Novel molecule as an inhibitor of DNA damage repair pathway

Abstract

The present application relates to novel compounds described herein, methods for preparing the same, pharmaceutical compositions thereof, and methods for using the same. In particular, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof that is useful as an inhibitor of ubiquitin-specific protease 1 (USP1) protein for the treatment, prevention, and / or alleviation of ubiquitin-specific protease 1 (USP1)-related diseases or disorders, including cancer.

Description

Technology Field

[0001] The present application claims the benefit of priority to Indian provisional patent application no. 202341076811 filed November 10, 2023; 202441000286 filed January 2, 2024; 202441001631 filed January 9, 2024; 202441037320 filed May 11, 2024; and U.S. provisional patent application no. 63 / 690,894 filed September 5, 2024, the disclosures of each of these being incorporated herein by reference in their entirety.

[0002] Field of invention

[0003] The present application relates to novel compounds described herein, methods for preparing the same, pharmaceutical compositions thereof, and uses thereof. In particular, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as an inhibitor of ubiquitin-specific protease 1 (USP1) protein, which is useful for the treatment, prevention, and / or improvement of diseases or disorders associated with ubiquitin-specific protease 1 (USP1), including cancer. Background Technology

[0004] Ubiquitin is a small, highly conserved protein of 76 amino acids that is conjugated post-translationally to substrate proteins, including itself, through a three-step enzymatic reaction. Initial covalent attachment occurs primarily between the C-terminal glycine of ubiquitin and the ε-amino group of the lysine residue(s) of the target protein. Additional ubiquitin molecules are linked to one of the seven inner lysines of ubiquitin, which can result in various ubiquitin chain topologies. The biological outcomes of ubiquitination are determined by both length and linkage topology. For example, Lys48-linked polyubiquitin chains are associated almost exclusively with allocating proteins for proteasome-dependent degradation, whereas monoubiquitin or chains linked through different lysines have been shown to provide numerous non-proteolytic functions. Like other types of post-translational modifications, ubiquitination is a reversible process inversely regulated by an enzyme known as deubiquitin (DUB), which catalyzes the removal of ubiquitin from modified proteins. More importantly, dysfunction of ubiquitin-dependent signaling pathways is associated with various human diseases, suggesting the inhibition of ubiquitin pathway components as novel therapeutic targets for drug discovery.

[0005] Pharmacological interventions in the ubiquitin-proteasome system have been well established by the successful use of proteasome inhibitors for anticancer therapy. Nevertheless, the ubiquitin-proteasome system offers additional opportunities for therapeutic interventions that may provide increased specificity and improved clinical efficacy, which are currently lacking with proteasome inhibitors. The most obvious targets include enzymes involved in ubiquitin conjugation and deconjugation (i.e., ubiquitin ligases and DUBs) and upstream processes of proteasome-mediated protein degradation.

[0006] Reversible protein ubiquitination is emerging as a key process for maintaining cellular homeostasis, and the enzymes involved in this process, particularly E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly considered candidates for drug discovery. Human DUBs are a group of approximately 100 proteins whose cellular functions and regulatory mechanisms remain unknown, and with a few exceptions, they are not well characterized. Among the DUBs, ubiquitin-specific protease 1 (USP1) has become an attractive anticancer target because it is involved in regulating DNA damage response pathways.

[0007] USP1 is also one of the most well-characterized human DUBs that plays a crucial role in the cellular response to DNA damage. USP1 levels, localization, and activity are regulated through various mechanisms, including protein-protein interactions, autocleavage / degradation, and phosphorylation, ensuring that USP1 function is performed in an appropriately regulated spatiotemporal manner. Importantly, USP1 expression exhibits dysregulation in certain types of human cancer, suggesting that USP1 may be an effective target for cancer therapy (see reference [Garcia-Santisteban et al., Molecular Cancer 2013, 12:91]).

[0008] UUSP1 is associated with UAF1 (USP1-associated factor 1) to form the heterodimeric USP1 / UAF1 complex required for deubiquitinase activity. The USP1 / UAF1 complex has been shown to regulate resistance to DNA damage induced by DNA crosslinkers through the deubiquitination of PCNA (proliferating cell nuclear antigen) and FANCD2 (Fanconi anemia complement D2), and these proteins function in damage-bypass DNA synthesis and the Fanconi anemia pathway, respectively. Williams et al. also recently reported that USP1 / UAF1 deubiquitinated ID (DNA binding inhibitor) proteins and prevented their proteasome degradation, and that these proteins activated multiple pathways involved in tumor progression, including the preservation of cancer stem cell phenotypes. Furthermore, evidence of abnormal overexpression of USP1 in some tumor types suggests that USP1 inhibitors may offer therapeutic benefits (see reference [Thomas S. Dexheimer et al., J. Med. Chem. 2014, 57, 8099-8110]).

[0009] Various research groups around the world have conducted research targeting USP1, and patent literature targeting USP1 includes the following patents and / or patent applications.

[0010] WO2024 / 208292, WO2024 / 153175, WO2024 / 153250, WO2024 / 146541, WO2024 / 131742, WO2024 / 094170, WO2024 / 086790, WO2024 / 083237, WO2024 / 078436, WO2024 / 064883, WO2024 / 046471, WO2024 / 041634, WO2024 / 032647, WO2024 / 022519, WO2024 / 022266, WO2024 / 006879, WO2023 / 250084, WO2023 / 216910, WO2023 / 208130, WO2023 / 196955, WO2023 / 148643, WO2023 / 155866, WO2023 / 143424, WO2023 / 066299, WO2023 / 083285, WO2023 / 083297, WO2023 / 083286, WO2023 / 147311, WO2023 / 030295, WO2022 / 216820, WO2022 / 199652, WO2022 / 253188, WO2022 / 214053, WO2022 / 174184, WO2022 / 197892, WO2022 / 228399, WO2022 / 233263, WO2021 / 163530, WO2021 / 247606, WO2020 / 132269, WO2020 / 139988, WO2017 / 087837, WO2014 / 105952 및 WO2011 / 137320.

[0011] For further review and literature disclosure regarding USP1 inhibitors, refer to the following: Li, XY et al., Leukemia 37, 164-177 (2023); Mallard HJ et al., Mol. Cancer Res. 2023 Nov. 1; 21(11):1186-1204; Thomas S. Dexheimer et al., J. Med. Chem. 2014, 57, 8099-8110; Qin Liang et al., Nat. Chem. Biol. 2014 Apr.; 10(4):298-304; and Iraia Garcia-Santisteban et al., Molecular Cancer 2013, 12:91. All of these patents and / or patent applications and literature disclosures are incorporated herein by reference in their entirety for all purposes.

[0012] The inventors believe that, in general, cancer has very few treatment options, especially when the cancer is the result of metastasis and is unresectable. On the one hand, there have been some advancements in treatment options, such as the use of chemotherapy alone or in combination with radiation therapy and / or surgery; on the other hand, however, there have still been significant difficulties regarding prognosis, particularly in cancers such as breast, ovarian, prostate, lung, gastric, endometrial, and colorectal cancers.

[0013] Therefore, there is an unmet medical need regarding treatments for such cancer, and the present invention aims to address this need.

[0014] Summary of the Invention

[0015] The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or composition, and a method of treatment using the same, and in particular, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof that is useful for the treatment, prevention and / or improvement of a disease or disorder associated with USP1.

[0016] In one embodiment of the present invention, the present invention relates to a compound of the following formula (I):

[0017]

[0018] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0019] Here,

[0020] X 1 is CR 1 or N and;

[0021] X 2 is CR 2 , NR 2 or N and;

[0022] X 3 is CR 3 , NR 3 or N and;

[0023] X 4 is CR 4 , NR 4 or N;

[0024] R 1 Each occurrence is hydrogen, hydroxy, halogen, CN (cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy-C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b-OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c, - NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b 또는 -CR b R c C(=S)R z, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rs a It can be bonded to a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may be the same or different and O, NR a Alternatively, it may optionally include a heteroatom selected from S.

[0025] R 2 , R 3 and R 4 Each occurrence is hydrogen, hydroxy, halogen, CN (cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c, - NR b C(=S)NRb R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b or -CR b R c C(=S)R z , substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rs a It can be bonded to substituted or unsubstituted saturated or unsaturated 3-6 member rings, and may be the same or different O, NR aor may optionally include a heteroatom selected from S; or R together with an attached ring 2 and R 3 or R 3 and R 4 Any two variables of can form arbitrarily substituted rings of 5 to 8 origins, which may be identical or different, and O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0026] L, L 1 and L 2 C is independently absent, substituted, or unsubstituted, respectively. 1-4 Alkyl, substituted, or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 alkynyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 3-10 Heterocycloalkyl, -(CR b R c ) n -, O, S, -S(=O) p -, -C(=O)- , -NR x -, -S(=O) p -NH-, -NH-S(=O) p -, -CO-NR x - and -NR x Selected independently from -CO-;

[0027] Cy 1 is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;

[0028] R and R 5Each occurrence is independently hydrogen, hydroxy, halogen, CN(cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c, - NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c, - NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b ORc , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , -CR b R c C(=S)R z , substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring or substituted heterocyclylalkyl ring;

[0029] R a Each occurrence is independently hydrogen, hydroxy, halogen, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy-C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NRb R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b 또는 -CR b R c C(=S)R z ;

[0030] R b 및 R cEach is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted R when bonded to an amino, or a common atom b and R c Any two of them may combine to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 member ring, which may optionally be the same or different and O, NR X or one or more heteroatoms selected from S, or (ii) oxo (=0), thio (= S) or imino (=NR x It may include ) and;

[0031] R x and R z Each occurrence of is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O)qR a , -NR a R b , -C(=Z')-R a , selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynoyls, and substituted or unsubstituted cycloalkyls;

[0032] of each occurrence

[0033] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8 and;

[0034] p and q are independently 0, 1, or 2, respectively.

[0035] step,

[0036] (a) If L does not exist, L 1 It is -NH- or -0-, and subsequently, ring A in the compound of formula (I) is not furo[3,2-d]pyrimidine.

[0037] (b) If L does not exist, L 1 It is -NH- and L 2 is CH2, and Cy 1 is an unsubstituted phenyl, and X 1 = X 2 = N and X 3 = CR 3 and X 4 = CR 4 and, here R 3 and R 4 It forms an unsubstituted phenyl together, and

[0038] (i) In the compound of chemical formula (I), R is not 2-trifluoromethylphenyl.

[0039] (ii) R in the compound of chemical formula (I) 5 is not an unsubstituted pyridine-3-yl.

[0040] (c) X 1 = X 2 = N and X 3 = CR 3 and X 4 = CR 4 and, if L does not exist, L 1 It is -NH- and L 2 is CH2, and Cy 1 is an unsubstituted phenyl, and R 5is unsubstituted pyridine-3-yl, and in the compound of formula (I), R is not 2-isopropylphenyl.

[0041] (d) The compound of chemical formula (I) is

[0042] (i) 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrido[3,2-d]pyrimidine-4-amine;

[0043] (ii) 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine; and

[0044] (iii) 2-(2-isopropylphenyl)-N-(4-(pyridine-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine

[0045] A compound having the chemical formula (I) is more preferred, where X 1 is CR 1 or is N.

[0046] A compound having the chemical formula (I) is more preferred, where X 2 is CR 2 or is N.

[0047] A compound having the chemical formula (I) is more preferred, where X 3 is CR 3 or is N.

[0048] A compound having the chemical formula (I) is more preferred, where X 4 is CR 4 or is N.

[0049] A compound having the chemical formula (I) is more preferred, where X 2 is N or NR 2 am.

[0050] A compound having the chemical formula (I) is more preferred, where X 3 is N or NR 3 am.

[0051] A compound having the chemical formula (I) is more preferred, where X 4 is N or NR 4 am.

[0052] A compound having the chemical formula (I) is more preferred, where X 2 is NR 2 and X 3 is CR 3 am.

[0053] A compound having the chemical formula (I) is more preferred, where X 3 is NR 3 and X 4 is CR 4 am.

[0054] Additionally, a compound having the chemical formula (I) is preferred, where X 2 is NR 2 and X 3 is CR 3 and R 2 and R 3 Each forms an arbitrarily substituted ring of 5 to 8 circles together with the ring to which they are attached, and these may be identical or different and O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0055] Additionally, a compound having the chemical formula (I) is preferred, where X 3 is NR 3 and X 4 is CR 4 and R 3 and R 4 Each forms an arbitrarily substituted ring of 5 to 8 circles together with the ring to which they are attached, and these may be identical or different and O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0056] Additionally, a compound having the chemical formula (I) is preferred, where X 2 is NR 2 and X 3is CR 3 and R 2 and R 3 Each forms a 5-membered arbitrarily substituted ring containing one or more N atoms together with the ring to which they are attached.

[0057] Additionally, a compound having the chemical formula (I) is preferred, where X 3 is NR 3 and X 4 is CR 4 and R 3 and R 4 Each forms a 5-membered arbitrarily substituted ring containing one or more N atoms together with the ring to which they are attached.

[0058] A compound having the chemical formula (I) is more preferred, where X 2 is CR 2 or is N.

[0059] A compound having the chemical formula (I) is more preferred, where X 4 is CR 4 or is N.

[0060] Additionally, a compound having the chemical formula (I) is preferred, where X 2 and X 3 are respectively CR 2 and CR 3 Selected from, where R 2 and R 3 Each forms an optionally substituted ring of 4 to 7 members, preferably an optionally substituted cycloalkyl ring of 4 to 7 members, together with the ring to which they are attached.

[0061] Additionally, a compound having the chemical formula (I) is preferred, where X 3 and X 4 are respectively CR 3 and CR 4 Selected from, where R 3 and R 4Each forms an optionally substituted ring of 4 to 7 members, preferably an optionally substituted cycloalkyl ring of 4 to 7 members, together with the ring to which they are attached.

[0062] Additionally, a compound having the chemical formula (I) is preferred, where X 2 and X 3 are respectively CR 2 and CR 3 Selected from, where R 2 and R 3 Each forms a cycloalkyl ring together with the ring to which it is attached.

[0063] Additionally, a compound having the chemical formula (I) is preferred, where X 3 and X 4 are respectively CR 3 and CR 4 Selected from, where R 3 and R 4 Each forms a cycloalkyl ring together with the ring to which it is attached.

[0064] Additionally, it is preferable to have a compound having the chemical formula (I), wherein R together with the attached ring. 2 and R 3 Any two variables of can form arbitrarily substituted rings of 5 to 8 origins, which may be identical or different, and O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0065] Additionally, it is preferable to have a compound having the chemical formula (I), wherein R together with the attached ring. 3 and R 4 Any two variables of can form arbitrarily substituted rings of 5 to 8 origins, which may be identical or different, and O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0066] Further preferred is a compound having the formula (I), wherein R is a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclic ring or a substituted heterocyclylalkyl ring;

[0067] Additionally, it is preferable to have a compound having the chemical formula (I), and R 5 ... is a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclic ring or a substituted heterocyclylalkyl ring;

[0068] In one embodiment of the present invention, the present invention relates to a compound of the following formula (IA) or (IB):

[0069]

[0070] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0071] Here,

[0072] Y 1 is -CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e -, -NR d -NR d -, -CR d =CR d-, -CR d =N-, -N=CR d -, -N=N-, -O-, -S- or -N-;

[0073] Y 2 is -CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e -, -NR d -NR e -, -CR d =CR d -, -CR a =N-, -N=CR a -, -N=N-, -O-, -S- or -N-;

[0074] Y 3 is CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e -, -NR d -NR d -, -CR d =CR d -, -CR d =N-, -N=CR d -, -N=N-, -O-, -S- or -N-;

[0075] R d or R e Each occurrence is independently hydrogen, hydroxy, halogen, oxo, CN(cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy-C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c, -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c, - NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b, -CR b R c C(=O)R b or -CR b R c C(=S)R z , substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rs a It can be bonded to substituted or unsubstituted saturated or unsaturated 3-6 member rings, and may be the same or different O, NR a or any two variables that may arbitrarily include a heteroatom selected from S; R together with an attached ring d and R e Any two variables of can form an oxo (=0) or arbitrarily substituted ring of 3 to 8, which may be identical or different, O, NR X Alternatively, it may optionally include one or more heteroatoms selected from S.

[0076] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , L, L 1 , L 2 , R, R 5 , and Cy 1 ) is independently as defined above in relation to the compound of formula (I);

[0077] step,

[0078] (a) If L does not exist, L 1It is -NH- or -0-, and subsequently, in the compound of chemical formula (IA), ring A is not a furo[3,2-d]pyrimidine.

[0079] (b) If L does not exist, L 1 It is -NH- and L 2 is CH2, and Cy 1 is an unsubstituted phenyl, and X 1 = X 2 = N and X 3 = CR 3 and X 4 = CR 4 and, here R 3 and R 4 It forms an unsubstituted phenyl together, and

[0080] (i) In the compound of chemical formula (IA), R is not 2-trifluoromethylphenyl.

[0081] (ii) R in the compound of chemical formula (IA) 5 It is not an unsubstituted pyridine-3-yl.

[0082] (c) X 1 = X 2 = N and X 3 = CR 3 and X 4 = CR 4 and, if L does not exist, L 1 is -NH-, and L 2 Silver CH 2 Igo, Cy 1 is an unsubstituted phenyl, and R 5 is unsubstituted pyridine-3-yl, and in the compound of chemical formula (IA), R is not 2-isopropylphenyl.

[0083] (d) The compound of chemical formula (IA) is

[0084] (i) 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrido[3,2-d]pyrimidine-4-amine;

[0085] (ii) 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine; and

[0086] (iii) It is not 2-(2-isopropylphenyl)-N-(4-(pyridine-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine.

[0087] In one embodiment of the present invention, the present invention relates to a compound of the formula (IA-1), (IA-2), (IB-1) or (IB-2):

[0088]

[0089] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0090] Here,

[0091] Unless otherwise noted, all variables (X 1 , X 2 , X 3 , X 4 , Y 3 , L, L 1 , L 2 , R, R 5 , R d , R e and Cy 1 ) is independently as defined above in relation to compounds of formula (I), (IA), or (IB).

[0092] Compounds having the chemical formula (I), (IA), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 1 is CR 1 or is N.

[0093] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where X 1 is CR1 , or N, where R 1 It is H or CN.

[0094] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 1 is N.

[0095] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 2 is CR 2 or is N.

[0096] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where X 2 is CR 2 , or N, where R 2 It is H or CN.

[0097] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 2 is N.

[0098] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 3 is CR 3 or is N.

[0099] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where X 3 is CR 3 , or N, where R 3 It is H or CN.

[0100] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 3 is CH or N.

[0101] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 3 is CH.

[0102] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 4 is CR 4 or is N.

[0103] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where X 4 is CR 4 , or N, where R 4 It is H or CN.

[0104] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein X 4 is CH.

[0105] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where Y 1 ne-CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e Selected from -, -O-, -S- or -N-;

[0106] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where Y 2 is -CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e Selected from -, -O-, -S- or -N-;

[0107] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where Y 3 is -CR d , -NR d , -CR d R e -CR d R e -, -CR d R e -N-, -N-CR d R e Selected from -, -O-, -S- or -N-;

[0108] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where R d is selected from hydrogen, hydroxy, halogen, oxo, CN (cyano), or substituted or unsubstituted alkyl;

[0109] A compound having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where R e is selected from hydrogen, hydroxy, halogen, oxo, CN (cyano), or substituted or unsubstituted alkyl;

[0110] Compounds having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, and

[0111] (i) R d is hydrogen and R e is a halogen;

[0112] (ii) R d is a halogen and R e is a halogen;

[0113] (iii) R d is hydrogen and R e is a substituted or unsubstituted alkyl;

[0114] (iv) R d is a halogen and R e is a substituted or unsubstituted alkyl;

[0115] (v) R d is a substituted or unsubstituted alkyl, and R e is a substituted or unsubstituted alkyl;

[0116] (vi) R d and R e All together form Oxo (=0);

[0117] (vii) R d is hydrogen and R e is hydroxy;

[0118] (viii) R d is a hydroxyl group, and R e is a hydroxyl group;

[0119] (ix) R d is hydroxy and R e is a halogen; or

[0120] (x) R d is hydroxy and R e is a substituted or unsubstituted alkyl;

[0121] Compounds having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, and

[0122] (i) R d is hydrogen and R e is fluorine or chlorine.

[0123] (ii) R d is fluorine or chlorine, and R e is fluorine or chlorine.

[0124] (iii) R d is hydrogen and R e is methyl or ethyl.

[0125] (iv) R d is fluorine or chlorine, and R e is methyl or ethyl.

[0126] (v) R d is methyl or ethyl, and R e is methyl or ethyl.

[0127] (vi) R d and R e All together form oxo (=0);

[0128] (vii) R d is hydrogen and R e is hydroxy;

[0129] (viii) R d is a hydroxyl group, and R e is a hydroxyl group;

[0130] (ix) R d is hydroxy and R e is fluorine or chlorine; or

[0131] (x) R d is hydroxy and R e　 is methyl or ethyl;

[0132] Additionally, it is preferable to have a compound having the formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), wherein L is an absent, substituted, or unsubstituted C 1-4 Alkyl, O, S, -S(=0) P or NRx Selected from

[0133] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein L is absent, substituted, or unsubstituted C 1-4 Selected from alkyls.

[0134] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein L is absent.

[0135] Additionally, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IB-2), (IB-1) or (IB-2) are preferred, wherein R is selected from substituted or unsubstituted aryls or substituted or unsubstituted heteroaryls.

[0136] Additionally, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are preferred, where variable X 1 , X 2 , X 3 and X 4 Ring A containing is selected from the following:

[0137]

[0138]

[0139]

[0140]

[0141]

[0142] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, where variable X 1 , X 2 , X 3 and X 4Ring A containing is selected from the following:

[0143]

[0144] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, where variable X 1 , X 2 , X 3 and X 4 Ring A containing is selected from the following:

[0145]

[0146] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, where variable X 1 , X 2 , X 3 and X 4 Ring A containing is selected from the following:

[0147]

[0148]

[0149] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, where variable X 1 , X 2 , X 3 and X 4 Ring A containing is

[0150]

[0151] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) Preferably, R is selected from substituted or unsubstituted aryls or substituted or unsubstituted heteroaryls.

[0152] Compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein R is hydrogen, halogen,

[0153]

[0154] Selected from,

[0155] R is one or more R f Arbitrarily substituted by;

[0156] R f Each occurrence is independently hydrogen, hydroxy, halogen, CN(cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NRb R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , -CR b R c C(=S)R z , substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring or substituted heterocyclylalkyl ring;

[0157] Chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where R is hydrogen, halogen,

[0158]

[0159] Selected from,

[0160] Chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2), where R is hydrogen, fluorine, chlorine,

[0161]

[0162]

[0163]

[0164] Selected from.

[0165] In addition, compounds having the formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are preferred, wherein Rf is hydrogen, hydroxyl, halogen, CN (cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, COOH, CONH2, -OR b , -SR b , -SOR c or -SO2R b Selected from.

[0166] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are preferred, wherein R f is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted cycloalkyl.

[0167] Compounds having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2) are more preferred, wherein Cy 1 is selected from substituted or unsubstituted aryls or substituted or unsubstituted heteroaryls.

[0168] In one embodiment of the present invention, the present invention relates to a compound of the formula (IA-1A) or (IA-1B):

[0169]

[0170] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0171] Here,

[0172] Cy 1 is selected from the following:

[0173]

[0174] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0175] All other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a , R d and R f ) is independently as defined above in relation to compounds of formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1) or (IB-2);

[0176] step,

[0177] (a) If L does not exist, L 1 The ring A of the compound of the chemical formula (IA-1A), or (IA-1B), is a furo[3,2-d]pyrimidine, and is -NH- or -O-.

[0178] (b) If L does not exist, L 1 It is -NH- and L 2 is CH2, and Cy 1 is an unsubstituted phenyl, and X 1 = X 2 = N and X 3 = CR 3 and X4 = CR 4 and, here R 3 and R 4 It forms an unsubstituted phenyl together, and

[0179] (i) R of the compound of formula (IA-1A) or (IA-1B) is not 2-trifluoromethylphenyl.

[0180] (ii) Among the compounds of chemical formula (IA-1A), R 5 , or (IA-1B) is not an unsubstituted pyridine-3-yl.

[0181] (c) X 1 = X 2 When = N, X 3 = CR 3 , X 4 = CR 4 , L is absent, and L 1 It is -NH- and L 2 is CH2, and Cy 1 is an unsubstituted phenyl, and R 5 is unsubstituted pyridine-3-yl, and in the compound of formula (IA-1A), R, or (IA-1B), is not 2-isopropylphenyl.

[0182] (d) Compounds of chemical formula (IA-1A) or (IA-1B)

[0183] (i) 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrido[3,2-d]pyrimidine-4-amine;

[0184] (ii) 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine; and

[0185] (iii) It is not 2-(2-isopropylphenyl)-N-(4-(pyridine-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine.

[0186] In one embodiment of the present invention, the present invention relates to a compound of the formula (IA-1A1) or (IA-1B1):

[0187]

[0188] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0189] Here,

[0190] Cy 1 is selected from the following:

[0191]

[0192] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0193] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a , R d and R f ) is as defined above in relation to compounds of chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), or (IA-1B).

[0194] In one embodiment of the present invention, the present invention relates to a compound of the following formula (IA-1A2) or (IA-1B2):

[0195]

[0196] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0197] Here,

[0198] Cy 1 is selected from the following:

[0199]

[0200]

[0201] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0202] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a , R d and R f ) is as defined above in relation to compounds of chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), or (IA-1B).

[0203] In one embodiment of the present invention, the present invention relates to a compound of the following formula (IA-1A3) or (IA-1B3):

[0204]

[0205] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0206] Here,

[0207] C y1 is selected from the following:

[0208]

[0209] Here, Cy 1 is one or more R a It is arbitrarily replaced with. 1

[0210] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a , R d and R f ) is as defined above in relation to compounds of chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), or (IA-1B).

[0211] In one embodiment of the present invention, the present invention relates to a compound of the formula (IA-1A4) or (IA-1B4):

[0212]

[0213] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0214] Here,

[0215] Cy 1 is selected from the following:

[0216]

[0217] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0218] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a , R d and R f ) is as defined above in relation to compounds of chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), or (IA-1B).

[0219] In one embodiment of the present invention, the present invention relates to a compound of the following formula (IA-1A5) or (IA-1B5):

[0220]

[0221] or its tautomer, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt, or its stereoisomer,

[0222] Here,

[0223] Cy 1 is selected from the following:

[0224]

[0225] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0226] Unless otherwise noted, all other variables (X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 5 , R a, R d and R f ) is as defined above in relation to compounds of chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), or (IA-1B).

[0227] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein Cy 1 is selected from the following:

[0228]

[0229] Here, Cy 1 is one or more R a It is arbitrarily replaced with.

[0230] In addition, compounds having the chemical formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein Cy 1 is selected from the following:

[0231]

[0232] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 1 C that is absent, substituted, or unsubstituted 1-4 Alkyl, O, S, -S(=O) P or NR X Selected from.

[0233] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 1 is NH or O.

[0234] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 1 is absent.

[0235] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 2 is substituted or unsubstituted C 1-4 Alkyl, O, S, -S(=O) P or NR x Selected from.

[0236] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 2 is substituted or unsubstituted C 1-4 It is an alkyl.

[0237] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 2 silver-(CR b R c ) n -am.

[0238] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are more preferred, wherein R b and R c Each is independently selected from hydrogen, halogen, or substituted or unsubstituted alkyl, and n is 1-2.

[0239] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, and R c = Methyl and n is i.

[0240] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein L 2 It is -CH2-, -CH(Me)-.

[0241] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein R 5 It is selected from substituted or unsubstituted aryls or substituted or unsubstituted heteroaryls.

[0242] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein R 5 It is selected from the following:

[0243]

[0244] In the above equation, R 5 is one or more R a It is arbitrarily replaced with.

[0245] In addition, compounds having the chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and / or (IA-1B5) are preferred, wherein R 5 It is selected from the following:

[0246]

[0247] Representative, non-limiting compounds of the present invention are those listed herein and their pharmaceutically acceptable salts. The present invention should not be interpreted as being limited to these compounds.

[0248] 1. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0249] 2. 3-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile;

[0250] 3. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0251] 4. 3-(2-isopropylphenyl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile;

[0252] 5. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0253] 6. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0254] 7. 7-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l, 2-c]pyrimidine-5-amine;

[0255] 8. 7-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l, 2-c]pyrimidine-5-amine;

[0256] 9. N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0257] 10. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0258] 11. 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0259] 12. 1-(2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)urea;

[0260] 13. 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

[0261] 14. 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea;

[0262] 15. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0263] 16. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0264] 17. 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0265] 18. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0266] 19. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0267] 20. 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

[0268] 21. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

[0269] 22. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0270] 23. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrrolo[2,1-f][1,2,4]triazine;

[0271] 24. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

[0272] 25. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine;

[0273] 26. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0274] 27. 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine;

[0275] 28. 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0276] 29. 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0277] 30. 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0278] 31. 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0279] 32. 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0280] 33. 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0281] 34. 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0282] 35. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0283] 36. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-7H-purine-6-amine;

[0284] 37. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-9-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9H-purine-6-amine

[0285] 38. 2-(2-chloro-3-methylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0286] 39. 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0287] 40. 2-(2,4-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0288] 41. 2-(3,5-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0289] 42. 2-(2,4-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0290] 43. 2-(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0291] 44. 2-(2-fluoro-5-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0292] 45. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0293] 46. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethoxy)phenyl)-7H-purine-6-amine

[0294] 47. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethoxy)phenyl)-7H-purine-6-amine

[0295] 48. 2-(2-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0296] 49. 2-fluoro-5-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzonitrile

[0297] 50. 2-(3,5-dimethylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0298] 51. 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0299] 52. 2-(4-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0300] 53. 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0301] 54. 2-(3-fluoro-2-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0302] 55. 3-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzamide

[0303] 56. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(methylthio)phenyl)-7H-purine-6-amine

[0304] 57. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0305] 58. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0306] 59. N-(3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)phenyl)acetamide

[0307] 60. 2-fluoro-5-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile

[0308] 61. 2-(5-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0309] 62. 2-(6-ethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0310] 63. 4-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile

[0311] 64. 2-([1,1'-biphenyl]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0312] 65. 2-(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0313] 66. 2-(2,5-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0314] 67. 2-(3-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0315] 68. 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0316] 69. 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0317] 70. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0318] 71. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0319] 72. 3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzamide

[0320] 73. 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0321] 74. N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0322] 75. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-7H-purine-6-amine

[0323] 76. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-7 H-purine-6-amine

[0324] 77. 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-7H-purine-6-amine and pharmaceutically acceptable salts thereof.

[0325] More preferably, the compound is selected from the following:

[0326] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0327] 3-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile;

[0328] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0329] 3-(2-isopropylphenyl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile;

[0330] N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0331] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0332] 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0333] 1-(2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)urea;

[0334] 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

[0335] 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea;

[0336] 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

[0337] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

[0338] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine;

[0339] N-(3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)phenyl)acetamide

[0340] 2-fluoro-5-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile

[0341] 2-(5-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0342] 2-(6-ethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0343] 4-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile

[0344] 2-([1,1'-biphenyl]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0345] 2-(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0346] 2-(2,5-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0347] 2-(3-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0348] 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0349] 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0350] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0351] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0352] 3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzamide

[0353] 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0354] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine and pharmaceutically acceptable salts thereof.

[0355] More preferably, the compound is selected from the following:

[0356] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0357] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0358] 7-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l,2-c]pyrimidine-5-amine;

[0359] 7-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l,2-c]pyrimidine-5-amine;

[0360] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0361] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrrolo[2,1-f][1,2,4]triazine; and pharmaceutically acceptable salts thereof.

[0362] A compound selected from 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0363] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0364] 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0365] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0366] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0367] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine;

[0368] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0369] 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine;

[0370] 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0371] 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0372] 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0373] 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0374] 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0375] 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0376] 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0377] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine;

[0378] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-7H-purine-6-amine;

[0379] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-9-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9H-purine-6-amine

[0380] 2-(2-chloro-3-methylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0381] 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0382] 2-(2,4-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0383] 2-(3,5-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0384] 2-(2,4-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0385] 2-(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0386] 2-(2-fluoro-5-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0387] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0388] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethoxy)phenyl)-7H-purine-6-amine

[0389] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethoxy)phenyl)-7H-purine-6-amine

[0390] 2-(2-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0391] 2-fluoro-5-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzonitrile

[0392] 2-(3,5-dimethylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0393] 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0394] 2-(4-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0395] 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0396] 2-(3-fluoro-2-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0397] 3-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzamide

[0398] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(methylthio)phenyl)-7H-purine-6-amine

[0399] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0400] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethyl)phenyl)-7H-purine-6-amine

[0401] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-7H-purine-6-amine

[0402] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-7H-purine-6-amine

[0403] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-7H-purine-6-amine and pharmaceutically acceptable salts thereof.

[0404] More preferably, the compound is selected from the following:

[0405] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0406] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0407] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine;

[0408] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0409] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0410] 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0411] 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine; and pharmaceutically acceptable salts thereof.

[0412] More preferably, the compound is 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine; and a pharmaceutically acceptable salt thereof.

[0413] More preferably, the compound is 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoroethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine; and a pharmaceutically acceptable salt thereof.

[0414] More preferably, the compound is 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine and a pharmaceutically acceptable salt thereof.

[0415] More preferably, the compound is 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine and pharmaceutically acceptable salts thereof.

[0416] More preferably, the compound is 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine and a pharmaceutically acceptable salt thereof.

[0417] More preferably, the compound is 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine and pharmaceutically acceptable salts thereof.

[0418] More preferably, the compound is 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine and pharmaceutically acceptable salts thereof.

[0419]

[0420]

[0421]

[0422] The non-limiting representative compounds of the present invention include the non-limiting representative compounds of the present invention as listed below, and pharmaceutically acceptable salts thereof.

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433] Another embodiment of the present invention is a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0434] Another embodiment of the present invention is a method for treating cancer in a subject in need of the present invention, comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the compound of the present invention, or a pharmaceutically acceptable salt thereof to a subject in need of the present invention.

[0435] Without being bound by any particular theory, the compounds provided herein are compounds capable of modifying (e.g., inhibiting) one or more members of the USP family. More specifically, and without being bound by any particular theory, the compounds described herein are considered to be capable of binding to one or more USP1s.

[0436] As such, in another embodiment, the present invention is a method for treating a USP1-mediated disorder in a subject in need of the same, comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the compound of the present invention, or a pharmaceutically acceptable salt thereof to a subject in need of the same.

[0437] Another embodiment of the present invention is the use of the compounds of the present invention to treat cancer or USP-mediated disorders, particularly USP1-mediated disorders, in a subject.

[0438] Another embodiment of the present invention is the use of the compounds of the present invention to treat cancer or USP-mediated disorders, particularly USP1-mediated disorders in subjects.

[0439] Another embodiment of the present invention is the use of the compounds of the present invention for the manufacture of a medicine for treating cancer or USP-mediated disorders, particularly USP1-mediated disorders in subjects.

[0440] Another embodiment of the present invention is the use of the compounds of the present invention for the manufacture of a medicine for treating cancer or USP-mediated disorders, particularly USP1-mediated disorders in subjects.

[0441] The compounds of the present invention, and their pharmaceutically acceptable salts and / or compositions are useful for treating various cancers, such as solid tumors, more specifically USP1-related solid tumors.

[0442] The compounds of the present invention, and their pharmaceutically acceptable salts and / or compositions are useful for treating various cancers, e.g., blood cancers, more specifically, USP1-related blood cancers. Brief explanation of the drawing

[0443] Fig. 1: Line graph showing the antitumor effect of the compound of the present invention in MDA-Mb-436 human breast cancer xenograft. Specific details for implementing the invention

[0444] An exemplary embodiment of the present invention is described.

[0445] definition

[0446] The compounds of the present invention generally include those described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are defined by reference to the periodic table of the elements (Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 7th 5th Ed. Additionally, general principles of organic chemistry are incorporated herein by reference to "Organic Chemistry", Thomas Sorrell, University Science Books, Sauslito: 1999, "March's Advanced Organic Chemistry", 5th Ed. Ed.: Smith, MB and March, J. John Wiley & Sons, New York: 2001).

[0447] Unless otherwise specified herein, the nomenclature used herein generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford (1979), which are incorporated herein by reference for exemplary chemical structure names and rules for nominating chemical structures. Optionally, names of compounds may be generated using the chemical nomenclature program: ACD / Chem Sketch, Version 5.09 / Sep 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0448] The compounds of the present invention may have an asymmetric center, a chiral axis, and a chiral plane (e.g., as described in the literature [EL Eliel and SH Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190]), racemies, racemic mixtures, and all possible isomers including atrop and / or optical isomers as individual diastereomers or enantiomers, and mixtures thereof are included in the present invention.

[0449] As used herein, the following definitions shall apply unless otherwise indicated. Additionally, many of the groups defined herein may be optionally substituted. The list of substituents in the definitions is exemplary and should not be construed as limiting to the substituents defined elsewhere in this specification.

[0450] Unless otherwise specified, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms having 1 to 8 carbon atoms, not unsaturated, and attached to the rest of the molecule by single bonds, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "C 1-3 "Alkyl" refers to an alkyl group having up to three carbon atoms as defined above. The term "C 1-6 "alkyl" refers to an alkyl group as defined above having up to six carbon atoms. Where appropriate, the term "heteroalkyl" refers to a hydrocarbon chain radical as mentioned above that is bivalent.

[0451] The term "alkenyl" refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, and may be, for example, ethenyl, 1-propphenyl, 2-propphenyl(allyl), iso-propphenyl, 2-methyl-1-propphenyl, 1-butenyl, and 2-butenyl. The term "C 2-6 "Alkenyl" refers to an alkenyl group as defined above having up to 6 carbon atoms. In appropriate situations, the term "alkenyl" refers to a hydrocarbon group as mentioned above that is divalent.

[0452] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbyl radical having at least one carbon-carbon triple bond and 2 to 12 or fewer carbon atoms (currently preferred having radicals within the range of 2 to 10 carbon atoms), e.g., ethinyl, propynyl, and butyryl. The term "C 2-6 "Alkynyl" refers to an alkynyl group having up to 6 carbon atoms as defined above. Where appropriate, the term "alkynyl" refers to a divalent hydrocarbyl radical as mentioned above.

[0453] Unless otherwise specified, the term “alkoxy” refers to an alkyl, cycloalkyl, or cycloalkylalkyl group as defined above attached to the remainder of the molecule via an oxygen bond. The term “substituted alkoxy” refers to an alkoxy group (i.e., -O-(substituted alkyl)) to which an alkyl component is substituted. For example, “alkoxy” refers to a group-O-alkyl comprising 1 to 8 carbon atoms in a straight-chain, branched-chain, cyclic configuration, and combinations thereof attached to the parent structure via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Where appropriate, the term “alkoxy” refers to a divalent group as mentioned above.

[0454] The term "cycloalkyl" refers, unless otherwise specified, to a non-aromatic mono- or multi-cyclic ring system of about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multi-cyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl groups, cross-linked cyclic groups, and spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having up to 6 carbon atoms as defined above.

[0455] The term "cycloalkylalkyl" refers to a cyclic cyclic radical attached to a main structure in the range of about 3 to 8 carbon atoms directly attached to an alkyl group (then any carbon from the alkyl group, e.g., cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl), unless otherwise specified.

[0456] The term “cycloalkenyl” refers to a cyclic Ringer radical containing about 3 to 8 carbon atoms having at least one carbon-carbon double bond, such as cyclopropphenyl, cyclobutenyl, and cyclopentenyl, unless otherwise specified. The term “cycloalkenylalkyl” refers to a cycloalkenyl group directly attached to an alkyl group, which is then attached to any carbon from the alkyl group to the main structure.

[0457] Unless otherwise specified, the term "aryl" refers to an aromatic radical having 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0458] Unless otherwise specified, the term "arylalkyl" refers to an aryl group as defined above that is directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.

[0459] Unless otherwise specified, the term “heterocyclic ring” refers to a non-aromatic 3 to 15-membered ring radical consisting of a carbon atom and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For the purposes of the present invention, the heterocyclic ring radical may be a mono-, bi-, tri-, or tetracyclic ring system that may include a fused, cross-linked, or spiro-ring system, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. Additionally, the nitrogen atom may be optionally quaternized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.

[0460] The term "heterocyclil" refers to a heterocyclic ring radical as defined above, unless otherwise specified. A heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.

[0461] The term "heterocyclylalkyl" means the heterocyclic radical defined above that is directly bonded to an alkyl group, unless otherwise specified. The heterocyclylalkyl radical may be bonded to the main structure at any carbon atom within the alkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolininyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperadinyl, 2-oxopiperadinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomophorinyl, thiamophorinyl, 1-oxo-thiomophorinyl, and 1,1-dioxo-thiomophorinyl is included.

[0462] The term “heteroaryl” refers to an optionally substituted 5 to 14-membered aromatic ring having one or more heteroatoms selected from N, O and S as ring atoms, unless otherwise specified. A heteroaryl may be a mono-, bi-, or tricyclic ring system. Examples of these "heterocyclic ring" or "heteroaryl" radicals include oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanil, benzofuranyl, carbazolyl, synorinyl, dioxolanyl, indolizinyl, naphthiridinyl, perhydroazinyl, perazinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, These are oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, timonamorolyl, timonamorolyl sulfoxide, timonamorolyl sulfone, dioxaphosphonyl, oxadiazolyl, chromanyl, and isochromanyl. Heteroaryl ring radicals may be attached to the main structure at any heteroatom or carbon atom. Terms "Substituted heteroaryls" also include ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxide.

[0463] The term "heteroarylalkyl" refers to a heteroaryl ring radical as defined above that is directly bonded to an alkyl group, unless otherwise specified. A heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group.

[0464] The term "cyclic ring" refers to a cyclic ring containing 3 to 10 carbon atoms.

[0465] Unless otherwise specified, the term "substituted" may be the same or different and independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclicalkyl ring, substituted or unsubstituted guanidine, - COOR x , -C(O)R x , -C(S)R x , -C(O)NR x R y , -C(O)ONR x R y , -NR y R z , -NR x CONR y R z , -N(R x )SOR y , -N(R x )SO2R y , -(=NN(R x )R y ), -NR x C(O)OR y , -NR x R y , -NR x C(O)R y -, -NR x C(S)R y -NR x C(S)NR y R z , -SONR x R y-, -SO2NR x R y -, -OR x , -OR x C(O)NR y R z , -OR x C(O)OR y -, -OC(O)R x , -OC(O)NR x R y , -R x NR y C(O)R z , -R x OR y , -R x C(O)OR y , -R x C(O)NR y R z , -R x C(O)R x , -R x OC(O)R y , -SR x , -SOR x , -SO2R x , and selected from -ONO2, and R in each of the above groups x , R y and R z may be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted amino, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted heterocyclic ring, or a substituted heterocyclylalkyl ring, or R x , R y and R z Any two of them may non-join to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, optionally identical or different, O, NR x (e.g., Rx is hydrogen or C 1-6 (may be alkyl) or S substitution or combinations of substituents conceived by the present invention are preferably those that result in the formation of a stable or chemically feasible compound. As used herein, the term stability refers to a compound or structure that is substantially unchanged when subjected to conditions that enable its manufacture, detection, and preferably its recovery, purification, and incorporation into a pharmaceutical composition. Substituents within the aforementioned "substituted" group may not be further substituted. For example, if a substituent on the "substituted alkyl" is a "substituted aryl," the substituent on the "substituted aryl" may not be a "substituted alkenyl."

[0466] The term "halo," "halide," or alternatively, "halogen" means fluoro, chloro, bromo, or iodo.

[0467] The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" each include haloalkyl and haloalkoxy groups in which the halo is fluorine.

[0468] The terms "protecting group" or "PG" refer to a substituent used to block or protect a specific functionality. Other functional groups on the compound retain reactivity. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functional group in a compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxyl group that blocks or protects the hydroxy functional group. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxyl group that blocks or protects the carboxy functional group. Suitable carboxy-protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their uses, refer to the literature [TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991].

[0469] Any compound described herein may contain one or more asymmetric centers to produce enantiomers, diastereomers, and other stereoisomer forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical substances, pharmaceutical compositions, and methods described herein are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Non-limiting examples of intermediate mixtures include mixtures of isomers in ratios of optically active (R)- and (S)- isomers of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers may be prepared using chiral synthesis or chiral reagents, or may be resolved using conventional techniques. Where a compound described herein contains an olefinic double bond or another center of geometric asymmetry, the compound is intended to include both E and Z geometric isomers unless otherwise specified.

[0470] The term "tautomer" refers to a compound characterized by relatively easy interconversion between isomer forms under equilibrium. Such isomers are intended to be included within the scope of the present invention. A "tautomer" is a structurally different isomer that is interconverted by tautomerization. "Tautomerization" is a form of isomerization and includes proton affinity or proton transfer tautomerization, which is considered a sub-concept of acid-base chemistry. "Proton affinity tautomerization" or "proton transfer tautomerization" involves the transfer of protons accompanied by a change in bond order and often involves an exchange between a single bond and an adjacent double bond. Where tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion between pentan-2,4-dione and the 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion between pyridin-4-ol and the pyridin-4(1H)-one tautomer.

[0471] Unless otherwise noted, the structures described herein also mean all isomers of the structure (e.g., enantiomeric, diastereomeric, and geometric (or conformal) forms; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoconformal isomers. Thus, enantiomeric, diastereomeric, and geometric (or conformal) mixtures of the compounds of the present invention, as well as monostereochemical isomers, are within the scope of the present invention. Unless otherwise noted, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0472] Additionally, unless otherwise noted, the structures described herein also imply that they contain different compounds only in the presence of one or more isotope-enriched atoms. For example, compounds produced by substituting hydrogen with deuterium or tritium, or by substituting a carbon having a C- or C-rich carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. For example, in the case of the variable Z, (C1-C4)alkyl, or -NZ-(C1-C4)alkyl -O-(C1-C4)alkyl, may be suitably deuteridetized (e.g., -CD3, -NH-CD3, -N-CD3, or -OCD3).

[0473] The compounds of the present invention may also contain non-natural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compounds may be activated into radioactive isotopes, such as tritium (H), iodine-125 (I), or carbon-14 (C). All isotopic variations and radioactivity of the compounds of the present invention are included within the scope of the present invention.

[0474] The term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes enantiomers (mirror image isomers), geometric (cis / trans) isomers, and isomers of compounds having one or more chiral centers that are not mirror images of each other (diastereoisomers).

[0475] “Electrophilic” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having electrons, a negative charge, a partial negative charge and / or excess electrons, e.g., a -SH group). Electrophiles typically comprise electron-deficient or electron-deficient atoms. In certain embodiments, the electrophile comprises a positive charge or partial positive charge, or is a moiety containing a positive charge or partial positive charge, or in which the deposition or polarization of electrons results in one or more atoms containing a positive charge or partial positive charge. In some embodiments, the electrophiles comprise conjugated double bonds, e.g., α, β-unsaturated carbonyl or β-unsaturated thiocarbonyl compounds.

[0476] A leaving group or atom (Lg or lg) is any group or atom that can be cleaved from the starting material under reaction conditions and thus promotes the reaction at a specific site. Unless otherwise specified, suitable examples of such groups are halogen atoms and mesooxy, p-nitrobenzenesulfonyloxy, and tosyloxy groups.

[0477] "Prodrug" means a compound that can be converted into a biologically active compound described herein (e.g., compounds of structures (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), or (IA-1B5) under physiological conditions or by solvation. Accordingly, the term "prodrug" means a precursor of a pharmaceutically acceptable biologically active compound. In some embodiments, the prodrug is in an inactive state when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrugs often provide the benefits of solubility, histocompatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions regarding prodrugs are found in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; and general discussions regarding prodrug design are found in Hardman et al. (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996), all of which are incorporated herein by reference in their entirety.The term "prodrug" is also intended to include a covalently bonded carrier that releases an active compound in vivo when the prodrug is administered to a mammalian subject. The prodrug of the active compound described herein is typically prepared by modifying a functional group present in the active compound, such modification being cleaved by conventional manipulation or in vivo to revert to the parent active compound. The prodrug comprises a compound in which a hydroxyl group, an amino group, or a mercapto group is attached to any group that is cleaved to form a free hydroxyl group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of the prodrug include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxyl functional group in the active compound, or acetamide, formamide, and benzamide derivatives of the amine functional group.

[0478] In some embodiments, the prodrug comprises compounds of structures (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), or (IA-1B5) having phosphate, phosphoalkoxy, ester, or boronic acid ester substituents. Although not bound by theory, these substituents are believed to convert to hydroxyl groups under physiological conditions. Accordingly, embodiments comprise any compound among the compounds disclosed herein in which the hydroxyl group is substituted with a phosphate, phosphoalkoxy, ester, or boronic acid ester group, e.g., a phosphate or phosphoalkoxy group. For example, in some embodiments, R 1 The hydroxyl group of the moiety is substituted with a phosphate, phosphoalkoxy, ester, or boron acid ester group, for example, a phosphate or alkoxyphosphate group.

[0479] The term "ester" refers to a compound formed by the reaction of an acid and an alcohol through the removal of water. Esters can be represented by the general formula RCOOR'.

[0480] These prodrugs and esters are intended to be included within the scope of the present invention.

[0481] In addition, the present invention also includes compounds that differ only in the presence of one or more isotope-enriched atoms, for example, compounds in which hydrogen is replaced with deuterium or tritium, or carbon is replaced with a 13C- or 14C-rich carbon.

[0482] When a range is used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, it is intended to include all combinations and sub-combinations of the range and specific embodiments within it.

[0483] When referring to a number or numerical range, the term “approximately” means that a number or numerical range referred to as an approximation within experimental variability (or statistical experimental error) may vary, for example, between 1% and 15% of the mentioned number or numerical range.

[0484] The term “comprise” (and related terms such as “comprise” or “having” or “including”) includes that these embodiments, for example, the described features “consist of” or “consist essentially of”.

[0485] The following abbreviations and terms have the meanings indicated throughout the specification; abbreviations used in this specification have their common meanings within chemical and biological technology.

[0486] The term "cell proliferation" refers to a phenomenon in which the number of cells changes as a result of division. This term also includes cell growth in which cell morphology undergoes changes consistent with proliferative signals (e.g., an increase in size).

[0487] As used herein, the terms “co-administration,” “administered in combination with,” and their grammatical equivalents refer to administering two or more preparations to an animal, thereby causing both preparations and / or their metabolites to be present in the animal simultaneously. Co-administration includes simultaneous administration of individual compositions, administration of separate compositions at different times, or administration of a composition in which both preparations are present.

[0488] The term “effective dose” or “therapeutic effective dose” refers to an amount of the compound described herein sufficient to be effective for an intended application, including but not limited to the treatment of a disease as defined below. The therapeutic effective dose may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated, e.g., the subject’s weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by a person skilled in the art. The term also applies to a dose that induces a specific response in target cells, e.g., a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on whether it is administered in combination with the specific compound selected, the subsequent administration regimen, the tissue to which it is administered, and the physical delivery system in which it is carried. In one embodiment, the amount of the compound administered is about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g of It is a range.

[0489] As used herein, “treatment,” “treatment,” or “improvement” refers to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic benefits and / or preventive benefits. By therapeutic benefit, the removal or improvement of the underlying disorder being treated is implied. Additionally, therapeutic benefit is also achieved by the removal or improvement of one or more physiological symptoms associated with the disorder of the lower extremities, such that improvement is observed in the patient, even though the patient may still be affine with the underlying disorder. For preventive benefit, the composition may be administered to a patient at risk of developing a specific disease, or to a patient reporting one or more physiological symptoms of the disease, although a diagnosis of such disease may not be made. These terms are used interchangeably.

[0490] The term “therapeutic effect” as used herein includes therapeutic benefits and / or preventive benefits as described above. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0491] As used herein, the amount of compound effective for treating a disorder, or “therapeutic effective amount,” refers to the amount of compound effective when administered in single or multiple doses to a target or cell to cure, alleviate, relieve, or improve one or more symptoms of the disorder.

[0492] As used herein, the amount of compound effective to prevent a disorder or a “preventive effective amount” refers to an amount effective when administered as a single or multiple doses to a subject to prevent or delay the onset or recurrence of the disorder or one or more symptoms of the disorder.

[0493] As used herein, the terms “subject” or “patient” are intended to include human and non-human animals. Exemplary human subjects include human patients having a disability, e.g., a disability described herein or a normal subject. The term “non-human animal” of the invention includes all vertebral bodies, e.g., non-mammals (e.g., ickens, amphibians, reptiles), mammals, e.g., non-human primates, animals useful for pesticides and / or agriculture, e.g., sheep, cows, pigs, etc., and companion animals (dogs, cats, horses, etc.).

[0494] The method described herein may be useful for both human therapeutics and veterinary uses (e.g., dogs, cats, cattle, sheep, pigs, horses, goats, rickets, turkeys, ducks, and jizz).

[0495] In some embodiments, the patient is a mammal, and in some embodiments, the patient is a human.

[0496] “Radiation therapy” means exposing a patient to an alpha-particle emitting radionuclide (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiators (i.e., beta emitters), switching electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation including X-rays, gamma rays and neutrons without limitation, using routine methods and compositions known to the operator.

[0497] The terms “pharmaceuticalally acceptable carrier” or “pharmaceuticalally acceptable excipient” include, but are not limited to, any and all non-toxic solvents, dispersants, excipients, adjuvants, fillers, salts, disintegrants, binders, lubricants, lubricants, wetting agents, controlled-release matrices, colorants / flavors, carriers, buffers, stabilizers, solubilizers, or other substances and combinations thereof that are mixed with an active ingredient to allow the formation of a pharmaceutical composition, i.e., a formulation that can be administered to a patient. An example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. Pharmaceutically acceptable carriers are widely known in the art.

[0498] It is understood that the substituents and substitution patterns on the compounds of the present invention provide a compound that is chemically stable and can be easily synthesized by techniques known in the art, as well as a compound that can be easily synthesized by the methods described below. Generally, the term “substituted” means that one or more hydrogens of a designated moiety are replaced by suitable substituents, regardless of whether the term “opportunistically” precedes it. Unless otherwise indicated, the “opportunistically substituted group” may have suitable substituents at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at all positions. Alternatively, the “opportunistically substituted group” may be unsubstituted.

[0499] The combination of substituents conceived by the present invention is preferably one that results in the formation of a stable or chemically feasible compound. Where a substituent is substituted with more than one group, it is understood that such multiple groups may be on the same carbon atom or on different carbon atoms, insofar as this results in a stable structure. As used herein, the term “stable” refers to a compound that, in certain embodiments, is substantially unchanged when subjected to conditions that enable its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0500] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt corresponding to a reasonable benefit / risk ratio within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the full text of which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases compatible with the treatment of patients.

[0501] Examples of pharmaceutically acceptable non-toxic acid addition salts are formed by using inorganic acids such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or other methods used in the industry such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobinate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, Includes pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salt, etc.

[0502] In some embodiments, exemplary inorganic acids that form a suitable salt include, but are not limited to, hydrochloric acid, hydrobromide, sulfuric acid, and phosphoric acid, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form a suitable salt include mono-, di-, and tricarboxylic acids. Examples of such acids include, for example, acetic acid, glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Mono- or di-acid salts may be formed, or these salts may exist in hydrated, solvated, or substantially anhydrous forms. Generally, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and generally exhibit a higher melting point compared to their free base forms.

[0503] In some embodiments, the acid addition salt of the compound of formula A is most appropriately formed from pharmaceutically acceptable acids, and includes, for example, inorganic acids, for example hydrochloric acid, sulfuric acid, or phosphoric acid, and organic acids, for example succinic acid, maleic acid, acetic acid, or fumaric acid.

[0504] Other non-pharmaceutical acceptable salts, e.g., oxalates, may be used for laboratory use or for the subsequent conversion of pharmaceutically acceptable acid addition salts, e.g., compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), or (IA-1B5)). Additionally, base addition salts (e.g., sodium, potassium, and ammonium salts), solvates, and hydrates of the compounds of the present invention are included within the scope of the present invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques well known to those skilled in the art.

[0505] "Anticancer agent," "antitumor agent," or "chemotherapy agent" refers to any agent useful for the treatment of a neoplastic condition. One class of anticancer agents includes chemotherapy agents. Chemotherapy refers to the administration of one or more chemotherapy drugs and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravenous, subcutaneous, transdermal, buccal, or inhalation, or in the form of suppositories. The term also includes cell growth in which cell morphology undergoes changes (e.g., increase in size) consistent with proliferative signals.

[0506] The terms "selective inhibition" or "to selectively inhibit" refer to the ability of a biologically active agent to preferentially reduce target signaling activity compared to off-target signaling activity through direct or indirect interaction with a target.

[0507] "Arbitrary" or "arbitrarily" means that the events of the situations described subsequently may or may not occur, and that the description includes cases where said event or situation occurs and instances where it does not. For example, "arbitrarily substituted aryl" means that the aryl radical may or may not be substituted, and the description includes both substituted aryl radicals and aryl radicals that do not have substitution.

[0508] "Pharmaceutical composition" refers to a combination of the compounds of the present invention and a medium generally accepted in the art for the delivery of said biologically active compounds to mammals, e.g., humans. Such a medium comprises any pharmaceutically acceptable carrier, diluent, or excipient.

[0509] When introducing elements disclosed herein, singular terms and "the above" are intended to mean that there is one or more elements. The terms "comprising," "having," and "including" are intended to be open-ended and mean that additional elements other than those enumerated may exist.

[0510] For example, a method for treating various cancers in mammals (including humans and non-humans) is provided, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof. Such cancers include hematological malignancies (leukemias, lymphomas, myeloomas, myelodysplastic and myeloproliferative syndromes) and solid tumors (carcinomas, e.g., oral, bladder, prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue, osteosarcoma, and stromal tumors).

[0511] Pharmaceutical composition

[0512] The present invention provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition may comprise one or more additional active ingredients as described herein. The pharmaceutical composition may be administered for any disorder described herein.

[0513] The pharmaceutical composition of the present invention is typically formulated to provide a therapeutically effective amount of the compound of the present invention as an active ingredient. If desired, the pharmaceutical composition contains the compound of the present invention as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and filters, diluents, comprising sterile aqueous solutions and various organic solvents, permeability enhancers, solubilizers and adjuvants.

[0514] The pharmaceutical composition may be administered alone or in combination with one or more other preparations, which is also typically administered in the form of the pharmaceutical composition. If desired, the target compound and other agent(s) may be mixed into a preparation, or the components of both may be formulated into separate preparations for use individually or in combination.

[0515] The method comprises administering the compound of the present invention as itself or in combination as described herein, and in each case optionally comprising one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, lubricants, wetting agents, controlled release matrices, colorants / flavoring agents, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

[0516] Formulations of various pharmaceutical compositions are known in the art. For example, Anderson, Philip O. Knoben, James E. Troutman, William G, eds. Handbook of Clinical Drug Data, 10th Edition, McGraw-Hill, 2002; Pract and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed. Basic and Clinical Pharmacology, 9th Edition, McGraw-Hill, 2003; Goodman and Gilman, eds. The Pharmaceutical Basis of Therapeutics, 10 th Refer to [Edition, McGraw Hill, 2001; Remington Pharmaceutical Sciences, 20th Ed. Lippincott Williams & Wilkins., 2000; Martindale, The Extracopoeia, 30-Second Edition (The Pharmaceutical Press, London, 1999)], the full text of all of which is incorporated herein by reference.

[0517] The compound or pharmaceutical composition of the present invention may be administered via any route capable of delivering the compound to the site of action, such as oral administration, administration into the duodenum, parenteral injection (including intravenous injection, arterial injection, subcutaneous injection, intramuscular injection, intravascular injection, intraperitoneal injection or infusion), local administration (e.g., transdermal application), rectal administration, local delivery via a catheter or stent, or inhalation. Additionally, the compound may be administered into fat or spinal cord.

[0518] The composition may be administered in solid, semi-solid, liquid, or gaseous form, or in a dry powder form such as a lyophilized form. The pharmaceutical composition may be packaged in a form convenient for administration, including solid dosage forms such as capsules, pouches, caskets, gelatin, paper, tablets, capsules, suppositories, pellets, pills, troches, and lozenges. The type of packaging is generally determined by the desired route of administration. Implantable sustained-release formulations and transdermal formulations are also considered.

[0519] Treatment methods

[0520] In a further aspect, the present invention provides a use of a pharmaceutically acceptable salt of the compound of the present invention for the manufacture of a medicine for the treatment of cancer. In some embodiments, the present invention provides a use of the compound of the present invention for the manufacture of a medicine for the treatment of cancer and / or neoplastic disorders.

[0521] The compounds or compositions described herein may be used to treat neoplastic disorders. “Neoplastic disorders” are, for example, diseases or disorders characterized by cells having a capacity for autonomous growth or replication, or abnormal states or conditions characterized by proliferative cell growth. Exemplary neoplastic disorders include, but are not limited to: carcinomas, sarcomas, metastatic diseases, solid tumors of the oral cavity, gallbladder, prostate, breast, lung, colon, pancreas, kidney, ovary, etc., soft tissue and osteosarcomas, stromal tumors, for example, tumors arising in the prostate, brain, bone, colon, pancreas, lung, breast, ovary, and liver, hematopoietic neoplastic diseases, for example, leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative syndrome, and other malignant plasma cell diseases, and metastatic tumors. Multivalent cancers include, but are not limited to, breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound may be an effective amount for improving at least one symptom of the neoplastic disorder, for example, reduced cell proliferation, reduced tumor mass, etc.

[0522] In another embodiment, the patient or group of patients to be treated with the pharmaceutical composition of the present disclosure has a solid tumor. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, the patient or group of patients to be treated with the pharmaceutical composition of the present disclosure has a blood cancer. In some embodiments, the patient has a blood cancer, for example, diffuse large B-cell lymphoma (“DLBCL”), Hodgkin lymphoma (“HL”), non-Hodgkin lymphoma (“NHL”), follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or multiple myeloma (“MM”). In some embodiments, the patient or group of patients to be treated has a cancer selected from the group consisting of ovarian cancer, lung cancer, and melanoma.

[0523] Exemplary cancers include, but are not limited to, the following tumors: renal cancer, renal cell carcinoma, glioblastoma pleomorphic, metastatic breast cancer; breast cancer; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinoma of the epidermis; leukemia, e.g., but not limited to, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, e.g., myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemic leukemia and myelodysplastic syndrome; chronic leukemia, e.g., but not limited to, chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, hair cell leukemia; polycythemia vera; lymphoma, e.g., but not limited to, Hodgkin's disease, non-Hodgkin's disease; Multiple myeloma, e.g., but not limited to, asymptomatic multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extrahydrational plasmacytoma; Waldenström macroglobulinemia; monoclonal gammaglobulinopathy of indeterminate significance; benign monoclonal gammaglobulinopathy; heavy chain disease; bone cancer and connective tissue sarcoma, e.g., but not limited to, osteosarcoma, myelomatous bone disease, multiple myeloma, cholesteatoma-induced osteosarcoma, Paget's disease, osteosarcoma, chondrosarcoma, Ewing sarcoma, malignant giant cell tumor, osteofibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (vascular endothelial sarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, schwannoma, rhabdomyosarcoma and synovial sarcoma; Brain tumors, e.g., but not limited to, gliomas, astrocytomas, brainstem gliomas, ependymomas, oligodendrocytes, non-glial tumors, acoustic neuromas, craniopharyngiomas, medulloblastomas, meningiomas, pineal cell tumors, pineal blastomas, and primary brain lymphomas; breast cancer, including but not limited to, adenocarcinomas, lobular (small cell) carcinomas, intraductal carcinomas, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease), and inflammatory breast cancer; adrenal cancers, e.g., but not limited to, pheochromocytomas and adrenocortical carcinomas;Thyroid cancer, e.g., but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; pancreatic cancer, e.g., but not limited to, insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancer, e.g., but not limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipidus; ocular cancer, e.g., but not limited to, ocular melanoma, e.g., iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; vaginal cancer, e.g., squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer, e.g., squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancer, e.g., but not limited to, squamous cell carcinoma and adenocarcinoma; Uterine cancer, e.g., but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancer, e.g., but not limited to ovarian epithelial carcinoma, borderline tumor, germ cell tumor and stromal tumor; cervical carcinoma; esophageal cancer, e.g., but not limited to squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma and oat cell (small cell) carcinoma; gastric cancer, e.g., but not limited to adenocarcinoma, mycosis fungoides (polypoid), ulcerative, superficially spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; colon cancer; colorectal cancer, KRAS mutation colorectal cancer; colorectal carcinoma; rectal cancer; liver cancer, e.g., but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancer, e.g., adenocarcinoma; Cholangiocarcinoma, e.g., but not limited to, papillary, nodular, and diffuse; lung cancer, e.g., KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; lung carcinoma; testicular cancer, e.g., but not limited to, germ cell tumors, spermatogonoma, anaplastic, atypical (protypical), spermatoblastic, asteroma, embryonic carcinoma, teratocarcinoma, choriocarcinoma (yolk sac tumor);Prostate cancer, e.g., but not limited to androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penile cancer; oral cancer, e.g., but not limited to squamous cell carcinoma; basal cancer; salivary gland cancer, e.g., but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; pharyngeal cancer, e.g., but not limited to squamous cell carcinoma and verrucous carcinoma; skin cancer, e.g., but not limited to basal cell carcinoma, squamous cell carcinoma, and melanoma, superficial spreading melanoma, nodular melanoma, malignant lentigo melanoma, acral lentigo melanoma; kidney cancer, e.g., but not limited to renal cell carcinoma, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell carcinoma (renal pelvis and / or ureter); renal carcinoma; Wilms tumor; Bladder cancer, e.g., but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma. Additionally, cancer includes myxosarcoma, osteogenesis imperfecta, endothelial sarcoma, lymphangioendothelial sarcoma, mesothelioma, synovoma, hemangioma, epithelial carcinoma, cystadenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma.;

[0524] In another embodiment, the present disclosure provides a method for treating cancer in a subject, comprising administering to the subject an effective amount of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the cancer may comprise cancer cells having increased levels of RAD 18 mRNA expression. In some embodiments, the increased level of RAD (18) is an increased level of the RAD 18 protein. In some embodiments, the RAD 18 level may be detected using a quantitative method such as a microarray, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, the RAD 18 level in cancer cells may be detected prior to administration of the compound described herein. In some embodiments, the RAD 18 level may be detected in a cancer sample obtained from the subject. In some embodiments, if the subject has an increased level of RAD 18, the subject may be treated with the compound described herein. In some embodiments, elevated levels of RAD 18 in cancer cells indicate that a subject administered with the compound or pharmaceutical composition described herein responds to treatment using the compound or pharmaceutical composition described herein. In some embodiments, the compound described herein is not administered to a subject having elevated levels of RAD 18.

[0525] In another embodiment, the cancer is a cancer deficient in the DNA damage repair pathway. In some embodiments, the cancer is a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer. In some embodiments, the cancer comprises cells having elevated levels of RAD 18, wherein the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and / or protein levels in Es2 cells or HEP3B217 cells.

[0526] In other embodiments, the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wild-type cancer. In some embodiments, the cancer is a BRCA1-deficient cancer. In some embodiments, the cancer is a BRCA2-deficient cancer. In some embodiments, the cancer comprising cancer cells comprises cancer cells having mutations in genes encoding BRCA1 and / or BRCA2. In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2-deficient cancer. In some embodiments, the cancer is a BRCA1-deficient cancer and a BRCA2 mutant cancer. In some embodiments, the cancer comprises cells having elevated levels of RAD 18, wherein the elevated level of RAD 18 is as high as the RAD 18 mRNA and / or protein levels in at least ES2 cells or HEP3B217 cells.

[0527] In addition, the present invention provides a method for inhibiting USP activity in cells, comprising the step of contacting cells in which inhibition of USP1 activity is desired with an effective amount of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5), pharmaceutically acceptable salts thereof, or compounds thereof or pharmaceutically acceptable salts thereof.

[0528] In one embodiment, a cell in which inhibition of USP1 activity is required is contacted with an effective amount of a compound of formula ((I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) to negatively regulate the activity of USP1.

[0529] In addition, a therapeutically effective amount of a pharmaceutically acceptable salt or pharmaceutical composition containing compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) may be used.

[0530] By negatively modulating the activity of USP1, the method described herein is designed to inhibit unwanted cell proliferation resulting from enhanced USP1 activity within cells. Cells may be exposed to a single dose or multiple doses according to a specific therapeutic regimen to perform the desired negative modulation of USP1.

[0531] Additionally, a method for treating cancer in a patient requiring this, comprising administering a therapeutically effective amount of a compound of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) to the patient is also preferred.

[0532] A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof or the compound or a pharmaceutically acceptable salt thereof is provided.

[0533] The compositions and methods provided herein may be used for the treatment of USP1-related cancer in patients requiring such treatment, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5), a pharmaceutically acceptable salt thereof, or a compound thereof or a pharmaceutically acceptable salt thereof. In one embodiment, the USP1-related cancer is breast cancer or ovarian cancer.

[0534] More preferably, the cancer is breast cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer, or pancreatic cancer.

[0535] More preferably, the cancer is prostate cancer or pancreatic cancer.

[0536] More preferably, the cancer is lung cancer or colorectal cancer.

[0537] More preferably, the cancer is breast cancer or ovarian cancer.

[0538] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The above compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising these compounds and salts may be administered with other anti-neoplastic compounds, e.g., chemotherapy, or in combination with other therapeutic agents, e.g., as preoperative or postoperative adjuvants, or in combination with other targeted agents or radiation or surgical interventions.

[0539] The present invention also provides compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) as defined herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof.

[0540] The present invention also provides compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) defined herein for use in the treatment of cancer, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof.

[0541] The present invention also provides compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5), or pharmaceutically acceptable salts or solvates thereof, for use in inhibiting USP1.

[0542] The present invention also provides compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) for use in inhibiting USP1, or pharmaceutically acceptable salts or solvates thereof.

[0543] The present invention further provides compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5), or pharmaceutically acceptable salts or solvates thereof or pharmaceutical compositions thereof for use in the treatment of USP1-related diseases or disorders.

[0544] The present invention also relates to the use of compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of drugs for the treatment of cancer.

[0545] The present invention also relates to the use of compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of agents for inhibiting the activity of USP1.

[0546] The present invention relates to the use of compounds of formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of medicines for the treatment of USP1-related diseases or disorders.

[0547] The present invention relates to (a) determining that cancer is associated with USP1 (e.g., USP1-associated cancer) (e.g., as determined using an assay or kit); and (b) administering a therapeutically effective amount of formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient.

[0548] The metastasis of the aforementioned cancer can also be treated or prevented according to the method described herein.

[0549] Combination therapy

[0550] In some embodiments, the compound described herein is administered together with an additional "second" therapeutic agent or treatment. The choice of the second therapeutic agent may be any formulation typically used in monotherapy to treat the indicated disease or condition. As used herein, the terms "administered together" and related terms refer to the simultaneous or sequential administration of the therapeutic agent according to the present invention. For example, the compound of the present invention may be administered in a separate unit dosage form or in a single unit dosage form together with another therapeutic agent or sequentially. Accordingly, the present invention provides a single unit dosage form comprising a compound of any formula described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0551] The above compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising these compounds and salts may also be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as other targeted agents or radiation or surgical interventions, as pre- or post-operative adjuvants.

[0552] The above compound relates to a compound comprising the step of administering at least one other anticancer agent, anti-inflammatory agent, immunosuppressant, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or mixture thereof to a subject requiring such agent simultaneously or sequentially, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising such compound.

[0553] Method for preparing the compound of the present invention

[0554] The present compound can be prepared by the following general process. The process provided herein may be similarly applied to synthesize all possible variations of the compound of the present invention, and in particular, without any intended or arbitrary variation, as provided herein, the formula (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) It may be similarly applied to synthesize compounds of. Unless otherwise indicated, used in various intermediates or compounds of the formula used herein X 1 , X 2 , X 3 , X 4 , R, R 1 , R 5 , L, L 1 , L 2 , n and Cy 1 Variables such as are compounds of the present invention, particularly chemical formulas ((I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5) It must be configured to be a variable defined in this specification in relation to the compound of .

[0555] Synthesis Reaction Scheme I: The schematic representation of these reaction schemes aims to provide possible routes for the preparation of compounds of chemical formulas (I), (IA), (IB), (IA-1), (IA-2), (IB-1), (IB-2), (IA-1A), (IA-1B), (IA-1A1), (IA-1A2), (IA-1A3), (IA-1A4), (IA-1A5), (IA-1B1), (IA-1B2), (IA-1B3), (IA-1B4), and (IA-1B5).

[0556] Reaction Equation 1

[0557]

[0558] The compound of formula (a) is coupled with the compound of formula (b) to form the compound of formula (c). The compound of formula (c) can be converted into the compound of formula (d). The compound of formula (d) can be converted into the compound of formula (e). The compound of formula (e) can be combined with the compound of formula (f), where Lg is a leaving group such as a halogen, to form the compound of formula (g).

[0559] The compound of formula (h), for example, Lg, is a leaving group, and for example, a halogen can be combined with bis(pinacolato)diboron under Suzuki reaction conditions in the presence of a palladium catalyst and a suitable base to form the compound of formula (i). The compound of formula (g) can be coupled with the compound of formula (i) under Suzuki reaction conditions in the presence of a palladium catalyst and a suitable base to form the desired compound of formula (I).

[0560] Example-1:

[0561]

[0562] Example-2:

[0563]

[0564] Example-3:

[0565]

[0566] Example-4:

[0567]

[0568] Example-5:

[0569] Example-6:

[0570]

[0571] Experimental details

[0572] The examples and formulations provided below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and formulations. In the following examples, unless otherwise noted, molecules having a single chiral center exist as a racemic mixture. Unless otherwise noted, these molecules having two or more chiral centers exist as a racemic mixture of diastereomers. A single enantiomer / diastereomer can be obtained by methods known to those skilled in the art. .

[0573] General Procedure-1:

[0574] To a solution of intermediate 15 (0.11 g), each boronic acid (0.15 g) was dissolved in dioxane. Cs2CO3 (3.0 eq) was added, and N2 gas was purged for 15 minutes. Tetrakis (0.05 eq) was added, and purging was performed again for 5 minutes. The reaction mixture was heated at 110 °C for 16 to 20 hours. The reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the organic layers were combined, and dried over Na2SO4. The mixture was purified by column chromatography using a compound eluted from 75 to 80% EtOAc-n-hexane to the intermediate.

[0575] General Procedure-2:

[0576] Each intermediate selected from intermediates 16 to 36 (1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml) was added. The reaction mixture was stirred at room temperature for 2 to 3 hours. The reaction mixture was evaporated under vacuum, a saturated NaHCO3 solution (~10 ml) was added and extracted with DCM (3 x 20 ml), the combined organic layer was dried over Na2SO4 and evaporated under vacuum to obtain the desired compound with or without column purification.

[0577] General Procedure-3:

[0578] In a solution of intermediate 8 (0.10 g, 1.0 eq), each boronic acid (2.0 eq) was dissolved in dioxane. N2 gas was purged in Cs2CO3 (3.0 eq) for 15 minutes. Tetrakis (0.05 eq) was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 6 hours. The reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the organic layers were combined, and dried over Na2SO4. The desired compound was obtained by purification using column chromatography of compounds eluted in 75-80% EtOAc-n-hexane.

[0579]

[0580]

[0581] Int: intermediate

[0582] Intermediate 1: 4-(4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile:

[0583] A solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (3.0 g, 1.0 eq) and NaOAc (0.93 g m, 1.0 eq) was dissolved in water (3 ml, 2 vol). The reaction mixture was heated at 100 °C for 1 hour. The reaction mixture was cooled at RT. 4-formylbenzonitrile (1.5 g m, 1 eq) was dissolved in MeOH (15 ml). 10 Vol) was added to the reaction mixture, followed by the addition of NH4OH (10 ml, 6 vol). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into water and extracted with (3X)EtOAc. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product was purified by column chromatography and eluted in 15–20% ethyl acetate-n-hexane to obtain 4-(4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile (0.5 gm). 1H NMR, CDCl3 (400 MHz): 10.1 (bs, 1H), 7.99–7.97 (m, 2H), 7.77–7.7 (m, 2H), 7.44 (s, 1H). Mass: 238.1 [M + 1].

[0584] Intermediate 2: 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile:

[0585] A solution of 4-(4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile (0.3 gm, 1.0 eq) was dissolved in THF (3 ml, 10 vol). The reaction mixture was cooled to 0 °C, and NaH (0.04 g, 1.3 eq) was added in fractions at the same temperature. Iodomethane (0.23 g, 1.3 eq) was added, and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was poured into water and extracted in EtOAc (3x), the organic layers were combined, and dried over evaporated Na2SO4 under vacuum. The crude product was purified by column chromatography and eluted in 10-25% ethyl acetate-n-hexane to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile (0.25 gm). 1H NMR, CDCl3 (400 Mhz): 7.81-7.72(m, 4H), 7.37(s, 1H), 3.83(s, 3H). Mass: 252.0[M + 1];

[0586] Intermediate 3: (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine:

[0587] EtOAc (3 ml, 10 vol) was added to a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzonitrile (0.25 gm, 1.0 eq). NH4OH (4-5 droplets) and Raney Ni (0.2 gm) were added. The reaction mixture was hydrogenated under an H2 balloon. The reaction mixture was stirred for 4 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was evaporated under vacuum to obtain (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine (0.15 gm). Mass: 256.7 [M + 1],

[0588] Intermediate 4: 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0589] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.18 g, 1 eq) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine (0.25 g m, 1 eq) were dissolved in DMF (2 ml). DIPEA (0.35 ml, 2 eq) was added to the reaction mixture and heated at 100 °C for 12 hours. The reaction mixture was cooled at RT and poured into ice-cold water for extraction with (3X) EtOAc. The organic layer was combined, dried over Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography and eluted in 40-45% EtOAc-n-hexane to obtain 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (0.14 gm). Mass: 408.1[M + 1],

[0590] Intermediate 5: 3-chloro-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile:

[0591] 1,3 - Dichloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.18 g, 1 eq) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine (0.25 gm, 1 eq) were dissolved in DMF (2 ml). DIPEA (0.35 ml, 2 eq) was added to the reaction mixture and heated at 100 °C for 12 hours. The reaction mixture was cooled at RT and poured into ice-cold water to extract with (3X)EtOAc. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product was purified by column chromatography and eluted in 40-45% EtOAc-n-hexane to obtain 3-chloro-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.14 gm). Mass: 432.1[M + 1],

[0592] Intermediate 6: 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2, 1-f][1,2,4]triazine-4-amine:

[0593] A solution of 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (0.5 g, 1 eq) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine (0.910 g / m, 1 eq) was dissolved in THF (2 ml). DIPEA (1.5 ml, 3 eq) was added to the reaction mixture and stirred at RT for 12 hours, the reaction mixture was cooled at RT, poured into ice-cold water, and extracted with (3X)EtOAc. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product was purified by column chromatography and eluted in 40-45% EtOAc-n-hexane to obtain 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2, 1-f][1,2,4]triazine-4-amine (0.43 gm). Mass: 407.0[M + 1],

[0594] Intermediate 7: 7-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l, 2-c]pyrimidine-5-amine

[0595] The title compound was synthesized using the procedure described in intermediate 6 with 5,7-dichloroimidazo[l, 2-c]pyrimidine and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine.

[0596] Intermediate 8: N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2- ( 2-Isopropylphenyl)-6,7-Dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0597] The title compound was synthesized using the procedure described in Intermediate 6 with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine.

[0598] Intermediate 9: 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0599] The title compound was synthesized using the procedure described in Intermediate 6 with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methanol.

[0600] Intermediate 10: 1-benzyl-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea

[0601] A solution of N-benzyl-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (1.0 eq) was dissolved in THF, cooled to 0 °C, and Et3N (20 equivalents) was added with DAMP (0.1 eq). Triphosgene (5.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. NN dimethylamine was added dropwise and stirred for 10 minutes, the reaction mixture was quenched with a saturated NaHCO3 solution (3X), and extracted with EtOAc. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product is purified by column chromatography and eluted in 65-80% EtOAc-n-hexane to obtain 1-benzyl-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea.

[0602] Intermediate 11: 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine:

[0603] 6-dichloro-9H-purine (1.0 g, 1.00 eq) was dissolved in DCM (10 ml) in the solution of 2. p-toluenesulfonic acid (0.05 g, 0.05 eq) and 3,4-dihydropyran (0.9 g, 2.00 eq) were added. The reaction mixture was stirred at RT for 12 hours, cooled at RT, and extracted with (3X)DCM by pouring into ice-cold water. The organic layer was combined, dried over Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography and eluted in 25-30% EtOAc-n-hexane to obtain 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.1 gm). Mass: 274.2 [M + 1],

[0604] Intermediate 12: 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

[0605] The title compound was synthesized using the procedure described in intermediate 6 with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine.

[0606] Intermediate 13: 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine

[0607] The title compound was synthesized using the procedure provided in intermediate 6 with 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine.

[0608] Intermediate 14: 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrrolo[2, 1-f][1,2,4]triazine

[0609] The title compound was synthesized using 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methanol by the procedure described in intermediate 6.

[0610] Intermediate 15: 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

[0611] The title compound was synthesized using intermediates 11 and 3 in the same manner as intermediate 4 to obtain 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine.

[0612] Intermediate 16: 2-(2-chloro-3-methylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0613] The title compound (45 mg) was synthesized using general procedure 1 with intermediate 15 and 2-chloro-3-methylphenylboronic acid. Mass: 583.03 [M + 1].

[0614] Intermediate 17: 2 -(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0615] The title compound (34 mg) was synthesized using General Procedure-1 with intermediate 15 and 3,5-dichlorophenylboronic acid. Mass: 603.21 [M + 1].

[0616] Intermediate 18: 2-(2,4-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0617] The title compound (38 mg) was synthesized using general procedure 1 with intermediate 15 and 2,4-difluorophenylboronic acid. Mass: 570.34 [M + 1].

[0618] Intermediate 19: 2-(3,5-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0619] The title compound (39 mg) was synthesized using general procedure 1 with intermediate 15 and 3,5-difluorophenylboronic acid. Mass: 570.35 [M + 1].

[0620] Intermediate 20: 2-(2,4-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0621] The title compound (28 mg) was synthesized using general procedure 1 with intermediate 15 and 2,4-dichlorophenylboronic acid. Mass: 603.22 [M + 1].

[0622] Intermediate 21: 2-fluoro-5-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-yl)benzonitrile:

[0623] The title compound (25 mg) was synthesized using General Procedure-1 with intermediate 15 and (2,6-dimethoxypyridine-3-yl)boronic acid. Mass: 577.34 [M + 1].

[0624] Intermediate 22: 2 -(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0625] The title compound (51 mg) was synthesized using General Procedure-1 with intermediate 15 and 2-fluoro-5-(trifluoromethyl)phenylboronic acid. Mass: 595.23 [M + 1].

[0626] Intermediate 23: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-2-(2-(trifluoromethyl)phenyl)-9H-purine-6-amine:

[0627] The title compound (40 mg) was synthesized using general procedure 1 with intermediate 15 and (2-trifluoromethyl)phenylboronic acid. Mass: 602.34 [M + 1].

[0628] Intermediate 24: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-2-(3-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6-amine:

[0629] The title compound (39 mg) was synthesized using General Procedure-1 with intermediate 15 and (3-(trifluoromethoxy)phenyl)boronic acid. Mass: 620.23 [M + 1].

[0630] Intermediate 25: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-2-(4-(trifluoromethoxy)phenyl)-9H-purine-6-amine:

[0631] The title compound (42 mg) was synthesized using general procedure 1 with intermediate 15 and (4-(trifluoromethoxy)phenyl)boronic acid. Mass: 618.39 [M + 1].

[0632] Intermediate 26: 2-(2-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0633] The title compound (38 mg) was synthesized using general procedure 1 with intermediate 15 and (2-fluoro-3-methoxyphenyl)boronic acid. Mass: 582.12 [M + 1].

[0634] Intermediate 27: 2-fluoro-5-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-yl)benzonitrile:

[0635] The title compound (45 mg) was synthesized using general procedure 1 with intermediate 15 and 3-cyano-4-fluorobenzeneboronic acid. Mass: 577.10 [M + 1].

[0636] Intermediate 28: 2-(3,5-dimethylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0637] The title compound (24 mg) was synthesized using intermediate 15 and 3,5-dimethylphenylboronic acid via general procedure 1. Mass: 562.31 [M + 1].

[0638] Intermediate 29: 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0639] The title compound (21 mg) was synthesized using general procedure 1 with intermediate 15 and 3,4-dimethoxyphenylboronic acid. Mass: 594.24 [M + 1].

[0640] Intermediate 30: 2-(4-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0641] The title compound (49 mg) was synthesized using General Procedure-1 with intermediate 15 and (4-fluoro-3-methoxyphenyl)boronic acid. Mass: 582.13 [M + 1].

[0642] Intermediate 31: 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0643] The title compound (19 mg) was synthesized using general procedure 1 with intermediate 15 and 2,4-dimethoxyphenylboronic acid. Mass: 594.21 [M + 1].

[0644] Intermediate 32: 2-(3-fluoro-2-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0645] The title compound (38 mg) was synthesized using general procedure 1 with intermediate 15 and (3-fluoro-2-(trifluoromethyl)phenyl)boronic acid. Mass: 620.40 [M + 1].

[0646] Intermediate 33: 3 -(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-yl)benzamide:

[0647] The title compound (24 mg) was synthesized using general procedure 1 with intermediate 15 and (3-carbamoylphenyl)boronic acid. Mass: 577.28 [M + 1].

[0648] Intermediate 34: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(methylthio)phenyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0649] The title compound (26 mg) was synthesized using general procedure 1 with intermediate 15 and (4-(methylthio)phenyl)boronic acid. Mass: 580.31 [M + 1].

[0650] Intermediate 35: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-2-(4-(trifluoromethyl)phenyl)-9H-purine-6-amine:

[0651] The title compound (21 mg) was synthesized using General Procedure-1 with intermediate 15 and (4-(trifluoromethyl)phenyl)boronic acid. Mass: 602.34 [M + 1].

[0652] Intermediate 36: N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-2-(3-(trifluoromethyl)phenyl)-9H-purine-6-amine:

[0653] The title compound (38 mg) was synthesized using General Procedure-1 with intermediate 15 and (3-(trifluoromethyl)phenyl)boronic acid. Mass: 602.40 [M + 1].

[0654] Intermediate 37: 1-(4-(4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-one

[0655] The title compound was synthesized using 4-acetylbenzaldehyde with intermediate 1 to obtain 1-(4-(4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-one. 255.12[M + 1],

[0656] Intermediate 38: 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-one:

[0657] The title compound was synthesized using 1-(4-(4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-one according to the procedure described in Intermediate 2 to obtain 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-one. MS: 269.24 [M+1].

[0658] Intermediate 39: 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)e-1-amine:

[0659] MeOH was used in a solution of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl). NH4OAc (10 eq) and NaCNBH3 (2.0 eq) were added. The reaction mixture was maintained at 60 °C for 16 hours. The reaction mixture was evaporated under vacuum, and the crude product was poured into water and extracted with (3X)EtOAc. The organic layer was combined, dried over Na2SO4, and evaporated under vacuum to obtain 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethane-1-amine. Mass: 270.18 [M + 1]

[0660] Intermediate 40: 2-chloro-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0661] The title compound was synthesized using intermediate 15 and 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)a-1-amine via the procedure described in intermediate 3 to obtain 2-chloro-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine. Mass: 506.12[M + 1],

[0662] Intermediate 41: 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0663] The title compound was synthesized in the same manner as in Example 1 using 2-chloro-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine) under Suzuki reaction conditions. Mass: 620.21 [M + 1].

[0664] Intermediate 42: 4-(pyridine-3-yl)benzonitrile:

[0665] A solution of 4-bromobenzonitrile (2.0 g) and pyridine-3-ylboronic acid (2.7 g) was dissolved in dioxane. N2 gas was added to Cs2CO3 (10.83 g) and purged for 15 minutes. Tetrakis (0.8 g) was added, and purging was performed again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and the mixture was dried over Na2SO4. 4-(pyridine-3-yl)benzonitrile (2.0 gm) was obtained by purification using column chromatography of the compound eluted in 20-25% EtOAc-n-hexane. Mass: 181.32 [M + 1],

[0666] Intermediate 43:(4-(pyridine-3-yl)phenyl)methaneamine:

[0667] (4-(pyridine-3-yl)benzonitrile was used to synthesize the title compound using the procedure described in Intermediate 3 to obtain (4-(pyridine-3-yl)phenyl)methaneamine. Mass: 185.26[M + 1],

[0668] Intermediate 44: 2-chloro-N-(4-(pyridine-3-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0669] The title compound was synthesized using intermediate 15 and (4-(pyridine-3-yl)phenyl)methaneamine in the same manner as intermediate 3 to obtain 2-chloro-N-(4-(pyridine-3-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine. Mass: 421.13[M + 1],

[0670] Intermediate 45: 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0671] The title compound was synthesized in the same manner as in Example 1 using 2-chloro-N-(4-(pyridine-3-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine under Suzuki reaction conditions. Mass: 536.15 [M + 1].

[0672] Intermediate 46: 4-(5-fluoropyridine-2-yl)benzonitrile:

[0673] A solution of 2-bromo-5-fluoropyridine (0.45 g) and (4-cyanophenyl)boronic acid (1.1 g) was dissolved in dioxane. N2 gas was added to Cs2CO3 (2.5 g) and purged for 15 minutes. Tetrakis (0.15 g) was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and the mixture was dried over Na2SO4. 4-(5-fluoropyridine-2-yl)benzonitrile (0.45 gm) was obtained by purification using column chromatography of the compound eluted in 20-25% EtOAc-n-hexane. Mass: 200.12 [M + 1],

[0674] Intermediate 47:(4-(5-fluoropyridine-2-yl)phenyl)methaneamine:

[0675] A solution of 4-(5-fluoropyridine-2-yl)benzonitrile was dissolved in THF and cooled to 0 °C. The reaction mixture was stirred at RT for 2 hours. DCM was added and stirred for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was evaporated under vacuum to obtain (4-(5-fluoropyridine-2-yl)phenyl)methaneamine. Mass: 204.34 [M + 1],

[0676] Intermediate 48: 2-chloro-N-(4-(5-fluoropyridine-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0677] The title compound was synthesized using intermediate 15 and (4-(5-fluoropyridine-2-yl)phenyl)methaneamine (4-(5-fluoropyridine-2-yl)phenyl)methaneamine) via the procedure described in intermediate 3 to obtain 2-chloro-N-(4-(5-fluoropyridine-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine. Mass: 439.18[M + 1],

[0678] Intermediate 49: 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0679] The present compound was synthesized according to the procedure provided in Example 1 using 2-chloro-N-(4-(5-fluoropyridine-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine under Suzuki reaction conditions. Mass: 553.20 [M + 1],

[0680] Example-1

[0681] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0682] This relates to a solution of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (0.11 g) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g) dissolved in dioxane. This was added to K2CO3 and purged with N2 gas for 15 minutes. Tetrakis was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and dried over Na2SO4. The compound was purified by column chromatography eluted in 75-80% EtOAc-n-hexane to obtain 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(C) (0.030 g). DMSO (400 Mhz): 8.57 (s, 1H), 7.91 (bs, 1H), 7.67-7.62 (m, 3H), 7.42-7.40 (m, 2H), 4.64-4.63 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.82-2.74(m, 4H), 2.08-2.04(m, 2H), 1.65-1.64(m, 1H), 0.93-0.92(m, 2H), 0.76-0.75(m, 2H). Mass: 522.1[M + 1], HPLC purity: 97.39%.

[0683] Example-2

[0684] 3-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile:

[0685] This relates to a solution of 3-chloro-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.12 g) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g) dissolved in dioxane. This was added to K2CO3 and purged with N2 gas for 15 minutes. Tetrakis was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and dried over Na2SO4. The compound was purified by column chromatography eluted in 75-80% EtOAc-n-hexane to obtain 3-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.035 g). DMSO (400 MHz): 8.64 (s, 1H), 7.91 (bs, 1H), 7.82-7.79 (m, 1H), 7.64-7.55 (m, 2H), 7.39-7.37 (m, 2H), 4.79-4.55 (m, 2H), 3.85 (s, 3H), 3.71(s, 3H), 3.00-2.96(m, 2H), 2.83-2.79(m, 2H), 2.20-2.17(m, 2H), 1.67-1.54(m, 1H), 0.96-0.94(m, 2H), 0.86-0.80(m, 1H), 0.64-0.59(m, 1H). Mass: 546.2[M + 1], HPLC purity: 97.47%.

[0686] Example-3

[0687] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0688] This relates to a solution of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (0.35 g) and (2-isopropylphenyl)boronic acid (0.211 g) dissolved in dioxane: H2O. N2 gas was purged in Cs2CO3 (0.84 g) for 15 minutes. Tetrakis (0.1 g) was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and the mixture was dried over Na2SO4. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (0.24 g) was obtained by purification with a column chromatography compound eluted in 75-80% EtOAc-n-hexane. 1H NMR, DMSO (400 Mhz): 7.91 (s, 1H), 7.66-7.64 (m, 2H), 7.59-7.56 (m, 1H), 7.44-7.39 (m, 3H), 7.33-7.28 (m, 2H), 7.18-7.14 (m, 1H), 4.71-4.70(m, 2H), 3.79(s, 3H), 3.49-3.44(m, 1H), 2.89-2.73(m, 4H), 2.10-2.03(m, 2H), 1.00-0.99(m, 6H). Mass: 492.2[M+1], HPLC purity: 98.41%.

[0689] Example-4

[0690] 3-(2-isopropylphenyl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile:

[0691] This relates to a solution of 3-chloro-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.1 g) and (2-isopropylphenyl)boronic acid (0.061 g) dissolved in dioxane: H2O. N2 gas was added to Cs2CO3 (0.24 g) and purged for 15 minutes. Tetrakis (0.015 g) was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours, the reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the combined organic layer was added, and the mixture was dried over Na2SO4. 3-(2-isopropylphenyl)-1-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (0.06 g) was obtained by purification by column chromatography of compounds eluted in 75-80% EtOAc-n-hexane. 1H NMR, DMSO (400 MHz): 7.91 (s, 1H), 7.74-7.71 (m, 1H), 7.62-7.60 (m, 1H), 7.38-7.35 (m, 4H), 7.24-7.20 (m, 1H), 7.16-7.14 (m, 1H), 4.68-4.67(m, 2H), 3.70(s, 3H), 3.00-2.98(m, 2H), 2.84-2.76(m, 3H), 2.20-2.14(m, 2H), 1.09-0.94(m, 6H). Mass: 516.0[M+l], HPLC purity: 95.40%.

[0692] Example-5

[0693] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2, 1-f / [l,2,4]triazine-4-amine:

[0694] A solution of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (0.1 g) and (2-isopropylphenyl)boronic acid (0.060 g) was dissolved in dioxane:H2O. N2 gas was added to Cs2CO3 (0.23 g) and purged for 15 minutes. Tetrakis (0.015 g) was added and purged again for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 x 50 ml), the organic layers were combined, and dried over Na2SO4. 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (0.05 g) was obtained by purification by column chromatography of compounds eluted in 75-80% EtOAc-n-hexane. DMSO (400 Mhz): 8.92-8.89 (m, 1H), 7.99-7.97 (bs, 1H), 7.69-7.67 (m, 3H), 7.46-7.40 (m, 3H), 7.38-7.37 (m, 2H), 7.23-7.19 (m, 1H), 6.99-6.98(m, 1H), 6.69-6.67(m, 1H), 4.84-4.82(m, 2H), 3.74(s, 3H), 3.39-3.36(m, 1H), 1.071.06(m, 6H). Mass: 491.1[M+l], HPLC purity: 89.97%.

[0695] Example-6

[0696] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2, 1-f][1,2,4]triazine-4-amine

[0697] Under Suzuki reaction conditions, the title compound (N) was synthesized in the same manner as in Example 1 using intermediate 6 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g). 1H NMR, DMSO (400 MHz): 9.01-8.98 (m, 1H), 8.60 (s, 1H), 7.98 (bs, 1H), 7.69 (s, lH), 7.64-7.62 (s, 2H), 7.45-7.43 (m, 2H), 6.98-6.97(m, 1H), 6.67-6.66(m, 1H), 4.84-4.82(m, 2H), 3.86(s, 3H), 3.71(s, 3H), 1.83-1.80(m, 1H), 0.96-0.95(m, 2H), 0.82-0.79(m, 2H). Mass: 521.43[M + 1], HPLC purity: 99.21%.

[0698] Example 7

[0699] 7-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l, 2-c]pyrimidine-5-amine

[0700] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 3 using intermediate 7 and (2-isopropylphenyl)boronic acid (0.060 g). 1H NMR, DMSO (400 MHz): 8.51-8.49 (m, 1H), 8.07 (bs, 1H), 7.91 (s, 1H), 7.68-7.66 (m, 2H), 7.62-7.61 (m, 1H), 7.57-7.55 (m, 2H), 7.38-7.36(m, 2H), 7.32-7.27(m, 1H), 7.22-7.18(m, 1H), 6.85(m, 1H)4.84-4.82(m, 2H), 3.75(s, 3H), 3.33-3.25(m, 1H), 1.3-1.01(m, 6H). Mass: 491.2[M + 1],

[0701] Example-8

[0702] 7-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)imidazole[l, 2-c]pyrimidine-5-amine

[0703] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 1 using intermediate 7 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g). 1H NMR, DMSO (400 Mhz): 8.51-8.48 (m, 1H), 8.08 (bs, 1H), 7.91 (s, 1H), 7.62-7.61 (m, 1H), 7.57-7.55 (m, 2H), 7.38-7.36 (m, 2H), 7.32-7.27(m, 1H), 7.22-7.18(m, 1H), 4.84-4.82(m, 2H), 3.86(s, 3H), 3.71(s, 3H), 1.83-1.80(m, 1H), 0.96-0.95(m, 2H), 0.82-0.79(m, 2H). Mass: 521.26[M + 1],

[0704] Example 9

[0705] N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0706] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 3 using intermediate 8 and (2-isopropylphenyl)boronic acid (0.060 g). 1 H NMR, DMSO (400 Mhz): 8.15 (bs, 1H), 7.59-7.56 (m, 1H), 7.50-7.48 (m, 2H), 7.41-7.39 (m, 3H), 7.31-7.30 (m, 2H), 7.17-7.13 (m, 1H), 4.72-4.70(m, 2H), 4.45-4.42(m, 1H), 3.47-3.44(m, 1H), 2.84-2.77(m, 4H), 2.09-2.05(m, 2H), 1.39-1.37(m, 6H), 0.98-0.96(m, 6H). Mass: 520.21[M + 1].

[0707] Example-10

[0708] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0709] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 1 using intermediate 8 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g). 1H NMR, DMSO (400 MHz): 8.57 (s, 1H), 7.91 (bs, 1H), 7.67-7.61 (m, 3H), 7.45-7.41 (m, 2H), 4.64-4.63 (m, 2H), 4.45-4.39 (m, 1H), 3.80(s, 3H), 2.83-2.74(m, 4H), 2.10-2.02(m, 2H), 1.66-1.63(m, 1H), 1.39-1.38(m, 6H), 0.94-0.91(m, 2H), 0.76-0.71(m, 2H). Mass: 550.3[M + 1], HPLC purity: 97.39%.

[0710] Example 11

[0711] 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

[0712] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 1 using intermediate 8 and 4-cyclopropyl-6-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g). 1H NMR, DMSO (400 Mhz): 8.75 (s, 1H), 8.16 (bs, 1H), 7.78-7.77 (m, 1H), 7.64-7.55 (m, 2H), 7.47-7.41 (m, 2H), 4.66-4.65 (m, 2H), 4.44-4.41(m, 1H), 2.85-2.74(m, 4H), 2.10-2.04(m, 2H), 1.39-1.37(m, 6H), 0.93-0.92(m, 2H), 0.76-0.75(m, 2H). Mass: 586.45[M + 1], HPLC purity: 95.32%.

[0713] Example-12

[0714] 1-(2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)urea

[0715] A solution of 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (1.0 equivalent) dissolved in THF was cooled to 0 °C, and DAMP (0.1 equivalent) and Et3N (20.0 equivalent) were added. Triphosgene (5.0 equivalent) was added in portions. The reaction mixture was stirred at room temperature for 2 hours. NH4OH (10 mL) was added dropwise and stirred for 2 hours. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3 times). The organic layers were combined, dried with Na2SO4, and evaporated under reduced pressure. The crude product was purified by column chromatography and eluted with 65-80% EtOAc-n-hexane to obtain 1-(2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)urea. 1H NMR, DMSO (400 MHz): δ 8.62-8.61 (m, 1H), 7.91-7.90 (m, 1H), 7.64-7.62 (m, 2H), 7.40-7.38 (m, 2H), 6.98 (bs, 2H), 3.80 (s, 3H), 3.71 (s, 3H), 2.82-2.74 (m, 4H), 2.08-2.04 (m, 2H), 1.65-1.64 (m, 1H), 0.93-0.92 (m, 2H), 0.76-0.75 (m, 2H). MS: 565.4 [M+1].

[0716] Example-13

[0717] 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0718] The title compound was synthesized in the same manner as in Example 3 using intermediate 9 and (2-isopropylphenyl)boronic acid (0.060 g) under Suzuki reaction conditions. 1H NMR, DMSO (400 MHz): 8.19 (s, 1H), 7.60-7.57 (m, 4H), 7.52-7.50 (m, 1H), 7.44-7.38 (m, 2H), 7.26-7.22 (m, 1H), 5.59 (s, 2H), 4.49-4.46(m, 1H), 3.50-3.45(m, 1H), 2.99-2.90(m, 4H), 2.16-2.11(m, 2H), 1.41-1.39(m, 6H), 1.11-1.10(m, 6H). Mass: 521.46[M + 1];

[0719] Example-14

[0720] 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea

[0721] This relates to a solution of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (1). 0 eq) was dissolved in THF, cooled to 0°C, and Et3N (20 eq) was added with DAMP (0.1 eq). Triphosgene (5.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. NN dimethylamine was added dropwise and stirred for 10 minutes, the reaction mixture was quenched with a saturated NaHCO3 solution and extracted with (3X)EtOAc. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product is purified by column chromatography and eluted in 65-80% EtOAc-n-hexane to obtain 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-1-(2-(2-isopropylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,3-dimethylurea. Example 9. 1H NMR, DMSO (400 MHz): 8.14 (s, 1H), 7.56-7.48 (m, 2H), 7.45-7.42 (m, 3H), 7.37-7.36 (m, 2H), 7.25-7.18 (m, 1H), 5.09 (s, 2H), 4.45-4.41(m, 1H), 3.47-3.31(m, 1H), 2.95-2.91(m, 2H), 2.84(s, 6H), 2.69-2.65(m, 2H), 2.07-1.98(m, 2H), 1.38-1.37(m, 6H), 0.98-0.96(m, 6H). Mass: 591.3[M + 1],

[0722] Example-15

[0723] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0724] The title compound (60 mg) was synthesized using General Procedure-2 with Example 18. 1H NMR, DMSO (400 MHz): 12.9 (s, 1H), 8.36 (bs, 1H), 8.176 (s, 1H), 7.91 (s, 1H), 7.65-7.63 (m, 2H), 7.36-7.34 (m, 2H), 7.32-7.30 (m, 2H), 7.20-7.17(m, 1H), 4.84-4.82(m, 2H), 3.74(s, 3H), 3.57-3.53(m, 1H), 1.3-1.01(m, 6H). Mass: 492.3[M + 1];

[0725] Example-16

[0726] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine

[0727] The title compound (A) (150 mg) was synthesized using General Procedure-2 with Example 19v. 1H NMR, DMSO (400 MHz): 13.0(s, 1H), 8.60(s, 1H), 8.40(s, 1H), 7.91(s, 1H), 7.64-7.62(m, 1H), 7.57-7.55(m, 2H), 7.47-7.45(m, 2H), 4.7(bs, 2H), 3.81(s, 3H), 3.74(s, 3H), 1.75-1.69(m, 1H), 0.96-0.95(m, 2H), 0.82-0.80(m, 2H). Mass: 522.3[M + 1],

[0728] Example-17

[0729] 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

[0730] 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.5 g, 1.00 eq) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)methaneamine (0.46 g m, 1.00 eq) were dissolved in IPA (5 ml). DIPEA (0.8 ml, 2 eq) was added to the reaction mixture, heated at 80 °C for 12 hours, the reaction mixture was evaporated under vacuum, and the crude product was poured into ice-cold water (3X)EtOAc for extraction. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product was purified by column chromatography and eluted in 90% EtOAc-n-hexane to obtain 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.2 gm). Mass: 493.4 [M + 1],

[0731] Example-18

[0732] 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

[0733] Example 17 The title compound was synthesized under Suzuki reaction conditions using (2-isopropylphenyl)boronic acid (0.060 g). Mass: 576.1 [m + 1],

[0734] Example-19

[0735] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

[0736] The title compound was synthesized under Suzuki reaction conditions using 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g) in Example 17. Mass: 606.1 [m + 1],

[0737] Example-20

[0738] 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

[0739] The title compound was synthesized in the same manner as in Example 3 using intermediate 12 and (2-isopropylphenyl)boronic acid (0.060 g) under Suzuki reaction conditions. Mass: 516.3 [M + 1].

[0740] Example-21

[0741] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

[0742] The title compound was synthesized in the same manner as in Example 1 using intermediate 12 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g) under Suzuki reaction conditions. Mass: 546.2 [M + 1].

[0743] Example-22

[0744] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)pyrrolo[2, 1-f][1,2,4]triazine-4-amine

[0745] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 1 using intermediate 13 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g). 1H NMR, DMSO (400 MHz): 9.01-8.98 (m, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.69 (s, lH), 7.49-7.44 (m, 4H), 6.98-6.97 (m, 1H), 6.68-6.66(m, 1H), 4.76-4.74(m, 2H), 4.41-4.38(m, 1H), 311(s, 1H), 1.82-1.80(m, 1H), 1.36-1.34(m, 6H), 0.96-0.95(m, 2H), 0.82-0.79(m, 2H). Mass: 549.47[M + 1].

[0746] Example-23

[0747] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)pyrrolo[2, 1-f][1,2,4]triazine

[0748] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 1 using intermediate 14 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.15 g).

[0749] Example-24

[0750] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine:

[0751] Under Suzuki reaction conditions, the title compound was synthesized in the same manner as in Example 3 using intermediate 9 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.060 g). 1H NMR, DMSO (400 MHz): 8.65 (s, 1H), 7.95 (bs, 1H), 7.73-7.71 (m, 2H), 7.64-7.56 (m, 2H), 5.56 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.98-2.83(m, 4H), 2.10-2.04(m, 2H), 1.66-1.63(m, 1H), 1.13-1.11(m, 2H), 0.86-0.84(m, 2H). Mass: 523.21[M + 1];

[0752] Example 25

[0753] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine:

[0754] The title compound was synthesized using the procedure provided in Example 1 with 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.060 g) under Suzuki reaction conditions. Mass: 607.23 [M + 1],

[0755] Example 26

[0756] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0757] A solution of 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to yield 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine (0.1 g). Mass: 523.1 [M + 1],

[0758] Example 27

[0759] 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine:

[0760] The title compound was synthesized according to the procedure described in Example 1 using 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine and (2-fluoro-6-methoxyphenyl)boronic acid (0.070 g) under Suzuki reaction conditions. MS: 583.40 [M+1].

[0761] Example 28

[0762] 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine;

[0763] 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to obtain 2-(2-fluoro-6-methoxyphenyl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)oxy)-7H-purine (0.1 g). Mass: 499.34[M + 1]

[0764] Example 29

[0765] 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

[0766] The title compound was synthesized in the same manner as in Example 1 using 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and (2-fluoro-6-methoxyphenyl)boronic acid under Suzuki reaction conditions. Mass: 582.24[M + 1]

[0767] Example 30

[0768] 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0769] A solution of 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to yield 2-(2-fluoro-6-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine (0.1 g). Mass: 4981.35 [M + 1],

[0770] Example 31

[0771] 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0772] The title compound was synthesized using the procedure provided in Example 1 with 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.070 g) under Suzuki reaction conditions. Mass: 565.20 [M + 1],

[0773] Example 32

[0774] 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0775] A solution of 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml) and extracted with DCM (3 x 20 ml), and the combined organic layer was dried over Na2SO4 to yield 2-(2-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine (0.1 g). Mass: 481.20 [M + 1],

[0776] Example 33

[0777] 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0778] The title compound was synthesized using the procedure provided in Example 1 with 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.070 g) under Suzuki reaction conditions. Mass: 565.20 [M + 1],

[0779] Example 34

[0780] 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine;

[0781] A solution of 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to obtain 2-(4-methoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine (0.1 g). Mass: 481.20 [M + 1],

[0782] Example 35

[0783] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine:

[0784] A solution of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (1.00 eq) and morpholine (2.00 eq) was dissolved in ACN (5 ml). DIPEA (4 eq) was added to the reaction mixture and heated at 80 °C for 12 hours. The reaction mixture was poured into ice-cold water (3X)EtOAc and extracted. The organic layer was combined and dried over Na2SO4, then evaporated under vacuum. The crude product was purified by column chromatography and eluted in 45% EtOAc-n-hexane to obtain N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.2 gm). Mass: 543.4 [M + 1],

[0785] Example 36

[0786] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-7H-purine-6-amine;

[0787] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (0.11 g, 1.0 eq) was dissolved in DCM (2 ml). TFA (2.0 ml, 100 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to obtain N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-morpholino-7H-purine-6-amine (0.1 g). Mass: 459.38[M + 1],

[0788] Example 37

[0789] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-9-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9H-purine-6-amine:

[0790] A solution of 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine (1.0 eq) was dissolved in THF (10 vol). The reaction mixture was cooled to 0 °C, and NaH (1.3 eq) was added in a partial manner at the same temperature. Iodomethane (1.3 eq) was added, and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was poured into water to extract on EtOAc (3x), the organic layers were combined, and dried on Na2SO4 evaporated under vacuum. The crude product was purified by column chromatography and eluted in 35-45% EtOAc-n-hexane to obtain 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-9-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-9H-purine-6-amine. Mass: 536.43[M + 1],

[0791] Example 38

[0792] 2-(2-chloro-3-methylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0793] The title compound (25 mg) was synthesized according to general procedure-2 using intermediate 16.

[0794] 1 H NMR, DMSO (400 MHz): δ 13.0 (s, 1H), 8.28 (s, 1H), 8.17-8.15 (m, 1H), 7.95 (s, 2H), 7.88 (s, 1H), 7.65-7.63 (m, 2H), 7.56-7.54 (m, 2H), 7.38-7.36 (m, 1H), 4.90 (bs, 2H), 3.71 (s, 3H), 2.32 (s, 3H). MS: 498.12 [M+1].

[0795] Example 39

[0796] 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0797] The title compound (15 mg) was synthesized according to general procedure-2 using intermediate 17. 1 H NMR, DMSO (400 MHz): δ 13.1 (s, 1H), 8.23 ​​(s, 1H), 8.19-8.10 (m, 2H), 7.87 (s, 1H), 7.66-7.60 (m, 2H), 7.59-7.53 (m, 3H), 7.16-7.12 (m, 1H), 4.82 (s, 2H), 3.72 (s, 3H). MS: 518.08 [M+1].

[0798] Example 40

[0799] 2-(2,4-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0800] The title compound (20 mg) was synthesized according to general procedure-2 using intermediate 18. 1H NMR, DMSO (400 MHz): δ 13.0 (s, 1H), 8.11 (s, 1H), 8.05-7.99 (m, 1H), 7.90 (s, 1H), 7.66-7.61 (m, 2H), 7.59-7.53 (m, 3H), 7.29-7.24 (m, 1H), 7.16-7.12 (m, 1H), 4.85 (s, 2H), 3.71 (s, 3H). MS: 486.43 [M+1].

[0801] Example 41

[0802] 2-(3,5-difluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0803] The title compound (24 mg) was synthesized according to general procedure-2 using intermediate 19. 1 H NMR, DMSO (400 MHz): δ 13.12 (s, 1H), 8.20 (s, 1H), 8.19-8.15 (m, 2H), 7.89 (s, 1H), 7.66-7.61 (m, 2H), 7.58-7.52 (m, 3H), 7.16-7.11 (m, 1H), 4.83 (s, 2H), 3.74 (s, 3H). MS: 486.22 [M+1].

[0804] Example 42

[0805] 2-(2,4-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0806] The title compound (15 mg) was synthesized according to general procedure-2 using intermediate 20. 1 H NMR, DMSO (400 MHz): δ 13.01 (s, 1H), 8.12 (s, 1H), 8.06-7.99 (m, 1H), 7.91 (s, 1H), 7.69-7.64 (m, 2H), 7.58-7.52 (m, 3H), 7.26-7.21 (m, 1H), 7.18-7.14 (m, 1H), 4.84 (s, 2H), 3.72 (s, 3H). MS: 518.16 [M+1].

[0807] Example 43

[0808] 2-(2,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0809] The title compound (12 mg) was synthesized according to General Procedure-2 using intermediate 21. ¹H NMR, DMSO (400 MHz): δ 12.99 (s, 1H), 8.27 (bs, 1H), 8.11 (s, 1H), 8.03-8.00 (m, 1H), 7.90 (s, 1H), 7.66-7.64 (m, 2H), 7.54-7.52 (m, 2H), 6.44-6.42 (m, 1H), 4.79 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H). MS: 511.24 [M+1].

[0810] Example 44

[0811] 2-(2-fluoro-5-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0812] The title compound (33 mg) was synthesized according to general procedure-2 using intermediate 22. 1 H NMR, DMSO (400 MHz): δ 13.18 (s, 1H), 8.61 (s, 1H), 8.33-8.31 (m, 1H), 8.22 (s, 1H), 7.90-7.84 (m, 3H), 7.66-7.59 (m, 2H), 7.52-7.50 (m, 2H), 4.96 (s, 2H), 3.74 (s, 3H). MS: 534.33 [M+1].

[0813] Example 45

[0814] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-7H-purine-6-amine:

[0815] The title compound (23 mg) was synthesized according to general procedure-2 using intermediate 23. 1H NMR, DMSO (400 MHz): δ 13.10 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.80-7.78 (m, 1H), 7.72-7.59 (m, 5H), 7.46-7.44 (m, 2H), 4.78 (s, 2H), 3.74 (s, 3H). MS: 518.15 [M+1].

[0816] Example 46

[0817] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethoxy)phenyl)-7H-purine-6-amine:

[0818] The title compound (21 mg) was synthesized according to general procedure-2 using intermediate 24. 1 H NMR, DMSO (400 MHz): δ 13.10 (s, 1H), 8.56 (s, 1H), 8.36-8.34 (m, 1H), 8.21-8.18 (m, 2H), 7.91 (s, 1H), 7.89-7.67 (m, 2H), 7.59-7.56 (m, 3H), 7.42-7.40 (m, 1H), 4.87 (bs, 2H), 3.74 (s, 3H). MS: 534.13 [M+1].

[0819] Example 47

[0820] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethoxy)phenyl)-7H-purine-6-amine:

[0821] The title compound (29 mg) was synthesized according to general procedure-2 using intermediate 25. 1 H NMR, DMSO (400 MHz): δ 13.06 (s, 1H), 8.49 (s, 1H), 8.47-8.44 (m, 2H), 8.16 (s, 1H), 7.89 (s, 1H), 7.68-7.66 (m, 2H), 7.58-7.56 (m, 2H), 7.44-7.42 (m, 2H), 4.87 (bs, 2H), 3.74 (s, 3H). MS: 534.21 [M+1].

[0822] Example 48

[0823] 2-(2-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0824] The title compound (24 mg) was synthesized according to general procedure-2 using intermediate 26. 1 H NMR, DMSO (400 MHz): δ 12.96 (s, 1H), 8.13 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.67-7.55 (m, 5H), 7.25-7.23 (m, 2H), 4.87 (bs, 2H), 3.83 (s, 3H), 3.74 (s, 3H). MS: 498.19 [M+1].

[0825] Example 49

[0826] 2-fluoro-5-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzonitrile:

[0827] The title compound (28 mg) was synthesized according to General Procedure-2 using intermediate 27. ¹H NMR, DMSO (400 MHz): δ 13.11 (s, 1H), 8.67 (s, 1H), 8.19 (s, 1H), 7.68–7.66 (m, 1H), 7.64–7.56 (m, 7H), 4.87 (bs, 2H), 3.71 (s, 3H). MS: 493.22 [M+1].

[0828] Example 50

[0829] 2-(3,5-dimethylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0830] The title compound (13 mg) was synthesized according to General Procedure-2 using intermediate 28. ¹H NMR, DMSO (400 MHz): δ 13.1 (s, 1H), 8.23 ​​(s, 1H), 8.19–8.10 (m, 2H), 7.87 (s, 1H), 7.66–7.60 (m, 2H), 7.59–7.53 (m, 3H), 7.16–7.12 (m, 1H), 4.82 (s, 2H), 3.72 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H). MS: 478.31 [M+1].

[0831] Example 51

[0832] 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0833] The title compound (11 mg) was synthesized according to the general procedure using intermediate 29. 1 H NMR, DMSO (400 MHz): δ 12.99 (s, 1H), 8.48 (s, 1H), 8.15 (s, 1H), 8.06-8.04 (m, 1H), 7.90 (m, 2H), 7.67-7.65 (m, 2H), 7.59-7.57 (m, 2H), 7.29-7.24 (m, 1H), 4.84 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73 (s, 3H). MS: 510.23 [M+1].

[0834] Example 52

[0835] 2-(4-fluoro-3-methoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0836] The title compound (35 mg) was synthesized according to standard procedure using intermediate 30. ¹H NMR, DMSO (400 MHz): δ 13.03 (s, 1H), 8.48 (s, 1H), 8.15 (s, 1H), 8.06–8.04 (m, 1H), 7.90 (m, 2H), 7.67–7.65 (m, 2H), 7.59–7.57 (m, 2H), 7.29–7.24 (m, 1H), 4.85 (bs, 2H), 3.92 (s, 3H), 3.74 (s, 3H). MS: 498.20 [M+1].

[0837] Example 53

[0838] 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0839] The title compound (06 mg) was synthesized according to standard procedure using intermediate 31. ¹H NMR, DMSO (400 MHz): δ 13.10 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 8.05–8.03 (m, 1H), 7.91 (m, 2H), 7.66–7.63 (m, 2H), 7.59–7.56 (m, 2H), 7.29–7.23 (m, 1H), 4.85–4.83 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H). MS: 510.16 [M+1].

[0840] Example 54

[0841] 2-(3-fluoro-2-(trifluoromethyl)phenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-7H-purine-6-amine:

[0842] The title compound (23 mg) was synthesized according to standard procedure using intermediate 32. ¹H NMR, DMSO (400 MHz): δ 13.1 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.97-7.77 (m, 3H), 7.67-7.65 (m, 2H), 7.62-7.57 (m, 2H), 4.85-4.83 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.70 (s, 3H). MS: 536.18 [M+1].

[0843] Example 55

[0844] 3-(6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-7H-purine-2-yl)benzamide:

[0845] The title compound (10 mg) was synthesized according to standard procedure using intermediate 33. MS: 493.20 [M+1].

[0846] Example 56

[0847] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(methylthio)phenyl)-7H-purine-6-amine:

[0848] The title compound (12 mg) was synthesized according to standard procedure using intermediate 34. MS: 496.23 [M+1].

[0849] Example 57

[0850] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-7H-purine-6-amine:

[0851] The title compound (10 mg) was synthesized according to standard procedure using intermediate 35. ¹H NMR, DMSO (400 MHz): δ 13.11 (s, 1H), 8.61 (s, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.95–7.89 (m, 2H), 7.72–7.70 (m, 2H), 7.67–7.65 (m, 2H), 7.62–7.57 (m, 2H), 4.84 (s, 2H), 3.73 (s, 3H). MS: 518.16 [M+1].

[0852] Example 58

[0853] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(3-(trifluoromethyl)phenyl)-7H-purine-6-amine:

[0854] The title compound (23 mg) was synthesized according to the general procedure using intermediate 36. 1 H NMR, DMSO (400 MHz): δ 13.1 (s, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.95-7.89 (m, 1H), 7.79-7.77 (m, 1H), 7.72-7.70 (m, 1H), 7 . 67-7.65 (m, 2H), 7.62-7.57 (m, 3H), 4.85-4.83 (m, 2H), 3.73 (s, 3H). MS: 518.12 [M+1].

[0855] Example 59

[0856] N-(3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)phenyl)acetamide:

[0857] The title compound (10 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. Mass: 507.24[M + 1],

[0858] Example 60

[0859] 2-fluoro-5-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile:

[0860] The title compound (09 mg) was synthesized using intermediate 8 and boronic acid via general procedure-3. 1H NMR, DMSO (400 MHz): 7.90(bs, 1H), 7.87-7.85(m, 1H), 7.82(s, 1H), 7.67-7.65(m, 2H), 7.60(s, 1H), 7.55-7.52(m, 2H), 6.98-6.96(m, 1H), 4.75-4.74(m, 2H), ss3.71(s, 3H), 2.83-2.81(m, 2H), 2.75-2.72(m, 2H), 2.06-2.02(m, 2H). Mass: 493.22[M+l],

[0861] Example 61

[0862] 2-(5-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0863] The title compound (35 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. DMSO (400 MHz): 7.91(bs, 1H), 7.83-7.81(m, 1H), 7.75(s, 1H), 7.67-7.59(m, 2H), 7.56-7.55(m, 2H), 7.49-7.47(m, 1H), 7.32-7.27 ss(m, 1H), 4.71-4.70(m, 2H), 3.72(s, 3H), 2.84-2.80(m, 2H), 2.78-2.74(m, 2H), 2.07-2.04(m, 2H). Mass: 502.19[M +l],

[0864] Example 62

[0865] 2-(6-ethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0866] The title compound (10 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. Mass: 495.18 [M + 1],

[0867] Example 63

[0868] 4-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzonitrile:

[0869] The title compound (42 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 8.43(bs, 1H), 8.41(s, 1H), 7.91-7.87(m, 3H), 7.80-7.77(m, 1H), 7.68-7.66(m, 2H), 7.53-7.51(m, 2H), 4.79-4.78(m, 2H), 3.71(s, 3H), 2.87-2.83(m, 2H), 2.78-2.75(m, 2H), 2.09-2.05(m, 2H). Mass: 475.21[M + 1],

[0870] Example 64

[0871] 2-([1,1'-biphenyl]-4-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0872] The title compound (32 mg) was synthesized using intermediate 8 and boronic acid via general procedure-3. 1H NMR, DMSO (400 MHz): 8.46(bs, 1H), 8.26-8.24(m, 1H), 7.89(s, 1H), 7.72-7.62(m, 6H), 7.56-7.52(m, 2H), 7.50-7.46(m, 2H), 7.38-7.35(m, 1H), 4.78-4.76(m, 2H), 3.63(s, 3H), 2.87-2.83(m, 2H), 2.79-2.76(m, 2H), 2.09-2.05(m, 2H). Mass: 526.26[M + 1].

[0873] Example 65

[0874] 2-( 2 ,6-dimethoxypyridine-3-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0875] The title compound (15 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 8.27 (bs, 1H), 8.1 l (s, 1H), 8.05-8.00 (m, 2H), 7.66-7.64 (m, 2H), 7.54-7.52 (m, 2H), 4.79-4.76 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.63 (s, 3H), 2.87-2.83 (m, 2H), 2.79-2.76 (m, 2H), 2.09-2.05 (m, 2H). Mass: 511.25 [M+l],

[0876] Example 66

[0877] 2-(2,5-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0878] The title compound (29 mg) was synthesized using intermediate 8 and boronic acid via general procedure-3. 1H NMR, DMSO (400 MHz): 7.90 (bs, 1H), 7.87-7.85 (m, 1H), 7.84 (s, 1H), 7.69-7.66 (m, 2H), 7.65 (s, 1H), 7.55-7.53 (m, 2H), 7.03-6.97 (m, 1H), 4.79-4.75 (m, 2H), 3.83-3.82 (m, 6H), 3.70 (s, 3H), 2.90-2.87 (m, 2H), 2.79-2.76 (m, 2H), 2.06-2.02 (m, 2H). Mass: 510.24[M + 1],

[0879] Example 67

[0880] 2-(3-chloro-2-fluorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0881] The title compound (30 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 7.91(bs, 1H), 7.82-7.78(m, 1H), 7.73-7.71(m, 1H), 7.70-7.59(m, 3H), 7.48-7.64(m, 2H), 7.27-7.23(m, 1H), 4.73-4.71(m, 2H), 3.72(s, 3H), 2.84-2.80(m, 2H), 2.77-2.74(m, 2H), 2.10-2.02(m, 2H). Mass: 502.18[M + 1],

[0882] Example 68

[0883] 2-(2,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0884] The title compound (23 mg) was synthesized using general procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 7.91(bs, 1H), 7.86-7.84(m, 1H), 7.83(s, 1H), 7.68-7.65(m, 2H), 7.62(s, 1H), 7.54-7.52(m, 2H), 6.99-6.97(m, 1H), 4.78-4.73(m, 2H), 3.85-3.84(m, 6H), 3.71(s, 3H), 2.92-2.89(m, 2H), 2.78-2.75(m, 2H), 2.10-2.06(m, 2H). Mass: 510.24[M + 1],

[0885] Example 69

[0886] 2-(3,4-dimethoxyphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0887] The title compound (29 mg) was synthesized using intermediate 8 and boronic acid via general procedure-3. 1H NMR, DMSO (400 MHz): 7.90(bs, 1H), 7.87-7.85(m, 1H), 7.82(s, 1H), 7.67-7.65(m, 2H), 7.60(s, 1H), 7.55-7.52(m, 2H), 6.98-6.96(m, 1H), 4.75-4.74(m, 2H), 3.77(s, 6H), 3.71(s, 3H), 2.83-2.81(m, 2H), 2.75-2.72(m, 2H), 2.06-2.02(m, 2H). Mass: 510.23[M + 1],

[0888] Example 70

[0889] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0890] The title compound (41 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 7.91 (bs, 1H), 7.77-7.75 (m, 1H), 7.68-7.55 (m, 6H), 4.70-4.69 (m, 2H), 3.71 (s, 3H), 2.83-2.78 (m, 2H), 2.76-2.75 (m, 2H), 2.08-2.05 (m, 2H). Mass: 518.20 [M + 1],

[0891] Example 71

[0892] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0893] The title compound (36 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 8.43-8.41(m, 2H), 7.91(bs, 1H), 7.89-7.87(m, 2H), 7.80-7.78(m, 1H), 7.68-7.66(m, 2H), 7.53-7.5l(m, 2H), 4.80-4.78(m, 2H), 3.71(s, 3H), 2.87-2.83(m, 2H), 2.77-2.75(m, 2H), 2.09-2.05(m, 2H). Mass: 518.17 [M+l],

[0894] Example 72

[0895] 3-(4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)benzamide:

[0896] The title compound (7 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. Mass: 493.29 [M + 1],

[0897] Example 73

[0898] 2-(3,5-dichlorophenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0899] The title compound (20 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 8.15-8.14 (m, 2H), 7.90 (bs, 1H), 7.84-7.81 (m, 1H), 7.68-7.65 (m, 3H), 7.53-7.51 (m, 2H), 4.76-4.74 (m, 2H), 3.71 (s, 3H), 2.85-2.82 (m, 2H), 2.78-2.75 (m, 2H), 2.08-2.05 (m, 2H). Mass: 518.14 [M + 1],

[0900] Example 74

[0901] N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)benzyl)-2-(2,3,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine:

[0902] The title compound (15 mg) was synthesized using General Procedure-3 with intermediate 8 and boronic acid. 1H NMR, DMSO (400 MHz): 7.91(bs, 1H), 7.81-7.78(m, 1H), 7.67-7.65(m, 2H), 7.60-7.58(m, 1H), 7.48-7.46(m, 3H), 4.73-4.71(m, 2H),

[0903] 3.72(s, 3H), 2.85-2.81(m, 2H), 2.78-2.75(m, 2H), 2.10-2.03(m, 2H). Mass: 504.21[M + 1];

[0904] Example 75

[0905] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-7H-purine-6-amine:

[0906] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (1.0 eq) was dissolved in DCM (2 ml). TFA (30 eq) was added. The reaction mixture is stirred at room temperature for 16 hours, the reaction mixture is evaporated under vacuum, the crude product is poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to provide 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2-yl)phenyl)ethyl)-7H-purine-6-linseed (0.06 g). Mass: 535.26[M + 1], 1H NMR, DMSO (400 MHz): 13.0 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.64-7.65 (m, 4H), 4.7(bs, 1H), 3.78(s, 3H), 3.75(s, 3H), 1.66-1.54(m, 1H), 1.58-1.56(m, 3H), 0.94-0.92(m, 2H), 0.87-0.85(m, 2H).

[0907] Example 76

[0908] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-7 H-purine-6-amine:

[0909] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (1.0 eq) was dissolved in DCM (2 ml). TFA (30 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to obtain 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(pyridine-3-yl)benzyl)-7H-purine-6-amine (0.05 g). Mass: 451.30[M + 1], 1H NMR, DMSO (400 MHz): 13.0 (s, 1H), 8.90 (s, 1H), 8.60-8.58 (m, 2H), 8.45 (s, 1H), 8.21 (s, 1H), 8.15-8.13 (m, 1H), 7.68-7.66(m, 2H), 7.57-7.54(m, 1H), 7.47-7.45(m, 2H)4.72(bs, 2H), 3.81(s, 3H), 1.72-1.70(m, 1H), 0.95-0.93(m, 2H), 0.86-0.84(m, 2H).

[0910] Example 77

[0911] 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-7H-purine-6-amine:

[0912] A solution of 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (1.0 eq) was dissolved in DCM (2 ml). TFA (30 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was evaporated under vacuum, the crude product was poured into a saturated NaHCO3 solution (10 ml), extracted with DCM (3 x 20 ml), and dried over Na2SO4 to yield 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-N-(4-(5-fluoropyridine-2-yl)benzyl)-7H-purine-6-amine (0.06 g). Mass: 469.23[M + 1], 1H NMR, DMSO (400 Mhz): 13.01(s, 1H), 8.63-8.62(m, 1H), 8.58(s, 1H), 8.11(bs, 1H), 8.00(s, 1H), 7.99-7.94(m, 3H), 7.79-7.78(m, 1H), 7.45-7.43(m, 2H), 4.73(bs, 2H), 3.80(s, 3H), 1.73-1.71(m, 1H), 0.95-0.94(m, 2H), 0.76-0.74(m, 2H).

[0913] Part C: Biological Activity

[0914] The biological and / or pharmacological properties of the compounds of the present invention can be confirmed by various tests. Biological and / or pharmacological tests that can be performed with the compounds according to the present invention and / or pharmaceutically acceptable salts thereof are exemplified below.

[0915] Test-1: USPI / UAF 1 Test:

[0916] The deubiquitin activity of USP1 / UAF1 was monitored in a fluorescence assay using ubiquitin-rhodamine 110 as a substrate. Briefly, the enzymatic reaction was performed in an assay buffer consisting of 50 mM HEPES, pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 1 mM TCEP, 0.1 mg / mL BSA, and 0.01% Tween-20 containing 1 nM USP1 / UAF1. The compounds were tested at desired concentrations. To achieve equilibrium, the plates were incubated for 15 minutes, and then the enzymatic reaction was initiated by dispensing 150 nM Ub-Rho solution. Fluorescence measurements were performed on a high-throughput CCD imager, where kinetic measurements of rhodamine fluorescence were acquired using a 480 nm excitation / 540 nm emission filter set. Changes in fluorescence intensity during a reaction period of 5 minutes (typically corresponding to a substrate conversion rate of less than 10%) were normalized against inhibitor-free and enzyme-free control groups, and the calculated inhibition rate (%) data were fitted to an S-shaped dose-response curve using a 4-parameter Hill equation. The data were analyzed, and the inhibition rate (%) and / or IC50 of each test compound were calculated.

[0917]

[0918] Test 2: Cell viability test (MTT test):

[0919] Cell viability assays were performed using medium supplemented with 10% FBS. Cells were seeded into 96-well plates at the desired density and incubated in a humidified CO2 incubator. After 24 hours from plating, test compounds within the desired concentration range were added to the plates, and the plates were incubated in the CO2 incubator for 72 hours. After 72 hours of treatment, 12.5 μL of MTT was added to all wells, including the DMSO control. After incubating the MTT-treated plates for an additional 3 hours, the MTT crystals were dissolved using 125 μL of DMSO. Absorbance was measured at a wavelength of 570 nm using a BIO-RAD iMark microplate reader. The data were analyzed, and the inhibition rate (IC50) by the test compounds relative to the control was calculated using GraphPad Prism.

[0920] Test-3: Cell Viability Test (MTT Test):

[0921] Cell viability assays were performed using medium supplemented with 10% FBS. Cells were seeded into 96-well plates at the desired density and incubated in a humidified CO2 incubator. After 24 hours from plating, test compounds within the desired concentration range were added to the plates, and the plates were incubated in the CO2 incubator for 168 hours. After 168 hours of treatment, 12.5 μL of MTT was added to all wells, including the DMSO control. After incubating the MTT-treated plates for an additional 3 hours, the MTT crystals were dissolved using 125 μL of DMSO. Absorbance was measured at a wavelength of 570 nm using a BIO-RAD iMark microplate reader. The data were analyzed, and the inhibition rate (IC50) by the test compounds relative to the control was calculated using GraphPad Prism.

[0922]

[0923] Test-4: Cell Viability Test (MTT Test):

[0924] Cell viability assays were performed using medium supplemented with 10% FBS. Cells were seeded into 96-well plates at the desired density and incubated in a humidified CO2 incubator. After 24 hours from plating, test compounds within the desired concentration range were added to the plates, and the plates were incubated in the CO2 incubator for 336 hours. After 168 hours of treatment, 12.5 μL of MTT was added to all wells, including the DMSO control. After incubating the MTT-treated plates for an additional 3 hours, the MTT crystals were dissolved using 125 μL of DMSO. Absorbance was measured at a wavelength of 570 nm using a BIO-RAD iMark microplate reader. The data were analyzed, and the inhibition rate (IC50) by the test compounds relative to the control was calculated using GraphPad Prism.

[0925] Results: Representative compounds of the present invention were found to have an IC50 value of less than 100 nM, some compounds had an IC50 of less than 50 nM, and some compounds had an IC50 of less than 30 nM.

[0926] Test 5: Cell Viability Test (CTG Test):

[0927] Growth inhibition assays were performed using medium supplemented with 10% FBS. Cells were seeded into well plates with a desired number of wells at desired concentrations of 1,000–6,000 cells / well. Test compounds were added at the desired concentration range after 24 hours. Growth was evaluated on day 7 after the addition of test compounds using Cell Titer-Glo (CTG, Cell Signaling), and chemiluminescence values ​​were measured using a plate reader. Data were analyzed, and the inhibition rate (%) and / or IC50 of each test compound were calculated.

[0928]

[0929] Test-6: Colony Formation Test:

[0930] For colony formation assays, cells were seeded at low densities in 12-well or 6-well plates and cultured overnight in a humidified incubator. The medium was replaced with growth medium containing various concentrations of the test compounds. After 48 hours, the medium was replaced with fresh compounds, and incubation was performed for an additional 7–8 days to induce colony formation. Subsequently, cells were fixed with methanol and stained with 0.1% crystal violet. The number of colonies consisting of 50 or more cells was counted. Cells treated with equal volumes of DMSO and saline were used as a control and designated as 100%. Dose-response curves were constructed using GraphPad Prism.

[0931] Test 7: Antitumor effect of the compound of the present invention in female Balb / c nude mice harboring an MDA-MB-436 human breast cancer xenograft model

[0932] Representative compounds of the present invention were tested using the MDA-MB-436 xenograft model, and cells were inoculated into a mouse model exhibiting breast cancer. The test groups consisted of a control group (vehicle administration, V1), a control group (vehicle administration, V2), and four treatment groups: olaparib (O, 50 mg / kg BID), Compound A (15 mg / kg BID), Compound C (30 mg / kg BID), and Compound N (15 mg / kg BID). Maximum tumor growth was 170 mm 3 Administration was initiated when the excess was reached.

[0933] Results: The test compound demonstrated the desired level of tumor growth inhibition (TGI) and was statistically significant (P<0.01^, n=4) (see Figure 1). No significant effect on total body weight was observed during the study period.

[0934] Test 8: Metabolic Stability

[0935] Metabolic stability studies were performed using mouse, rat, and human liver microsomes. The study protocols using mouse and human liver microsomes (Gibco-Thermo) are described below.

[0936] Briefly, 0.25 mg of protein was pre-incubated in phosphate buffer (pH ~7.4) at 37°C for 5 minutes, followed by the addition of 1 μM of the test substance and then 1 mM NADPH (cofactor), and incubated for an additional 60 minutes in two replicates. The reaction was terminated with acetonitrile containing an internal standard, and after centrifugation, the residual test substance in the supernatant was analyzed by LC-MS / MS at various time intervals. The percentage of the residual parent compound was calculated by comparison with the same sample terminated at the 0-minute mark. T 1 / 2 The results of (minutes) are presented in the table below.

[0937]

[0938] The data shown in Table 7 surprisingly demonstrates that the compounds of the present invention exhibit significantly greater metabolic stability in mouse liver microsomes compared to those of the reference compounds, namely Ml323 and Ml52 (compound 52 / 105952 of Table 3 on page 37).

[0939]

[0940] The data shown in Table 8 above surprisingly demonstrates that the compound of the present invention exhibits significantly greater metabolic stability in human liver microsomes compared to the reference compound Ml323.

[0941] The present invention has been described above with the help of functional building blocks that exemplify the implementation of specific functions and their relationships. The boundaries of these functional building blocks are arbitrarily defined in this specification for convenience of explanation. Alternative boundaries may be defined as long as the specified functions and their relationships are properly performed. .

[0942] The foregoing description of specific embodiments will fully reveal the general nature of the invention, and it will fully reveal the general nature of the invention that various applications such as these specific embodiments can be easily modified and / or adapted without excessive experimentation by applying knowledge to a person skilled in the art without departing from the general concept of the invention. Accordingly, such modifications and alterations are intended to be within the meaning and scope of equivalents of the disclosed embodiments based on the teachings and guidelines set forth in this specification. It should be understood that the terminology or technical terms in this specification are for illustrative purposes only, and that the terms or terms in this specification should be interpreted by a person skilled in the art in consideration of the teachings and guidelines.

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