Patent Application
20170273922
The invention relates generally to compounds, their preparation and their use in the treatment of medical conditions that may or may not involve hormones. In certain embodiments, the compounds are useful in the treatment of androgen-dependent diseases or disorders and androgen receptor (AR)-mediated diseases or disorders. In other embodiments, the compounds are useful in the treatment of diseases or disorders that are AR negative.
The growth and survival of androgen-dependent cells such as prostate cancer cells critically depend on the signaling of the AR. The AR comprises three functional domains: the N-terminal domain (NTD), the DNA-binding domain (DBD) and the ligand-binding domain (LBD). Androgens activate the AR by binding at the AR-LBD. Current therapeutic strategy for advanced prostate cancer is to reduce serum level of androgens (via castration) and by disrupting binding of androgens to the AR-LBD by antiandrogens. Thus, treatment focuses on blocking the AR signaling and the battle field is at the AR-LBD (
Various laboratory and clinical studies have revealed that the AR-LBD is not a good ‘battle field’ for inhibiting the AR activation. Firstly, mutations in the AR-LBD could render the LBD-directed antiandrogen useless. In particular, enzalutamide is the second-generation of antiandrogen that was approved by FDA in 2012 to treat CRPC, but many patients have already developed resistance to this drug as the treatment selects for the AR mutant with F876L mutation at the LBD, which is paradoxically activated by enzalutamide. Secondly, an even more alarming problem is the emergence of AR variants lacking the LBD (such as AR-V7) in CRPC patients and such AR variants are constitutively active even in the absence of androgens, resulting in resistance to LBD-directed antiandrogens such as enzalutamide and androgen-depleting agents such as abiraterone. Unfortunately, all of the FDA-approved antiandrogens are directed towards the AR-LBD and are therefore inactive against AR-v7 (
Prostate cancer cells are very versatile in circumventing therapeutic block of activation of the AR. The rationale to develop chemical inhibitors that target the AR-NTD has at least two folds. Firstly, the AR-NTD is the “Achilles' heel” of AR activity.1 All of the known mechanisms that could account for AR reactivation in CRPC cells critically depend on the AR-NTD to reactivate AR. Secondly, among the NTD, DBD and LBD domains, the NTD is the most different domain between the AR and other members of steroid receptors (
As outlined herein above, current mainstay treatment for advanced (metastatic) prostate cancer is to suppress the AR signaling by androgen deprivation therapy (ADT) via castration and use of antiandrogens. Currently available antiandrogens, such as enzalutamide, bicalutamide and nilutamide, are chemical compounds that inhibit the AR transcriptional activation by binding with the hormone-binding pocket of the AR-LBD (
Recent emerging biological observations in prostate cancer have provided the explanation for the failure of the ADT in CRPC and the rationale for developing novel AR inhibitors for the CRPC. The most important pieces of these observations are as follows:5 i) Most CRPC cells are still dependent on the AR signaling for proliferation and survival and the AR therefore remains as the drug target for the CRPC; ii) In CRPC cells, the AR is activated by multiple mechanisms that can no longer be suppressed by castration and currently available antiandrogens; and iii) Accumulated evidence indicates the existence of multiple different malignant clones that could have developed different mechanisms of resistance to castration and antiandrogens in the same CRPC patients.6
The proposed mechanisms that may account for the sustained AR activation in the CRPC cells are as follows: 1) Elevated level of AR, resulting in AR activation at low level of androgen due to mass action; 2) Mutations in AR, rendering the AR promiscuous so that it can be activated by a broad range of non-androgen ligands, even antiandrogens; 3) Conversion of adrenal androgens to testosterone and intratumoral synthesis of androgens in CRPC cells; and 4) Androgen-independent activation of the AR via cross-talk with other factors/pathways.7-9 Recently, a series of AR splice variants lacking the LBD (referred to as AR-Vs) have been discovered from cell lines and patients. Several AR-Vs, such as AR-v7 and ARv567es, have been shown to be constitutively active even in the absence of the androgens, and lack the ability to bind the androgens due to truncation of the AR-LBD.10-12 Thus, expression of constitutively active AR-Vs could be an important mechanism underlying the sustained AR signaling in CRPC and development of resistance to AR-LBD-directed therapies.
In patients, Hu et al. found that AR-v7 showed an average 20-fold higher expression in CRPC when compared with hormone-naïve prostate cancer specimens, and among the hormone-naïve prostate cancer, higher expression of AR-v7 predicted biochemical recurrence following surgical treatment.10 Guo et al. found that AR-v7 (referred to as AR3 in Guo's work) is significantly up-regulated during prostate cancer progression, and AR-v7 expression level is correlated with the risk of tumor recurrence after radical prostatectomy.11 Sun et al. have demonstrated that castration resistance in human prostate cancer is conferred by frequently occurring AR splice variants. Importantly, of 46 metastases derived from 13 patients with CRPC, 20 out of 46 (43%) expressed ARv567es, 11 out of 46 (24%) expressed AR-v7.12 Several specimens contained more than one AR variant, and nearly all of the specimen that contained one or more of the variants also contained full-length AR.12 By a novel immunohistochemical approach, Zhang et al. have investigated the prevalence of AR-Vs in multiple metastatic sites of 42 CRPC patients. The study found that 23 out of 42 patients (55%) had at least one metastatic site with decreased C-terminal AR immunoreactivity and they concluded that C-terminal truncated AR splice variants occur frequently in CRPC metastases.13
Another recent study found that expression of AR-v7 and ARv567es are detected in ⅓ (33%) of all prostate cancer bone metastases in patients and levels of these AR-Vs are increased in CRPC. More importantly, detectable ARv567es and/or AR-v7 mRNA was associated with short patient survival.14 The pioneer work of Dr. Sadar and his team have demonstrated that it is feasible to target the AR-NTD and inhibit AR variant lacking the LBD by a small organic molecule called EPI-001.15 EPI-001 is a derivative of bisphenol A diglycidic ether, which was reported in the work of Biles et al. (1999).16
To date, EPI-001 is the best characterized compound targeting the AR-NTD.15,17 The IC50 of EPI-001 in PSA-luc reporter assay in LNCaP cells was 12.63±4.33 μM.17 On other hand, the F876L mutation at full-length AR is sufficient to confer enzalutamide resistance in cell lines and xenograft model.18 Importantly, the AR F876L mutant is detected in CRPC patients treated with an enzalutamide analogue (ARN-509), suggesting selective outgrowth of AR F876L is a clinically relevant mechanism of enzalutamide resistance.19 A series of mutations in AR-LBD, such as T877A, H874Y, W741C, L701H and V715M were identified from tissue specimens of CRPC patients, and found to produce mutated ARs which can be activated by a series of non-androgen ligands even the antiandrogens.7,20-24
There is a need for compounds that act as antiandrogens. More specifically, there is a need for compounds that target the AR, its mutants and its variants; in particular the N-terminal domain of the AR (AR-NTD).
As indicated above, the compound EPI-001 known in the art targets the AR-NTD.15 The compounds of the invention are structurally different from EPI-001. In embodiments of the invention, the chemical structure of the compounds comprises at least one urea moiety. A few compounds of similar structures are disclosed in U.S. Pat. No. 6,093,742, however, for completely different uses.
In addition to the prostate cancer, recent studies indicated that the AR is an important mediator of other tumors, such as for example the breast cancer, hepatocellular carcinoma and ovarian cancer.
The inventors have designed and prepared novel chemical compounds. The compounds may be used in the treatment of medical conditions that may or may not involve hormones. In certain embodiments, the compounds may be used in the treatment of androgen-dependent diseases or disorders and androgen receptor (AR)-mediated diseases or disorders. In other embodiments, the compounds may be used in the treatment of diseases or disorders that are AR negative.
The disease or disorder may be selected from: prostate cancer including AR positive prostate cancers and AR negative prostate cancers, castration-resistant prostate cancers, breast cancer including AR positive breast cancers and AR negative breast cancers as well as ovarian cancer, hepatocellular carcinoma, endometrial cancer, benign prostatic hyperplasia, endometriosis, male pattern baldness, spinal and bulbar muscular atrophy.
The compounds according to the invention may target the AR and/or its mutants and/or its variants (AR-Vs). In particular, the compounds according to the invention may target the N-terminal domain of the androgen receptor (AR-NTD). More specifically, the compounds may antagonize a series of the clinically-relevant mutants of the full-length ARs, such as for example the F876L mutated AR. Also, the compounds may inhibit the constitutive activity of AR-Vs, such as for example AR-v7, which lacks the LBD. Moreover, the compounds may antagonize the aberrant AR signaling in CRPC cells that express AR-Vs, such as for example AR-v7. The compounds according to the invention may modulate other targets different from the AR.
The invention thus provides for the following according to aspects thereof:
wherein:
U1, U2, U4, U5, U6 and U7 are each independently selected from a heteroatom and NR1R2 wherein R1 and R2 are each independently selected from H, alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, a 5 to 8-member ring comprising one or more heteroatom which are the same or different, or R1 and R2 together form a 5 to 8-member ring comprising one or more heteroatom; optionally, the ring is substituted with a substituent selected from alkyl, cycloalkyl alkoxy, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2 and COOH;
V1, V3 and V4 are each independently selected from a heteroatom and carbon atom;
W1 and W2 are each independently present of absent, and are each independently selected from alkylene, alkenyl, alkynyl, a 5 to 20-member ring or bicycle ring comprising one or more heteroatom which are the same or different; optionally, the ring or bicycle ring is substituted with a group selected from alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2, COOH and NR3R4 wherein R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, or R3 and R4 together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different;
Q1 is selected from alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, a 5 to 20-member ring or bicycle ring optionally comprising one or more heteroatom which are the same or different; optionally, the ring or bicycle ring is substituted with a substituent selected from alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2, COOH, acyloxycarbonyl, NR3R4 and C(═O)NR3R4 wherein R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, or R3 and R4 together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different; optionally, the 5 to 8-member ring is attached to an alkyl, a cycloalkyl, an alkene, an alkynyl, an aryl, aralkylryl or an acyloxycarbonyl; optionally, two consecutive substituents on the 5 to 20-member ring or bicycle ring together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different;
Q2 is as defined above for Q1, or is -Q′2-U3—C(═V2)Q3, wherein: U3 is as defined above for U1, U2, U4, U5, U6 and U7; V2 is as defined above for V1, V3 and V4; and Q′2 and Q3 are each independently as defined above for Q1;
L is selected from alkylene, alkenyl, alkynyl, a 5 to 20-member ring or bicycle ring comprising one or more heteroatom which are the same or different; optionally, the ring or bicycle ring is substituted with a group selected from alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2, COOH and NR3R4 wherein R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, or R3 and R4 together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different;
optionally L together with either U5 or U6 or both U5 and U6 form a 5 to 20-member ring or bicycle ring optionally comprising one or more heteroatom which are the same or different; optionally, the ring or bicycle ring is substituted with a substituent selected from alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2, COOH acyloxycarbonyl, NR3R4 and C(═O)NR3R4 wherein R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkene, alkyne, aryl and alkylaryl, or R3 and R4 together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different; optionally, the 5 to 8-member ring is attached to an alkyl, a cycloalkyl, an alkene, an alkynyl, an aryl, analkylryl or an acyloxycarbonyl; optionally, two consecutive substituents on the 5 to 20-member ring or bicycle ring together form a 5 to 8-member ring optionally comprising one or more heteroatom which are the same or different;
the heteroatom is selected from O, N and S.
wherein:
n is an integer selected from 0 to 5, and each Ri is independently selected from alkyl, cycloalkyl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2 and COOH; optionally, two consecutive Ri together form a 5 to 8-member ring which optionally comprises one or more heteroatom which are the same or different;
m is an integer selected from 0 to 4, and each R′i is independently selected from alkyl, cycloalkyl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2 and COOH; optionally, two consecutive R′i together form a 5 to 8-member ring which optionally comprises one or more heteroatom which are the same or different; and
l is an integer selected from 0 to 5, and each R″i is independently selected from alkyl, cycloalkyl, alkoxy, thioalkoxy, OH, SH, NH2, a halogen atom, a halogeno alkyl, a halogeno alkoxy, a halogeno thioalkoxy, CN, NO2, SO2 and COOH; optionally, two consecutive R″i together form a 5 to 8-member ring which optionally comprises one or more heteroatom which are the same or different.
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Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.
In the appended drawings:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains.
As used herein, the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
Term “alkyl” or “alk” as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon comprising, unless otherwise specified, from 1 to 15 carbon atoms and is exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two, three or, in the case of alkyl groups comprising two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) OC(O)RA, where RA is selected from the group consisting of (a) substituted or unsubstituted C1-6 alkyl, (b) substituted or unsubstituted C6 or C10 aryl, (c) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C1-9 heterocyclyl, and (e) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(O)RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CO2RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(O)NRCRD, where each of RC and RD is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(O)RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(O)2RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(O)2NRFRG, where each of RF and RG is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) —NRHRI, where each of RH and RI is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, (j) alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (l) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.
The term “alkoxy” or “alkyloxy” as used interchangeably herein, represents an alkyl group attached to the parent molecular group through an oxygen atom.
The term “alkylthio” or “thioalkoxy” as used interchangeably herein, represents an alkyl group attached to the parent molecular group through a sulfur atom.
The term “alkylene” as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.
The term “alkenyl” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 15 carbons, such as, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms, containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) OC(O)RA, where RA is selected from the group consisting of (a) substituted or unsubstituted C1-6 alkyl, (b) substituted or unsubstituted C6 or C10 aryl, (c) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C1-9 heterocyclyl, and (e) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(O)RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CO2RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(O)NRCRD, where each of RC and RD is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(O)RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(O)2RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(O)2NRFRG, where each of RF and RG is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) —NRHRI, where each of RH and RI is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms; (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, (j) alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (l) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.
The term “alkynyl” as used herein, represents monovalent straight or branched chain groups of from two to six carbon atoms comprising a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) alkynyl of two to six carbon atoms; (5) amino; (6) aryl; (7) arylalkoxy, where the alkylene group comprises one to six carbon atoms; (8) azido; (9) cycloalkyl of three to eight carbon atoms; (10) halo; (11) heterocyclyl; (12) (heterocycle)oxy; (13) (heterocycle)oyl; (14) hydroxyl; (15) hydroxyalkyl of one to six carbon atoms; (16) N-protected amino; (17) nitro; (18) oxo or thiooxo; (19) perfluoroalkyl of 1 to 4 carbon atoms; (20) perfluoroalkoxyl of 1 to 4 carbon atoms; (21) spiroalkyl of three to eight carbon atoms; (22) thioalkoxy of one to six carbon atoms; (23) thiol; (24) OC(O)RA, where RA is selected from the group consisting of (a) substituted or unsubstituted C1-6 alkyl, (b) substituted or unsubstituted C6 or C10 aryl, (c) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (d) substituted or unsubstituted C1-9 heterocyclyl, and (e) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (25) C(O)RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (26) CO2RB, where RB is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-6 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group comprises one to six carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group comprises one to six carbon atoms; (27) C(O)NRCRD, where each of RC and RD is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (28) S(O)RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (29) S(O)2RE, where RE is selected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl, where the alkylene group comprises one to six carbon atoms, and (d) hydroxyl; (30) S(O)2NRFRG, where each of RF and RG is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; and (31) —NRHRI, where each of RH and RI is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, (j) alkanoyl of one to six carbon atoms, (k) aryloyl of 6 to 10 carbon atoms, (l) alkylsulfonyl of one to six carbon atoms, and (m) arylsulfonyl of 6 to 10 carbons atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.
The term “aryl” as used herein, represents mono- and/or bicyclic carbocyclic ring systems and/or multiple rings fused together and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups are independently comprised of one to six carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group comprises one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group comprises one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group comprises one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms and the alkylene group comprises one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group comprises one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (36) (CH2)qCO2RA, where q is an integer ranging from zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (37) (CH2)qC(O)NRBRC, where RB and RC are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (38) (CH2)qS(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (39) (CH2)qS(O)2NRERF, where each of RE and RF is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (40) (CH2)qNRGRH, where each of RG and RH is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms, and (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.
The term “alkylaryl” as used herein, represents an aryl group attached to the parent molecular group through an alkyl group.
The term “cycloalkyl” as used herein, represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of three to eight carbon atoms, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl and the like. The cycloalkyl groups of the present disclosure can be optionally substituted with: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group comprises one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group comprises one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group comprises one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms and the alkylene group comprises one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group comprises one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups independently comprise from one to six carbon atoms; (36) (CH2)qCO2RA, where q is an integer ranging from zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (37) (CH2)qC(O)NRBRC, where each of RB and RC is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (38) (CH2)qS(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group comprises one to six carbon atoms; (39) (CH2)qS(O)2NRERF, where each of RE and RF is independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group comprises one to six carbon atoms; (40) (CH2)qNRGRH, where each of RG and RH is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group comprises one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) alkcycloalkyl, where the cycloalkyl group comprises three to eight carbon atoms, and the alkylene group comprises one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.
The term “halogen” or “halo” as used interchangeably herein, represents F, Cl, Br and I.
The term “heteroatom”, as used herein, is understood as being oxygen, sulfur or nitrogen.
The term “carbonyl” as used herein, represents a C(O) group, which can also be represented as C═O.
The term “acyl” or “alkanoyl” as used interchangeably herein, represents an alkyl group, as defined herein, or hydrogen attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups comprise from 2 to 10 carbons.
The term “analogue” as used herein, is understood as being a substance similar in structure to another compound but differing in some slight structural detail.
The term “salt(s)” as used herein, is understood as being acidic and/or basic salts formed with inorganic and/or organic acids or bases. Zwitterions (internal or inner salts) are understood as being included within the term “salt(s)” as used herein, as are quaternary ammonium salts such as alkylammonium salts. Nontoxic, pharmaceutically acceptable salts are preferred, although other salts may be useful, as for example in isolation or purification steps. Examples of acid addition salts include but are not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, phosphoric, 2-hydroxyethanesulfonate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Examples of base addition salts include but are not limited to alkali metal salts and alkaline earth metal salts. Non limiting examples of alkali metal salts include lithium, sodium and potassium salts. Non-limiting examples of alkaline earth metal salts include magnesium and calcium salts.
The term “androgen-dependent diseases or disorders” as used herein, refers to diseases or disorders wherein the cells implicated need androgens for survival, proliferation or for maintaining aberrant states.
The “AR-mediated diseases or disorders” as used herein, refers to diseases or disorder that are directly or indirectly driven or maintained by the AR signaling from the wild-type AR, mutants of the full-length AR, the AR variants, or the AR variants that lack certain AR domains or parts of certain AR domains such as the LBD, or a combination of the above ARs.
Two compounds according to the invention, namely, compounds 562 and 746, novel AR-NTD inhibitors are outlined in
We found that when the AR-NTD is fused with the IRF3-DBD domain, the resulted fusion protein IRF3DBD-AR-NTD has potent transcriptional activity, which could be inhibited by the AR-NTD inhibitors (
Six compounds according to the invention, AR-NTD inhibitors are outlined in
Compounds 442, 467 and 492, but not the LBD-targeting bicalutamide, inhibited constitutive activation of AR-v7 (
To evaluate selectivity of our AR-NTD inhibitors, we showed that compounds 467, 442 and 492 at 5 μM were a non-agonist of GR, and were inactive in suppressing GR transactivation induced by 10 nM DEX (
We further demonstrated that compounds 442, 467 and 492 dose-dependently inhibit the wild type and the F876L, W741C, T877A and H874Y mutants of the full-length ARs (
Furthermore, compounds 467 and 442 are active against endogenous AR-Vs (lacking the LBD) in androgen-starved 22Rv1 cells. In contrast, the AR-LBD-directed bicalutamide and enzaluamide are inactive (
Three additional compounds according to the invention, AR-NTD inhibitors (compounds 562, 566 and 746) inhibit AR-v7 at a dose of 2.5 μM (
Furthermore, compounds 562, 566 and 746 present a greater inhibitory activity than EPI-001 against the endogenous AR-Vs in 22Rv1 cells (
Referring to the reaction schemes provided herein below, Scheme 1 outlines the chemical synthesis of compound 746. Another embodiment of the synthesis of this compound is outlined at Scheme 4. Also, Schemes 2.1, 2.2, 2.3, 2.4 and 2.6 outline chemical syntheses of various analogues of the 562 compound.
Scheme 2 outlines the chemical synthesis of compound 562. Another embodiment of the synthesis of this compound is outlined at Scheme 3. Also, Schemes 1.1, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10 and 1.11 outline the chemical synthesis of compound 746 and its analogues.
Scheme 5 outlines the chemical synthesis of compound 566. Also, Schemes 4.1 and 4.2 outline chemical syntheses of various analogues of the 566 compound.
Scheme 1.2 outlines the chemical synthesis of compound 789. Scheme 3.1 outlines the chemical synthesis of compound 804. Scheme 2.5 outlines the chemical synthesis of compound 454. And Scheme 5.1 outlines the chemical synthesis of the bis-urea compounds according to the invention.
More detail information on the various chemical syntheses of the compounds according to the invention is provided herein below.
Preparation of Compound 736:
Referring to Scheme 1.1 reproduced above, to a solution of compound 442 (1 mmol) in EtOH (10 mL), iron powder (1.4 g, 25 mmol) was added at reflux. Then 1 mL NH4Cl solution (0.16 N) was added. The reaction mixture was refluxed for 1 h. The solid was filtered while hot, the filtrate was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc=4:1) to give compound 736 (0.326 g, 89.8%) as white solid.
General Procedure for the Synthesis of the 746 Analogues Following Route (a)—Scheme 1.1:
To a solution of 736 (0.18 g, 0.5 mmol) and triethylamine (0.1 mL, 1 mmol) in dry THF (10 mL), substituted benzoyl chloride was added dropwise. The reaction mixture was stirred at room temperature overnight. Then water was added to the mixture which was extracted with dichloromethane. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by column chromatography.
General Procedure for the Synthesis of the 746 Analogues Following Route (b)—Scheme 1.1:
746 was prepared from 736 by following route (a): White solid, yield: 28.7%. 1H NMR (500 MHz, acetone-d6) δ 9.01 (d, J=11.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 2H), 8.15 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 8.04-7.99 (m, 2H), 7.78-7.70 (m, 2H), 7.70-7.63 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.44-7.31 (m, 3H). MS (ESI) calculated for C22H15F7N3O2[M+H] 486.1047. Found 486.1056.
743 was prepared from 736 by following route (a): White solid, yield: 36.7%. 1H NMR (500 MHz, acetone-d6) δ 9.13 (br, 1H), 8.60-8.57 (m, 2H), 8.16-8.04 (m, 4H), 7.78-7.65 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 7.39-7.26 (m, 3H). MS (ESI) calculated for C22H15F7N3O2 [M+H] 486.1047. Found 486.1058.
806 was prepared from 736 by following route (b). White solid, yield: 33.5%. 1H NMR (500 MHz, acetone-d6) δ 9.35 (br, 1H), 8.38 (br, 1H), 8.16 (br, 1H), 8.09 (s, 1H), 7.85-7.81 (m, 1H), 7.79-7.71 (m, 2H), 7.70-7.65 (m, 1H), 7.62-7.52 (m, 3H), 7.51-7.46 (m, 1H), 7.37-7.23 (m, 3H). MS (ESI) calculated for C21H15F4N3O2[M+H] 417.1100. Found 417.1178.
808 was prepared from 736 by following route (b). White solid, yield: 22.5%. 1H NMR (500 MHz, acetone-d6) δ 9.67 (br, 1H), 8.58 (d, J=3.9 Hz, 1H), 8.12-8.05 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.82-7.75 (m, 4H), 7.71 (d, J=8.0 Hz, 1H), 7.65-7.60 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.35 (d, J=7.8 Hz, 1H). MS (ESI) calculated for C22H15F4N4O2[M+H] 443.1125. Found 443.1135.
814 was prepared from 736 by following route (b). White solid, yield: 36.7%. 1H NMR (500 MHz, acetone-d6) δ 9.67 (br, 1H), 8.99-8.99 (m, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.10-8.05 (m, 2H), 8.01-7.98 (m, 1H), 7.86 (td, J=7.6, 1.8 Hz, 1H), 7.74-7.65 (m, 2H), 7.65-7.58 (m, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.41-7.26 (m, 3H). MS (ESI) calculated for C22H15F7N3O2[M+H] 486.1047. Found 486.1056.
815 was prepared from 736 by following route (a): White solid, yield: 23.4%. 1H NMR (500 MHz, acetone-d6) δ 9.20 (br, 1H), 8.60 (br, 1H), 8.58 (br, 1H), 8.14 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.87-7.83 (m, 1H), 7.79-7.71 (m, 3H), 7.70-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.35 (d, J=7.8 Hz, 1H). MS (ESI) calculated for C22H15F7N3O2[M+H] 486.1047. Found 486.1057.
820 was prepared from 736 by following route (b). White solid, yield: 42.5%. 1H NMR (500 MHz, acetone-d6) δ 9.09 (br, 1H), 8.60 (br, 1H), 8.56 (br, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.84-7.74 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.58-7.43 (m, 4H), 7.35 (d, J=7.7 Hz, 1H). MS (ESI) calculated for C22H15ClF6N3O2 [M+H] 502.0751. Found 502.0761.
813 was prepared from 736 by following route (b). White solid, yield: 38.5%. 1H NMR (500 MHz, acetone-d6) δ 1H NMR (500 MHz, acetone-d6) δ 8.52 (br, 1H), 8.03 (br, 1H), 7.71-7.66 (m, 3H), 7.54-7.50 (m, 2H), 7.36-7.24 (m, 4H), 7.20-7.15 (m, 1H), 7.16-7.09 (m, 2H). MS (ESI) calculated for C21H15F4N3O2[M+H] 436.1078. Found 436.1082.
789 White solid, yield: 34.7%. 1H NMR (500 MHz, CDCl3) δ 8.09 (br, 1H), 7.89 (br, 1H), 7.68 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.23-7.21 (m, 1H), 3.87-3.35 (m, 8H). MS (ESI) calculated for C21H15F4N3O2[M+H] 462.1246. Found 462.1259.
822 White solid, yield: 67.5%.1H NMR (800 MHz, acetone-d6) δ 9.84 (br, 1H), 9.33 (br, 1H), 8.74-8.72 (m, 1H), 8.63-8.60 (m, 1H), 8.28 (br, 1H), 8.25-8.22 (m, 1H), 8.09 (d, J=21.0 Hz, 2H), 7.83 (d, J=8.1 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.26-7.17 (m, 2H). MS (ESI) calculated for C21H15F4N3O2[M+H]486.1047. Found 486.1057.
824: White solid. Yield: 47.3%. 1H NMR (500 MHz, Acetone-de) δ 8.67 (br, 1H), 8.60 (br, 1H), 8.11-8.04 (m, 2H), 7.80-7.78 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 3.74-3.63 (m, 4H), 3.63-3.49 (m, 2H), 3.31-3.14 (m, 2H).
825: White solid. Yield: 88.2%. 1H NMR (500 MHz, Acetone-d6) δ 10.32 (s, 2H), 8.53 (d, J=13.2 Hz, 2H), 8.41 (d, J=8.9 Hz, 1H), 8.24-8.22 (m, 1H), 8.15 (d, J=2.5 Hz, 1H), 8.08 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.69-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.19-7.14 (m, 1H), 4.13 (s, 3H).
847: White solid. Yield: 45.8%. 1H NMR (500 MHz, Acetone-d6) δ 8.54 (br, 1H), 8.38 (br, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.68-7.66 (m, 1H), 7.58-7.49 (m, 4H), 7.32 (d, J=7.7 Hz, 1H), 3.74-3.67 (m, 4H), 3.55-3.54 (m, 4H).
850: white solid. Yield: 48.3%. 1H NMR (500 MHz, Acetone-d6) δ 8.50 (br, 1H), 8.45 (br, 1H), 8.06 (s, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.7, 2.5 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.56-7.49 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 3.78-3.68 (m, 4H), 2.92-2.82 (m, 4H).
863: White solid. Yield: 87.6%. 1H NMR (500 MHz, Acetone-d6) δ 9.02 (d, J=10.9 Hz, 1H), 8.56 (br, 1H), 8.49 (br, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.09-7.93 (m, 2H), 7.73 (dd, J=8.8, 2.4 Hz, 1H), 7.71-7.62 (m, 1H), 7.60-7.57 (m, 1H), 7.41-7.38 (m, 1H), 7.37-7.27 (m, 2H), 7.24-7.17 (m, 1H), 6.81-6.72 (m, 1H).
864: White solid. Yield: 83.5%. 1H NMR (500 MHz, Acetone-d6) δ 9.02 (d, J=10.9 Hz, 1H), 8.60 (br, 1H), 8.48 (br, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.09-7.94 (m, 2H), 7.80 (t, J=2.0 Hz, 1H), 7.73 (dd, J=8.8, 2.4 Hz, 1H), 7.69-7.62 (m, 1H), 7.43-7.26 (m, 4H), 7.04-7.02 (m, 1H).
886: White solid. Yield: 91.2%. 1H NMR (500 MHz, Acetone-d6) δ 9.03 (d, J=11.0 Hz, 1H), 8.62 (br, 1H), 8.60 (br, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.06-7.96 (m, 2H), 7.75 (dd, J=8.8, 2.4 Hz, 1H), 7.71-7.62 (m, 1H), 7.51 (s, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.43-7.37 (m, 1H), 7.37-7.30 (m, 1H), 6.87 (s, 1H), 3.88 (s, 3H).
The 789 compound was prepared as follows:
The 746 analogues of Formula (II) were prepared as follows:
Compound 847 was prepared as follows:
Compound 850 was prepared as follows:
Preparation of Compound 789:
Referring to Schemes 1.2 and 1.3 above: (i) to a suspension of 1b (0.235 g, 1 mmol) in 10 mL of dichloromethane, thionyl chloride (0.15 mL, 2 mmol) and DMF (2 drops) were added dropwise. The mixture was refluxed for 2 h. Excess thionyl chloride was distilled under reduced pressure to give crude chloride, which was dissolved in dry THF (10 mL), morpholone and triethylamine were added. The reaction mixture was refluxed for 3 h. After cooling to room temperature, water was added to the mixture and extracted with dichloromethane. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by column chromatography to give amide 4b. (ii) Synthesis of 5b: This was performed according to the procedure for the preparation of compound 736 outlined above. (iii) A mixture of aryl isocyanate 3a (1 mmol) and 5b (1 mmol) in toluene was heated at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene. Colorless syrup, yield: 56.5%.
Preparation of Compound 847:
Referring to Scheme 1.4 above: To a solution of triphosgene (0.296 g, 1 mmol) in CH2Cl2 (5 mL) at rt under N2 was added 736 (0.36 g, 1 mmol). The reaction mixture was stirred for 30 min at rt. Then Et3N (2 equiv) in CH2Cl2 (1 mL) was added. The mixture was stirred for 30 min. To this mixture was then added morpholine (1 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred for 30 min. Water was added to quench the reaction and extracted with dichloromethane. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by column chromatography to give 847.
Preparation of Compound 850:
Referring to Scheme 1.5 above: A mixture of 3a (0.5 mmol) and amine 4c (0.5 mmol) in toluene (10 mL) was heated at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene to afford 850 as white solid.
The chemical structures of compounds 743, 746, 747, 789, 806, 808, 814, 815, 816, 820, 822, 824, 825, 847, 850, 863, 864 and 886 prepared as described above are depicted in the following Table 1.1.
Compound 849 was prepared as follows:
General Procedure for the synthesis of compound 849: referring to the Scheme 1.6 above, morpholine (6.0 mmol) was added to a solution of compound 1 (3.0 mmol) in 20.0 mL DMSO. The mixture was stirred at 100° C. for 4 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 2, which were purified through flash chromatography on silica gel (Hexane/EtOAc 10:1 to 4:1 as the eluent). Compound 2 (2.0 mmol) was dissolved in EtOH (10.0 mL), Fe powder (200 mg) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1 to 1:1 as the eluent) to afford compound 3. To a solution of triphosgene (2.0 mmol) in dry DCM (4.0 mL), amine 4 (2.0 mmol) in DCM (8.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.6 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 3 (2.0 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by recrystallization (solvent: DCM) to afford compound 5. Compound 5 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (100 mg) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 6. Compound 6 (0.1 mmol) was dissolved in dry THF (5.0 mL). Triethylamine (0.2 mmol) was added followed by acyl chloride 7 (0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Then the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 5:1 to 1:1 as the eluent) to afford compound 849.
Compounds 861 and 862 were prepared as follows:
General Procedure for synthesis of compounds 861 and 862: referring to Scheme 1.7 above, a suspension of compound 1 (5.0 mmol), KF (6.0 mmol) and phthalic anhydride (4.0 mmol) in 8.0 mL DMSO. The mixture was stirred at 150° C. for 4 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 2, which were purified through flash chromatography on silica gel (Hexane/EtOAc 50:1 to 15:1 as the eluent). Marpholine (6.0 mmol) was added to a solution of compound 2 (3.0 mmol) in 20.0 mL DMSO. The mixture was stirred at 100° C. for 4 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 3, which were purified through flash chromatography on silica gel (Hexane/EtOAc 10:1 to 4:1 as the eluent). Compound 3 (2.0 mmol) was dissolved in EtOH (10.0 mL), Fe powder (200 mg) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1 to 1:1 as the eluent) to afford compound 4. To a solution of triphosgene (2.0 mmol) in dry DCM (4.0 mL), amine 5 (2.0 mmol) in DCM (8.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.6 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 4 (2.0 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 6. Compound 6 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (100 mg) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 7. Compound 7 (0.1 mmol) was dissolved in dry THF (5.0 mL). Triethylamine (0.2 mmol) was added followed by acyl chloride 8 (0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Then the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 5:1 to 1:1 as the eluent) to afford compound 861 or 862.
Characterization of Additional Analogues of 746.
Additional 746 analogues were synthesized according to Schemes 1.1-1.7 above. These compounds were verified by NMR and MS analysis, as outlined below. The structures of these 746 analogues are shown in Table 1.2 below.
849 White solid, 82.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.01 (d, J=10.9 Hz, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 8.07-7.97 (m, 2H), 7.96 (s, 1H), 7.75 (t, J=9.1 Hz, 2H), 7.66 (d, J=7.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.34 (dd, J=11.6, 8.1 Hz, 1H), 3.74 (t, J=4.5 Hz, 4H), 2.87 (t, J=4.5 Hz, 4H). TOF MS (ESI), m/z: 571.16 [M+H]+.
861 White solid, 76.5% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.01 (d, J=11.0 Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.14 (d, J=2.3 Hz, 1H), 8.10-7.95 (m, 2H), 7.73 (dd, J=8.8, 2.3 Hz, 1H), 7.70-7.62 (m, 1H), 7.41 (dd, J=12.5, 4.8 Hz, 2H), 7.38-7.28 (m, 2H), 6.90 (s, 1H), 3.80 (t, J=5.0 Hz, 4H), 3.22 (t, J=5.0 Hz, 4H). TOF MS (ESI), m/z: 571.16 [M+H]+.
862 White solid, 72.4% in yield. 1H NMR (500 MHz, acetone-d) δ 9.01 (d, J=11.0 Hz, 1H), 8.61 (d, J=4.4 Hz, 1H), 8.48 (d, J=4.2 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 8.07-7.96 (m, 2H), 7.74 (dd, J=8.8, 2.3 Hz, 1H), 7.70-7.62 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.30 (m, 2H), 6.88 (s, 1H), 3.26 (t, J=5.0 Hz., 4H), 2.86 (s, 3H), 2.52 (t, J=5.0 Hz., 4H). TOF MS (ESI), m/z: 584.19 [M+H]+.
878 White solid, 87.0% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.03 (d, J=11.0 Hz, 1H), 8.77 (s, 1H), 8.66 (s, 1H), 8.12 (s, 1H), 8.02 (t, J=7.8 Hz, 2H), 7.79-7.70 (m, 3H), 7.70-7.62 (m, 1H), 7.40 (td, J=7.7, 1.0 Hz, 1H), 7.34 (dd, J=11.8, 8.4 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H).
879 White solid, 87.0% in yield. 1H NMR (500 MHz, acetone-d6) δ 10.98 (s, 1H), 8.60 (s, 2H), 8.15-8.10 (m, 2H), 8.08 (s, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.73 (t, J=9.2 Hz, 2H), 7.53 (t, J=8.0 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.25-7.17 (m, 1H), 7.11-7.03 (m, 1H), 3.80-3.74 (m, 4H), 3.15-3.10 (m, 4H).
890 White solid, 93.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.08 (s, 1H), 8.59 (s, 2H), 8.12 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=4.9 Hz, 1H), 7.73 (t, J=9.9 Hz, 2H), 7.67 (t, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.22 (s, 1H).
893 White solid, 52.6% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.58 (s, 1H), 8.74 (s, 1H), 8.64 (s, 1H), 8.12-8.04 (m, 2H), 7.87-7.77 (m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.26-7.16 (m, 1H), 7.16-7.09 (m, 1H), 6.92-6.71 (m, 1H).
894 White solid, 84.9% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.10 (s, 1H), 8.60 (d, J=15.5 Hz, 2H), 8.14 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.63-7.48 (m, 2H), 7.44-7.31 (m, 2H). HRMS (ESI) calcd for C22H13F8N3O2[M+H]+ 504.0953. Found 504.0952.
896 White solid (hard to dissolve in acetone-d6), 79.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.01 (d, J=12.1 Hz, 1H), 8.78 (s, 1H), 8.49 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.07-7.97 (m, 2H), 7.77 (d, J=13.1 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.69-7.62 (m, 2H), 7.46-7.36 (m, 2H), 7.34 (t, J=8.1 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H). HRMS (ESI) calcd for C22H14F7N3O2[M+H]+ 486.1047. Found 486.1046.
897 White solid, 92.7% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.02 (d, J=10.8 Hz, 1H), 8.61 (d, J=17.1 Hz, 2H), 8.15 (d, J=2.3 Hz, 1H), 8.02 (dd, J=14.2, 8.5 Hz, 2H), 7.83-7.71 (m, 3H), 7.70-7.59 (m, 3H), 7.45-7.37 (m, 1H), 7.37-7.29 (m, 1H). HRMS (ESI) calcd for C22H14F7N3O2[M+H]+ 486.1047. Found 486.1063.
898 White solid, 67.4% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.66 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.07 (t, J=2.9 Hz, 2H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.64 (dd, J=8.9, 2.5 Hz, 1H), 7.59-7.48 (m, 4H), 7.34 (d, J=7.7 Hz, 1H), 7.06 (t, J=8.9 Hz, 2H).
900 White solid, 89.0% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.36 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.80-7.70 (m, 3H), 7.59-7.51 (m, 2H), 7.35 (d, J=7.7 Hz, 1H), 7.16-7.10 (m, 2H). HRMS (ESI) calcd for C22H13F8N3O2[M+H]+ 504.0953. Found 504.0965.
901 White solid, 91.3% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.09 (d, J=10.2 Hz, 1H), 8.60 (d, J=13.9 Hz, 2H), 8.15 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.76 (dd, J=8.9, 2.2 Hz, 1H), 7.74-7.65 (m, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.49-7.37 (m, 2H), 7.35 (d, J=7.8 Hz, 1H). HRMS (ESI) calcd for C22H13F8N3O2[M+H]+ 504.0953. Found 504.0967.
902 White solid, 85.3% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.99 (d, J=10.8 Hz, 1H), 8.58 (d, J=10.3 Hz, 2H), 8.14 (d, J=2.3 Hz, 1H), 8.12-8.03 (m, 2H), 7.95 (d, J=8.9 Hz, 1H), 7.78-7.68 (m, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.28-7.19 (m, 2H). HRMS (ESI) calcd for C22H13F8N3O2[M+H]+ 504.0953. Found 504.0969.
903 White solid, 90.0% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.21 (d, J=8.6 Hz, 1H), 8.60 (d, J=16.9 Hz, 2H), 8.27 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=9.3 Hz, 1H), 7.78 (dd, J=8.6, 2.3 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.65-7.56 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H).
904 White solid, 57.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.72 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.14-8.02 (m, 2H), 7.84 (dd, J=8.1, 2.0 Hz, 1H), 7.78 (d, J=11.6 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.39 (dd, J=15.0, 8.3 Hz, 2H), 6.90 (td, J=8.7, 2.6 Hz, 1H).
905 White solid, 48.7% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.83 (s, 1H), 8.51 (d, J=23.6 Hz, 2H), 8.07 (d, J=2.5 Hz, 2H), 7.92 (t, J=8.2 Hz, 1H), 7.74-7.55 (m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.32-7.24 (m, 1H), 7.16 (dd, J=8.2, 1.2 Hz, 1H), 6.75 (td, J=8.4, 2.6 Hz, 1H). HRMS (ESI) calcd for C22H15F7N4O2[M+H] 501.1156. Found 501.1167.
906 White solid, 76.8% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.84 (s, 1H), 8.57 (s, 2H), 8.13 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.76-7.68 (m, 2H), 7.53 (t, J=8.0 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.25 (dt, J=3.5, 0.8 Hz, 1H), 6.74-6.66 (m, 1H). HRMS (ESI) calcd for C20H13F6N3O3[M+H]+ 458.0934. Found 458.0950.
907 White solid, 94.2% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.10 (d, J=9.1 Hz, 1H), 8.61 (d, J=15.1 Hz, 2H), 8.15 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.98-7.90 (m, 2H), 7.76 (dd, J=8.8, 2.4 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.69-7.64 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.40 (dd, J=10.7, 8.9 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H). HRMS (ESI) calcd for C22H13ClF7N3O2 [M+H]+ 520.0657. Found 520.0668.
911 White solid, 69.6% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.18 (d, J=8.4 Hz, 1H), 8.61 (d, J=14.6 Hz, 2H), 8.49 (t, J=8.6 Hz, 1H), 8.47-8.33 (m, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.78 (dd, J=8.8, 2.5 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.61-7.50 (m, 2H), 7.38-7.33 (m, 1H).
912 White solid, 92.2% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.18 (d, J=8.4 Hz, 1H), 8.61 (d, J=14.6 Hz, 2H), 8.49 (t, J=8.6 Hz, 1H), 8.47-8.33 (m, 2H), 8.14 (d, J=2.5 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.78 (dd, J=8.8, 2.5 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.61-7.50 (m, 2H), 7.38-7.33 (m, 1H).
921 White solid, 76.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.25 (d, J=7.3 Hz, 1H), 8.75-8.61 (m, 2H), 8.59 (d, J=4.9 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.89-7.81 (m, 3H), 7.79 (d, J=9.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H).
922 White solid, 39.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.10-8.04 (m, 1H), 8.00 (d, J=15.5 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.73-7.62 (m, 2H), 7.50 (dt, J=12.5, 8.0 Hz, 2H), 7.40 (dd, J=8.5, 2.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.31-7.27 (m, 1H), 7.19-7.11 (m, 1H), 6.88 (d, J=8.8 Hz, 1H).
930 White solid, 90.4% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.08 (d, J=10.3 Hz, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.90 (s, 1H), 7.74 (dd, J=8.8, 2.4 Hz, 1H), 7.72-7.66 (m, 1H), 7.65-7.60 (m, 1H), 7.48-7.36 (m, 3H), 7.23 (d, J=7.7 Hz, 1H), 6.88 (t, J=56.2 Hz, 1H).
941 White solid, 91.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.20 (d, J=7.7 Hz, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.27 (d, J=4.0 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.05-7.98 (m, 1H), 7.90 (s, 2H), 7.76 (dd, J=8.8, 2.3 Hz, 1H), 7.66-7.56 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.89 (t, J=56.2 Hz, 1H).
945 White solid, 83.9% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.99 (d, J=9.9 Hz, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.15 (d, J=2.5 Hz, 1H), 8.12-8.02 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=8.8, 2.4 Hz, 1H), 7.67-7.59 (m, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.30-7.18 (m, 3H), 6.88 (t, J=56.2 Hz, 1H).
952 White solid, 78.9% in yield. 1H NMR (500 MHz, acetone) δ 9.09 (d, J=8.6 Hz, 1H), 8.63 (d, J=14.2 Hz, 2H), 8.29-8.22 (m, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 7.34 (dd, J=7.7, 0.8 Hz, 1H), 7.19 (dd, J=11.0, 8.7 Hz, 1H), 7.13 (dd, J=10.6, 8.7 Hz, 1H).
971 White solid, 92.5% in yield. 1H NMR (500 MHz, acetone) δ 9.43 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.78 (s, 2H), 7.74 (d, J=8.2 Hz, 1H), 7.58-7.49 (m, 2H), 7.41-7.34 (m, 2H), 7.27 (t, J=8.6 Hz, 1H).
983 White solid, 72.1% in yield. 1H NMR (500 MHz, acetone) δ 9.11-9.01 (m, 2H), 8.82 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H), 8.04 (t, J=7.4 Hz, 2H), 7.79 (d, J=8.5 Hz, 1H), 7.72 (d, J=5.5 Hz, 1H), 7.70-7.65 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.36 (dd, J=11.7, 8.4 Hz, 1H).
Synthesis of 746 Analogues with Side Chain at Meta Position
746 analogues with side chain at meta position were prepared acceding to the followings Schemes 1.8 and 1.9:
Characterization of 746 Analogues with Side Chain at Meta Position.
746 analogues with side chain at meta position were synthesized according to Schemes 1.8 and 1.9 above. These compounds were verified by NMR analysis as outlined below. The structures of these 746 analogues are shown in Table 1.3 below.
908 White solid, 94.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.17 (d, J=9.5 Hz, 1H), 8.41 (d, J=37.0 Hz, 3H), 8.10 (s, 1H), 8.03-7.94 (m, 1H), 7.75-7.60 (m, 2H), 7.57-7.46 (m, 2H), 7.42-7.35 (m, 1H), 7.35-7.28 (m, 2H), 7.18 (dd, J=10.6, 9.0 Hz, 1H).
909 White solid, 87.5% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.55 (s, 1H), 8.82 (s, 1H), 8.56 (dd, J=7.3, 2.6 Hz, 1H), 8.18-8.13 (m, 2H), 7.84 (td, J=7.5, 1.8 Hz, 1H), 7.76-7.69 (m, 1H), 7.63 (dd, J=8.1, 2.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.38-7.31 (m, 2H), 7.27 (ddd, J=10.8, 8.3, 1.0 Hz, 1H), 7.17 (dd, J=11.0, 8.9 Hz, 1H).
910 White solid, 89.0% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.45 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.83 (td, J=7.5, 1.8 Hz, 1H), 7.67 (dd, J=8.2, 2.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.53-7.47 (m, 2H), 7.38-7.23 (m, 5H).
913 White solid, 90.9% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.71 (s, 1H), 8.47 (s, 1H), 8.43-8.33 (m, 2H), 8.09 (s, 1H), 7.71 (dd, J=8.1, 1.8 Hz, 1H), 7.64-7.53 (m, 2H), 7.51 (t, J=8.0 Hz, 1H), 7.37-7.27 (m, 1H), 7.23-7.08 (m, 3H).
914 White solid, 86.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.65 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 8.12-8.06 (m, 1H), 7.88 (ddd, J=7.7, 1.6, 0.9 Hz, 1H), 7.78 (ddd, J=9.7, 2.5, 1.5 Hz, 1H), 7.66 (dd, J=8.2, 1.9 Hz, 1H), 7.62-7.54 (m, 2H), 7.51 (t, J=7.9 Hz, 1H), 7.41-7.29 (m, 2H), 7.29-7.26 (m, 2H).
915 White solid, 84.7% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.62 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 8.13-8.05 (m, 3H), 7.65 (d, J=6.3 Hz, 1H), 7.60-7.53 (m, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.38-7.21 (m, 5H).
928 White solid, 35.3% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.75 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.85 (td, J=7.5, 1.8 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.65-7.58 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.29 (ddd, J=10.9, 8.3, 1.0 Hz, 1H).
929 White solid, 92.4% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.27 (d, J=5.5 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 2H), 8.10 (s, 1H), 7.92 (dd, J=6.3, 2.7 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.65 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.57-7.49 (m, 2H), 7.38 (dd, J=10.5, 8.9 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.18 (dd, J=10.6, 9.0 Hz, 1H).
942 White solid, 92.2% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.25 (s, 1H), 8.52 (s, 1H), 8.48-8.35 (m, 2H), 8.10 (s, 1H), 7.74-7.64 (m, 2H), 7.58-7.47 (m, 2H), 7.46-7.35 (m, 2H), 7.32 (d, J=7.7 Hz, 1H), 7.18 (dd, J=10.6, 9.0 Hz, 1H).
944 White solid, 89.5% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.40 (s, 1H), 8.49 (s, 1H), 8.45-8.37 (m, 2H), 8.25 (dd, J=6.3, 2.2 Hz, 1H), 8.10 (s, 1H), 8.04-7.96 (m, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.57 (dd, J=16.7, 7.2 Hz, 1H), 7.55-7.47 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.19 (dd, J=10.6, 9.0 Hz, 1H).
946 White solid, 94.1% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.32 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.18 (d, J=6.2 Hz, 1H), 8.09 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.77 (d, J=9.4 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.64-7.55 (m, 1H), 7.55-7.45 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.0 Hz, 1H), 7.16 (t, J=9.7 Hz, 1H).
947 White solid, 89.7% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.26 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.19 (dd, J=6.9, 2.7 Hz, 1H), 8.15-8.06 (m, 3H), 7.68 (d, J=8.2 Hz, 1H), 7.55-7.43 (m, 2H), 7.34-7.25 (m, 3H), 7.15 (dd, J=10.4, 9.0 Hz, 1H).
948 White solid, 92.6% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.29 (s, 1H), 8.48 (s, 1H), 8.43-8.34 (m, 2H), 8.09 (s, 1H), 7.70 (d, J=7.9 Hz, 2H), 7.58-7.48 (m, 3H), 7.41-7.34 (m, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.18 (dd, J=10.5, 9.0 Hz, 1H).
949 White solid, 81.4% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H).
950 White solid, 38.8% in yield. 1H NMR (500 MHz, acetone-d6) δ 8.51 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.35 (dd, J=7.3, 2.8 Hz, 1H), 8.33-8.28 (m, 2H), 8.09 (s, 1H), 7.70 (dd, J=8.2, 2.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (ddd, J=8.9, 4.4, 2.7 Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.13 (m, 2H), 7.09 (dd, J=11.1, 8.9 Hz, 1H), 7.05-6.99 (m, 1H).
951 White solid, 83.2% in yield. 1H NMR (500 MHz, acetone-d6) δ 9.27 (s, 1H), 8.46 (s, 1H), 8.39 (s, 2H), 8.23 (dd, J=6.9, 2.2 Hz, 1H), 8.09 (s, 1H), 8.01-7.92 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.59-7.46 (m, 2H), 7.32 (d, J=7.7 Hz, 1H), 7.18 (dd, J=10.7, 8.9 Hz, 2H).
953 White solid, 87.2% in yield. 1H NMR (500 MHz, acetone) δ 8.63 (s, 2H), 8.58 (s, 2H), 8.09 (s, 2H), 7.99 (t, J=1.8 Hz, 1H), 7.69 (dd, J=8.2, 2.0 Hz, 2H), 7.64 (d, J=1.7 Hz, 2H), 7.52 (t, J=8.0 Hz, 2H), 7.34 (d, J=7.7 Hz, 2H).
954 White solid, 74.7% in yield. 1H NMR (500 MHz, acetone) δ 9.42 (s, 1H), 8.64 (s, 2H), 8.54 (s, 1H), 8.42 (s, 2H), 8.25 (d, J=6.3 Hz, 1H), 8.04-7.95 (m, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.19 (dd, J=10.5, 9.1 Hz, 1H).
955 White solid, 83.7% in yield. 1H NMR (500 MHz, acetone) δ 8.61 (s, 4H), 8.01-7.96 (m, 1H), 7.77 (d, J=8.5 Hz, 4H), 7.68-7.59 (m, 6H).
956 White solid, 89.2% in yield. 1H NMR (500 MHz, acetone) δ 9.17 (d, J=7.0 Hz, 1H), 8.53 (s, 1H), 8.45-8.38 (m, 2H), 8.09-8.01 (m, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.56-7.48 (m, 1H), 7.27-7.12 (m, 3H).
957 White solid, 92.0% in yield. 1H NMR (500 MHz, acetone) δ 9.57 (s, 1H), 8.86 (s, 1H), 8.53 (dd, J=7.3, 2.6 Hz, 1H), 8.15 (s, 2H), 7.98-7.88 (m, 1H), 7.76-7.66 (m, 1H), 7.63 (d, J=10.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.38-7.30 (m, 1H), 7.22-7.09 (m, 3H).
958 White solid, 82.2% in yield. 1H NMR (500 MHz, acetone) δ 9.77 (s, 1H), 8.87 (s, 1H), 8.54 (dd, J=7.3, 2.6 Hz, 1H), 8.24-8.17 (m, 1H), 8.15 (s, 1H), 8.02-7.88 (m, 2H), 7.73 (ddd, J=8.9, 4.4, 2.6 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58-7.46 (m, 2H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (dd, J=11.0, 8.9 Hz, 1H).
959 White solid, 87.8% in yield. 1H NMR (500 MHz, acetone) δ 9.42 (d, J=4.7 Hz, 1H), 8.95 (s, 1H), 8.43 (dd, J=6.7, 2.2 Hz, 1H), 8.26 (d, J=6.2 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.07-7.99 (m, 1H), 7.73-7.63 (m, 3H), 7.62-7.54 (m, 2H), 7.29 (t, J=8.1 Hz, 1H), 7.20 (dd, J=10.5, 9.1 Hz, 1H).
960 White solid, 90.1% in yield. 1H NMR (500 MHz, acetone) δ 9.18 (d, J=7.3 Hz, 1H), 8.93 (s, 1H), 8.43 (dd, J=6.8, 2.4 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.11-8.02 (m, 1H), 7.71-7.63 (m, 3H), 7.60-7.53 (m, 1H), 7.33-7.16 (m, 4H).
963 White solid, 81.2% in yield. 1H NMR (500 MHz, acetone) δ 9.41 (d, J=4.6 Hz, 1H), 8.40 (d, J=4.5 Hz, 1H), 8.34 (s, 1H), 8.28 (t, J=11.3 Hz, 2H), 8.06-7.98 (m, 1H), 7.59 (t, J=9.6 Hz, 1H), 7.57-7.51 (m, 3H), 7.48-7.41 (m, 2H), 7.19 (dd, J=10.2, 9.3 Hz, 1H).
964 White solid, 74.6% in yield. 1H NMR (500 MHz, acetone) δ 8.53 (s, 2H), 8.44 (s, 2H), 7.95 (s, 1H), 7.64 (s, 2H), 7.60 (dt, J=11.9, 2.2 Hz, 2H), 7.32 (dd, J=14.9, 8.2 Hz, 2H), 7.20 (dd, J=8.1, 1.4 Hz, 2H), 6.78 (td, J=8.4, 2.4 Hz, 2H).
966 White solid, 87.3% in yield. 1H NMR (500 MHz, acetone) δ 8.45 (s, 2H), 8.29 (s, 2H), 8.12 (s, 2H), 7.86 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.52 (t, J=8.0 Hz, 2H), 7.33 (d, J=7.7 Hz, 2H), 7.24-7.20 (m, 3H).
970 White solid, 85.7% in yield. 1H NMR (500 MHz, acetone) δ 9.80 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.01-7.87 (m, 2H), 7.79 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.26-7.14 (m, 3H).
972 White solid, 71.9% in yield. 1H NMR (500 MHz, acetone) δ 8.53 (s, 2H), 8.39 (s, 2H), 7.96 (s, 1H), 7.82 (t, J=1.9 Hz, 2H), 7.63 (s, 2H), 7.42-7.35 (m, 2H), 7.31 (t, J=8.1 Hz, 2H), 7.09-7.02 (m, 2H).
973 White solid, 80.2% in yield. 1H NMR (500 MHz, acetone) δ 8.59 (s, 1H), 8.55 (d, J=3.9 Hz, 2H), 8.38 (s, 1H), 8.11 (s, 1H), 8.01-7.95 (m, 2H), 7.71 (d, J=8.3 Hz, 1H), 7.64 (d, J=13.5 Hz, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.43 (ddd, J=8.1, 1.9, 0.9 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.20 (ddd, J=7.9, 1.7, 1.0 Hz, 1H).
Synthesis of 746 Analogues with Side Chain at Ortho Position.
746 analogues with side chain at ortho position were prepared according to the following Schemes 1.10 and 1.11:
General Procedure for the Synthesis of 746 Analogues with Side Chain at Ortho Position:
Referring to the Scheme 1.10 above, to a solution of triphosgene (1.5 mmol) in dry DCM (4.0 mL), amine 2 (1.5 mmol) in DCM (12.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.9 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 1 (1.5 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 3. Compound 3 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (100 mg) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residues was purified by recrystallization (solvent: DCM) to afford compound 4. Compound 4 (0.05 mmol) was dissolved in dry THF (5.0 mL). Triethylamine (0.2 mmol) was added followed by acyl chloride 5 (0.1 mmol) at rt. The reaction mixture was stirred at rt for 1 h. Then the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 10:1 to 2:1 as the eluent) to afford compound 6, such as 961 or 962.
Referring to the Scheme 1.11 above, to a solution of triphosgene (1.5 mmol) in dry DCM (4.0 mL), amine 2 (1.5 mmol) in DCM (12.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.9 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 1 (1.5 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 10:1 to 2:1 as the eluent) to afford compound 3. Compound 3 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (0.5 g) was added followed by 1.0 mL 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residues was purified by recrystallization (solvent: DCM) to afford compound 4. To a solution of triphosgene (0.5 mmol) in dry DCM (4.0 mL), amine 5 (0.5 mmol) in DCM (4.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.3 mL) in DCM (2.0 mL) over 2 min at room temperature. The mixture was stirred for 20 min. Then compound 4 (0.5 mmol) in DCM (6.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 10:1 to 2:1 as the eluent) to afford compound 6, such as 968.
Characterization of 746 Analogues with Side Chain at Ortho Position.
746 analogues with a side chain at meta position were synthesized according to Schemes 1.10 and 1.11 above. These compounds were verified by NMR analysis as outlined below. The structures of these 746 analogues are shown in Table 1.4 below.
961 White solid, 85.4% in yield. 1H NMR (500 MHz, acetone) δ 9.66 (d, J=5.9 Hz, 1H), 9.15 (s, 1H), 8.27 (s, 1H), 8.15-8.05 (m, 2H), 7.85 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.55 (dd, J=8.8, 5.9 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.24-7.12 (m, 2H), 7.01 (td, J=8.5, 3.0 Hz, 1H).
962 White solid, 79.5% in yield. 1H NMR (500 MHz, acetone) δ 9.32 (d, J=5.0 Hz, 1H), 8.79 (s, 1H), 8.17-8.01 (m, 2H), 7.75 (dd, J=11.0, 2.8 Hz, 1H), 7.57 (dd, J=8.8, 6.0 Hz, 1H), 7.50 (d, J=8.9 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H), 7.29-7.15 (m, 2H), 6.93 (td, J=8.5, 2.9 Hz, 1H).
965 White solid, 83.0% in yield. 1H NMR (500 MHz, acetone) δ 9.31 (d, J=5.6 Hz, 1H), 8.78 (s, 1H), 8.13-8.04 (m, 1H), 7.98 (s, 1H), 7.75 (dd, J=11.0, 2.8 Hz, 1H), 7.61-7.51 (m, 2H), 7.35-7.19 (m, 3H), 7.14 (dd, J=8.2, 1.0 Hz, 1H), 6.94 (td, J=8.5, 2.9 Hz, 1H), 6.76 (td, J=8.3, 2.0 Hz, 1H).
967 White solid, 86.0% in yield. 1H NMR (500 MHz, acetone) δ 8.80 (s, 2H), 8.06 (s, 2H), 7.97 (s, 2H), 7.71-7.63 (m, 4H), 7.50 (t, J=8.0 Hz, 2H), 7.32 (d, J=7.7 Hz, 2H), 7.22-7.15 (m, 2H).
968 White solid, 79.1% in yield. 1H NMR (500 MHz, acetone) δ 9.70 (d, J=5.6 Hz, 1H), 8.83 (s, 1H), 8.06 (s, 1H), 8.00-7.90 (m, 2H), 7.81 (dd, J=10.3, 2.6 Hz, 1H), 7.73-7.62 (m, 2H), 7.55 (dd, J=8.8, 5.9 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.11-7.00 (m, 1H).
968 White solid, 79.1% in yield. 1H NMR (500 MHz, acetone) δ 9.70 (d, J=5.6 Hz, 1H), 8.83 (s, 1H), 8.06 (s, 1H), 8.00-7.90 (m, 2H), 7.81 (dd, J=10.3, 2.6 Hz, 1H), 7.73-7.62 (m, 2H), 7.55 (dd, J=8.8, 5.9 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.11-7.00 (m, 1H).
974 White solid, 91.2% in yield. 1H NMR (500 MHz, acetone) δ 9.59 (d, J=7.5 Hz, 1H), 8.71 (s, 1H), 8.17-8.03 (m, 1H), 7.91-7.77 (m, 2H), 7.64-7.49 (m, 2H), 7.29 (td, J=8.2, 6.7 Hz, 1H), 7.26-7.15 (m, 3H), 7.03 (td, J=8.4, 3.0 Hz, 1H), 6.76 (tdd, J=8.6, 2.6, 0.8 Hz, 1H).
975 White solid, 89.3% in yield. 1H NMR (500 MHz, acetone) δ 9.60 (d, J=7.6 Hz, 1H), 8.72 (s, 1H), 8.02 (td, J=7.8, 1.6 Hz, 1H), 7.84 (s, 2H), 7.71-7.61 (m, 1H), 7.61-7.51 (m, 2H), 7.39 (td, J=7.7, 1.0 Hz, 1H), 7.35-7.24 (m, 2H), 7.18 (ddd, J=8.2, 2.0, 0.8 Hz, 1H), 7.02 (ddd, J=8.8, 8.1, 3.0 Hz, 1H), 6.76 (tdd, J=8.6, 2.6, 0.9 Hz, 1H).
General Procedure for the Synthesis of Aryl Azid 2—Scheme 2.1:
To a solution of 1 (1 mmol) in dry acetone (10 mL), triethylamine (1.1 mmol) and ethyl chlorocarbamate (1.1 mmol) were added dropwise at 0° C. After stirring at 00° C. for 1 h, sodium azide (1.1 mmol, 0.215 g) dissolved in 5 mL water was added dropwise. Stirring was continued at 00° C. for 5 h. Ice water was added. The mixture was extracted by dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic phase was concentrated under reduced pressure. Colorless oil was obtained and used in the following reaction without further purification.
General Procedure for the Synthesis of the 562 “Analogues of Formula (I)”-Scheme 2.1:
A solution of aryl azide 2 (0.5 mmol) in toluene (10 mL) was heated at 120° C. for 3 h to give aryl isocyanate 3, which is not isolated and treated in situ with the respective 4 at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene.
480: White solid, mp. 236-238° C., yield: 26.9%. 1H NMR (500 MHz, acetone-d6) δ 8.97 (br. d, J=10.4 Hz, 1H), 8.95 (br, 1H), 8.30 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.74-7.71 (m, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.46 (d, J=14.4 Hz, 1H).
481: White solid, mp. 223-225° C., yield: 58.8%. 1H NMR (500 MHz, acetone-d6) δ 10.3 (br, 1H), 9.32 (br, 1H), 8.67 (s, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.8 Hz, 1H), 7.79-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 6.57 (d, J=14.4 Hz, 1H).
482: White solid, mp. 214-216° C., yield: 48.1%. 1H NMR (500 MHz, acetone-d6) δ 8.88 (br, 1H), 8.79 (br. d, J=12.0 Hz, 1H), 8.74 (s, 1H), 8.30 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 7.99 (s, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 1H), 7.73 (s, 1H), 6.32 (d, J=14.4 Hz, 1H). HRMS-ESI calcd for [M+H]+ 401.0832. Found: 400.085.
483: White solid, mp. 231-233° C., yield: 48.1%. 1H NMR (500 MHz, acetone-d6) δ 10.27 (br, 1H), 9.32 (br, 1H), 8.66 (s, 1H), 8.13 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 8.02 (s, 2H), 7.83-7.79 (m, 1H), 7.75 (s, 2H), 6.45 (d, J=14.4 Hz, 1H). HRMS-ESI calcd for [M+H]+ 401.0832. Found: 400.0849.
487: White solid, mp. 247-249° C., yield: 82.1%. 1H NMR (500 MHz, acetone-d6) δ 10.34 (br, 1H), 9.51 (br, 1H), 9.14 (s, 1H), 8.56 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 8.15 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85-7.83 (m, 1H), 7.75-7.72 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 6.62 (d, J=14.4 Hz, 1H).
489: White solid, mp. 247-248° C., yield: 73.2%. 1H NMR (500 MHz, acetone-d6) δ 10.29 (br, 1H), 9.52 (br, 1H), 9.13 (s, 1H), 8.56 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 8.02 (s, 2H), 7.84-7.80 (m, 2H), 7.75 (s, 1H), 6.49 (d, J=14.4 Hz, 1H).
503: White solid, mp. 206-208° C., yield: 76.7%. 1H NMR (500 MHz, acetone-d6) δ 8.67 (br, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.44 (br, 1H), 8.26 (dd, J1=1.5 Hz, J2=1.5 Hz, 1H), 8.09-8.07 (m, 1H), 8.01 (s, 2H), 7.87-7.82 (m, 1H), 7.75 (s, 1H), 7.33 (dd, J1=8.5 Hz, J2=8.0 Hz, 1H), 6.29 (d, J=15.0 Hz, 1H).
504: White solid, mp. 246-247° C., yield: 85.3%. 1H NMR (500 MHz, acetone-d6) δ 8.84 (br. d, J=9.5 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.49 (br, 1H), 8.27 (d, J=3.5 Hz, 1H), 8.17 (s, 1H), 8.09-8.07 (m, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.8-7.76 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.33 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H), 6.44 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H).
510: White solid, mp. 208-210° C., yield: 33.9%. 1H NMR (500 MHz, acetone-d6) δ 8.89 (br, 1H), 8.78-8.77 (m, 1), 8.69 (br. d, J=10.0 Hz, 1H), 8.34 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.72-7.63 (m, 3H), 7.55 (t, J=7.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 6.26 (d, J=14.5 Hz, 1H).
511: White solid, mp. 215-217° C., yield: 70.0%. 1H NMR (500 MHz, acetone-d6) δ 10.24 (br, 1H), 9.32 (br, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.16 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.79-7.66 (m, 4H), 7.56 (t, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.39 (d, J=14.5 Hz, 1H).
512: White solid, mp. 203-205° C., yield: 38.8%. 1H NMR (500 MHz, acetone-d6) δ 8.84 (br, 1H), 8.80-8.76 (m, 1H), 8.53 (br. d, J=10.0 Hz, 1H), 8.34 (dd, J1=2.5 Hz, J2=3.0 Hz, 1H), 7.86 (d, J=10.0 Hz, 1H), 7.54-7.49 (m, 1H), 7.37 (dd, J1=1.0 Hz, J2=1.0 Hz, 2H), 7.33-7.29 (m, 2H), 7.19-7.16 (m, 1H), 6.16 (d, J=14.5 Hz, 1H).
527: White solid, mp. 202-204° C., yield: 50.6%. 1H NMR (500 MHz, acetone-d6) δ 9.33 (br.d, J=10.0 Hz, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.09-8.08 (m, 1H), 8.03 (s, 2H), 7.93 (br, 1H), 7.86-7.82 (m, 1H), 7.76 (s, 1H), 7.45-7.42 (m, 1H), 6.32 (d, J=15.0 Hz, 1H).
528: White solid, mp. 243-245° C., yield: 67.8%. 1H NMR (500 MHz, acetone-d6) δ 10.20 (br, 1H), 9.15 (br, 1H), 8.96 (s, 1H), 8.30 (s, 2H), 8.06 (s, 2H), 7.86 (d, J=15.0 Hz, 1H), 7.78 (s, 1H), 6.47 (d, J=15.0 Hz, 1H). HRMS-ESI calcd for [M+Na]+ 399.0651. Found: 399.0665.
531: White solid, mp. 266-268° C., yield: 62.5%. 1H NMR (500 MHz, acetone-d6) δ 11.54 (br, 1H), 9.20 (br, 1H), 8.70 (s, 2H), 8.07 (s, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.78 (s, 1H), 7.20 (d, J=4.0 Hz, 1H), 6.54 (d, J=14.5 Hz, 1H).
533: White solid, mp. 188-190° C., yield: 57.4%. 1H NMR (500 MHz, acetone-d6) δ 9.43 (d, J=3.0 Hz, 1H), 9.14 (br. d, J=9.0 Hz, 1H), 8.27-8.25 (m, 1H), 8.09 (br, 1H), 8.04 (s, 2H), 7.87-7.83 (m, 1H), 7.76 (s, 1H), 7.51 (dt, J1=2.5 Hz, J2=5.0 Hz, 1H), 6.32 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H).
535: White solid, mp. 181-183° C., yield: 38.8%. 1H NMR (500 MHz, acetone-d6) δ 8.76 (br, 1H), 8.73 (br, 1H), 8.43 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.09 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 8.02 (s, 2H), 7.86-7.81 (m, 1H), 7.76 (s, 1H), 6.33 (d, J=14.5 Hz, 1H).
536: White solid, mp. 209-211° C., yield: 78.4%. 1H NMR (500 MHz, acetone-d6) δ 8.63 (br.d, J=10.0 Hz, 1H), 8.53 (s, 1H), 8.34 (br, 1H), 7.99 (s, 2H), 7.94 (d, J=8.5 Hz, 1H), 7.87-7.82 (m, 1H), 7.74 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.27 (d, J=15.0 Hz, 1H).
537: White solid, mp. 199-201° C., yield: 60.4%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (br.d, J=10.0 Hz, 1H), 8.29 (dt, J1=6.5 Hz, J2=8.0 Hz, 1H), 8.20 (d, J=4.5 Hz, 1H), 8.00 (s, 2H), 7.88-7.83 (m, 1H), 7.78 (br, 1H), 7.75 (s, 1H), 7.21 (dt, J1=5.0 Hz, J2=7.5 Hz, 1H), 6.27 (d, J=15.0 Hz, 1H).
538: White solid, mp. 223-224° C., yield: 52.3%. 1H NMR (500 MHz, acetone-d6) δ 9.65 (br, 1H), 9.07 (dd, J1=1.5 Hz, J2=2.0 Hz, 1H), 8.09 (s, 2H), 7.90-7.85 (m, 1H), 7.81 (s, 1H), 7.61 (dd, J1=1.5 Hz, J2=2.5 Hz, 1H), 7.27-7.17 (m, 1H), 6.55 (dd, J1=1.5 Hz, J2=2.0 Hz, 1H).
539: White solid, mp. 185-186° C., yield: 68.8%. 1H NMR (500 MHz, acetone-d6) δ 8.79 (br.d, J=9.5 Hz, 1H), 8.68 (br, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.01 (s, 2H), 7.83 (dd, J1=8.5 Hz, J2=9.5 Hz, 1H), 7.76 (s, 1H), 6.33 (d, J=14.5 Hz, 1H).
540: White solid, mp. 204-205° C., yield: 71.6%. 1H NMR (500 MHz, acetone-d6) δ 8.73 (br.d, J=9.5 Hz, 1H), 8.59 (br, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.04 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 8.01 (s, 2H), 7.83 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 6.31 (d, J=15.0 Hz, 1H).
541: White solid, mp. 191-193° C., yield: 71.9%. 1H NMR (500 MHz, acetone-d6) δ 8.96 (s, 1H), 8.84 (br.d, J=10.5 Hz, 1H), 8.22 (d, J=5.0 Hz, 1H), 8.00 (s, 2H), 7.88-7.81 (m, 2H), 7.74 (s, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.27 (d, J=14.5 Hz, 1H), 2.33 (s, 3H).
543: White solid, mp. 244-245° C., yield: 59.2%. 1H NMR (500 MHz, acetone-d6) δ 11.70 (br, 1H), 9.26 (br, 1H), 8.76 (s, 1H), 8.26 (s, 2H), 8.10 (s, 2H), 7.90 (d, J=13.5 Hz, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.66 (s, 3H), 6.55 (d, J=14.0 Hz, 1H).
546: White solid, mp. 216-218° C., yield: 64.2%. 1H NMR (500 MHz, acetone-d6) δ 8.67 (br.d, J=10.0 Hz, 1H), 8.48 (s, 1H), 8.39 (br, 1H), 8.12 (s, 1H), 7.99 (s, 2H), 7.89 (s, 1H), 7.87-7.82 (m, 1H), 7.74 (s, 1H), 6.29 (d, J=14.0 Hz, 1H), 2.34 (s, 3H).
548: White solid, mp. 245-247° C., yield: 65.4%. 1H NMR (500 MHz, acetone-d6) δ 10.57 (br, 1H), 9.34 (br, 1H), 8.66 (s, 1H), 8.15 (d, J=7.5 Hz, 1H), 8.07 (s, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.78 (d, J=11.5 Hz, 2H), 6.50 (d, J=14.0 Hz, 1H).
549: White solid, mp. 244-246° C., yield: 70.5%. 1H NMR (500 MHz, acetone-d6) δ 10.29 (br, 1H), 9.25 (br, 1H), 8.58 (s, 1H), 8.06 (s, 2H), 7.98 (s, 1H), 7.87 (dt, J1=9.0 Hz, J2=8.0 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 6.48 (d, J=14.0 Hz, 1H).
550: White solid, mp. 184-186° C., yield: 51.5%. 1H NMR (500 MHz, acetone-d6) δ 8.68 (br, 1H), 8.58 (br.d, J=10.0 Hz, 1H), 8.42 (s, 1H), 8.17 (d, J=3.0 Hz, 1H), 8.11-8.08 (m, 1H), 7.71-7.69 (m, 1H), 7.67-7.64 (m, 2H), 7.54 (dt, J1=8.0 Hz, J2=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 6.22 (d, J=14.5 Hz, 1H).
551: White solid, mp. 179-181° C., yield: 68.0%. 1H NMR (500 MHz, acetone-d6) δ 9.46 (d, J=3.5 Hz, 1H), 9.02 (br.d, J=10.0 Hz, 1H), 8.25 (d, J=5.0 Hz, 1H), 8.06 (br, 1H), 7.73-7.70 (m, 1H), 7.68-7.65 (m, 2H), 7.54 (dt, J1=7.5 Hz, J2=7.5 Hz, 1H), 7.50-7.48 (m, 2H), 6.21 (d, J=15.0 Hz, 1H).
552: White solid, mp. 185-187° C., yield: 40.8%. 1H NMR (500 MHz, acetone-d6) δ 8.65 (br, 2H), 8.57 (d, J=2.0 Hz, 1H), 8.44 (dt, J1=2.0 Hz, J2=2.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.70-7.63 (m, 3H), 7.54 (dt, J1=8.0 Hz, J2=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.23 (d, J=14.5 Hz, 1H).
553: White solid, mp. 183-185° C., yield: 65.4%. 1H NMR (500 MHz, acetone-d6) δ 8.57 (br.d, J=10.0 Hz, 1H), 8.55 (br, 1H), 8.50 (d, J=3.0 Hz, 1H), 8.05-8.03 (m, 1H), 7.69-7.63 (m, 3H), 7.55-7.52 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 6.21 (d, J=14.5 Hz, 1H).
554: White solid, mp. 190-192° C., yield: 17.3%. 1H NMR (500 MHz, acetone-d6) δ 8.53 (d, J=2.5 Hz, 1H), 8.47 (br.d, J=11.0 Hz, 1H), 8.30 (br, 1H), 7.96-7.94 (m, 1H), 7.70-7.64 (m, 3H), 7.53 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.17 (d, J=15.0 Hz, 1H), 2.58 (s, 3H).
555: White solid, mp. 174-176° C., yield: 73.9%. 1H NMR (500 MHz, acetone-d6) δ 8.98 (d, J=7.5 Hz, 1H), 8.68 (br.d, J=10.0 Hz, 1H), 8.21 (d, J=4.5 Hz, 1H), 7.76 (br, 1H), 7.71-7.66 (m, 3H), 7.53 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.21 (d, J=5.0 Hz, 1H), 6.16 (d, J=14.5 Hz, 1H), 2.34 (s, 3H).
556: White solid, mp. 181-183° C., yield: 71.6%. 1H NMR (500 MHz, acetone-d6) δ 8.49 (br.d, J=10.5 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.34 (br, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.71-7.64 (m, 3H), 7.53 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 6.18 (d, J=15.0 Hz, 1H), 2.33 (s, 3H).
557: White solid, mp. 166-168° C., yield: 60.7%. 1H NMR (500 MHz, acetone-d6) δ 8.72 (br.d, J=10.5 Hz, 1H), 8.32-8.28 (m, 1H), 8.19 (dd, J1=1.0 Hz, J2=1.0 Hz, 1H), 7.73 (br, 1H), 7.71-7.64 (m, 3H), 7.53 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.20 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H), 6.16 (d, J=15.0 Hz, 1H), 2.50 (s, 3H).
558: White solid, mp. 203-205° C., yield: 17.3%. 1H NMR (500 MHz, acetone-d6) δ 10.13 (br, 1H), 9.13 (br, 1H), 8.94 (s, 1H), 8.30-8.28 (m, 2H), 7.73-7.68 (m, 3H), 7.56 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.37 (d, J=14.5 Hz, 1H).
559: White solid, mp. 242-244° C., yield: 60.0%. 1H NMR (500 MHz, acetone-d6) δ 11.42 (br, 1H), 9.08 (br, 1H), 8.71 (d, J=7.0 Hz, 2H), 7.74-7.69 (m, 3H), 7.56 (dt, J1=7.5 Hz, J2=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.19 (dt, J1=4.5 Hz, J2=5.0 Hz, 1H), 6.44 (d, J=15.0 Hz, 1H).
560: White solid, mp. 201-203° C., yield: 17.3%. 1H NMR (500 MHz, acetone-d6) δ 11.07 (br.d, J=8.5 Hz, 1H), 9.58 (br, 1H), 9.07 (d, J=5.0 Hz, 2H), 7.76-7.69 (m, 3H), 7.61-7.52 (m, 3H), 6.44 (d, J=15.0 Hz, 1H).
561: White solid, mp. 227-228° C., yield: 71.6%. 1H NMR (500 MHz, acetone-d6) δ 11.59 (br.d, J=10.0 Hz, 1H), 9.14 (br, 1H), 8.75 (d, J=5.5 Hz, 1H), 8.27-8.24 (m, 2H), 7.78-7.71 (m, 4H), 7.68-7.64 (m, 3H), 7.57 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 6.43 (d, J=14.5 Hz, 1H).
564: White solid, mp. 208-210° C., yield: 56.7%. 1H NMR (500 MHz, acetone-d6) δ 10.33 (br, 1H), 9.12 (br, 1H), 8.49 (s, 1H), 7.96 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.59-7.51 (m, 4H), 7.39 (t, J=7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 6.23 (d, J=15.0 Hz, 1H).
583: White solid, mp. 213-21° C., yield: 77.1%. 1H NMR (500 MHz, acetone-d6) δ 10.25 (br, 1H), 9.16 (br, 1H), 8.98 (s, 1H), 8.32-8.29 (m, 2H), 8.19 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.79 (d, J=9.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 6.62-6.57 (m, 1H).
542: White solid, mp. 209-212° C., yield: 29.8%. 1H NMR (500 MHz, acetone-d6) δ 8.89 (br, 1H), 8.62 (s, 1H), 8.12 (br, 1H), 7.87 (s, 2H), 7.64-7.60 (m, 2H), 6.18 (d, J=14.5 Hz, 1H).
544: White solid, mp. 223-225° C., yield: 58.5%. 1H NMR (500 MHz, acetone-d6) δ 10.53 (br, 1H), 9.26 (br, 1H), 8.83 (s, 1H), 8.60 (dd, J1=1.5 Hz, J2=1.0 Hz, 1H), 8.07 (s, 2H), 7.85 (dd, J1=14.5 Hz, J2=15.0 Hz, 1H), 7.79 (s, 1H), 7.55 (d, J=5.0 Hz, 1H), 6.51 (d, J=14.5 Hz, 1H).
545: White solid, mp. 224-226° C., yield: 23.1%. 1H NMR (500 MHz, acetone-d6) δ 11.15 (br, 1H), 9.09 (s, 2H), 8.10 (s, 2H), 7.83 (s, 2H), 6.65 (d, J=14.5 Hz, 1H).
562: White solid, mp. 207-209° C., yield: 60.0%. 1H NMR (500 MHz, acetone-d6) δ 10.43 (br, 1H), 9.21 (br, 1H), 8.83 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 7.74-7.65 (m, 3H), 7.58-7.50 (m, 3H), 6.41 (d, J=14.5 Hz, 1H).
766: White solid, yield: 83.2%. 1H NMR (500 MHz, acetone-d6) δ 10.08 (br, 1H), 9.54 (br, 1H), 8.18 (d, J=9.4 Hz, 1H), 7.85 (d, J=9.4 Hz, 1H), 7.78-7.67 (m, 2H), 7.54-7.45 (m, 3H), 6.26 (d, J=14.7 Hz, 1H).
875: White solid. Yield: 67.8%. 1H NMR (500 MHz, Acetone-de) δ 10.40 (br, 1H), 9.21 (br, 1H), 8.79 (d, J=1.1 Hz, 1H), 8.55 (d, J=5.8 Hz, 1H), 7.59 (d, J=14.7 Hz, 1H), 7.52 (d, J=5.8 Hz, 1H), 7.45-7.39 (m, 2H), 7.32 (s, 1H), 7.17-7.05 (m, 1H), 6.32 (d, J=14.7 Hz, 1H).
The chemical structures of compounds 480, 481, 483, 487, 489, 503, 504, 510, 511, 512, 527, 528, 531, 533, 535, 536, 537, 538, 539, 540, 541, 543, 546, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 564, 583, 542, 544, 545, 562, 766 and 875 prepared as described above are provided in Table 2.1 herein below.
General Procedure for the Synthesis of the 562 “Analogues of Formula (II)”-Scheme 2.2:
An equimolar mixture of aryl isocyanate 3 and aryl amine 4 in toluene was heated at 90° C. overnight. After cooling to room temperature, white solid was precipitated, which was collected by filtration and washed with toluene.
403: White solid, mp. 129-131° C., yield: 38.8%. 1H NMR (500 MHz, acetone-d6) δ 8.61 (br, 1H), 8.54 (br. d, J=10.0 Hz, 1H), 8.10 (s, 1H), 7.73-7.65 (m, 4H), 7.56-7.52 (m, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.20 (d, J=14.5 Hz, 1H).
404: White solid, mp. 208-210° C., yield: 4.8%. 1H NMR (500 MHz, acetone-d6) δ M.P. 208-210° C. 9.19 (br, 1H), 8.93 (br. d, J=10.0 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.02 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.65-7.59 (m, 2H), 7.39 (t, J=8.0 Hz, 1H), 6.49-6.44 (m, 1H).
405: White solid, mp. 233-235° C., yield: 73.7%. 1H NMR (500 MHz, acetone-d6) δ 9.09 (br, 1H), 8.90 (d, J=10.5 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.97 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.65-7.59 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 6.46 (dd, J1=2.0 Hz, J2=2.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 400.09.
406: White solid, mp. 158-160° C., yield: 53.5%. 1H NMR (500 MHz, acetone-d6) δ 8.72 (br. d, J=10.5 Hz, 1H), 8.62 (br, 1H), 8.10 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.68-7.60 (m, 3H), 7.54 (t, J=8.0 Hz, 1H), 7.38-7.35 (m, 2H), 6.41-6.38 (m, 1H).
407: White solid, mp. 213-215° C., yield: 64.4%. 1H NMR (500 MHz, acetone-d6) δ 9.20 (br, 1H), 8.79 (br. d, J=10.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H) 8.02 (dd, J1=2.0 Hz, J2=2.5 Hz, 1H), 7.69 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.65-7.59 (m, 4H), 6.25 (d, J=14.5 Hz, 1H).
408: White solid, mp. 178-180° C., yield: 70.1%. 1H NMR (500 MHz, acetone-d6) δ 8.66 (br, 1H), 8.57 (br. d, J=10.5 Hz, 1H), 8.09 (s, 1H), 7.74-7.69 (m, 2H), 7.64-7.53 (m, 5H), 7.69 (d, J=7.5 Hz, 1H), 6.18 (d, J=14.5 Hz, 1H).
409: White solid, mp. 175-177° C., yield: 47.2%. 1H NMR (500 MHz, acetone-d6) δ M 9.09 (br, 1H), 8.57 (br. d, J=10.0 Hz, 1H), 8.31-8.28 (m, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.99 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 7.52 (dd, J1=10.5 Hz, J2=10.5 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 6.96-6.94 (m, 2H), 6.77-6.74 (m, 1H), 6.14 (d, J=14.5 Hz, 1H), 3.83 (s, 3H). LHMS-ESI, m/z [M+H]+ 382.10.
410: White solid, mp. 181-183° C., yield: 55.1%. 1H NMR (500 MHz, acetone-d6) δ 9.12 (br, 1H), 8.74 (br. d, J=10.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.00-7.94 (m, 2H), 7.72-7.63 (m, 3H), 7.57-7.54 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.27 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 400.09.
411: White solid, mp. 145-147° C., yield: 32.7%. 1H NMR (500 MHz, acetone-de) δ 8.55 (br, 1H), 8.36 (br. d, J=10.5 Hz, 1H), 8.11 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.35 (d, J=8.0 Hz, 1H), 7.23-7.19 (m, 1H), 6.94-6.92 (m, 2H), 6.75-6.72 (m, 1H), 6.07 (d, J=14.5 Hz, 1H), 3.83 (s, 3H).
412: White solid, mp. 213-215° C., yield: 32.0%. 1H NMR (500 MHz, acetone-d6) δ 9.14 (br, 1H), 8.67 (br. d, J=10.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.00 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.57 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.37-7.32 (m, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.18-7.15 (m, 1H), 6.93 (ddd, J1=3.0 Hz, J2=2.5 Hz, J3=2.5 Hz, 1H), 6.17 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 307.08.
413: White solid, mp. 179-181° C., yield: 78.4%. 1H NMR (500 MHz, acetone-d6) δ 8.41 (br. d, J=10.5 Hz, 1H), 8.28 (br, 1H), 7.72-7.67 (m, 2H), 7.64 (s, 1H), 7.58-7.51 (m, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.33-7.29 (m, 2H), 7.05-7.01 (m, 1H), 6.14 (d, J=15.0 Hz, 1H).
414: White solid, mp. 171-173° C., yield: 65.4%. 1H NMR (500 MHz, acetone-d6) δ 8.59 (br, 1H), 8.46 (br. d, J=10.5 Hz, 1H), 8.09 (s, 1H), 7.73-7.71 (m, 1H), 7.60 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.55-7.52 (m, 1H), 7.37-7.30 (m, 2H), 7.19 (d, J=7.5 Hz, 1H), 7.13 (dd, J1=1.5 Hz, J2=1.5 Hz, 1H), 6.92-6.88 (m, 1H), 6.11 (d, J=15.0 Hz, 1H).
415: White solid, mp. 159-161° C., yield: 51.6%. 1H NMR (500 MHz, acetone-d6) δ 9.56 (br, 1H), 8.37 (br. d, J=10.0 Hz, 1H), 8.10 (s, 1H), 7.72 (d, J=10.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.36-7.34 (m, 3H), 7.32-7.29 (m, 2H), 7.17-7.14 (m, 1H), 6.10 (d, J=14.5 Hz, 1H).
416: White solid, mp. 195-197° C., yield: 60.4%. 1H NMR (500 MHz, acetone-d6) δ 8.76 (br, 1H), 8.57 (br. d, J=10.5 Hz, 1H), 7.79-7.76 (m, 2H), 7.73-7.69 (m, 3H), 7.67-7.64 (m, 2H), 7.56-7.53 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.22 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 332.10.
417: White solid, mp. 144-146° C., yield: 78.6%. 1H NMR (500 MHz, acetone-d6) δ 8.39 (br. d, J=6.5 Hz, 1H), 8.28 (br, 1H), 7.71-7.66 (m, 2H), 7.64 (s, 1H), 7.54-7.50 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.34 (t, J=2.0 Hz, 1H), 7.04-7.02 (m, 1H), 6.63-6.60 (m, 1H), 6.15 (d, J=15.0 Hz, 1H).
421: White solid, mp. 199-201° C., yield: 71.2%. 1H NMR (500 MHz, acetone-d6) δ 9.06 (br, 1H), 8.71 (br. d, J=10.0 Hz, 1H), 8.29 (s, 1H), 8.00-7.94 (m, 2H), 7.71-7.58 (m, 5H), 6.25 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 400.09.
429: White solid, mp. 166-168° C., yield: 16.1%. 1H NMR (500 MHz, acetone-d6) δ 8.57 (br. d, J=10.5 Hz, 1H), 8.26 (b, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.67-7.59 (m, 3H), 7.37-7.33 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.05-7.03 (m, 1H), 6.62 (dd, J1=3.0 Hz, J2=2.5 Hz, 1H), 6.35 (dd, J1=2.0 Hz, J2=2.5 Hz, 1H), 3.80 (s, 3H).
430: White solid, mp. 154-156° C., yield: 67.1%. 1H NMR (500 MHz, acetone-d6) δ 8.23 (br, 1H), 8.20 (br, 1H), 7.55 (dd, J1=15.0 Hz, J2=15.0 Hz, 1H), 7.35-7.33 (m, 1H), 7.21-7.18 (m, 2H), 7.03-7.00 (m, 1H), 6.93-6.91 (m, 2H), 6.73-6.71 (m, 1H), 6.62-6.59 (m, 1H), 6.02 (d, J=15.0 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H).
433: White solid, mp. 193-196° C., yield: 44.7%. 1H NMR (500 MHz, acetone-d6) δ 9.04 (br, 1H), 8.63 (br. d, J=10.0 Hz, 1H), 8.29-8.28 (m, 1H), 8.02-7.94 (m, 2H), 7.58 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.36-7.32 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.17-7.14 (m, 1H), 6.95-6.90 (m, 1H), 6.17 (d, J=15.0 Hz, 1H). LHMS-ESI, m/z [M+H]+ 350.09.
435: White solid, mp. 193-195° C., yield: 82.5%. 1H NMR (500 MHz, acetone-d6) δ 8.28 (br. d, J=10.5 Hz, 1H), 7.92 (b, 1H), 7.74-7.67 (m, 2H), 7.63 (s, 1H), 7.53 (t, J=3.0 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 6.11 (d, J=14.5 Hz, 1H), 2.93 (s, 6H).
436: White solid, mp. 228-230° C., yield: 36.5%. 1H NMR (500 MHz, acetone-d6) δ 9.25 (br, 1H), 9.07 (br. d, J=10.0 Hz, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.20-8.17 (m, 2H), 8.04 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.81-7.72 (m, 2H), 6.52 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H). HRMS-ESI calcd for [M+H]+ 488.06512. Found: 488.06578.
437: White solid, mp. 202-204° C., yield: 25.5%. 1H NMR (500 MHz, acetone-d6) δ 9.15 (br, 1H), 8.72 (br. d, J=10.0 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.47-7.45 (m, 2H), 7.35 (s, 1H), 7.14 (d, J=5.0 Hz, 1H), 6.24 (d, J=15.0 Hz, 1H). LHMS-ESI, m/z [M+H]+ 436.07.
438: White solid, mp. 196-198° C., yield: 14.0%. 1H NMR (500 MHz, acetone-d6) δ 9.16 (br, 1H), 8.87 (br. d, J=10.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.04-8.00 (m, 3H), 7.84 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.78 (s, 1H), 6.38 (d, J=15.0 Hz, 1H). HRMS-ESI calcd for [M+H]+ 488.06512. Found: 488.06599.
441: White solid, mp. 215-217° C., yield: 48.9%. 1H NMR (500 MHz, acetone-d6) δ 9.09 (br. d, J=10.5 Hz, 1H), 8.57 (d, J=9.0 Hz, 1H), 8.47 (b, 1H), 7.95 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.72-7.65 (m, 3H), 7.55 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 6.20 (d, J=15.0 Hz, 1H), 4.09 (s, 3H).
445: White solid, mp. 202-204° C., yield: 27.0%. 1H NMR (500 MHz, acetone-d6) δ 8.96 (br. d, J=10.5 Hz, 1H), 8.49-8.47 (m, 1H), 8.14-8.11 (m, 2H), 8.04 (b, 1H), 7.72-7.65 (m, 3H), 7.54 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 6.21 (d, J=15.0 Hz, 1H), 2.45 (s, 3H).
446: White solid, mp. 163-166° C., yield: 42.4%. 1H NMR (500 MHz, acetone-d) δ 8.53 (br, 1H), 7.74-7.67 (m, 5H), 7.65 (s, 1H), 7.63-7.61 (m, 2H), 7.56-7.52 (m, 3H), 7.47 (d, J=8.0 Hz, 1H), 6.18 (d, J=14.5 Hz, 1H).
449: White solid, mp. 165-167° C., yield: 30.7%. 1H NMR (500 MHz, acetone-d6) δ 9.08 (br, 1H), 8.66 (br. d, J=10.5 Hz, 1H), 8.23 (d, J=9.5 Hz, 2H), 8.83 (d, J=3.0 Hz, 2H), 7.71-7.65 (m, 3H), 7.55 (t, J=7.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.25 (d, J=14.5 Hz, 1H).
456: White solid, mp. 195-197° C., yield: 29.3%. 1H NMR (500 MHz, acetone-d6) δ 9.11 (br, 1H), 8.77 (br. d, J=10.5 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.18-8.14 (m, 2H), 8.02-8.00 (m, 2H), 7.86 (t, J=5.5 Hz, 1H), 7.75-7.69 (m, 1H), 7.62-7.58 (m, 1H), 6.32 (dd, J1=4.0 Hz, J2=4.0 Hz, 1H). LHMS-ESI, m/z [M+H]+ 397.08.
462: White solid, mp.>300° C., yield: 51.1%. 1H NMR (500 MHz, acetone-d6) δ 8.80 (br. d, J=10.5 Hz, 1H), 8.32 (br, 1H), 7.57-7.48 (m, 5H), 7.07 (d, J=8.5 Hz, 2H), 6.51 (d, J=14.5 Hz, 2H), 6.04-5.97 (m, 1H), 4.83 (br, 2H).
463: White solid, mp. 233-235° C., yield: 29.9%. 1H NMR (500 MHz, acetone-d6) δ 9.08 (br, 1H), 8.84 (br. d, J=10.5 Hz, 1H), 8.29 (s, 1H), 8.03 (s, 2H), 8.00-7.94 (m, 2H), 7.86-7.81 (m, 1H), 7.77 (s, 1H), 6.37 (d, J=14.5 Hz, 1H). HRMS-ESI calcd for [M+H]+ 468.05729. Found: 468.07602.
464: White solid, mp. 228-230° C., yield: 50.9%. 1H NMR (500 MHz, acetone-d6) δ 9.12 (br, 1H), 9.00 (br. d, J=10.0 Hz, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.99-7.95 (m, 2H), 7.92 (d, J=8.5 Hz, 1H), 7.78-7.69 (m, 2H), 6.52-6.48 (m, 1H). HRMS-ESI calcd for [M+H]+ 468.05729. Found: 468.07611.
468: White solid, mp. 256-258° C., yield: 53.9%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (br. d, J=10.5 Hz, 1H), 8.79 (br, 1H), 8.17 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.79-7.77 (m, 3H), 7.75-7.69 (m, 3H), 6.49-6.44 (m, 1H). HRMS-ESI calcd for [M+H]+ 400.08791. Found: 400.08927.
469: White solid, mp. 212-214° C., yield: 43.2%. 1H NMR (500 MHz, acetone-d6) δ 8.75 (br, 1H), 8.69 (br. d, J=10.5 Hz, 1H), 8.02 (s, 2H), 7.86-7.77 (m, 6H), 6.32 (d, J=14.5 Hz, 1H). HRMS-ESI calcd for [M+H]+ 400.08791. Found: 400.08976.
472: White solid, mp. 257-259° C., yield: 22.3%. 1H NMR (500 MHz, acetone-d6) δ 9.36 (br. d, J=11.0 Hz, 1H), 8.57 (d, J=9.0 Hz, 1H), 8.50 (br, 1H), 8.19 (s, 1H), 7.97-7.92 (m, 2H), 7.85 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.70 (d, J=8.5 Hz, 1H), 6.47-6.43 (m, 1H), 4.11 (s, 3H).
473: White solid, mp. 253-255° C., yield: 26.8%. 1H NMR (500 MHz, acetone-d6) δ 8.98 (br, 1H), 8.91 (br. d, J=10.5 Hz, 1H), 8.24 (d, J=9.0 Hz, 2H), 8.18 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.78 (dd, J1=14.0 Hz, J2=14.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 6.49 (dd, J1=3.0 Hz, J2=3.0 Hz, 1H).
474: White solid, mp. 251-253° C., yield: 69.8%. 1H NMR (500 MHz, acetone-d6) δ 9.19 (br. d, J=10.5 Hz, 1H), 8.48-8.46 (m, 1H), 8.19 (s, 1H), 8.15-8.13 (m, 2H), 8.05 (br, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.79 (dd, J1=14.0 Hz, J2=14.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 6.44 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 2.48 (s, 3H).
488: White solid, mp. 249-251° C., yield: 60.5%. 1H NMR (500 MHz, acetone-d6) δ 8.91 (br, 1H), 8.89 (br, 1H), 8.12 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.69 (m, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.58-7.57 (m, 1H), 6.45 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H).
490: White solid, mp. 231-233° C., yield: 58.2%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (br, 1H), 8.73 (br. d, J=10.4 Hz, 1H), 8.00 (s, 1H), 7.97 (s, 2H), 7.79-7.74 (m, 2H), 7.72 (s, 1H), 7.56 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H), 6.31 (d, J=14.4 Hz, 1H).
723: White solid, yield: 91.4%. 1H NMR (500 MHz, acetone-d6) δ 8.39 (d, J=10.5 Hz, 1H), 7.93 (s, 2H), 7.91 (br, 1H), 7.85-7.79 (m, 1H), 7.68 (s, 1H), 7.37-7.28 (m, 2H), 6.76-6.67 (m, 2H), 6.16 (d, J=14.6 Hz, 1H), 2.88 (s, 6H).
The chemical structures of compounds 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 421, 429, 430, 433, 435, 436, 437, 438, 441, 445, 446, 449, 456, 462, 463, 464, 468, 469, 472, 473, 474, 488, 490 and 723 prepared as described above are provided in Table 2.2 herein below.
General Procedure for the Synthesis of the 562 “Analogues of Formula (III)”-Scheme 2.3:
An equimolar mixture of aryl isocyanate 3 and aryl amine 4 in toluene was heated at 90° C. overnight. After cooling to room temperature, white solid was precipitated, which was collected by filtration and washed with toluene.
418: White solid, mp. 177-179° C., yield: 88.0%. 1H NMR (500 MHz, acetone-d6) δ 8.34 (br. d, J=10.5 Hz, 1H), 8.18 (br, 1H), 7.70-7.65 (m, 2H), 7.62 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.32-7.31 (m, 1H), 6.85 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.13 (d, J=15.0 Hz, 1H), 6.99 (s, 2H).
427: White solid, mp. 192-194° C., yield: 77.1%. 1H NMR (500 MHz, acetone-d6) δ M.P. 192-194° C. 1H NMR (500 MHz, CD3COCD3): δ 8.50 (br. d, J=10.5 Hz, 1H), 8.14 (b, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.66-7.58 (m, 3H), 7.36-7.31 (m, 2H), 6.86 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.35-6.31 (m, 1H), 5.99 (s, 2H).
431: White solid, mp. 178-180° C., yield: 67.9%. 1H NMR (500 MHz, acetone-d6) δ 8.15 (br. d, J=10.5 Hz, 1H), 8.10 (b, 1H), 7.54 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.92-6.89 (m, 2H), 6.84 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.73-6.70 (m, 1H), 6.00 (d, J=15.0 Hz, 1H), 5.99 (s, 2H), 3.82 (s, 3H).
432: White solid, mp. 180-182° C., yield: 71.0%. 1H NMR (500 MHz, acetone-d6) δ 8.36 (br. d, J=10.5 Hz, 1H), 8.19 (b, 1H), 7.71 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.62-7.54 (m, 4H), 7.32 (t, J=2.0 Hz, 1H), 6.85 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.11 (d, J=14.5 Hz, 1H), 5.99 (s, 2H).
515: White solid, mp. 199-201° C., yield: 75.3%. 1H NMR (500 MHz, acetone-d6) δ 8.80 (dd, J1=1.5 Hz, J2=1.0 Hz, 1H), 8.67 (br. d, J=10.5 Hz, 1H), 8.68 (br, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.01-7.98 (m, 3H), 7.90 (ddd, J1=14.5 Hz, J2=1.5 Hz, J3=1.5 Hz, 1H), 7.80 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 7.75 (s, 1H), 7.47 (dd, J1=8.0 Hz, J2=8.5 Hz, 1H), 6.31 (d, J=14.5 Hz, 1H).
516: White solid, mp. 214-216° C., yield: 77.5%. 1H NMR (500 MHz, acetone-d6) δ 10.21 (br, 1H), 8.45 (br. d, J=10.5 Hz, 1H), 8.07 (br, 1H), 7.96 (s, 2H), 7.89 (dd, J1=14.5 Hz, J2=15.0 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.38 (d, J=10.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.45 (d, J=3.0 Hz, 1H), 6.21 (d, J=14.5 Hz, 1H).
517: White solid, mp. 226-228° C., yield: 83.5%. 1H NMR (500 MHz, acetone-d6) δ 8.84 (br.d, J=10.0 Hz, 1H), 8.80 (dd, J1=1.5 Hz, J2=1.5 Hz, 1H), 8.66 (br, 1H), 8.28 (d, J=1.5 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.17 (s, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.86-7.79 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.48 (dd, J1=8.0 Hz, J2=8.5 Hz, 1H), 6.45 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H).
518: White solid, mp. 216-218° C., yield: 72.3%. 1H NMR (500 MHz, acetone-d6) δ 10.21 (br, 1H), 8.64 (br. d, J=10.5 Hz, 1H), 8.14 (s, 1H), 8.08 (br, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.85 (dd, J1=14.0 Hz, J2=14.5 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 6.37 (dd, J1=1.5 Hz, J2=2.0 Hz, 1H).
519: White solid, mp. 197-199° C., yield: 86.8%. 1H NMR (500 MHz, acetone-d6) δ 8.79 (d, J=1.0 Hz, 1H), 8.59 (br, 1H), 8.51 (br. d, J=9.5 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.79 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.66 (s, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.49-7.45 (m, 2H), 6.21 (d, J=15.0 Hz, 1H).
520: White solid, mp. 215-217° C., yield: 76.8%. 1H NMR (500 MHz, acetone-d6) δ 10.19 (br, 1H), 8.29 (br. d, J=10.5 Hz, 1H), 8.04 (br, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.34 (t, J=2.5 Hz, 1H), 7.21 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 6.46-6.44 (m, 1H), 6.09 (d, J=14.5 Hz, 1H).
523: White solid, mp. 208-209° C., yield: 81.7%. 1H NMR (500 MHz, acetone-d6) δ 8.88 (s, 1H), 8.76 (br.d, J=10.0 Hz, 1H), 8.71 (br, 1H), 8.63 (s, 1H), 8.02-7.99 (m, 3H), 7.91-7.87 (m, 2H), 7.76 (s, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.0 Hz, 1H), 6.34 (d, J=14.5 Hz, 1H).
524: White solid, mp. 220-221° C., yield: 61.7%. 1H NMR (500 MHz, acetone-d6) δ 8.93 (br.d, J=10.0 Hz, 1H), 8.89 (s, 1H), 8.75 (br, 1H), 8.63 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.92 (t, J=9.0 Hz, 2H), 7.84 (t, J=9.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.58 (t, J=6.0 Hz, 1H), 6.48 (d, J=14.0 Hz, 1H).
525: White solid, mp. 203-205° C., yield: 81.2%. 1H NMR (500 MHz, acetone-d6) δ 8.88 (s, 1H), 8.67 (br, 1H), 8.63 (s, 1H), 8.60 (br, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.75-7.61 (m, 4H), 7.59-7.53 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 6.24 (d, J=15.0 Hz, 1H).
The chemical structures of compounds 418, 427, 431, 432, 515, 516, 517, 518, 519, 520, 523, 524 and 525 prepared as described above are provided in Table 2.3 herein below.
General Procedure for the Synthesis of Aryl Azid 2—Scheme 2.4:
To a solution of 1 (1 mmol) in dry acetone (10 mL), triethylamine (1.1 mmol) and ethyl chlorocarbamate (1.1 mmol) were added dropwise at 0° C. After stirring at 0° C. for 1 h, sodium azide (1.1 mmol, 0.215 g) dissolved in 5 mL water was added dropwise. Stirring was continued at 0° C. for 5 h. Ice water was added. The mixture was extracted by dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic phase was concentrated under reduced pressure. Colorless oil was obtained and used in the following reaction without further purification.
General Procedure for the Synthesis of the 562 “Analogues of Formula (IV)”-Scheme 2.4:
A solution of aryl azide 2 (0.5 mmol) in toluene (10 mL) was heated at 120° C. for 3 h to give aryl isocyanate 3, which is not isolated and treated in situ with the respective 4 at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene.
419: White solid, mp. 189-190° C., yield: 19.0%. 1H NMR (500 MHz, acetone-d6) δ 9.12 (br, 1H), 8.58 (br. d, J=10.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 8.00 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.35 (dd, J1=14.5.0 Hz, J2=14.5 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 6.98 (dd, J1=5.0 Hz, J2=5.0 Hz, 1H), 6.93 (d, J=3.5 Hz, 1H), 6.39 (d, J=14.0 Hz, 1H). LHMS-ESI, m/z [M+H]+ 358.05.
420 White solid, mp. 172-174° C., yield: 74.3%. 1H NMR (500 MHz, acetone-d6) δ 8.58 (br, 1H), 8.36 (br. d, J=10.0 Hz, 1H), 8.09 (s, 1H), 7.71 (dd, J1=1.5 Hz, J2=2.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.41-7.34 (m, 2H), 7.19 (d, J=5.0 Hz, 1H), 6.96 (dd, J1=5.0 Hz, J2=5.0 Hz, 1H), 6.89 (d, J=3.5 Hz, 1H), 6.32 (d, J=14.5 Hz, 1H).
424 White solid, mp. 183-185° C., yield: 73.3%. 1H NMR (500 MHz, acetone-d6) δ 8.68 (br, 1H), 8.36 (br. d, J=10.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.36 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.20 (d, J=5.0 Hz, 1H), 6.97-6.95 (m, 1H), 6.90 (d, J=3.5 Hz, 1H), 6.34 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 270.07.
425 White solid, mp. 181-183° C., yield: 83.9%. 1H NMR (500 MHz, acetone-d6) δ 8.19 (br, 1H), 8.18 (br, 1H), 7.39 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.33-7.32 (m, 1H), 7.20-7.16 (m, 2H), 7.02-7.00 (m, 1H), 6.96-6.94 (m, 1H), 6.87 (d, J=3.0 Hz, 1H), 6.61-6.59 (m, 1H), 6.27 (d, J=14.5 Hz, 1H), 3.79 (s, 3H).
426: White solid, mp. 203-205° C., yield: 81.9%. 1H NMR (500 MHz, acetone-d6) δ 8.14 (br. d, J=10.5 Hz, 1H), 8.10 (b, 1H), 7.38 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.31-7.29 (m, 1H), 7.16 (d, J=5.5 Hz, 1H), 6.94 (dd, J1=5.5 Hz, J2=5.0 Hz, 1H), 6.86-6.82 (m, 2H), 6.77 (d, J=8.5 Hz, 1H), 6.24 (d, J=14.5 Hz, 1H), 5.98 (s, 2H).
428: White solid, mp. 199-201° C., yield: 45.7%. 1H NMR (500 MHz, acetone-d6) δ M.P. 199-201° C. 9.01 (br, 1H), 8.52 (br. d, J=10.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.98-7.92 (m, 2H), 7.34 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 6.97 (dd, J1=5.0 Hz, J2=5.0 Hz, 1H), 6.93 (d, J=3.5 Hz, 1H), 6.38 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 338.06.
434: White solid, mp. 163-165° C., yield: 17.6%. 1H NMR (500 MHz, acetone-d6) δ 9.11 (br, 1H), 8.58 (br. d, J=10.0 Hz, 1H), 8.31-8.28 (m, 1H), 8.21-8.16 (m, 1H), 8.03-8.01 (m, 1H), 7.48 (s, 1H), 7.45-7.40 (m, 1H), 6.44 (d, J=1.5 Hz, 1H), 6.35 (d, J=3.5 Hz, 1H), 6.11 (d, J=15.0 Hz, 1H). LHMS-ESI, m/z [M+H]+ 342.07.
443: White solid, mp. 129-131° C., yield: 21.5%. 1H NMR (500 MHz, acetone-d6) δ 9.03 (br, 1H), 8.42 (br. d, J=10.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.97 (dd, J1=3.0 Hz, J2=3.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.24 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 6.71 (d, J=1.0 Hz, 1H), 6.04 (d, J=14.5 Hz, 1H).
444: White solid, mp. 187-189° C., yield: 33.3%. 1H NMR (500 MHz, acetone-d6) δ 9.04 (br, 1H), 8.47 (br. d, J=10.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.98 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 7.37 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 6.98 (s, 1H), 6.79 (s, 2H), 6.11 (d, J=14.5 Hz, 1H), 5.99 (s, 2H). LHMS-ESI, m/z [M+H]+ 396.08.
447: White solid, mp. 118-120° C., yield: 21.6%. 1H NMR (500 MHz, acetone-d6) δ 8.48 (br. d, J=10.5 Hz, 1H), 8.26-8.23 (m, 2H), 7.66-7.63 (m, 3H), 7.63 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 6.06 (d, J=15.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H).
448: White solid, mp. 118-120° C., yield: 44.2%. 1H NMR (500 MHz, acetone-d6) δ 8.93 (br, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.88 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 7.64 (s, 1), 7.62-7.56 (m, 3H), 6.34 (br, 1H), 3.61-3.57 (m, 2H), 3.02 ((t, J=7.0 Hz, 2H). LHMS-ESI, m/z [M+H]+ 422.09.
450: White solid, mp. 191-193° C., yield: 23.3%. 1H NMR (500 MHz, acetone-d6) δ 9.14 (br, 1H), 8.64 (br. d, J=10.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.01 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.60 (dd, J1=14.5 Hz, J2=15.0 Hz, 1H), 7.42-7.30 (m, 2H), 6.32 (d, J=14.5 Hz, 1H), 1.71 (s, 9H). LHMS-ESI, m/z [M+H]+ 491.15.
453: White solid, mp. 121-123° C., yield: 52.4%. 1H NMR (500 MHz, acetone-d6) δ 9.09 (br, 1H), 8.55 (br. d, J=10.5 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 8.07 (s, 1H), 8.01 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.71 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 7.26 (s, 1H), 6.05 (d, J=14.5 Hz, 1H), 1.65 (s, 9H). LHMS-ESI, m/z [M+Na]+ 464.12.
459: White solid, mp. 130-132° C., yield: 66.2%. 1H NMR (500 MHz, acetone-d6) δ 8.13 (br, 1H), 7.66-7.54 (m, 7H), 7.49 (t, J=7.5 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.08-6.04 (br. m, 1H), 5.99 (d, J=14.5 Hz, 1H), 3.57-3.53 (m, 2H), 2.98 (t, J=7.0 Hz, 2H).
460: White solid, mp. 80-82° C., yield: 29.4%. 1H NMR (500 MHz, acetone-d6) δ 8.40 (br. d, J=8.5 Hz, 1H), 7.70-7.51 (m, 7H), 7.50 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.60 (br, 1H), 6.04 (d, J=14.5 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H).
461: White solid, mp. 152-153° C., yield: 60.4%. 1H NMR (500 MHz, acetone-d6) δ M 9.03 (br, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (dd, J1=2.0 Hz, J2=2.5 Hz, 1H), 7.73-7.70 (m, 2H), 7.64-7.59 (m, 2H), 6.85 (br.d, J=5.0 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H). LHMS-ESI, m/z [M+H]+ 408.08.
633: White solid, yield: 63.1%. 1H NMR (500 MHz, acetone-d6) δ 8.22 (br, 1H), 7.69-7.52 (m, 7H), 7.47 (d, J=8.3 Hz, 2H), 6.03 (br, 1H), 5.94 (d, J=14.6 Hz, 1H), 3.53 (dt, J=13.2, 7.1 Hz, 2H), 2.95 (t, J=7.1 Hz, 2H).
634: White solid, yield: 66.7%. 1H NMR (500 MHz, acetone-d6) δ 7.57 (t, J=7.7 Hz, 2H), 7.49 (d, J=7.7 Hz, 1H), 7.46-7.35 (m, 5H), 7.21 (t, J=7.7 Hz, 1H), 6.48 (d, J=11.0 Hz, 1H), 6.16 (d, J=11.0 Hz, 1H), 4.58 (t, J=5.6 Hz, 1H), 3.55 (dd, J=5.6, 7.0 Hz, 2H), 2.91 (t, J=7.0 Hz, 2H).
635: White solid, yield: 66.2%. 1H NMR (500 MHz, acetone-d6) δ 7.99 (d, J=10.4 Hz, 1H), 7.59-7.50 (m, 4H), 7.41-7.36 (m, 1H), 7.35-7.34 (m, 1H), 6.33-6.32 (m, 1H), 6.01-6.00 (m, 1H), 5.94 (br, 1H), 5.76 (d, J=14.6 Hz, 1H), 3.49 (dd, J=10.4, 7.1 Hz, 2H), 2.93 (t, J=7.1 Hz, 2H).
642: White solid, yield: 55.4%. 1H NMR (500 MHz, acetone-d6) δ 7.98 (d, J=10.7 Hz, 1H), 7.62-7.50 (m, 4H), 7.50-7.42 (m, 1H), 7.28-7.18 (m, 4H), 7.07-7.03 (m, 1H), 5.91 (br, 1H), 5.84 (d, J=14.7 Hz, 1H), 3.52-3.44 (m, 2H), 2.93 (t, J=7.1 Hz, 2H).
982 White solid, 72.3% in yield. 1H NMR (500 MHz, acetone) δ 9.25 (s, 1H), 8.27 (s, 1H), 8.20-8.14 (m, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.41-7.27 (m, 2H), 6.61 (s, 1H), 4.82 (d, J=4.9 Hz, 2H).
Compound 454 was prepared according to the following scheme:
Preparation of Compound 454:
Referring to Scheme 2.5 reproduced above, to a solution of 453 (50 mg, 0.113 mmol) in 4 mL methanol, sodium methoxide (13 mg, 0.24 mmol) dissolved in 3 mL methanol was added. The mixture was stirred at room temperature for 1 h. Then 12 mL water was added to the mixture when the reaction was completed (detected by TLC. Yellow solid precipitated from the reaction mixture and was collected by filtration. The product was dried under reduced pressure. 37 mg (96% in yield) of 454 was obtained as yellow solid. mp. 145-147° C., yield: 96%. 1H NMR (500 MHz, acetone-d6) δ 9.06 (br, 1H), 8.39 (br, 1H), 8.26 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.51 (dd, J1=14.5 Hz, J2=14.5 Hz, 1H), 6.97 (s, 1H), 6.11 (d, J=14.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 342.08.
The chemical structures of compounds 419, 420, 424, 425, 426, 428, 434, 443, 444, 447, 448, 450, 453, 454, 459, 460, 461, 633, 634, 635 and 642 prepared as described above are provided in Table 2.4 herein below.
General Procedure for the Synthesis of Intermediate 7:
Referring to Scheme 2.6 reproduced above, to a solution of arylamine 4 (2.1 mmol) and aldehyde 5 (2.3 mmol) in dichloromethane (20 mL), magnesium sulfate (4.2 mmol, 0.5 g) was added. The mixture was refluxed for 24 h. The crude product was obtained after filtering the solid and distilling off the solvent, which was used directly in the following step. Then the residue was dissolved in 15 mL of methanol. Sodium borohydride was added and the resulting mixture was stirred at room temperature for 5 h. Ammonium chloride (2M, 20 mL) was then added to quench the reaction. The solution was extracted with ethyl acetate (3×20 mL). The organic layer was dried over MgSO4 and then removed in vacuo. The residue was purified by column chromatography.
General Procedure for the Synthesis of the 562 “Analogues of Formula (V)”—Scheme 2.6:
A mixture of aryl isocyanate 3 and amine 7 in toluene was heated at 90° C. overnight. After cooling to room temperature, white solid was precipitated, which was collected by filtration and washed with toluene.
534: White solid, mp. 181-183° C., yield: 38.8%. 1H NMR (500 MHz, acetone-d6) δ 8.76 (s, 1H), 8.67 (d, J=9.0 Hz, 1H), 8.05-8.00 (m, 2H), 7.94 (s, 1H), 7.82 (d, J=14.5 Hz, 1H), 7.74 (s, 1H), 6.16 (d, J=14.5 Hz, 1H), 5.31 (s, 1H), 4.48 (s, 2H), 2.02-1.95 (m, 2H), 1.68 (s, 3H), 0.87-0.84 (m, 3H).
547: White solid, mp. 179-180° C., yield: 60.8%. 1H NMR (500 MHz, acetone-d6) δ 8.38 (br.d, J=10.0 Hz, 1H), 7.92-7.86 (m, 3H), 7.68 (s, 1H), 6.20 (d, J=15.0 Hz, 1H), 3.92-3.87 (m, 2H), 1.34 (s, 6H), 1.33 (s, 6H).
563: White solid, mp. 112-114° C., yield: 10.8%. 1H NMR (500 MHz, acetone-d6) δ 8.76 (d, J=2.5 Hz, 1H), 8.51 (br.d, J=10.0 Hz, 1H), 8.08-7.99 (m, 2H), 7.68-7.59 (m, 3H), 7.51 (t, J=7.5 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.08 (d, J=14.5 Hz, 1H), 5.33-5.29 (m, 1H), 4.48 (s, 2H), 2.04-1.99 (m, 2H), 1.68 (s, 3H), 0.89-0.83 (m, 3H).
591: White solid, mp. 56-58° C., yield: 21.3%. 1H NMR (500 MHz, acetone-d6) δ 11.93 (br.d, J=9.5 Hz, 1H), 9.71 (t, J=1.5 Hz, 1H), 7.98 (t, J=1.0 Hz, 2H), 7.96 (s, 2H), 7.88-7.83 (m, 1H), 7.74 (s, 1H), 7.38-7.28 (m, 5H), 6.14 (d, J=15.0 Hz, 1H), 5.16 (s, 2H).
620: White solid. Yield: 56.7%. 1H NMR (500 MHz, CDCl3) δ 7.66-7.61 (m, 1H), 7.58 (s, 2H), 7.54 (s, 1H), 7.45-7.33 (m, 3H), 7.20-7.14 (m, 1H), 7.11 (d, J=6.9 Hz, 2H), 6.82-6.74 (m, 3H), 6.32 (d, J=10.9 Hz, 1H), 5.70 (d, J=14.6 Hz, 1H), 4.86 (s, 2H), 3.73 (s, 3H).
621: White solid. Yield: 53.5%. 1H NMR (500 MHz, CDCl3) δ 7.65-7.57 (m, 3H), 7.55 (s, 1H), 7.24-7.22 (m, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.0, 2.1 Hz, 1H), 6.78 (d, J=8.0 Hz, 3H), 6.30 (d, J=10.8 Hz, 1H), 5.75 (d, J=14.6 Hz, 1H), 4.82 (s, 2H), 3.75 (s, 3H), 2.37 (s, 3H).
622: White solid. Yield: 49.5%. 1H NMR (800 MHz, CDCl3) δ 7.63 (m, 2H), 7.60 (s, 2H), 7.56 (s, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 6.82-6.72 (m, 3H), 6.20 (d, J=10.7 Hz, 1H), 5.76 (d, J=14.6 Hz, 1H), 4.87 (s, 2H), 3.74 (s, 3H).
623: White solid. Yield: 60.1%. 1H NMR (800 MHz, CDCl3) δ 7.69 (d, J=8.4 Hz, 2H), 7.64-7.56 (m, 4H), 7.29-7.25 (m, 5H), 7.19 (d, J=6.9 Hz, 2H), 6.29 (d, J=10.7 Hz, 1H), 5.79 (d, J=14.6 Hz, 1H), 4.93 (s, 2H).
The chemical structures of compounds 534, 547, 563, 591, 620, 621, 622 and 623 prepared as described above are outlined in Table 2.5 below.
General Procedure for the Synthesis of Compound 2-Amino-Oxazoles 4:
A mixture of substituted 2-bromoacetonphenone (2 mmol) and urea (20 mmol, 10 eq) were reflux overnight in acetonitrile (25 mL). After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography.
General Procedure for the Synthesis of Compound 804 and its Analogues—Scheme 3.1:
A mixture of 3-(trifluoromethyl)benzyl isocyanate 3a, and amine 4 in toluene was heated at 90° C. for overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene.
804: White solid, yield: 69.4%. 1H NMR (800 MHz, acetone-d6) δ 11.15 (br, 1H), 10.13 (br, 1H), 8.15 (s, 1H), 7.93-7.90 (m, 4H), 7.77-7.74 (m, 2H), 7.26-7.19 (m, 2H). MS (ESI) calculated for C17H12FN4O2[M+H] 323.0938. Found 323.0944.
790: White solid, yield: 45.5%. 1H NMR (500 MHz, acetone-d6) δ 11.14 (br, 1H), 9.87 (br, 1H), 8.23 (s, 1H), 7.76-7.73 (m, 3H), 7.60-7.57 (m, 1H), 7.50-7.47 (m, 2H), 7.43-7.41 (m, 1H), 7.38-7.35 (m, 1H), 2.94 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H).
791: White solid, yield: 76.5%. 1H NMR (500 MHz, acetone-d6) δ 11.09 (br, 1H), 8.23 (br, 1H), 7.79-7.72 (m, 3H), 7.63-7.55 (m, 3H), 7.51-7.36 (m, 8H).
797: White solid, yield: 77.5%. 1H NMR (500 MHz, acetone-d6) δ 10.89 (br, 1H), 10.15 (br, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.14-8.06 (m, 2H), 7.90-7.84 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H).
798: White solid, yield: 74.5%. 1H NMR (500 MHz, acetone-d6) δ 10.99 (br, 1H), 10.09 (br, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.92-7.86 (m, 2H), 7.78 (d, J=8.2 Hz, 1H), 7.59 (t, J=8.2 Hz, 1H), 7.50-7.46 (m, 2H), 7.44 (d, J=8.2 Hz, 1H).
799: White solid, yield: 69.7%. 1H NMR (800 MHz, acetone-d6) δ 11.02 (br, 1H), 10.06 (br, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.97-7.89 (m, 2H), 7.80-7.78 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.27-7.20 (m, 2H).
803: White solid, yield: 53.9%. 1H NMR (800 MHz, acetone-d6) δ 11.12 (s, 1H), 10.15 (s, 1H), 8.22 (s, 1H), 7.94-7.88 (m, 4H), 7.77 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H).
805: White solid, yield: 76.5%. 1H NMR (500 MHz, acetone-d6) δ 11.11 (br, 1H), 10.05 (br, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.88-7.87 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.48-7.44 (m, 3H), 7.40-7.35 (m, 1H).
783:16-113-E157F98 White solid. Yield, 57.1%. 1H NMR (500 MHz, acetone-d6) δ 8.59 (br, 1H), 8.07 (s, 1H), 7.69-7.56 (m, 5H), 7.53-7.33 (m, 7H), 7.26 (d, J=7.7 Hz, 1H), 6.59 (br, 1H), 4.66 (d, J=5.5 Hz, 2H).
885: White solid. Yield: 37.7%. 1H NMR (500 MHz, Acetone-d6) δ 11.33 (br, 1H), 10.50 (br, 1H), 8.88 (d, J=1.0 Hz, 1H), 8.66 (d, J=5.8 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.93-7.84 (m, 2H), 7.32-7.21 (m, 2H).
The chemical structures of compounds 804, 790, 791, 798, 803, 802, 805, 797, 799, 803, 805, 783, 788 and 885 prepared as described above are depicted in the following Table 3.1.
General Procedure for the Synthesis of Aryl Azid 2:
Referring to Scheme 4.1 reproduced above, to a solution of 1 (1 mmol) in dry acetone (10 mL), triethylamine (1.1 mmol) and ethyl chlorocarbamate (1.1 mmol) were added dropwise at 0° C. After the mixture was stirred at 0° C. for 1 h, sodium azide (1.1 mmol, 0.215 g) dissolved in 5 mL water was added dropwise. Stirring was continued at 00° C. for 5 h. Ice water was added. The mixture was extracted by dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic phase was concentrated under reduced pressure. Colorless oil was obtained and used in the following reaction without further purification.
General Procedure for the Synthesis of Compound 566 and its “Analogues of formula (I)”—Scheme 4.1:
A solution of aryl azide 2 (0.5 mmol) in toluene (10 mL) was heated at 120° C. for 3 h to give aryl isocyanate 3, which is not isolated and treated in situ with the respective 4 at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene.
484: White solid, mp. 239-241° C., yield: 39.9%. 1H NMR (500 MHz, acetone-d6) δ 10.85 (br, 1H), 9.32 (br, 1H), 8.72 (s, 1H), 8.13 (s, 2H), 7.79 (d, J=7.2 Hz, 1H), 7.65 (t, J=9.6 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H).
486: White solid, mp. 238-240° C., yield: 7.8%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (br, 1H), 8.74 (d, J=1.6 Hz, 2H), 8.32 (dd, J1=2.4 Hz, J2=2.4 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H).
491: White solid, mp. 249-251° C., yield: 18.4%. 1H NMR (500 MHz, acetone-d6) δ) 10.77 (br, 1H), 9.39 (br, 1H), 9.10 (d, J=3.0 Hz, 1H), 8.43 (dd, J1=2.5 Hz, J2=3.0 Hz, 1H), 8.05 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H).
495: White solid, mp.>300° C., yield: 32.6%. 1H NMR (500 MHz, acetone-d6) δ M.P.>300° C. 11.39 (br, 1H), 9.52 (br, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.36 (s, 2H), 8.20 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 7.73 (s, 1H), 7.65 (t, J=7.0 Hz, 1H).
496: White solid, mp. 239-241° C., yield: 28.4%. 1H NMR (500 MHz, acetone-d6) δ 11.49 (br, 1H), 9.72 (br, 1H), 9.28 (d, J=3.0 Hz, 1H), 8.63 (dd, J1=2.5 Hz, J2=3.0 Hz, 1H), 8.41 (s, 2H), 7.75 (s, 1H), 7.71-7.68 (m, 1H).
498: White solid, mp. 232-234° C., yield: 41.8%. 1H NMR (500 MHz, acetone-d6) δ 8.88 (br, 1H), 8.81 (br, 1H), 8.78 (dd, J1=0.5 Hz, J2=0.5 Hz, 1H), 8.35 (dd, J1=3.0 Hz, J2=2.5 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H).
499: White solid, mp. 255-257° C., yield: 79.1%. 1H NMR (500 MHz, acetone-d6) δ 10.84 (br, 1H), 9.36 (br, 1H), 8.77 (d, J=1.5 Hz, 1H), 8.18 (dd, J1=2.5 Hz, J2=2.0 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.74-7.69 (m, 3H).
501: White solid, mp. 255-257° C., yield: 92.6%. 1H NMR (500 MHz, acetone-d6) δ 10.89 (br, 1H), 9.55 (br, 1H), 9.26 (s, 1H), 8.61 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.80-7.76 (m, 1H), 7.72 (d, J=9.0 Hz, 2H).
506: White solid, mp. 214-216° C., yield: 49.8%. 1H NMR (500 MHz, acetone-d6) δ 8.91 (br, 1H), 8.67 (d, J=2.5 Hz, 1H), 8.57 (br, 1H), 8.29 (dd, J1=1.0 Hz, J2=1.5 Hz, 1H), 8.24 (s, 2H), 8.12-8.09 (m, 1H), 7.67 (s, 1H), 7.36-7.33 (m, 1H).
507: White solid, mp. 206-207° C., yield: 88.2%. 1H NMR (500 MHz, acetone-d6) δ 8.67 (d, J=1.5 Hz, 1H), 8.65 (br, 1H), 8.41 (br, 1H), 8.27 (d, J=4.0 Hz, 1H), 8.11-8.08 (m, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.33 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H).
565: White solid, mp. 158-160° C., yield: 7.8%. 1H NMR (500 MHz, acetone-d6) δ 9.55 (br, 1H), 8.58 (s, 2H), 8.37 (s, 1H), 8.29 (br, 1H), 8.24 (s, 2H), 7.69 (s, 1H).
566: White solid, mp.>300° C., yield: 26.3%. 1H NMR (500 MHz, acetone-d6) δ 8.81 (br, 1H), 8.56 (br, 1H), 8.35 (s, 1H), 8.07 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=8.5 Hz, 1H).
567: White solid, mp. 216-218° C., yield: 41.8%. 1H NMR (500 MHz, acetone-d6) δ 8.69 (br, 1H), 8.67 (br, 1H), 8.42 (t, J=2.0 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 8.12-8.09 (m, 2H), 7.73 (dd, J1=1.5 Hz, J2=1.5 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H).
568: White solid, mp. 162-164° C., yield: 32.5%. 1H NMR (500 MHz, acetone-d6) δ 9.28 (d, J=4.0 Hz, 1H), 8.97 (br, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 7.91 (br, 1H), 7.57 (dd, J1=1.0 Hz, J2=1.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H).
569: White solid, mp. 206-208° C., yield: 43.7%. 1H NMR (500 MHz, acetone-d6) δ 8.66 (br, 1H), 8.56 (br, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.08 (s, 1H), 8.06 (dd, J1=2.5 Hz, J2=3.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.38 (d, J=7.5 Hz, 1H).
570: White solid, mp. 172-174° C., yield: 29.7%. 1H NMR (500 MHz, acetone-d6) δ 8.96 (d, J=7.0 Hz, 1H), 8.76 (br, 1H), 8.22 (d, J=4.5 Hz, 1H), 8.09 (s, 1H), 7.76 (br, 1H), 7.72 (dd, J1=1.5 Hz, J2=2.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 2.35 (s, 3H).
571: White solid, mp. 206-208° C., yield: 77.1%. 1H NMR (500 MHz, acetone-d6) δ 10.68 (br, 1H), 9.14 (br, 1H), 8.88 (d, J=4.5 Hz, 1H), 8.34 (s, 1H), 8.30 (d, J=3.0 Hz, 1H), 8.18 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H).
572: White solid, mp. 218-219° C., yield: 39.8%. 1H NMR (500 MHz, acetone-d6) δ 12.07 (br, 1H), 9.16 (br, 1H), 8.79 (d, J=5.0 Hz, 1H), 8.28-8.25 (m, 2H), 8.20 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.72 (d, J=5.5 Hz, 1H), 7.68-7.60 (m, 4H), 7.43 (d, J=8.0 Hz, 1H).
573: White solid, mp. 213-215° C., yield: 24.5%. 1H NMR (500 MHz, acetone-d6) δ 8.98 (br, 1H), 8.85 (br, 1H), 8.45 (t, J=1.5 Hz, 1H), 8.24 (s, 2H), 8.20 (d, J=3.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.69 (s, 1H).
575: White solid, mp. 202-204° C., yield: 56.6%. 1H NMR (500 MHz, acetone-d6) δ 11.19 (br, 1H), 9.29 (br, 1H), 8.74 (s, 1H), 8.20 (s, 1H), 8.14 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H).
576: White solid, mp. 219-211° C., yield: 29.3%. 1H NMR (500 MHz, acetone-d6) δ 11.14 (br, 1H), 9.31 (br, 1H), 8.86 (s, 1H), 8.36 (s, 3H), 8.33 (d, J=2.5 Hz, 1H), 7.72 (s, 1H).
579: White solid, mp. 216-218° C., yield: 33.1%. 1H NMR (500 MHz, acetone-d6) δ 8.85 (br, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.48 (br, 1H), 8.24 (s, 2H), 7.97 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.65 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 2.47 (s, 3H).
580: White solid, mp. 164-166° C., yield: 47.1%. 1H NMR (500 MHz, acetone-d6) δ 11.54 (br, 1H), 9.62 (br, 1H), 9.11 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.62 (d, J=4.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 1H).
584: White solid, mp. 210-212° C., yield: 10.8%. 1H NMR (500 MHz, acetone-d6) δ 11.93 (br, 1H), 9.84 (br, 1H), 9.12 (d, J=5.5 Hz, 1H), 8.38 (s, 2H), 7.76 (s, 1H), 7.65 (d, J=5.5 Hz, 1H).
739: White solid, yield: 84.6%. 1H NMR (500 MHz, acetone-d6) δ 8.63 (br, 1H), 8.48 (br, 1H), 8.35-8.29 (m, 1H), 8.26-8.18 (m, 1H), 8.09 (s, 1H), 7.74-7.69 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.07 (dd, J=8.8, 3.4 Hz, 1H).
740: White solid, yield: 75.6%. 1H NMR (500 MHz, acetone-d6) δ 8.79 (br, 1H), 8.70 (br, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.13-8.11 (m, 1H), 8.07 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41-7.31 (m, 2H).
741: White solid, yield: 84.6%. 1H NMR (500 MHz, acetone-d6) δ 8.79 (br, 1H), 8.70 (br, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.13-8.11 (m, 1H), 8.07 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41-7.31 (m, 2H).
754: White solid. Yield, 83.2%. 1H NMR (500 MHz, acetone-d6) δ 8.90 (br, 1H), 8.60 (br, 1H), 8.29 (s, 1H), 8.23-8.15 (m, 3H), 7.64 (s, 1H), 7.07-7.04 (m, 1H).
755: White solid. Yield, 88.4%. 1H NMR (500 MHz, acetone-d6) δ 8.93 (br, 1H), 8.69 (br, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.20 (s, 2H), 8.13 (dd, J=8.7, 2.8 Hz, 1H), 7.65 (s, 1H), 7.40 (d, J=8.7 Hz, 1H).
758: White solid, yield: 65.3%. 1H NMR (500 MHz, acetone-d6) δ 10.50 (br, 1H), 8.67 (s, 2H), 8.51 (s, 2H), 8.35 (s, 1H), 7.84 (s, 1H).
763: White solid, yield: 63.2%. 1H NMR (500 MHz, acetone-d6) δ 9.13 (br, 1H), 8.21 (s, 2H), 8.17 (d, J=4.9 Hz, 1H), 7.90 (br, 1H), 7.62 (s, 1H), 7.33 (d, J=4.9 Hz, 1H).
764: White solid, yield: 54.5%. 1H NMR (500 MHz, acetone-d6) δ 9.07 (br, 1H), 8.42-8.40 (m, 1H), 8.20 (s, 2H), 7.93 (s, 1H), 7.62 (br, 1H), 6.99 (d, J=2.5 Hz, 1H), 2.39 (s, 3H).
773: White solid, yield: 88.5%. 1H NMR (500 MHz, acetone-d6) δ 8.62 (br, 1H), 8.53 (br, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.03 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.78-7.75 (m, 1H), 7.53-7.49 (m, 2H), 7.41 (d, J=7.6 Hz, 1H).
522: White solid, mp. 299-301° C., yield: 31.9%. 1H NMR (500 MHz, acetone-d6) δ 10.18 (br, 1H), 8.34 (br, 1H), 8.15 (s, 1H), 8.00 (br, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.34 (t, J=2.5 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.21 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H).
530: White solid, mp. 192-194° C., yield: 9.6%. 1H NMR (500 MHz, acetone-d6) δ 10.22 (br, 1H), 8.69 (br, 1H), 8.26 (s, 2H), 8.17 (br, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.36 (s, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.47 (s, 1H).
574: White solid, mp. 200-202° C., yield: 73.6%. 1H NMR (500 MHz, acetone-d6) δ 11.06 (br, 1H), 9.24 (br, 1H), 8.89 (s, 1H), 8.60 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.49-7.43 (m, 2H).
578: White solid, mp. 215-217° C., yield: 27.1%. 1H NMR (500 MHz, acetone-d6) δ 11.56 (br, 1H), 9.40 (br, 1H), 8.90 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.37 (s, 2H), 7.74 (s, 1H), 7.45 (t, J=6.0 Hz, 1H).
737: White solid, yield: 38.6%. 1H NMR (500 MHz, acetone-d6) δ 8.82 (br, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.65 (s, 1H), 8.37 (dd, J=8.6, 2.4 Hz, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 4.51 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).
738: White solid, yield: 51.6%. 1H NMR (500 MHz, acetone-d6) δ 9.07 (s, 1H), 8.37 (s, 1H), 8.01 (s, 1H), 7.28-7.22 (m, 1H), 7.02-6.99 (m, 3H), 6.95 (d, J=8.2 Hz, 1H), 6.92-6.82 (m, 3H), 6.56 (t, J=7.4 Hz, 1H).
744: White solid, yield: 38.6%. 1H NMR (500 MHz, acetone-d6) δ 10.08 (br, 1H), 8.76 (d, J=2.6 Hz, 1H), 8.68 (br, 1H), 8.35 (dd, J=8.6, 2.6 Hz, 1H), 8.19 (br, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.20-7.11 (m, 1H), 7.08-7.01 (m, 1H).
753: White solid. Yield, 86.4%. 1H NMR (500 MHz, acetone-d6) δ 8.75 (d, J=2.2 Hz, 1H), 8.69 (br, 1H), 8.34 (dd, J=8.6, 2.2 Hz, 1H), 8.24 (br, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.56-7.54 (m, 2H), 7.40 (d, J=8.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 3.83 (s, 3H).
The chemical structures of compounds 484, 486, 491, 495, 496, 498, 499, 501, 506, 507, 565, 566, 567, 568, 569, 570, 571, 572, 573, 575, 576, 579, 580, 584, 739, 740, 741, 754, 755, 758, 763, 764, 773, 522, 530, 574, 578, 737, 738, 744 and 753 prepared as described above are provided in Table 4.1 herein below.
General Procedure for the Synthesis of the 566 “Analogues of Formula (II)”-Scheme 4.2:
A mixture of aryl isocyanate 3 and amine 4 in toluene was heated at 90° C. overnight. The solvent was cooled to room temperature and the precipitate was collected by filtration and washed with toluene.
442: White solid, mp. 198-200° C., yield: 23.4%. 1H NMR (500 MHz, acetone-d6) δ 9.17 (br, 1H), 8.82 (br, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.04 (s, 1H), 8.02 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H), 7.77-7.75 (m, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H). LHMS-ESI, m/z [M+H]+ 394.06.
465: White solid, mp. 286-289° C., yield: 47.8%. 1H NMR (500 MHz, acetone-d6): δ 9.29 (br, 1H), 9.25 (br, 1H), 8.29-8.27 (m, 2H), 8.17 (d, J=9.0 Hz, 1H), 8.06-7.99 (m, 3H). LHMS-ESI, m/z [M+H]+ 419.06.
467: White solid, mp. 235-237° C., yield: 47.8%. 1H NMR (500 MHz, acetone-d6): δ 9.05 (br, 1H), 8.76 (br, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.08 (s, 1H), 7.99-7.96 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.43-7.41 (m, 1H).
492: White solid, mp. 285-287° C., yield: 10.0%. 1H NMR (800 MHz, acetone-d6): δ 8.83 (br, 1H), 8.66 (br, 1H), 8.03 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.55 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H).
494: White solid, mp. 279-281° C., yield: 12.7%. 1H NMR (500 MHz, acetone-d6): δ 9.22 (br, 1H), 9.08 (br, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.25 (s, 2H), 8.03-7.98 (m, 2H), 7.72 (1H).
500: White solid, mp. 291-294° C., yield: 14.7%. 1H NMR (500 MHz, acetone-d6): δ 9.05 (br, 1H), 9.01 (br, 1H), 8.23 (s, 2H), 8.06 (d, J=2.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.71 (s, 1H), 7.63 (dd, J1=2.0 Hz, J2=2.5 Hz, 1H).
502: White solid, mp. 257-259° C., yield: 48.3%. 1H NMR (500 MHz, acetone-d6): δ 8.87 (br, 1H), 8.74 (br, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.80-7.77 (m, 3H), 7.68 (d, J=8.5 Hz, 2H), 7.60 (dd, J1=2.5 Hz, J2=2.5 Hz, 1H).
509: White solid, mp. 228-230° C., yield: 14.5%. 1H NMR (500 MHz, acetone-d6): δ 9.04 (br, 1H), 8.81 (br, 1H), 8.30 (d, J=1.5 Hz, 1H), 7.97 (m, 2H), 7.81-7.95 (d, J=8.5 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H).
646: White solid, yield: 83.2%. 1H NMR (500 MHz, acetone-d6) δ 8.70 (br, 1H), 8.33 (br, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.53 (dd, J=8.6, 2.1 Hz, 1H), 7.27 (t, J=2.1 Hz, 1H), 7.19 (t, J=8.2 Hz, 1H), 7.01-6.99 (m, 1H), 6.63-6.60 (m, 1H), 3.77 (s, 3H).
647: White solid, yield: 87.3%. 1H NMR (500 MHz, acetone-d6) δ 8.77 (br, 1H), 8.50 (br, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.77-7.75 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.54 (dd, J=8.6, 2.1 Hz, 1H), 7.37-7.35 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.07-7.04 (m, 1H).
680: White solid, yield: 77.9%. 1H NMR (500 MHz, acetone-d6) δ 8.72 (br, s, 1H), 8.34 (br, s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.55-7.52 (m, 3H), 7.32-7.25 (m, 2H), 7.06-7.03 (m, 1H).
701: White solid, yield: 87.3%. 1H NMR (500 MHz, acetone-d6) δ 8.96 (br, 1H), 8.57 (br, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 1.9 Hz, 1H), 7.77 (s, 1H), 7.43-7.35 (m, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.08-7.06 (m, 1H).
702: White solid, yield: 84.4%. 1H NMR (500 MHz, acetone-d6) δ 8.89 (br, 1H), 8.38 (br, 1H), 8.27 (d, J=1.8 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.90 (dd, J=8.6, 1.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.31 (t, J=7.9 Hz, 2H), 7.05 (t, J=7.4 Hz, 1H).
703: White solid, yield: 86.5%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (br, 1H), 8.30 (br, 1H), 8.27 (d, J=2.1 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.88 (dd, J=8.6, 2.1 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 2.30 (s, 3H).
704: White solid, yield: 88.5%. 1H NMR (500 MHz, acetone-d6) δ 8.94 (br, 1H), 8.60 (br, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 2.0 Hz, 1H), 7.56-7.53 (m, 1H), 7.37-7.28 (m, 1H), 7.21-7.20 (m, 1H), 6.82-6.78 (m, 1H).
705: White solid, yield: 89.7%. 1H NMR (500 MHz, acetone-d6) δ 8.87 (br, 1H), 8.39 (br, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.90 (dd, J=8.6, 2.0 Hz, 1H), 7.28 (s, 1H), 7.20 (t, J=8.2 Hz, 1H), 7.02-7.01 (m, 1H), 6.63-7.61 (m, 1H).
706: White solid, yield: 86.5%. 1H NMR (500 MHz, acetone-d6) δ 9.62 (br, 1H), 8.58-8.56 (m, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.12 (br, 1H), 7.98 (t, J=7.8 Hz, 2H), 7.92 (dd, J=8.6, 1.9 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H).
736: White solid, yield: 90%. 1H NMR (500 MHz, acetone-d6) δ 8.37 (br, 1H), 8.06 (s, 1H), 8.00 (br, 1H), 7.68-7.65 (m, 2H), 7.48 (t, J=8.0 Hz, 1H), 7.40 (dd, J=8.7, 2.3 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 4.93 (br, 2H).
745: White solid, yield: 83.4%. 1H NMR (500 MHz, acetone-d6) δ 8.26 (br, 1H), 8.08 (s, 1H), 7.77 (br, 1H), 7.67-7.62 (m, 1H), 7.48-7.44 (m, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.21-7.16 (m, 2H), 6.65-6.60 (m, 2H), 4.45 (br, 2H).
772: White solid, yield: 79.5%. 1H NMR (500 MHz, acetone-d6) δ 8.87 (br, 1H), 8.68 (br, 1H), 8.03 (s, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.58-7.49 (m, 2H), 7.44-7.39 (m, 1H).
774: White solid, yield: 63.1%. 1H NMR (800 MHz, acetone-d6) δ 8.62 (br, 1H), 8.04 (br, 1H), 7.77 (m, 2H), 7.51 (t, J=8.0 Hz, 3H), 7.41 (d, J=8.0 Hz, 2H).
792: White solid. Yield, 43.5%. 1H NMR (500 MHz, acetone-d6) δ 9.04 (br, 1H), 8.20 (s, 1H), 8.12-7.97 (m, 2H), 7.89-7.78 (m, 1H), 7.76-7.66 (m, 2H), 7.47-7.35 (m, 1H).
829: White solid. Yield: 57.5%. 1H NMR (500 MHz, Acetone-d6) δ 9.10 (br, 1H), 8.74 (br, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.04-8.02 (m, 1H), 7.99 (dd, J=9.0, 2.4 Hz, 1H), 7.84-7.77 (m, 1H), 7.38 (t, J=9.7 Hz, 1H).
887: White solid. Yield: 77.8%. 1H NMR (500 MHz, Acetone-de) δ 9.13 (br, 1H), 8.77 (br, 1H), 8.25-8.24 (m, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.03-7.95 (m, 1H), 7.51 (s, 1H), 7.43 (t, J=2.0 Hz, 1H), 6.91 (s, 1H), 3.87 (d, J=5.8 Hz, 3H).
The chemical structures of compounds 442, 465, 467, 492, 494, 500, 502, 509, 646, 647, 680, 701, 702, 703, 704, 705, 706, 736, 745, 772, 774, 792, 829 and 887 prepared as described above are outlined in Table 4.1 below.
The bis-urea Compounds
General Procedure for the Synthesis of aryl azid 2:
Referring to Scheme 5.1 reproduced above, to a solution of 1 (1 mmol) in dry acetone (10 mL), triethylamine (1.1 mmol) and ethyl chlorocarbamate (1.1 mmol) were added dropwise at 0° C. After stirring at 0° C. for 1 h, sodium azide (1.1 mmol, 0.215 g) dissolved in 5 mL water was added dropwise. Stirring was continued at 0° C. for 5 h. Ice water was added. The mixture was extracted by dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic phase was concentrated under reduced pressure. Colorless oil was obtained and used in the following reaction without further purification.
General Procedure for the Synthesis of the bis-ureas of the Invention—Scheme 5.1:
A solution of aryl azide 2 (0.5 mmol) in toluene (10 mL) was heated at 120° C. for 3 h to give aryl isocyanate 3, which is not isolated and treated in situ with the respective diamine 4 at 90° C. overnight. After cooling to room temperature, white solid was precipitated, which was collected by filtration and washed with toluene.
Characterization of the bis-urea Compounds
439: White solid, mp.>300° C., yield: 66.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=11.0 Hz, 2H), 8.63 (b, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.55 (s, 2H), 7.49-7.41 (m, 4H), 7.35 (d, J=9.0 Hz, 2H), 7.31 (s, 4H), 6.02 (d, J=14.5 Hz, 2H).
440: White solid, mp.=214-216° C., yield: 78.1%. 1H NMR (500 MHz, acetone-d6) δ 8.36 (d, J=11.5 Hz, 2H), 8.28 (b, 2H), 7.82 (d, J=1.5 Hz, 1H), 7.71-7.63 (m, 6H), 7.52 (t, J=8.0 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.26-7.19 (m, 3H), 6.16 (d, J=14.5 Hz, 2H).
451: White solid, mp.=162-165° C., yield: 82.7%. 1H NMR (500 MHz, acetone-d6) δ 8.78 (d, J=10.5 Hz, 2H), 8.04 (br, 2H), 7.69-7.62 (m, 8H), 7.52 (t, J=7.5 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.19-7.16 (m, 2H), 6.14 (d, J=14.5 Hz, 2H).
452: White solid, mp.>300° C., yield: 58.5%. 1H NMR (500 MHz, acetone-d6) 8.26 (br. d, J=10.5 Hz, 2H), 8.21 (br. d, J=8.5 Hz, 2H), 8.16 (s, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.66-7.61 (m, 4H), 7.39 (s, 3H) 7.39-7.30 (m, 5H), 6.18 (d, J=14.5 Hz, 2H), 1.70 (s, 18H).
455: White solid, mp.>300° C., yield: 53.0%. 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=10.5 Hz, 2H), 8.64 (s, 2H), 7.41-7.39 (m, 2H), 7.37 (s, 4H), 7.31 (d, J=7.5 Hz, 4H), 7.27 (t, J=8.0 Hz, 4H), 7.27 (t, J=7.5 Hz, 2H), 5.99 (d, J=14.5 Hz, 2H).
457: solid, mp.>300° C., yield: 69.1%. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (br. d, J=10.5 Hz, 1H), 8.18 (s, 1H), 7.35 (s, 2H), 7.25-7.19 (m, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.82-6.79 (m, 2H), 6.74-6.70 (m, 2H), 6.50 (t, J=3.5 Hz, 2H), 5.95 (d, J=5.0 Hz, 4H), 5.92-5.85 (m, 2H).
458: White solid, mp.>300° C., yield: 53.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.33 (s, 1H), 8.09 (d, J=12.5 Hz, 2H), 7.93-7.89 (m, 2H), 7.82-7.77 (m, 2H), 7.62-7.50 (m, 4H), 7.39 (s, 2H), 7.08 (d, J=8.5 Hz, 2H), 6.52 (d, J=8.5 Hz, 2H), 6.10 (dd, J1=15.0 Hz, J2=15.0 Hz, 2H).
466: White solid, mp.>300° C., yield: 46.4%. 1H NMR (500 MHz, acetone-d6) δ 8.86 (d, J=10.5 Hz, 2H), 8.67 (br, 2H), 7.53-7.51 (m, 5H), 7.49-7.45 (m, 5H), 7.32 (s, 4H), 6.01 (d, J=14.5 Hz, 2H).
532: White solid, mp. 228-230° C., yield: 59.4%. 1H NMR (500 MHz, DMSO-d6) δ 11.38 (br, 1H), 10.24 (br, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.77-7.74 (m, 3H), 7.64 (s, 2H), 7.34 (s, 1H), 7.27 (d, J=11.5 Hz, 1H), 6.24 (d, J=12.0 Hz, 1H), 5.77 (d, J=8.0 Hz, 1H), 5.41 (d, J=13.5 Hz, 1H).
The chemical structures of compounds 439, 440, 451, 452, 455, 457, 458, 466 and 532 prepared as described above are outlined in Table 4.1 below.
MTT assays: LNCaP, 22Rv1, Du145, H1975, A549, MB231 and MCF-7 cells are maintained in RPMI 1640 supplemented with 10% FBS. Cells were seeded at a density of 6-7×103 cells per well in 96-well plates. After overnight incubation, cells in fresh RPMI 1640 supplemented with 10% FBS were exposed to DMSO vehicle control or test compounds at designated concentrations for 72 h. Viable cells were evaluated by MTT assays. Experiments were performed in triplicate and repeated at least twice. The results are outlined in the tables below.
As will be understood by a skilled person considering the present specification, in certain embodiments, compounds according to the invention present activities against the LNCaP and 22Rv1 AR positive prostate cancer cells. Also, in other embodiments, compounds according to the invention present activities against DU145 AR negative prostate cancer cells, suggesting that such compounds can modulate other target(s) different from the AR.
Although the present invention has been described hereinabove by way of specific embodiments thereof, it may be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CA2015/050994 | 10/2/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62059597 | Oct 2014 | US |
