0.061 mmol, 73% yield over two steps) was obtained as a clear oil and was used as such.

[0652] Intermediate 67: (2S)-2-amino-N-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-3- yl) pro panamide 2,2,2-trifluoroacetate Title compound was prepared according to General Procedure A2,a with (2S) -2-((tert- butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-3-yl)propanoic acid (38 mg, 0.14 mmol) and l-methyl-lH-pyrazol-4-amine (18 pL, 0.21 mmol). In step 2, TFA (61 equiv.) was used instead of 4 M HCI in dioxane. (2S)-2-amino-N-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro- 2H-pyran-3-yl)propanamide 2,2,2-trifluoroacetate (94 mg, 0.19 mmol, quant, yield) was obtained as a turbid waxy solid and was used as such.

[0653] Intermediate 68: (2S) -2 -a mi no- N -eye Io propyl -3 -(tetra hydro -2 H- pyran -3-yl) propanam ide 2,2,2-trifluoroacetate

[0654] Title compound was prepared according to General Procedure A2,a with (2S) -2-((tert- butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-3-yl)propanoic acid (38 mg, 0.14 mmol) and cyclopropylamine (14 pL, 0.21 mmol). In step 2, TFA (68.0 equiv.) was used instead of 4 M HCI in dioxane. (2S)-2-amino-N-cyclopropyl-3-(tetrahydro-2H-pyran-3-yl)propanamide 2,2,2-trifluoroacetate (54 mg, 0.17 mmol, quant, yield) was obtained as a turbid waxy solid and was used as such.

[0655] Intermediate 69: 2 -a mino-N-(l -methyl -IH-pyrazol -4-yl) -3-(tetrahydrofu ran -2- yl)pro panamide 2,2,2-trifluoroacetate

[0656] Title compound was prepared according to General Procedure A2,a with 2-((tert- butoxycarbonyl)amino)-3-(tetrahydrofuran-2-yl)propanoic acid (75 mg, 0.29 mmol) and 1- methyl-lH-pyrazol-4-amine (37 pL, 0.43 mmol). DIPEA (3 equiv.) was used instead of TEA and the reaction was performed in DMF (0.1 M) instead of DCM. The reaction mixture was filtered and purified by reversed phase chromatography according to Method B2. In step 2, TFA (50 equiv.) was used instead of 4 M HCI in dioxane. 2-amino-N-(l-methyl-lH-pyrazol- 4-yl)-3-(tetrahydrofuran-2-yl)propanamide 2,2,2-trifluoroacetate (61 mg, 0.17 mmol, 60% yield over two steps) was obtained as a waxy solid and was used as such.

[0657] Intermediate 70: 2-amino-N-cyclopropyl-3-(tetrahydrofuran-2-yl)propanamide 2,2,2- trifluoroacetate

[0658] Title compound was prepared according to General Procedure A2,a with 2-((tert- butoxycarbonyl)amino)-3-(tetrahydrofuran-2-yl)propanoic acid (75 mg, 0.29 mmol) and cyclopropylamine (30 pL, 0.43 mmol). DIPEA (3 equiv.) was used instead of TEA and the reaction was performed in DMF (0.1 M) instead of DCM. The reaction mixture was filtered and purified by reversed phase chromatography according to Method B2. In step 2, TFA (50 equiv.) was used instead of 4 M HCI in dioxane. 2-amino-N-cyclopropyl-3-(tetrahydrofuran- 2-yl)propanamide 2,2,2-trifluoroacetate (69 mg, 0.22 mmol, 76% yield over two steps) was obtained as a waxy solid and was used as such.

[0659] Intermediate 71: (S)-2-amino-N-(l-methyl-lH-pyrazol-4-yl)-3-(3-

[0660] (trif I u ore methyl) cyclobutyl) propanam ide hydrochloride

[0661] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-(3-(trifluoromethyl)cyclobutyl)propanoic acid (100 mg, 0.321 mmol) and l-methyl-lH-pyrazol-4-amine (32.8 mg, 0.337 mmol) to obtain (S)-2-amino-N- (l-methyl-lH-pyrazol-4-yl)-3-(3-(trifluoromethyl)cyclobutyl)propanamide hydrochloride (102 mg, 0.312 mmol, 97% yield over two steps) as a clear oil and was used as such.

[0662] In ter mediate 72: (S) -2 -ami no-3 -(6, 6-difluoros pi ro[3.3]heptan -2 -yl)-N-(l- methyl- 1 IH- py razo I -4-yl) propanam ide hydrochloride

[0663] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-(6,6-difluorospiro[3.3]heptan-2-yl)propanoic acid (100 mg, 0.313 mmol) and l-methyl-lH-pyrazol-4-amine (31.9 mg, 0.329 mmol) to obtain (S)-2-amino-3- (6,6-d ifluorospiro[3.3] hepta n -2-yl) -N-(l -methyl- IH-pyrazol -4-yl) propanam ide hydrochloride (105 mg, 0.314 mmol, 86% yield over two steps) as a clear oil and was used as such.

[0664] Intermediate 73: (S)-2-amino-3-(4-fluorocyclohexyl)-N-(l-methyl-lH-pyrazol-4- yl)propanamide hydrochloride

[0665] Title compound was prepared according to General Procedure A2,c with (S)-2-((tert- butoxycarbonyl)amino)-3-(4-fluorocyclohexyl)propanoic acid (76 mg, 0.26 mmol) and 1- methyl-lH-pyrazol-4-amine (27 mg, 0.28 mmol) to obtain (S)-2-amino-3-(4- fluorocyclohexyl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (71 mg, 0.23 mmol, 88% yield over two steps) as a clear oil and was used as such.

[0666] Intermediate 74: (3-fluorocyclopentyl)methyl 4-methylbenzenesulfonate

[0667] A solution of (3-fluorocyclopentyl)methanol (1.00 g, 8.46 mmol) in DCM (56 mL) was cooled to 0 ° C to which were added TEA (1.5 mL, 11 mmol), N,N-dimethylpyridin-4-amine (52 mg, 0.42 mmol) and 4-methylbenzene-l-sulfonyl chloride (1.61 g, 8.46 mmol) in one portion and the reaction was allowed to reach r.t. overnight. Then the reaction mixture was washed with a 1 M aqueous solution of HCI, a saturated solution of NaHCO3and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-40%) to afford (3-fluorocyclopentyl)methyl 4-methylbenzenesulfonate (1.86 g, 6.83 mmol, 81% yield) as a clear oil.

[0668] Intermediate 75: (2S) -2- ((tert- butoxycarbonyl) ami no) -3- (3-fluorocyclopenty I) propanoic acid

[0669] Title compound was prepared according to General Procedure Al with (R)-2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (1.10 g, 5.97 mmol) and (3-fluorocyclopentyl)methyl 4- methylbenzenesulfonate (1.79 g, 6.57 mmol). In step 1, the tosylate was used instead of the bromide. In step 2, a saturated aqueous solution of NaHCO3(10 mL) and water (5 mL) were added to the concentrate and the product was extracted with EtOAc. In step 3, the reaction was performed in DCM (0.1 M) and 2.0 equiv. of di-tert-butyl dicarbonate was used. In step 4, lithium hydroxide (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF / water (2:1, 0.2 M) instead of MeOH. (2S)-2-((tert- butoxycarbonyl)amino)-3-(3-fluorocyclopentyl)propanoic acid (331 mg, 1.20 mmol, 15% yield over four steps) was obtained as a clear oil and was used as such.

[0670] Intermediate 76: (2S)-2-ami no- N -eye Io propyl -3- (3-fluorocyclopentyl)propanam ide hydrochloride

[0671] Title compound was prepared according to General Procedure A2,c with (2S)-2-((tert- butoxycarbonyl)amino)-3-(3-fluorocyclopentyl)propanoic acid (165 mg, 0.600 mmol) and cyclopropanamine (43.7 pL, 0.630 mmol) to obtain (2S) -2-amino-N-cyclopropyl-3-(3- fluorocyclopentyl)propanamide hydrochloride (23 mg, 0.092 mmol, 15% yield over two steps) as a clear oil. Intermediate 77: (2S) -2 -a min o-3 -(3 -fluorocyclopen tyl)-N-(l-methyl-lH-pyrazo 1-4- yl) propanamide hydrochloride

[0672] Title compound was prepared according to General Procedure A2,c with (2S)-2-((tert- butoxycarbonyl)amino)-3-(3-fluorocyclopentyl)propanoic acid (165 mg, 0.600 mmol) and 1 - methyl-lH-pyrazol-4-amine (61.2 mg, 0.630 mmol) to obtain (2S) -2-amino-3-(3- fluorocyclopentyl)-N-(l-methyl-lH-pyrazol-4-yl) propanamide hydrochloride (154 mg, 0.530 mmol, 89% yield over two steps) as a yellow solid.

[0673] Intermediate 78: (5,5-difluorotetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

[0674] A solution of (5,5-difluorotetrahydro-2H-pyran-2-yl) methanol (500 mg, 3.29 mmol) in DCM (11 mL) was cooled to 0 ° C to which were added TEA (573 pL, 4.11 mmol), N,N- dimethylpyridin-4-amine (20 mg, 0.16 mmol) and 4-methylbenzene-l-sulfonyl chloride (627 mg, 3.29 mmol) in one portion and the reaction was allowed to reach r.t. overnight. The reaction mixture was washed with a 1 M aqueous solution of HCI, a saturated solution of NaHCO3and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-30%) to afford (5,5-difluorotetrahydro-2H-pyran-2-yl) methyl 4- methylbenzenesulfonate (810 mg, 2.64 mmol, 80% yield) as a clear oil.

[0675] Intermediate 79: (2S) -2- ((tert- butoxycarbonyl) ami no) -3- (5, 5-d if I uorotetra hydro -2 H -pyran - 2-yl)propanoic acid

[0676] Title compound was prepared according to General Procedure Al with (R)-2-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine (438 mg, 2.38 mmol) and (5,5-difluorotetrahydro-2H- pyran-2-yl)methyl 4-methylbenzenesulfonate (810 mg, 2.64 mmol). In step 1, the tosylate was used instead of the bromide. In step 2, the reaction was performed in MeCN at a concentration of 0.06 M instead of 0.2 M, a 0.2 M aqueous solution of TFA (6 equiv.) was used instead of a 0.1 M aqueous solution of TFA (3 equiv.) and the aqueous layer was first extracted with EtOAc and then with 15% MeOH in EtOAc. In step 3, 2 equiv. instead of 1 equiv. of di-tert-butyl dicarbonate was used. I n step 4, lithium hydroxide was used instead of NaOH, and the reaction was performed in a mixture of THF / MeOH / water (2:1:1 , 0.02 M) instead of MeOH. (2S)-2-((tert-butoxycarbonyl)amino) -3-(5,5-difluorotetrahydro-2H-pyran- 2-yl)propanoic acid (110 mg, 0.356 mmol, 13% yield over four steps) was obtained as a clear oil and was used as such. Intermediate 80: (2S)-2-amino-3-(5,5-difluorotetrahydro-2H-pyran -2-yl) -N-(l-methyl-l Pipy razo I -4-yl) propana mid e 2,2,2-trifluoroacetate

[0677] Title compound was prepared according to General Procedure A2,c with (2S)-2-((tert- butoxycarbonyl)amino)-3-(5,5-difluorotetrahydro-2H-pyran-2-yl)propanoic acid (110 mg, 0.356 mmol) and l-methyl-lH-pyrazol-4-amine (36.3 mg, 0.374 mmol). In step 2, TFA (78 equiv.) was used instead of 4 M HCI in dioxane. (2S)-2-amino-3-(5,5-difluorotetrahydro-2H- pyran-2-yl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide 2,2,2-trifluoroacetate (67.2 mg, 0.167 mmol, 47% yield over two steps) was obtained as a white solid.

[0678] Intermediate 81: (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan- 2 -y I) -5 -for my I th iophene-2 -carboxamide

[0679] To a solution of 5-formylthiophene-2-carboxylic acid (1.52 g, 9.72 mmol) in anhydrous DMF (10 mL) was added HATU (4.44 g, 11.7 mmol). After stirring at r.t. for 15 min, (S)-2- amino-3-cyclopentyl-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (2.65 g, 9.72 mmol) and DIPEA (8.5 mL, 49 mmol) were added and stirring was continued at r.t. for 18h. The reaction mixture was diluted with EtOAc and was washed with a 1 M aqueous solution of NaOH, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) and subsequently purified by reversed phase chromatography according to Method B3. (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4- yl)amino)-l-oxopropan-2-yl)-5-formylthiophene-2-carboxamide (1.32 g, 3.53 mmol, 36% yield) was obtained as a light yellow solid.

[0680] Intermediate 82: (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid

[0681] Step 1 To a mixture of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (200 mg, 0.586 mmol) and molecular sieves (4 A) (400 mg, 0.586 mmol) in 1,3-propanediol (2.1 mL, 29 mmol) was added pyridinium p-toluenesulfonate (36.8 mg, 0.146 mmol). After stirring at 80 ° C for 18h, the reaction mixture was filtered over Celite® and the residue was washed with EtOAc. Water was added to the filtrate and the layers were separated . The aqueous layer was extracted with EtOAc and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Benzyl (S)-2- (((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl) was obtained as a colorless oil and was used as such.

[0682] Step 2 To a solution of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2- yl)propanoate (234 mg, 0.586 mmol) in THF (2.0 mL) and water (2.0 mL) was added NaOH (188 mg, 4.69 mmol). After stirring at r.t. for Ih, the reaction mixture was neutralized with formic acid (0.18 mL, 4.7 mmol) and purified by reversed phase chromatography according to Method B2. (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid (46 mg, 0.15 mmol, 25% yield over two steps) was obtained as a colorless oil.

[0683] In ter mediate 83: (S) -2 -a mino-N -cyclopropyl -3- (l,3-dioxan-2-y I) propanam ide

[0684] Step 1 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid (23 mg, 0.074 mmol), HATU (37 mg, 0.097 mmol) and DIPEA (65 pL, 0.37 mmol) in DMF (1.0 mL) was added cyclopropylamine (10 pL, 0.15 mmol). After stirring at r.t. for 5 days, the reaction mixture was filtered and purified by reversed phase chromatography according to Method Bl to afford benzyl (S)-(l-(cyclopropylamino)-3-(l,3-dioxan-2-yl)-l- oxopropan-2-yl)carbamate (18 mg, 0.052 mmol, 70% yield) as a white solid.

[0685] Step 2 To a solution of benzyl (S)-(l-(cyclopropylamino)-3-(l,3-dioxan-2-yl)-l- oxopropan-2-yl)carbamate (18 mg, 0.052 mmol) in THF (2.0 mL) was added 10% palladium on activated carbon (4 mg, 2 pmol). The reaction mixture was stirred under a hydrogen atmosphere at r.t. for 18h. The reaction mixture was filtered and concentrated in vacuo o obtain (S)-2-amino-N-cyclopropyl-3-(l,3-dioxan-2-yl)propanamide (12 mg, 0.056 mmol, quant, yield) as a colorless oil.

[0686] Intermediate 84: (S) -2 -ami no-3 -(1,3 -dioxan-2-yl)-N-(l -methyl -IH-pyrazo 1-4- yl)propanamide

[0687] Step 1 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid (46 mg, 0.15 mmol), HATU (73.5 mg, 0.193 mmol) and DIPEA (0.13 mL, 0.74 mmol) in DMF (1.0 mL) was added l-methyl-lH-pyrazol-4-amine (25 pL, 0.30 mmol). After stirring at r.t. for 18h, the reaction mixture was filtered and purified by reversed phase chromatography according to Method B2 to afford benzyl (S) -(3-(l,3-dioxan-2-yl)-l-((l- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.13 mmol, 90% yield) as a purple oil.

[0688] Step 2 To a solution of benzyl (S)-(3-(l,3-dioxan-2-yl)-l-((l-methyl-lH-pyrazol-4- yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.13 mmol) in THF (2.0 mL) was added 10% palladium on activated carbon (10 mg, 4.7 pmol). The reaction mixture stirred under a hydrogen atmosphere at r.t. for 5h. Additional 10% palladium on activated carbon (10 mg, 4.7 pmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at r.t. for 20h. The reaction mixture was filtered and concentrated in vacuo to obtain (S)-2- amino-3-(l,3-dioxan-2-yl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide (34 mg, 0.13 mmol, quant, yield) as a colorless oil.

[0689] Intermediate 85: (S)-2-amino-3-(5,5-difluoro-l,3-dioxan-2-yl)-N-(l-methyl-lH-pyrazol-4- yl)propanamide

[0690] Step 1 A mixture of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (100 mg, 0.293 mmol), molecular sieves (4 A) (300 mg, 0.293 mmol), 2,2-difluoropropane-l,3-diol (32.8 mg, 0.293 mmol) and p-toluenesulfonic acid monohydrate (8.4 mg, 0.044 mmol) in anhydrous toluene (1 mL) was stirred at 100 ° C for 3h. The reaction mixture was filtered over Celite® and the residue was washed with DCM. The resulting filtrate was concentrated in vacuo. Benzyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5-difluoro-l,3-dioxan-2- yl)propanoate was obtained as a colorless oil and was used as such.

[0691] Step 2 To a solution of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5-difluoro-l,3- dioxan-2-yl)propanoate (115 mg, 0.264 mmol) in THF (1.5 mL), MeOH (1.0 mL) and water (1.5 mL) was added sodium hydroxide (85 mg, 2.1 mmol). After stirring at r.t. for Ih, the reaction mixture was neutralized with formic acid (80 pL, 2.1 mmol) and purified by reversed phase chromatography according to Method B2. (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5- difluoro-l,3-dioxan-2-yl)propanoic acid (62 mg, 0.18 mmol, 61% yield over two steps) was obtained as a colorless oil.

[0692] Step 3 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5-difluoro-l,3-dioxan-2- yl)propanoic acid (62 mg, 0.18 mmol), HATU (89 mg, 0.23 mmol) and DIPEA (0.16 mL, 0.90 mmol) in DMF (2 mL) was added l-methyl-lH-pyrazol-4-amine (31 pL, 0.36 mmol). After stirring at r.t. for 18h, the reaction mixture was filtered and purified by reversed phase chromatography according to Method B2 to afford benzyl (S)-(3-(5,5-difluoro-l,3-dioxan-2- yl)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.12 mmol, 68% yield) as a white solid.

[0693] Step 4 To a solution of benzyl (S)-(3-(5,5-difluoro-l,3-dioxan-2-yl)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.12 mmol) in THF (2 mL) was added 10% palladium on activated carbon (20 mg, 9.4 pmol). The reaction mixture was stirred under a hydrogen atmosphere at r.t. for 2h. The reaction mixture was filtered and concentrated in vacuo o obtain (S)-2-amino-3-(5,5-difluoro-l,3-dioxan-2-yl)-N-(l-methyl- lH-pyrazol-4-yl)propanamide (36 mg, 0.13 mmol, quant, yield) as a white solid.

[0694] Intermediate 86 and 87: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- methoxycyclohexyl)propanoate and methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)- 4- meth oxycyclo hexyl) pro pa noate To a nitrogen-purged solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- methoxyphenyl)propanoate (5 g, 0.02 mol) in MeOH (54 mL) was added rhodium on carbon (5%) (1.66 g, 0.808 mmol). The reaction mixture was purged with hydrogen and was stirred under hydrogen atmosphere (9 bar) at 65 ° C for 72h. The reaction mixture was cooled to r.t., filtered under nitrogen over Celite® and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to afford the two diastereomers which were separated by SFC according to Method C8 to obtain methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- methoxycyclohexyl)propanoate (1.26 g, 3.99 mmol, 25% yield) and methyl (S) -2-((tert- butoxycarbonyl)amino)-3-((lr,4S)-4-methoxycyclohexyl)propanoate (680 mg, 2.16 mmol, 13% yield).

[0695] Intermediate 88: (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- methoxycyclohexyl)propanoic acid

[0696] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4- methoxycyclohexyl)propanoate (200 mg, 0.634 mmol) in THF (1.7 mL) / water (0.8 mL) was added lithium hydroxide monohydrate (133 mg, 3.17 mmol). After stirring at r.t. for 18h the reaction mixture was acidified with a 4 M aqueous solution of HCI and the resulting mixture was extracted with DCM. The combined organic layers were concentrated in vacuo afford (S)-2-((tert-butoxycarbonyl)amino)-3-((ls,4R)-4-methoxycyclohexyl)propanoic acid as a clear oil and was used as such.

[0697] Intermediate 89: (S)-2-amino-N-cyclopropyl-3-((ls,4R)-4- methoxycyclohexyl)propanamide hydrochloride

[0698] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-((ls,4R)-4-methoxycyclohexyl)propanoic acid (96 mg, 0.32 mmol) and cyclopropanamine (19 mg, 0.33 mmol). (S)-2-amino-N-cyclopropyl-3-((ls,4R)-4- methoxycyclohexyl)propanamide hydrochloride (61 mg, 0.22 mmol, 70% yield over two steps) was obtained as a clear oil.

[0699] Intermediate 90: (S) -2 -ami no-3 -((Is, 4 R) -4- meth oxycycloh exyl)-N-(l-m ethyl-lH-pyrazo I- 4-yl)propanamide hydrochloride Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-((ls,4R)-4-methoxycyclohexyl)propanoic acid (96 mg, 0.32 mmol) and l-methyl-lH-pyrazol-4-amine (32 mg, 0.33 mmol). (S)-2-amino-3-((ls,4R)-4- methoxycyclohexyl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (75 mg, 0.24 mmol, 74% yield over two steps) was obtained as a clear oil.

[0700] Intermediate 91: (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4- methoxycyclohexyl)propanoic acid

[0701] To a solution of methyl methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4- methoxycyclohexyl)propanoate (200 mg, 0.634 mmol) in THF (1.7 mL) / water (0.8 mL) was added lithium hydroxide monohydrate (133 mg, 3.17 mmol). After stirring at r.t. for 18h the reaction mixture was acidified with a 4 M aqueous solution of HCI and the resulting mixture was extracted with DCM. The combined organic layers were concentrated in vacuo o afford (S)-2-((tert-butoxycarbonyl)amino)-3-((lr,4S)-4-methoxycyclohexyl)propanoic acid as a clear oil.

[0702] Intermediate 92: (S)-2-amino-N -cyclopropyl -3- ((lr,4S)-4-methoxycyclohexyl)propanam ide hydrochloride

[0703] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-((lr,4S)-4-methoxycyclohexyl)propanoic acid (96 mg, 0.32 mmol) and cyclopropanamine (23 pL, 0.33 mmol). (S) -2-amino-N-cyclopropyl-3-((lr,4S)-4- methoxycyclohexyl)propanamide hydrochloride (60 mg, 0.22 mmol, 69% yield over two steps) was obtained as a clear oil.

[0704] Intermediate 93: (S)-2-amino-3-((lr,4S)-4-methoxycyclohexyl)-N-(l-methyl-lH-pyrazol-4- yl)propanamide hydrochloride

[0705] Title compound was prepared according to General Procedure A2,c with (S) -2-((tert- butoxycarbonyl)amino)-3-((lr,4S)-4-methoxycyclohexyl)propanoic acid (96 mg, 0.32 mmol) and l-methyl-lH-pyrazol-4-amine (32 mg, 0.33 mmol). (S)-2-amino-3-((lr,4S)-4- methoxycyclohexyl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (89 mg, 0.28 mmol, 89% yield over two steps) was obtained as a clear oil.

[0706] Intermediate 94: (S)-2-amino-3-cyclopentyl-N-(isoxazol-4-yl)propanamide hydrochloride

[0707] Title compound was prepared according to General Procedure A2,a with (S)-2-((tertbutoxycarbonyl)amino)-3-cyclopentylpropanoic acid (100 mg, 0.39 mmol) and 4- isoxazolylamine (32.7 mg, 0.39 mmol). Instead of r.t. the reaction mixture was cooled to

[0708] 0 ° C at the start of the reaction. After the boc deprotection, the product was triturated with Et2O, solids were filtered and residue was dried to the air. (S) -2-amino-3-cyclopentyl-N- (isoxazol-4-yl)propanamide hydrochloride (54 mg, 0.21 mmol, 53% yield over two steps) was obtained as a white solid. The crude material was used without further purification.

[0709] Synthetic procedures examples:

[0710] General Procedure Bl:

[0711] Anhydrous magnesium sulfate (4.8 equiv.) was suspended in 2,2 ,2 -trif luoroetha nol (0.2 M). Aldehyde (1.1-1.2 equiv.) and 7 M ammonia in MeOH (3.8 equiv.) were added. The solution was pre-stirred at r.t. for l-3h. Then 5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxylic acid (1 equiv.), isocyanide (1.1 equiv.) and 2,2,2- trifluoroethanol (0.2 M) were added and the mixture was stirred at r.t. for 16-88h.

[0712] General Procedure B2:

[0713] (S)-2-(5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamido)-3- cyclopentylpropanoic acid (1 equiv.) and amine (1.1 equiv.) were dissolved in anhydrous DMF (0.05 M) to which was added DIPEA (1.5 equiv.) followed by HATU (1.5 equiv.). The mixtures were stirred at r.t. overnight.

[0714] General Procedure B3:

[0715] To the amine intermediate (1 equiv.) was added DMF (0.05-0.2 M). This was added to a pre-stirred solution of the caboxylic intermediate (1 equiv.), DIPEA (3-5 equiv.) and HATU (1.2 equiv.) in DMF (0.05-0.2 M). It was stirred at r.t. for 2-20h.

[0716] Reference Example 1: (S)-N-(5-chloro-2-methylpyridin-3-yl)-N-((5-((3-cyclopentyl-l-

[0717] (cyc lop ropy lam i no) -1 -oxopropan -2-yl) carbamoyl) th io phen -2 -y I) methyl) glycine

[0718] A solution of 5-chloro-2-methylpyridin-3-amine (8.38 g, 58.8 mmol), methyl 5- formylthiophene-2-carboxylate (10.0 g, 58.8 mmol) and acetic acid (3.4 mL, 59 mmol) in DCM (280 mL) / MeOH (20 mL) was stirred at r.t. for 18h. The reaction mixture was concentrated in vacuo and redissolved in DCM (280 mL) / MeOH (20 mL) and the solution was stirred at r.t. for 3h. The reaction mixture was concentrated in vacuo and the concentrate was co-evaporated with toluene and DCM. The concentrate was suspended in THF (170 mL) and acetic acid (1.9 mL, 34 mmol) and sodium borohydride (1.41 g, 37.3 mmol) was added portion-wise. The mixture was stirred at 60 ° C for 2h, then at r.t. for 18h. The reaction mixture was concentrated in vacuo and the concentrate was suspended in a saturated aqueous solution of NaHCO3and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (5-75%) to afford methyl 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylate (4.63 g, 15.0 mmol, 44% yield) as an orange gum.

[0719] To a solution of methyl 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2- carboxylate (2.00 g, 6.74 mmol) and tert-butyl 2-bromoacetate (1.47 mL, 10.1 mmol) in anhydrous DMF (44.9 mL) was added sodium hydride (0.48 g, 12 mmol) portion -wise. After stirring the reaction mixture at r.t. for 5h the reaction mixture was concentrated in vacuo and redissolved in EtOAc. The resulting solution was washed with a saturated aqueous solution of NaHCO3and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (1-35%) to afford methyl 5-(((2-(tert- butoxy)-2-oxoethyl)(5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylate (1.53 g, 3.61 mmol, 53% yield) as a brown liquid.

[0720] To a solution of methyl 5-(((2-(tert-butoxy)-2-oxoethyl)(5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxylate (100 mg, 0.243 mmol) in MeCN (0.9 mL) was added lithium hydroxide monohydrate (11.2 mg, 0.27 mmol) in water (649 pL). The mixture was stirred at 30 ° C for 3h. To the solution was added more lithium hydroxide monohydrate (2.55 mg, 0.06 mmol) and the mixture was stirred at 30 ° C for Ih and then at r.t. for 18h. The reaction mixture was purified by reversed phase chromatography according to Method B2 to obtain 5-(((2-(tert-butoxy)-2-oxoethyl)(5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxylic acid (46.0 mg, 0.12 mmol, 47% yield) as a white solid. To a solution of 5-(((2-(tert-butoxy)-2-oxoethyl)(5-chloro-2-methyl pyridin-3- yl)amino) methyl)thiophene-2-carboxylic acid (46 mg, 0.12 mmol) and TEA (48.5 pL, 0.35 mmol) in DCM (1.26 mL) was added HATU (48.5 mg, 0.13 mmol). After stirring at r.t. for 10 min (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide hydrochloride (29.7 mg, 0.13 mmol) was added and stirring was continued for 2 days. To the reaction mixture was added a saturated aqueous solution of NaHCO3and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (1-75%) to afford tert-butyl (S)-N-(5-chloro-2-methylpyridin-3-yl)-N-((5- ((3 -eye Io pen ty 1-1- (eye lop ropy lam ino)-l -oxopropan -2-yl)carbamoy I) thiophen -2- yl) methyl)glycinate (52.0 mg, 0.09 mmol, 76% yield) as a clear gum.

[0721] A solution of tert-butyl (S)-N-(5-chloro-2-methylpyridin-3-yl)-N-((5-((3-cyclopentyl-l- (cyc lop ropy lam i no) -1 -oxopropan -2-yl) carbamoyl) th io phen -2 -y I) methyl) glycin ate (13.0 mg, 0.02 mmol) in 4 M HCI in dioxane (0.1 mL, 0.4 mmol) was stirred at r.t. for 18h. The reaction mixture was purified by reversed phase chromatography according to Method B2. (S) -N-(5- chloro-2-methylpyridin-3-yl)-N-((5-((3-cyclopentyl-l-(cyclopropylamino) -l-oxopropan-2- yl)carbamoyl)thiophen-2-yl) methyl)glycine (3.0 mg, 5.7 pmol, 25% yield) was obtained as a white solid. LCMS >95% (Method A6).

[0722] Reference Example 2: 5-(l-((5-chloro-2-methylpyridin-3-yl)amino)ethyl) -N-((S) -3- cyclopenty I -l-(cyclopropy la mino)-l -oxopropan -2-yl) th iophene-2-carboxam ide

[0723] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-cyclopropylpropanamide hydrochloride (27.5 mg, 0.118 mmol)) and 5-(l-((5- chloro-2-methylpyridin-3-yl)amino)ethyl)thiophene-2-carboxylic acid (35 mg, 0.12 mmol). The reaction mixture was purified by reversed phase according to Method Bl. 5 -(l-((5- chloro-2-methylpyridin-3-yl)amino)ethyl)-N-((S)-3-cyclopentyl-l-(cyclopropylamino) -l- oxopropan-2-yl)thiophene-2-carboxamide (39 mg, 0.08 mmol, 70% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0724] Reference Example 3: 5-(l-((5-chloro-2-methylpyridin-3-yl)amino) -2,2,2-trifluoroethyl) -N-

[0725] ((S)-3-cyclopentyl-l-(cyclopropylamino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0726] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-cyclopropylpropanamide hydrochloride (10.6 mg, 0.046 mmol)) and 5-(l-((5- chloro-2-methylpyridin-3-yl)amino)-2,2,2-trifluoroethyl)thiophene-2-carboxylic acid (16 mg, 0.046 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B2, fol lowed by an additional purification by reversed phase chromatography according to Method Bl. 5-(l-((5-chloro-2-methylpyridin-3-yl)amino) - 2,2,2-trifluoroethyl)-N-((S)-3-cyclopentyl-l-(cyclopropylamino)-l-oxopropan-2- yl)thiophene-2-carboxamide (7.5 mg, 0.014 mmol, 31% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0727] Example 4: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lR,2S)-l-cyclopentyl -3- (cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide

[0728] Title compound was prepared according to General Procedure B3 with (2S,3R)-2-amino-3- cyclopentyl-N-cyclopropyl-3-hydroxypropanamide hydrochloride (29 mg, 0.12 mmol)) and 5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (33.0 mg, 0.117 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl. 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lR,2S)-l-cyc Io pentyl -3- (cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide (21 mg, 0.044 mmol, 38% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0729] Example 5: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(4,4-dimethyl-l-oxo-l- ((pyrid in -3-yl methyl) ami no) pen tan -2-yl) th iophene-2-carboxam ide

[0730] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (30.0 mg, 0.106 mmol), 3,3- dimethylbutyraldehyde (15.1 pL, 0.120 mmol) and 3-(isocyanomethyl)pyridine (13.8 mg, 0.117 mmol). The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2- methyl pyrid in -3-yl)amino) methyl) -N-(4,4-dimethyl-l-oxo-l-((pyridin -3- ylmethyl)amino)pentan-2-yl)thiophene-2-carboxamide (32 mg, 0.064 mmol, 60% yield) as an off white solid. LCMS >95% (Method A3).

[0731] Example 6: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l- ((pyrid in -3-yl methyl) ami no) propan -2-yl) th iophene-2-carboxam ide

[0732] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (30.0 mg, 0.106 mmol), 2- cyclopentylacetaldehyde (14.8 pL, 0.120 mmol) and 3-(isocyanomethyl)pyridine (13.8 mg, 0.117 mmol). The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2- methyl pyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-((pyridin -3- ylmethyl)amino)propan-2-yl)thiophene-2-carboxamide (13 mg, 0.025 mmol, 24% yield) as an off white solid. LCMS >95% (Method A3).

[0733] Example 7: N -(l-(benzylami no) -l-oxo-3-(tetra hyd ro-2 H- pyran -4-yl) propan -2-yl) -5- (((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide

[0734] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (30.0 mg, 0.106 mmol), 2- (oxan-4-yl)acetaldehyde (15.9 pL, 0.120 mmol) and benzyl isocyanide (14.2 pL, 0.117 mmol). The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford N -(l-(benzylamino)-l-oxo-3- (tetrahyd ro-2H- pyran -4-yl) propan -2-yl) -5-(((5-chloro-2-methy I py rid in -3- yl)amino) methyl)thiophene-2-carboxamide (6 mg, 0.01 mmol, 11% yield) as an off white solid. LCMS >95% (Method A3).

[0735] Example 8: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino) -l- oxo-3 - (tetra hyd ro-2 H - py ra n -4-y I) pro pan -2 -y I) th io phene -2 -carboxamide

[0736] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (30.0 mg, 0.106 mmol), 2- (oxan-4-yl)acetaldehyde (15.9 pL, 0.120 mmol) and cyclopropyl isocyanide (7.8 mg, 0.12 mmol). The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(l- (eye lop ropy I amino) -1 -oxo-3 -(tetra hydro -2 H- pyran -4-y I) propan -2- yl)thiophene-2-carboxamide (16 mg, 0.034 mmol, 32% yield) as an off white solid. LCMS >95% (Method A3).

[0737] Example 9: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-oxo-l-((pyridin-3- ylmethyl)amino) -3- (tetra hyd ro-2 H- pyran -4-y I) pro pan -2 -yl)thiophene-2-carboxam ide

[0738] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (30.0 mg, 0.106 mmol), 2- (oxan-4-yl)acetaldehyde (15.9 pL, 0.120 mmol) and 3-(isocyanomethyl) pyridine (13.8 mg, 0.117 mmol). The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2- methyl pyridin-3-yl)amino) methyl) -N-(l-oxo- l-((pyridin -3 -ylm ethyl) ami no) -3 -(tetra hydro - 2H-pyran-4-yl)propan-2-yl)thiophene-2-carboxamide (35 mg, 0.065 mmol, 62% yield) as an off white solid. LCMS >95% (Method A3).

[0739] Example 10: 5-(((5-chloro-2-methyl yridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino)-

[0740] 3-(3,3-difluorocyclobutyl)-l-oxo ro an-2-yl)thio hene-2-carboxamide

[0741] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (79.2 mg, 0.280 mmol), 2- (3,3-difluorocyclobutyl)acetaldehyde (17.2 mg, 0.317 mmol) and cyclopropyl isocyanide (20.7 mg, 0.309 mmol) at 50 ° C instead of r.t.. The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method Bl to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(l-(cyclopropylamino)-3-(3,3- difluorocyclobutyl)-l-oxopropan-2-yl)thiophene-2-carboxamide (15 mg, 0.031 mmol, 11% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0742] Example 11: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino)-

[0743] 3-(l-methylcyclopropyl)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0744] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (125.0 mg, 0.442 mmol), 2-(l- methylcyclopropyl)acetaldehyde (46.9 mg, 0.478 mmol) and cyclopropyl isocyanide (31.3 mg, 0.466 mmol) at 50 ° C instead of r.t.. The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method Bl to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(l- methylcyclopropyl)-l-oxopropan-2-yl)thiophene-2-carboxamide (32 mg, 0.072 mmol, 16% yield) as a light-yellow solid. LCMS >95% (Method A5).

[0745] Example 12: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-

[0746] (cyclopropylamino)-3-(4,4-difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0747] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (60.0 mg, 0.212 mmol), 2- (4,4-difluorocyclohexyl)acetaldehyde (41.7 mg, 0.257 mmol) and cyclopropyl isocyanide (15.7 mg, 0.234 mmol) at 50 ° C instead of r.t.. The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method Bl.

[0748] Enantiomers were separated by chiral separation according to Method Cl to afford (S) -5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)-N-(l -(cyclopropylamino) -3 -(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide (14 mg, 0.027 mmol, 13% yield) as a white solid. LCMS >95% (Method A5).

[0749] Example 13: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- d if I uorocyclohexy I)- 1 -oxo-1 - ((pyrid in -3-yl methyl) a mine) pro an -2 -y I) th iop he ne -2- carboxamide

[0750] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (70.0 mg, 0.248 mmol), 2- (4,4-difluorocyclohexyl)acetaldehyde (48.6 mg, 0.300 mmol) and 3-(isocyanomethyl) pyridine (32.2 mg, 0.273 mmol) at 50 ° C instead of r.t.. The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl) -l- oxo-l-((pyridin-3-ylmethyl)amino) propan-2-yl)thiophene-2-carboxamide (28 mg, 0.051 mmol, 20% yield) as a light-yellow solid. LCMS >95% (Method A5).

[0751] Example 14: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- dif lu orocyc I oh exyl) -l-((2 - m eth oxyethyl) ami no) -1-oxo pro pan -2 -yl) thio phene -2 -carboxamide

[0752] Title compound was prepared according to General Procedure Bl with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (70.0 mg, 0.248 mmol), 2- (4,4-difluorocyclohexyl)acetaldehyde (48.6 mg, 0.300 mmol) and l -isocyano-2- methoxyethane (10.0 mg, 0.117 mmol) at 50 ° C instead of r.t.. The reaction mixture was diluted with DMSO (1 mL) and was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-(4,4- dif lu orocyc I oh exyl) -l-((2 - m eth oxyethyl) ami no) -1-oxo pro pan -2 -yl) thio phene -2 -carboxamide (25 mg, 0.047 mmol, 19% yield) as a light-yellow solid. LCMS >95% (Method A5).

[0753] Example 15: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1-

[0754] ((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0755] Title compound was prepared according to General Procedure B2 with (S) -2- (5- (((5- ch loro-2-methy I pyrid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-methyl-lH-pyrazol-4-amine (5.0 mg,

[0756] 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N- (3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l -oxo pro pan -2 -y I) th iophene -2- carboxamide (21 mg, 0.042 mmol, 89% yield) as an off white solid. LCMS >95% (Method A5).

[0757] Example 16: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -((pyrid in -4-yl methyl) ami no) pro pan -2-yl) th iophene-2-carboxam ide

[0758] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I pyrid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 4-(aminomethyl) pyridine (5.6 mg, 0.052 mmol). Instead of HATU, EDCI.HCI (9.5 mg, 0.050 mmol) and Oxyma Pure (7.4 mg, 0.052 mmol) were added. The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N- (3 -eye I open tyl-l-oxo-l-((pyridin-4-ylmethyl)a mi no) pro pan -2 -yl) thiophene -2 -carboxamide (16 mg, 0.031 mmol, 65% yield) as a white solid. LCMS >95% (Method A3).

[0759] Example 17: (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1- oxo-1 -((pyrid in -2-yl methyl) ami no) propan -2-yl) th iophene-2-carboxam ide

[0760] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I pyrid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-aminomethylpyridine (5.6 mg, 0.052 mmol). Instead of HATU, EDCI.HCI (9.5 mg, 0.050 mmol) and Oxyma Pure (7.4 mg, 0.052 mmol) were added. The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-

[0761] (3 -eye I open tyl-l-oxo-l-((pyridin-2-ylmethyl)a mi no) pro pan -2 -yl) thiophene -2 -carboxamide (19 mg, 0.037 mmol, 78% yield) as a white solid. LCMS >95% (Method A3). Example 18: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-l-((pyrimidin-5-ylmethyl)amino) propan-2-yl)thiophene-2-carboxamide

[0762] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-y I) a mino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 5-pyrimidinemethanamine (5.6 mg, 0.052 mmol). Instead of HATU, EDCI.HCI (1.05 equiv.) and Oxyma Pure (1.1 equiv.) were added. The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3- cyclopentyl-1 -oxo- l-((pyrim id in -5-yl methyl) am ino) propan-2-yl)thiophene-2-carboxam ide (14 mg, 0.027 mmol, 58% yield) as a light-yellow solid. LCMS >95% (Method A5).

[0763] Example 19: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid in-4-y la mino) propan -2-yl) th iophene-2-carboxam ide

[0764] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-y l)a mino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (40 mg, 0.095 mmol,) and 4-aminopyridine (9.8 mg, 0.11 mmol). HTCF (1.2 equiv.) was used instead of HATU and MeCN (1 mL) was used instead of DMF. Temperature was 30 ° C instead of r.t.. The reaction mixture was purified by reversed phase chromatography according to Method Bl. Enantiomers were separated via chiral separation according to Method C2 to afford (S)-5-(((5-chloro-2-methylpyridin-3- y I) a mino) methyl) -N-(3 -eye I o pentyl- 1-oxo- l-(pyridin-4-ylamino) pro pan -2 -y I) th iop hen e -2- carboxamide (12.0 mg, 0.024 mmol, 23% yield) as a white solid. LCMS >95% (Method A5).

[0765] Example 20: (S)-N-(l-((lH-pyrazol-4-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in -3-y I) a mino) methyl) th io phene-2 -carboxamide

[0766] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-y I) a mino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 4-amino-lH-pyrazole (4.3 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-N-(l-((lH-pyrazol-4-yl)amino) -3-cyclopentyl-l-oxopropan-2-yl)-5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)thiophene-2-carboxamide (8 mg, 0.02 mmol, 33% yield) as a purple-grey solid. LCMS >95% (Method A3). Example 21: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-l-((l-(trifluoromethyl)-lH-pyrazol-4-yl)amino) pro pan -2 -y I) th iophene -2 -carboxamide

[0767] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-(trifluoromethyl)-lH-pyrazol-4-amine hydrochloride (9.8 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(3 -eye I o pentyl- 1-oxo- 1-((1- (trifluoro methyl) -IH-pyrazo 1-4- yl)amino)propan-2-yl)thiophene-2-carboxamide (6 mg, 0.01 mmol, 24% yield) as a light yellow solid. LCMS >95% (Method A3).

[0768] Example 22: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-

[0769] ((5-methyl-l,3,4-thiadiazol -2-yl) ami no) -1 -oxo pro pan -2 -yl)thiophene-2-carboxam ide

[0770] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-amino-5-methyl-l,3,4-thiadiazole (6.0 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (3-cyclopentyl-l-((5-methyl-l,3,4-thiadiazol-2-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide (9 mg, 0.02 mmol, 37% yield) as a light-yellow solid. LCMS >95% (Method A4).

[0771] Example 23: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l- (th iazol-2-y la mino) propan -2-yl) th iophene-2-carboxam ide

[0772] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-y l)a mino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-aminothiazole (5.2 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l- (thiazol-2-ylamino)propan-2-yl)thiophene-2-carboxamide (5 mg, 0.01 mmol, 21% yield) as a light-yellow solid. LCMS >95% (Method A3). Example 24: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5- methy I isoxazol -3-yl)amino)-l-oxopropan-2-y I) thiophene-2-carboxam ide

[0773] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 3-amino-5-methylisoxazole (5.1 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-1 -((5- methyl isoxazol -3-yl) ami no) -l-oxopropan-2-yl)thiophene-2-carboxam ide (10 mg, 0.019 mmol, 40% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0774] Example 25: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1-

[0775] ((l-methyl-lH-pyrazol-3-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0776] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-methyl-lH-pyrazol-3-amine (4.5 pL, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (3-cyclopentyl-l-((l-methyl-lH-pyrazol-3-yl)amino)-l -oxo pro pan -2 -y I) th iophene -2- carboxamide (11 mg, 0.021 mmol, 45% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0777] Example 26: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- (isoxazol-3-y lam i no) -1 -oxopropan -2-yl) th iophene-2-carboxam ide

[0778] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 3-aminoisoxazole (3.8 pL, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l- (isoxazol-3-ylamino)-l-oxopropan-2-yl)thiophene-2-carboxamide (12 mg, 0.024 mmol, 50% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0779] Example 27: N-(l-((l,3,4-thiadiazol-2-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide

[0780] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-amino-l,3,4-thiadiazole (5.3 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford N-(l-((l,3,4-thiadiazol-2-yl)amino)-3-cyclopentyl-l- oxopropa n-2-y I) -5-(((5-chloro-2-methy I py rid in-3-yl)amino) methyl) th iophene-2- carboxamide (5 mg, 0.01 mmol, 20% yield) as a light-yellow solid. LCMS >90% (Method A4).

[0781] Example 28: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5- methylthiazol-2-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0782] Title compound was prepared according to General Procedure B2 with (S) -2- (5- (((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-amino-5-methylthiazole (5.9 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((5-methylthiazol-2-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide (7 mg, 0.01 mmol, 27% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0783] Example 29: (S)-N-(l-((lH-pyrazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide

[0784] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and lH-pyrazol-3-amine (4.3 mg, 0.047 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-N-(l-((lH-pyrazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide (1 mg, 0.002 mmol, 4% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0785] Example 30: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0786] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 2-methyl-2H-pyrazol-3-ylamine (5.1 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide (7 mg, 0.01 mmol, 28% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0787] Example 31: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-imidazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0788] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-methyl-lh-imidazol-4-amine hydrochloride (7.0 mg, 0.052 mmol). The reaction mixture was stirred for 30h instead of overnight. Additional DIPEA (0.029 mL, 0.166 mmol) was added and the mixture was stirred at r.t. for another 8h. The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopenty 1-1- ((1- methyl- IH-imidazol -4-yl) ami no)- 1 -oxopropan -2-yl) th iophene-2- carboxamide (4 mg, 0.007 mmol, 15% yield) as a light-yellow solid. LCMS >95% (Method A4).

[0789] Example 32: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-

[0790] ((5-(trifluoromethyl)-4H-l,2,4-triazol-3-yl)amino)propan-2-yl)thiophene-2-carboxamide

[0791] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 5-(trifluoromethyl)-4H-l,2,4-triazol-3- amine (7.9 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye I o pentyl- 1-oxo- 1-((5- (trifluoro methyl) -4 H- 1,2, 4 -triazo 1-3- yl)amino)propan-2-yl)thiophene-2-carboxamide (4 mg, 0.007 mmol, 14% yield) as a lightyellow solid. LCMS >95% (Method A3). Example 33: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((3- methy I pyrid in -4-yl)amino)-l -oxo pro pan -2-yl) th iophene-2-carboxam ide

[0792] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 3-methyl-4-aminopyridine (5.6 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((3-methylpyridin-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide (4 mg, 0.008 mmol, 17% yield) as a light-yellow solid. LCMS >95% (Method A3).

[0793] Example 34: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1- ((l-methyl-lH-indol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0794] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-methyl-lH-indol-5-amine (7.6 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (3-cyclopentyl-l-((l-methyl-lH-indol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide (13 mg, 0.023 mmol, 47% yield) as a yellow light brown solid. LCMS >95% (Method A3).

[0795] Example 35: N - (1- ((1 H- benzo [d]imidazol-5-yl)ami no) -3-cyclopentyl-l -oxopropan -2-yl) -5- (((5 -ch loro-2- methy I pyrid in -3-yl) ami no) methyl) th iophene-2-carboxam ide

[0796] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch I oro-2 -methy I pyrid in -3-yl)amino) methy I) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 5-aminobenzimidazole (6.9 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford N-(l-((lH-benzo[d]imidazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-

[0797] 2-yl)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide (5 mg, 9 pmol, 19% yield) as a dark brown solid. LCMS >95% (Method A3). Example 36: N-(l-((lH-indazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide

[0798] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 5-aminoindazole (6.9 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford N-(l-((lH-indazol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5-chloro- 2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide (10 mg, 0.018 mmol, 37% yield) as a light brown solid. LCMS >90% (Method A3).

[0799] Example 37: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-benzo[d]imidazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0800] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and l-methyl-lH-benzimidazol-5-amine (7.7 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((l-methyl-lH-benzo[d]imidazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide (8 mg, 0.02 mmol, 30% yield) as a chestnut brown solid. LCMS >90% (Method A3).

[0801] Example 38: (S)-N-(l-((lH-indol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide

[0802] Title compound was prepared according to General Procedure B2 with (S) -2-(5-(((5- ch loro-2-methy I py rid in -3-yl)amino) methyl) th io phene-2 -carboxamido) -3- cyclopentylpropanoic acid (20 mg, 0.047 mmol) and 5-aminoindole (6.9 mg, 0.052 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B4 and B3 to afford (S)-N-(l-((lH-indol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide (10.0 mg, 0.019 mmol, 39% yield) as a brown solid. LCMS >95% (Method A5). Reference Example 39: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3- cyclopenty I -l-(cyclo ro y la mino)-l -oxo pro pan -2-yl) th iazole-5-carboxam ide

[0803] Title compound was prepared according to General Procedure B3 with 2-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (20 mg, 0.07 mmol), (S) -2- amino-3-cyclopentyl-N-cyclopropylpropanamide (15.22 mg, 0.08 mmol) and TEA instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3- cyclopentyl-l-(cyclopropylamino)-l-oxopropan-2-yl)thiazole-5-carboxamide (13.3 mg, 0.03 mmol, 40% yield) as a white solid. LCMS >95% (Method Al).

[0804] Example 40: (S)-N-(3-(bicyclo[l.l.l] pentan-l-yl)-l-(cyclopropylamino) -l-oxopropan-2- yl)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide

[0805] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- (bicyclo[l.l.l] pentan-l-yl)-N-cyclopropylpropanamide hydrochloride (43.9 mg, 0.168 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)thiophene-2-carboxylic acid (47.5 mg, 0.168 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S) -N-(3-(bicyclo[l.l.l]pentan-l-yl)-l- (cyc lop ropy lam i no)- 1 -oxopropan -2-yl) -5- (((5 -ch loro-2- methyl py rid in -3- yl)amino) methyl)thiophene-2-carboxamide (53 mg, 0.12 mmol, 69% yield) as a white solid. LCMS >95% (Method A5).

[0806] Example 41: 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-3-(4,4- difluorocyclohexyl)-l-(((lr,3S)-3-hydroxycyclobutyl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide

[0807] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- (4,4-difluorocyclohexyl)-N-((lr,3S)-3-hydroxycyclobutyl) propanamide hydrochloride (60.6 mg, 0.190 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2- carboxylic acid (53.7 mg, 0.190 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford 5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-((S) -3- (4, 4-difluorocyc I oh exyl)-l-(((lr,3S) -3 -hydroxycyclo butyl) ami no) - l-oxopropan-2-yl)thiophene-2-carboxamide (60 mg, 0.11 mmol, 58% yield) as a white solid. LCMS >95% (Method A5). Example 42: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-3-(4, 4- difluorocyclohexyl)-l-(((lr,3S)-3-hydroxy-3-methylcyclobutyl)amino)-l-oxopropan-2- y I) th iophene-2 -carboxamide

[0808] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- (4,4-difluorocyclohexyl)-N-((lr,3S)-3-hydroxy-3-methylcyclobutyl)propanamide hydrochloride (78 mg, 0.16 mmol) and 5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxylic acid (46.1 mg, 0.163 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-l-(((lr,3S)-3- hydroxy-3- methylcyclobutyl)amino)-l -oxo pro pan -2-yl) th iophene-2-carboxam ide (44.7 mg, 0.081 mmol, 49% yield) as a light-yellow solid. LCMS >95% (Method A5).

[0809] Reference Example 43: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(4- cyclohexyl-l-(cyclopropylamino)-l-oxobutan-2-yl)thiophene-2-carboxamide

[0810] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (56.4 mg, 0.20 mmol) and (S)- 2-amino-4-cyclohexyl-N-cyclopropylbutanamide hydrochloride (52.0 mg, 0.20 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(4-cyclohexyl-l- (cyclopropylamino)-l-oxobutan-2-yl)thiophene-2-carboxamide (58.0 mg, 0.12 mmol, 59% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0811] Example 44: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-(4,4- difluorocyclohexyl)-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide

[0812] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- (4,4-difluorocyclohexyl)-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (49 mg,

[0813] 0.15 mmol)) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (46.1 mg, 0.163 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S) -5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)-N-(3-(4,4-difluorocyclohexyl)-l-((l-methyl-lH-pyrazol-4-yl)amino) -l- oxopropan-2-yl)thiophene-2-carboxamide (7 mg, 0.01 mmol, 8% yield) as a beige solid. LCMS >95% (Method Al).

[0814] Example 45: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-1-

[0815] (cyc lo ropy lam i no) -3-((ls,4R) -4- hydroxycyclohexy I)- 1 -oxo ro an -2-yl) th iophene-2- carboxamide

[0816] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (152 mg, 0.54 mmol) and (S) - 2 -a mi no- N -eye Io propyl -3- ((ls,4R) -4- hydroxycyclohexy I) propanam ide hydrochloride (141 mg, 0.54 mmol) to obtain 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S) -l- (cyc lop ropy lam i no) -3-((ls,4R) -4- hydroxycyclohexy I)- 1 -oxopropan -2-yl) th iophene-2- carboxamide (54.0 mg, 0.11 mmol, 20% yield) as a white solid. LCMS >95% (Method Al).

[0817] Example 46: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-1-

[0818] (cyc lop ropy lam i no) -3-((lr,4S) -4- hydroxycyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide

[0819] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (90 mg, 0.32 mmol) and (S)- 2-amino-N-cyclopropyl-3-((lr,4S)-4-hydroxycyclohexyl)propanamide hydrochloride (84 mg, 0.32 mmol) to obtain 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-l- (cyc lop ropy lam i no) -3-((lr,4S) -4- hydroxycyclohexy I) -1 -oxopropan -2-yl) th iophene-2- carboxamide (53 mg, 0.11 mmol, 33% yield) as a white solid. LCMS >95% (Method Al).

[0820] Example 47: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide

[0821] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyridazin-4-yl) propanamide hydrochloride (40.6 mg, 0.15 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (42.4 mg, 0.15 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopenty 1-1 -oxo- l-(pyridazin-4-y la mino) propan -2-yl) th iophene-2-carboxam ide (41 mg, 0.082 mmol, 54% yield) as a tan solid. LCMS >95% (Method Al).

[0822] Example 48: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iazole-5-carboxam ide

[0823] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyridazin-4-yl)propanamide hydrochloride (40.6 mg, 0.15 mmol) and 2-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (42.6 mg, 0.15 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo- l-(pyridazin-4-ylamino)propan-2-yl)thiazole-5-carboxamide (17.6 mg, 0.035 mmol, 23% yield) as a white solid. LCMS >95% (Method Al).

[0824] Example 49: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -5-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide

[0825] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyrimidin-5-yl)propanamide hydrochloride (27.1 mg, 0.1 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (28.3 mg, 0.1 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo- l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2-carboxamide (6.7 mg, 0.013 mmol, 13% yield) as a tan solid. LCMS >95% (Method Al).

[0826] Example 50: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -5-y lam i no) pro pan -2-yl) th iazole-5-carboxam ide

[0827] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyrimidin-5-yl)propanamide hydrochloride (27.1 mg, 0.1 mmol) and 2-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (28.4 mg, 0.1 mmol). The reaction mixture was purified by reversed phase chromatography according to Method Bl to afford (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo- Ill l-(pyrimidin-5-ylamino)propan-2-yl)thiazole-5-carboxamide (33 mg, 0.66 mmol, 66% yield) as a yellow solid. LCMS >95% (Method Al).

[0828] Example 51: (S)-5-(((5-chloro-2-methyl yridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -4-y lam i no) pro pan -2-yl) th io hene-2-carboxam ide

[0829] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyrimidin-4-yl)propanamide hydrochloride (23.1 mg, 0.085 mmol) and 5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (24.3 mg, 0.086 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-oxo-l-(pyrimidin-4-ylamino)propan-2-yl)thiophene-2-carboxamide (25 mg, 0.051 mmol, 59% yield) as a white solid. LCMS >95% (Method A3).

[0830] Example 52: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid in-3-y la mino) propan -2-yl) th iophene-2-carboxam ide

[0831] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyridin-3-yl)propanamide hydrochloride (44.3 mg, 0.143 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (40.7 mg, 0.144 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopenty 1-1 -oxo- l-(py rid in -3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide (45 mg, 0.091 mmol, 64% yield) as a white solid. LCMS >95% (Method A3).

[0832] Example 53: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-! -oxo-1 -(pyrim id in-5-ylami no) pro pan -2-yl)thiophene-2-carboxam ide

[0833] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (20.0 mg, 0.07 mmol), (S)-2- amino-3-(4,4-difluorocyclohexyl)-N-(pyrimidin-5-yl)propanamide hydrochloride (22.7 mg, 0.07 mmol) and TEA instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(3-(4,4-difluorocyclohexyl)-l-oxo-l-(pyrimidin-5-ylamino)propan-2- yl)thiophene-2-carboxamide (18.3 mg, 0.03 mmol, 46% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0834] Example 54: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino)propan-2-yl)thiophene-2-carboxamide

[0835] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (20.0 mg, 0.07 mmol), (S)-2- amino-3-(4,4-difluorocyclohexyl)-N-(pyridazin-4-yl)propanamide hydrochloride (22.7 mg, 0.07 mmol) and TEA instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S)-5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(3- (4, 4-difluorocyc I oh exyl)- 1-oxo- l-(pyridazin-4-ylam in o) propan -2 - yl)thiophene-2-carboxamide (21.2 mg, 0.04 mmol, 54% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0836] Example 55: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(pyridazin-3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide

[0837] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyridazin-3-yl)propanamide hydrochloride (32.2 mg, 0.087 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (24.9 mg, 0.088 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopenty 1-1 -oxo- 1 - (py ridazi n -3 -y la mino) propan -2-yl) th iophene-2-carboxam ide (27 mg, 0.054 mmol, 62% yield) as an off white / light brown solid. LCMS >95% (Method A5).

[0838] Example 56: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rid in-2-y la mino) propan -2-yl) th iophene-2-carboxam ide

[0839] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(pyridin-2-yl)propanamide hydrochloride (23.7 mg, 0.066 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (18.9 mg, 0.067 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- eye I open ty 1-1 -oxo- l-(py rid in -2-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide (12 mg, 0.024 mmol, 37% yield) as an off white solid. LCMS >95% (Method A5).

[0840] Example 57: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-! -oxo-1 -(pyrim id in-5-ylami no) pro pan -2-y I) thiazole -5 -carboxam ide

[0841] Title compound was prepared according to General Procedure B3 with 2-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (15.0 mg, 0.05 mmol), (S)-2- amino-3-(4,4-difluorocyclohexyl)-N-(pyrimidin-5-yl) propanamide hydrochloride (17.0 mg, 0.05 mmol) and TEA instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S) -2-(((5-chloro-2-methylpyridin-3- yl)amino) methyl)-N-(3-(4,4-difluorocyclohexyl)-l-oxo-l-(pyrimidin-5-ylamino)propan-2- yl)thiazole-5-carboxamide (13.3 mg, 0.02 mmol, 45% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0842] Example 58: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino) propan-2-yl)thiazole-5-carboxamide

[0843] Title compound was prepared according to General Procedure B3 with 2-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (20.0 mg, 0.07 mmol), (S) -2- amino-3-(4,4-difluorocyclohexyl)-N-(pyridazin-4-yl) propanamide hydrochloride (22.6 mg, 0.07 mmol) and TEA instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S) -2-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(3- (4, 4-difluorocyc I oh exyl)- 1-oxo- l-(pyridazin-4-ylam in o) propan -2 - yl)thiazole-5-carboxamide (13.1 mg, 0.02 mmol, 33% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0844] Example 59: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -2-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide

[0845] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- cyclopentyl-N-(pyrimidin-2-yl)propanamide hydrochloride (20.6 mg, 0.066 mmol) and 5- (((5-chloro-2-methylpyridin-3-yl)amino) methyl)thiophene-2-carboxylic acid (18.9 mg, 0.067 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-2-ylamino)propan-2-yl)thiophene-2-carboxamide (25 mg, 0.050 mmol, 76% yield) as a white solid. LCMS >95% (Method A5).

[0846] Example 60: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-l- ((2-methyl-2H-l,2,3-triazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0847] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- cyclopentyl-N-(2-methyl-2H-l,2,3-triazol-4-yl)propanamide hydrochloride (27.0 mg, 0.088 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)thiophene-2-carboxylic acid (25.2 mg, 0.089 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S) -5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) - N-(3-cyclopenty 1-1- ((2-methyl-2H -1,2, 3 -triazol -4-yl) ami no)- 1 -oxopropan - 2-yl)thiophene-2-carboxamide (21 mg, 0.043 mmol, 48% yield) as an off white solid. LCMS >95% (Method A3).

[0848] Example 61: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py razin-2-y la mino) propan -2-yl) th iophene-2-carboxam ide

[0849] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- cyclopentyl-N-(pyrazin-2-yl)propanamide hydrochloride (17.0 mg, 0.045 mmol) and 5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (13.6 mg, 0.048 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrazin-2-ylamino) propan-2-yl)thiophene-2-carboxamide (19 mg, 0.038 mmol, 84% yield) as a white solid. LCMS >95% (Method A3).

[0850] Example 62: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1-

[0851] ((l-methyl-lH-l,2,4-triazol-3-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

[0852] Title compound was prepared according to General Procedure B3 with (S) -2-amino-3- cyclopentyl-N-(l-methyl-lH-l,2,4-triazol-3-yl)propanamide hydrochloride (32.2 mg, 0.079 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)thiophene-2-carboxylic acid (22.6 mg, 0.080 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S) -5-(((5-chloro-2-methylpyridin-3- y I) a mino) methyl) -N-(3 -eye I opentyl-l-((l-m ethyl -1H- 1,2, 4 -triazol -3 -y I) a mino) -1 -oxopropan- 2-yl)thiophene-2-carboxamide (33 mg, 0.065 mmol, 82% yield) as a white solid. LCMS >95% (Method A3).

[0853] Example 63: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-

[0854] (cyc lop ropy lam i no) -3 -(3, 3-d i methyl eye I obuty I) -1 -oxopropan -2-y l)thiophene-2-carboxam ide

[0855] Title compound was prepared according to General Procedure B3 with 5-(((5-chloro-2- methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (28 mg, 0.10 mmol) and (S) - 2-amino-N-cyclopropyl-3-(3,3-dimethylcyclobutyl) propanamide hydrochloride (34 mg, 0.14 mmol). TEA was used instead of DIPEA. The reaction mixture was purified by reversed phase chromatography according to Method Bl. (S) -5-(((5-chloro-2-methylpyridin-3- y I) a min o) methyl) -N-(l- (eye lop ropy I amino) -3 -(3, 3 -di methyl cyclobutyl) -1 -oxopropan -2- yl)thiophene-2-carboxamide (29.1 mg, 0.06 mmol, 61.6% yield) was obtained as a white solid. LCMS >95% (Method Al).

[0856] Example 64: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l- (cyclopropylami no) -1 -oxo-3- (spiro [3.3] heptan -2-yl) propan-2-yl)thiophene-2-carboxam ide

[0857] Title compound was prepared according to General Procedure B3 with (S)-2-amino-N- cyclopropyl-3-(spiro[3.3] heptan-2-yl)propanamide hydrochloride (12.5 mg, 0.048 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (13.7 mg, 0.048 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N- (1 -(eye lop ropy lam ino)-l -oxo-3- (spiro [3.3] heptan -2-yl) pro pan -2-y l)th iophene -2- carboxamide (10.6 mg, 0.022 mmol, 45% yield) as a white solid. LCMS >95% (Method Al).

[0858] Example 65: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l- (cyclopropylami no) -1 -oxo-3- (spiro [3.3] heptan -2-y I) propan-2-yl)thiazole-5-carboxam ide

[0859] Title compound was prepared according to General Procedure B3 with (S)-2-amino-N- cyclopropyl-3-(spiro[3.3] heptan-2-yl)propanamide hydrochloride (12.5 mg, 0.048 mmol) and 2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (13.7 mg, 0.048 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B2 and Method B3 to afford(S) -2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) - N -(1- (eye I op ropy lam ino)-l -oxo-3- (spiro [3.3] hepta n -2-y I) propan -2-y I) th iazole-5- carboxamide (7.8 mg, 0.016 mmol, 33% yield) as a white solid. LCMS >95% (Method Al).

[0860] Example 66: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-((l-methyl-l IH- py razol -4-y l)amino)-l -oxo-3- (spiro [3.3] hepta n -2-y I) propan -2-y l)thiophene-2-carboxam ide

[0861] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (12.5 mg, 0.042 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (11.8 mg, 0.042 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxo-3-(spiro[3.3]heptan-2-yl) pro pan -2- yl)thiophene-2-carboxamide (10.7 mg, 0.02 mmol, 48% yield) as a white solid. LCMS >95% (Method Al).

[0862] Example 67: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-((l-methyl-l Pipy razol-4-yl)am ino)-l -oxo-3- (spiro [3.3] hepta n -2-yl) propan -2-yl)thiazole-5-carboxam ide

[0863] Title compound was prepared according to General Procedure B3 with (S)-2-amino-3- cyclopentyl-N-(l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (12.5 mg, 0.042 mmol) and 2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (11.9 mg, 0.042 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxo-3-(spiro[3.3]heptan-2-yl) pro pan -2-y I) th iazole- 5-carboxamide (12.8 mg, 0.024 mmol, 57% yield) as a white solid. LCMS >95% (Method Al).

[0864] Example 68: (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-oxo-l-(pyridazin- 4-y lam i no) -3- (spiro [3.3] hepta n -2-y I) pro pan -2-y I) th iophene-2-carboxam ide

[0865] Title compound was prepared according to General Procedure B3 with (S)-2-amino-N- (pyridazin-4-yl)-3-(spiro[3.3]heptan-2-yl)propanamide hydrochloride (12.5 mg, 0.042 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (11.9 mg, 0.042 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (1 -oxo-1 -(py rid azin -4-y lam ino) -3- (spiro [3.3] hepta n -2-y I) propan -2-y I) th iophene -2- carboxamide (8.2 mg, 0.016 mmol, 37% yield) as a white solid. LCMS >95% (Method Al).

[0866] Example 69: (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-oxo-l-(pyridazin-

[0867] 4-y lam ino) -3- (spiro [3.3] hepta n -2-y I) pro pan -2-y I) th iazole-5-carboxam ide

[0868] Title compound was prepared according to General Procedure B3 with (S)-2-amino-N- (pyridazin-4-yl)-3-(spiro[3.3]heptan-2-yl)propanamide hydrochloride (12.5 mg, 0.042 mmol) and 2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiazole-5-carboxylic acid (12 mg, 0.042 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- (1 -oxo-1 - (py rid azin -4-y lam ino) -3- (spiro [3.3] hepta n -2-yl) propan -2-yl) th iazole-5- carboxamide (3.5 mg, 0.006 mmol, 15% yield) as a pink solid. LCMS >95% (Method Al).

[0869] Example 70: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((2S)-3-(cyclohex-3-en- 1 -y I) -l-(cyclopropy lam i no) -1 -oxopropan -2-y I) thiophene-2-carboxam ide

[0870] Title compound was prepared according to General Procedure B3 with (2S) -2-amino-3- (cyclohex-3-en-l-yl)-N-cyclopropylpropanamide hydrochloride (25.8 mg, 0.083 mmol) and 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (27.1 mg, 0.096 mmol). The reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N- ((2S) -3 - (eye Io hex-3 -en- 1-yl) -l-(cyclopropy lam ino) -1 -oxopropan -2-y I) th iophene -2- carboxamide (14.1 mg, 0.030 mmol, 35% yield) as an off-white solid. LCMS >95% (Method A5).

[0871] Example 71: 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lS,2S)-l-cyclopentyl-

[0872] 3-(cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide

[0873] Title compound was prepared according to the procedure described for 5-(((5...

Claims

Claims1. A compound of formula (I)or a salt, stereoisomer, tautomer, or N-oxide thereof, whereinX1is CH or N;L1is CH2, CHCH3, CHCF3, or S(=O)2;L2is CH2, CH2CH2, CHOH, CHOCH3or absent;R1is H, C1-C4-al kyl, C1-C4-alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx;R2is 5- to 10-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;R3is H, C1-C2-alkyl, or CH2C(=0)0H;R4is H, C1-C2-alkyl, 3- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz;R5is H or C1-C2-alkyl; and whereinRxis halogen, CN, OH, S(=O)2CH3, S(=O)(=NH)CH3, NHC(=O)CH3, NH2, Cj-C^alkyl, C C4-alkoxy, Cj-Cj-haloalkyl, or Cj-C^i- hyd roxya I kyl;RYis halogen, CN, Cj-C^i-alkyl, Cj-C^j-alkoxy, Cj-C^haloalkyl, Cj-Cj-haloalkoxy, or Cj-Ci- hyd roxya I ky I ;Rzis halogen, CN, OH, C1-C4-alkyl, C1-C4-ha loa I ky I , Cj-C^-haloalkoxy, or Cj-C4- hydroxyal kyl; or two Rzattached to the same atom form a C Cg-alkylene chain. with the proviso that at least one of the following conditions is met:R1is(i) a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx; or(ii) a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rx;R4is(i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or(ii) a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or(iii) a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or(iv) a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents Rz; orL2is CHOH or CHOCH3.

2. The compound according to claim 1, wherein the proviso applies that at least one of the following conditions is met:R1is 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents Rx;wherein Rxis F, CF3, or CH3;(i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents Rz; or(ii) a 4-membered saturated carbocyclyl; wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; or(iii) a 4- to 6-membered saturated heterocyclyl, or 5- to 7-membered saturated carbobicyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and / or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents Rz; whereinRzis F, CF3, or CH3; or two Rzattached to the same atom form a C3-alkylene chain; orL2and R4together formwherein the dotted line marks the connection to the remainder of the molecule.

3. The compound according to claim 1 or 2, wherein the proviso applies that at least one of the following conditions is met:R1iswherein the dotted line in each case marks the connection to the remainder of the molecule; orL2and R4together formwherein the dotted line in each case marks the connection to the remainder of the molecule.

4. The compound according to any one of claims 1 to 3, wherein the proviso applies that at least one of the following conditions is met: R1iswherein the dotted line in each case marks the connection to the remainder of the molecule; orL2and R4together form:wherein the dotted line marks the connection to the remainder of the molecule.

5. The compound according to any one of claims 1 to 4, whereinR1iswherein the dotted line in each case marks the connection to the remainder of the molecule; andL2and R4together form:wherein the dotted line in each case marks the connection to the remainder of the molecule.

6. The compound according to any one of claims 1 to 5, whereinX1is N.

7. The compound according to any one of claims 1 to 5, whereinX1is CH.

8. The compound according to any one of claims 1 to 7, whereinL1is CH2; and / orL2is CH2.

9. The compound according to any one of claims 1 to 8, whereinR5is H.

10. The compound according to any one of claims 1 to 9, whereinR3is H.

11. The compound according to any one of claims 1 to 10, wherein R2is any one ofwherein the dotted line in each case marks the connection to the remainder of the molecule.

12. The compound according to any one of claims 1 to 11, wherein the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyridin-3-ylamino) propan -2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l-(pyridazin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino)methyl)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2- y I) th iophene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- 1 - (py ridazi n -3 -y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5- (((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-(4,4-difluorocyclohexyl)-l-oxo-l- (py rim id in-5-y lam i no) propan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch I oro-2 - methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino)-3-(4,4-difluorocyclohexyl)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, (S) -5- (((5 -ch loro -2- methyl pyrid in -3- yl)a min o) methyl) -N-(3- (4, 4-difluorocyc I oh exyl)- 1-oxo- l-(pyridazin-4-ylami no) propan-2- y I) th iophene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino)propan-2-yl)thiazole-5-carboxamide, (S)-2-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4,4-difluorocyclohexyl)-l-oxo-l- (pyridazin-4-ylamino)propan-2-yl)thiazole-5-carboxamide, 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-((l R, 2S)-l-cyc I open tyl-3- (eye Io propyl a mino) -1 -hydroxy-3 -oxopropan- 2 -y I) th io phene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((S)-3- (4,4-difluorocyclohexyl)-l-(((lr,3S)-3-hydroxycyclobutyl)amino)-l -oxopropan -2- y I) th iophene-2 -carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S) -3- (4,4-difluorocyclohexyl)-l-(((lr,3S)-3-hydroxy-3- methylcyclobutyl) ami no) -1 -oxopropan -2- y I) th iophene-2 -carboxamide, (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo- l-(py ridazi n-4-y la mino) propan -2-yl) th iazole-5-carboxam ide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-4- y la mino) propan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloro-2-methylpyridin-3- yl)amino) methyl) -N-(3-cyclopentyl-l-((2-methyl-2H-l, 2, 3-triazol-4-yl)amino)-l-oxopropan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-ch loro-2- methyl pyrid in -3-yl) ami no) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrazin-2-ylamino)propan-2-yl)thiophene-2-carboxamide, (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-l,2,4-triazol- 3-yl)amino)-l -oxopropan -2-yl) th iophene-2-carboxam ide, (S)-5-(((5-chloropyridin-3- yl)amino)methyl)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2- y I) th iophene-2 -carboxamide, (S) -N-(3-cyclopentyl-l-((l -methyl -lH-pyrazol-4-yl)amino)-l- oxopropan-2-yl)-5-(((5-(difluoromethyl)-2-methylpyridin-3-yl)amino)methyl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxo-3-((R) -tetra hydrofuran -2-yl) propan -2-yl)thiophene-2- carboxamide, 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxo-3-((S) -tetra hydrofuran -2-yl) propan -2-yl)thiophene-2- carboxamide, (S) -N-(3-(l, 3-dioxan-2-yl) -l-((l-methyl- lH-pyrazol -4-yl) amino) -1- oxopropa n-2-y I) -5-(((5-chloro-2-methy I py rid in-3-yl)amino) methyl) th iophene-2- carboxamide, (S)-N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2- yl)-5-(((2,5-dimethylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide, and (S)-5-(((5- chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-(isoxazol-4-ylamino)-l- oxop ropa n -2 -y I) th iophene-2 -carboxamide.

13. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 12 and optionally a pharmaceutically acceptable carrier or excipient.

14. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in medicine.

15. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre- cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre-cancerous syndromes, and neurological diseases.

16. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

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