Patent Application
20230133600
The invention relates to the field of medicine, in particular to the medical use of a ketoamide compound.
In acute infectious diseases, most of them are viral infectious diseases. The incidence of viral infectious diseases is high and the mortality is also high. Due to the limited means of detection and diagnosis, new outbreaks caused by new viruses are often characterized by suddenness, randomness and unpredictability. Once an outbreak occurs, if there is no effective means of prevention and control, it is easy to cause a large-scale epidemic and seriously threaten people's health and life safety. Novel coronavirus (2019-nCoV or SARS-CoV-2) infection causes severe pneumonia. 2019-nCoV virus can be transmitted through droplets and contact, and there is a risk of person-to-person transmission and infection among medical staff. There is also a risk of community transmission, and the virus has the possibility of mutation. At present, there are no specific prevention and treatment methods for diseases caused by new coronavirus.
2019-nCoV coronavirus belongs to the genus Coronavirus of the Coronaviridae, and is a single-stranded positive sense RNA virus with an envelope. Similar to other known coronaviruses, the 2019-nCoV coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, decapsidation, biosynthesis, and assembly and release of progeny viruses. The 2019-nCoV coronavirus infection of the host cell starts from the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell, and then membrane fusion occurs. The virus enters the host cell and releases the viral genetic material, single-stranded positive sense RNA, under the action of organelles such as cell lysosomes, which translates and produces polyproteins under the action of protein synthesis elements such as mitochondria and ribosomes of the host cell as well as essential raw materials, etc.
Afterwards, the two essential cysteine proteases of 2019-nCoV coronavirus: papain-like protease (PLpro) and 3C-like protease (3CLpro), cleave and process the polyprotein precursors at specific sites to produce multiple nonstructural proteins important for the viral life cycle. In the presence of these non-structural proteins, viral RNA replicates the progeny viral nucleic acid material and translates the required structural proteins in large quantities to complete the assembly and release of the progeny viruses. Any link or key enzyme in the life cycle of cells infected by the 2019-nCoV coronavirus can be used as a research target for antiviral drugs, such as cysteine proteases PLpro and 3CLpro that hydrolyze and cleave polyprotein precursors, and RNA polymerase that completes the replication of genetic material of progeny viruses.
3CL protease (3 chymotrypsin-like protease, 3CLpro), also known as main protease (Mpro), is a key protease in the process of hydrolysis of polyproteins pp1a and pp1ab after the coronavirus RNA is translated to produce multiple non-structural proteins. It is very important for virus replication and infection. Inhibiting the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block virus replication, thus inhibiting the generation of the progeny virus. 3CLpro belongs to cysteine protease and is a key protease that catalyzes the proteolysis of single positive-stranded RNA viral precursor. It plays an important role in 2019-nCoV and other coronavirus replication activity. Therefore, 3CLpro is currently recognized as an ideal target for the development of anti-coronavirus drugs.
Human cathepsin L belongs to cysteine proteases of the lysosomal papain—like protease family, and it has a variety of biological functions, and its use as a target has been widely used in the development of drugs against parasitic infections, such as Chagas disease caused by Trypanosome infection. Cathepsin L first exists in the form of inactive zymogen in the cell, and needs to be cut by itself in the acidic environment of the endosome or lysosome, or activated by other proteases to form a mature enzyme with catalytic activity. A large number of studies have reported that human cathepsin L is closely related to the occurrence of various tumors and also plays an important role in heart diseases. In addition, studies have also found that human cathepsin is also involved in pathogenic microorganisms infecting host cells. More and more evidences show that human cathepsin L can be used as a drug target for the research and development of anti-tumor, heart disease and anti-infective drugs. The SARS-CoV-2 spike protein (S protein) needs to be hydrolyzed and activated by the host protease to mediate the membrane fusion of the virus and the host cell to promote the virus to invade the host cell. According to the difference in the action stage of the host protease, the virus invasion pathway can be divided into type II Transmembrane serine protease (TMPRSSII) mediated surface membrane fusion pathway, human cathepsin L mediated endocytosis membrane fusion pathway, therefore, these host proteases can be used as entry inhibitors for coronavirus invasion into host cells. Inhibition of human cathepsin L can effectively prevent virus from invading host cells, so human cathepsin L inhibitor is an ideal target for anti-SARS-CoV-2 research and development, and is expected to solve the potential risks and problems of mutation resistance of antiviral drugs targeting virus.
Currently, there are no specific vaccines and antiviral drugs for severe pneumonia caused by 2019-nCoV coronavirus. These infectious diseases have seriously affected people's lives and health, and it is urgent to develop small molecule antiviral drugs with good effects. It is of great social significance to develop antiviral drugs with novel structure, low toxicity and high efficiency and independent intellectual property rights for 2019-nCoV coronavirus 3CLpro and/or human cathepsin L to meet the clinical needs of patients infected with 2019-nCoV coronavirus at home and abroad.
In summary, there is an urgent need in the art to develop inhibitors for 2019-nCoV coronavirus 3CL protease and/or human cathepsin L for the treatment of pneumonia caused by novel coronavirus infection.
The object of the present invention is to provide a new use of ketoamide compound.
Specifically, the present invention provides the use of the ketoamide compound represented by the formula A as a 2019 novel coronavirus (2019-nCov) 3CL protease inhibitor and/or human cathepsin L inhibitor in the manufacture of a medicament for treating and/or preventing and alleviating respiratory tract infection, pneumonia and other related diseases caused by 2019 novel coronavirus infection.
In the first aspect of the present invention, it provides a use of a ketoamide compound represented by formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, for the manufacture of (a) a 3CL protease inhibitor and/or a human cathepsin L inhibitor against 2019 novel coronavirus (2019-nCov); and (b) a medicament for treating and/or preventing and alleviating related diseases caused by 2019 novel coronavirus (2019-nCov) infection:
wherein,
* indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene , substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene , substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl and sulfonyl
R3 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkynylene;
R4 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkynylene;
R6 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
when —NR5 and its adjacent —(C═O)—CH2- form a ring, R5 is —(CH2)n-, n is 2 or 3; when —NR5 does not form a ring with its adjacent —(C═O)—CH2-, R5 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C 1-C 10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
wherein, in R1, R2, R3, R4, R5 and R6, the “substituted” each independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl; the heterocycloalkyl and the heteroaryl each independently comprise 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In another preferred embodiment, when R6 is H, —NR5 (or —NR5R6) and its adjacent —(C═O)—CH2- can form a ring (e. g., a 5-6-membered heterocycle) or they do not form a ring. The 5-6 membered heterocycle contains one N heteroatom on the ring, and the remaining ring atoms are C. In another preferred embodiment, when —NR5 and its adjacent —(C═O)—CH2- form a ring, R5 is substituted or unsubstituted —(CH2)n-, n is 2 or 3, wherein the “substituted” each independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, C1-C8 alkyl, C3-C8 cycloalkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, and trifluoromethyl.
In another preferred embodiment, the moiety is a substituted or unsubstituted 5-6-membered heterocyclyl, wherein the “substituted” each independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, oxo, amino, imino, tertiary amino, azido, C1-C8 alkyl, C3-C8 cycloalkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl; preferably the
moiety is
wherein n1 is 1 or 2.
In another preferred embodiment, the related diseases caused by 2019 novel coronavirus infection is selected from the group consisting of respiratory infections, pneumonia and complications thereof, or a combination thereof.
In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C3-C10 heteroaryl C1-C5 alkylene, substituted or unsubstituted C6-C10 aryl C2-C5 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C2-C5 alkenylene, acyl, and sulfonyl;
R3 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C10 aryl C1-C5 alkylene, substituted or unsubstituted C3-C10 heteroaryl C1-C5 alkylene, substituted or unsubstituted C6-C10 aryl C2-C4 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C2-C4 alkenylene, substituted or unsubstituted C6-C10 aryl C2-C4 alkynylene, and substituted or unsubstituted C3-C10 heteroaryl C2-C4 alkynylene;
wherein, in R1, R2 and R3, the “substituted” each independently refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, and trifluoromethyl; the heterocycloalkyl and the heteroaryl each independently contain 1 or 2 heteroatoms selected from N, O and S.
In another preferred embodiment, the compound is a compound represented by formula AA,
wherein, R1, R2, R3, R4, R5 and n are as defined above;
* indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively.
In another preferred embodiment, R4 is selected from the group consisting of 9-10-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, and 5-6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; the above groups are substituted or unsubstituted; wherein, the “substituted” refers to the hydrogen atom on the group is substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio and halogenated C1-C6 alkylthio.
In another preferred embodiment, R6 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl.
In another preferred embodiment, the heteroaryl is a 5-, 6-, 7-, 8-, 9- or 10-membered saturated or partially saturated heteroaromatic ring.
In another preferred embodiment, the heterocycloalkyl is a 5-, 6-, 7-, 8-, 9- or 10-membered unsaturated heterocyclic ring.
In another preferred embodiment, R4 is selected from the group consisting of
substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted cinnolinyl,
substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl,
substituted or unsubstituted 1,3-benzodioxolyl,
substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazolyl,
substituted or unsubstituted imidazole[1,2-A]pyridyl, substituted or unsubstituted imidazole[1,5-A]pyridyl,
substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted 1,2,3-triazolyl, substituted or unsubstituted 1,2-thiadiazolyl, substituted or unsubstituted 1,2,4-triazinyl,
substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl,
substituted or unsubstituted 3,8a dihydro-2H-benzopyranyl, substituted or unsubstituted benzopyranyl,
substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl,
substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl,
substituted or unsubstituted benzothienyl, and
substituted or unsubstituted benzofuranyl;
wherein, the substituted means that the hydrogen atom on the group is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkylthio.
As used herein, R4 is imidazole [1,2-A]pyridine corresponding to the compounds numbered as A156 to A161 of the present invention.
As used herein, “imidazole[1,2-A]pyridine”, “imidazole[1,2-a]pyridine”, “imidazo[1,2-A]pyridine” and “imidazo[1,2-a]pyridine” can be used interchangeably.
As used herein, “imidazole[1,5-A]pyridine”, “imidazole[1,5-a]pyridine”, “imidazo[1,5-A]pyridine” and “imidazo[1,5-a]pyridine” can be used interchangeably.
As used herein, R4 is 3,8a dihydro-2H-benzopyran corresponding to the compounds numbered as A132 to A137 of the present invention.
In another preferred embodiment, when R6 is H, —NR5 and its adjacent —(C═O)—CH2- can form a ring (e. g., a 5-6-membered heterocycle) or they do not form a ring.
In another preferred embodiment, when —NR5 (or —NR5R6) and its adjacent —(C═O)—CH2- form a ring, R5 is —(CH2)n-, n is 3;
when —NR5 (or —NR5R6) and its adjacent —(C═O)—CH2- do not form a ring, R5 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C10 aryl C1-C4 alkylene, substituted or unsubstituted C6-C10 aryl C2-C4 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C1-C4 alkylene, and substituted or unsubstituted C3-C10 heteroaryl C2-C4 alkenylene;
wherein, the “substituted” each independently refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylthio; the heterocycloalkyl and the heteroaryl each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
In another preferred embodiment, R1, R2, R3, R4, R5 and R6 are each independently a corresponding group of the specific compounds (A1-A310) in the Examples.
In another preferred embodiment, the compound of formula (A) is selected from the group consisting of
In the second aspect of the present invention, it provides a pharmaceutical composition comprising (a) a therapeutically effective amount of the ketoamide compound represented by formula (A), or pharmaceutically acceptable salt, enantiomer, diastereomer or racemate or prodrug thereof, and (b) a pharmaceutically acceptable carrier, wherein, the ketoamide compound represented by formula (A) is as described in the first aspect of the present invention.
In the third aspect of the present invention, it provides a use of the pharmaceutical composition according to the second aspect of the present invention in the manufacture of a medicament for treating and/or preventing and alleviating related diseases caused by 2019 novel coronavirus (2019-nCov) infection.
In another preferred embodiment, the related diseases caused by 2019 novel coronavirus infection is selected from the group consisting of respiratory infections, pneumonia and complications thereof, and a combination thereof.
In the fourth aspect of the present invention, it provides a method for treating, preventing, and/or alleviating related diseases caused by 2019 novel coronavirus (2019-nCov) infection, comprising the step of administering to a subject in need a safe and effective amount of the ketoamide compound represented by formula (A), or pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein the ketoamide compound represented by formula (A) is described above.
In another preferred embodiment, the subject is a primate mammal, such as a human.
In the fifth aspect of the present invention, it provides a method for inhibiting the activity of the 3CL protease of 2019 novel coronavirus (2019-nCov), comprising the step of contacting the ketoamide compound represented by formula (A), or pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof with the 3CL protease and/or human cathepsin L of 2019-nCov, thereby inhibiting the activity of 3CL protease and/or human cathepsin L of 2019-nCov.
In another preferred embodiment, the method is non-therapeutic and non-diagnostic. In another preferred embodiment, the method is in vitro. In another preferred embodiment, the 3CL protease of 2019-nCov is a 3CL protease recombinant or expressed by 2019-nCov.
In the sixth aspect of the present invention, it provides the compound of formula (A), or pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof described in the first aspect,
wherein,
* indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C 1-C 10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl, and sulfonyl;
R3 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkynylene; R4 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl
C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkynylene;
R6 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
when —NR5 and its adjacent —(C═O)—CH2- form a ring, R5 is —(CH2)n-, n is 2 or 3; when —NR5 does not form a ring with its adjacent —(C═O)—CH2-, R5 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C 1-C 10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
wherein, in R1, R2, R3, R4, R5 and R6, each of the “substituted” independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 al kyl carb onyl, C1-C6 alkylthi o, C1-C8 alkoxycarbonyl, and trifluoromethyl; the heterocycloalkyl and the heteroaryl each independently comprise 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In another preferred embodiment, the compound is a compound represented by formula AA,
wherein, R1, R2, R3, R4, R5 and n are as defined above;
* indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively.
In another preferred embodiment, the compound is the compounds A254-A310 (i. e., Examples 254-310).
It should be understood that in the present invention, any of the technical features specifically described above and below (such as in the Examples) can be combined with each other, so as to constitute new or preferred technical solutions which will not redundantly be described one by one herein.
After extensive and intensive research and extensive screening, the present inventors have unexpectedly developed, for the first time, a class of active ingredients that can effectively inhibit 2019 novel coronavirus (2019-nCov), namely the compound shown in formula A or the pharmaceutically acceptable salt, enantiomer, diastereoisomer or racemate thereof. The test shows that the active ingredient of the present invention can effectively inhibit the activity of 3CL protease and/or human cathepsin L of 2019 novel coronavirus (2019-nCov), thereby inhibiting the replication and vitality of 2019-nCov. On above basis, the present invention has been completed.
As used herein, the terms “novel coronavirus”, “2019-nCov” or “SARS-CoV-2” are used interchangeably. The novel coronavirus is the seventh coronavirus known to infect humans and causes new coronary pneumonia (COVID-19), which is one of the serious infectious diseases threatening human health worldwide. In addition, the term includes wild-type and mutant virus strains.
As used herein, unless otherwise specified, the term “substituted” refers to that one or more hydrogen atoms on the group is substituted by the substituent selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxyl, carboxyl(—COOH), C1-C10 aldehyde group, C2-C10 acyl, C2-C10 ester group, amino, and phenyl; the phenyl includes unsubstituted phenyl or phenyl substituted with 1-3 substituents selected from halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, amino.
Unless otherwise specified, each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration among all the compounds of the present invention.
The term “C1-C6 alkyl” refers to a linear or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term “3-8 membered heterocyclyl” refers to a group formed by the loss of one hydrogen atom from a 3-8 membered saturated ring having 1-3 heteroatoms selected from the group consisting of N, S and O; such as pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, or the like.
The term “6-10 membered aryl” refers to a group formed by the loss of a hydrogen atom from 6-10 membered aryl, such as phenyl, naphthyl, or the like. The term “5-10-membered heteroaryl” refers to a group formed by the loss of one hydrogen atom from a 5-8 membered aryl having 1-3 heteroatoms selected from the group consisting of N, S and O, wherein the cyclic system of each heteroaryl may be monocyclic or polycyclic, such as pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidyl, benzothienyl, indolyl, imidazopyridyl, quinolyl, or the like. The term “C1-C6 alkoxy” refers to a linear or branched chain alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
The term “C2-C6 ester group” refers to R—O—C(═O)— having 2-6 carbon atoms, such as —COOCH3, —COOC2H5, —COOC3H7, —COOC4H9, or the like.
The term “C2-C6 alkenyl” refers to a group formed by the loss of one or two hydrogen atoms from an olefin having 2-6 carbon atoms. The olefin may be a monoolefin, a diene or a triolefin, such as —CH═CH2, -C2H4═CH2, —CH═C2H4, or the like.
The term “halogen” refers to F, Cl, Br and I.
Unless otherwise specified, the structural formula described herein are intended to include all isomeric forms (e.g., enantiomer, diastereomer, and geometric isomers (or conformational isomer): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Thus, a single stereochemical isomer or a mixture of enantiomers, diastereoisomers or geometric isomers (or conformational isomers) thereof of the compound of the invention is within the scope of the invention.
The term “tautomer” means that structural isomers with different energies can exceed the low energy barrier, thus transforming into each other. For example, proton tautomers (i.e. proton shift) include intertransformation through proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo [d] imidazole and 3H-benzo [d] imidazole, valence tautomers include intertransformation through some bonded electron recombination.
Herein, the form “C1-C6” indicates that the group may have 1 to 6 carbon atoms, for example, 1, 2, 3, 4, or 5 carbon atoms.
In the present invention, it provides an active ingredient that can effectively inhibit the replication of 2019 novel coronavirus (2019-nCov). The active ingredient is a compound represented by formula A, which is effective in preventing, treating and/or alleviating 2019-nCov-related diseases.
The tests have shown that the active ingredient of the present invention can effectively inhibit the 3CL protease and/or human cathepsin L of 2019 novel coronavirus (2019-nCov), thereby inhibiting the replication of 2019 novel coronavirus (2019-nCov), thereby preventing, treating and/or alleviating 2019-nCov related diseases.
It should be understood that the active ingredient of the present invention includes the ketoamide compound of formula (A), or the pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, or a prodrug thereof. It should be understood that the active ingredient of the present invention also includes crystalline forms of the compound of formula (A), amorphous compounds, and deuterated compounds, etc.
The “pharmaceutically acceptable salt” is a conventional non-toxic salt formed by the reaction of the compound of formula (A) with an inorganic acid or an organic acid. For example, conventional non-toxic salts can be prepared by reacting compounds of formula (A) with inorganic acids or organic acids, the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amino sulfonic acid and phosphoric acid, etc, and the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acid, ethylsulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, embonic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and hydroxyethanesulfonic acid; or the compound of formula (A) first forms an ester with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid, and then forms sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with inorganic bases; or the compound of formula (A) forms methylamine salt, ethylamine salt or ethanolamine salt with organic bases; or the compound of formula (A) first forms an ester with lysine, arginine, ornithine and then forms a corresponding inorganic acid salts with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or forms a corresponding organic acid salts with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.
The present invention also provides a use of a ketoamide compound represented by formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or prodrug thereof or a mixture of one or more of the above as an active ingredient in the manufacture of a medicament for treating and/or preventing and alleviating respiratory tract infection, pneumonia and other related diseases caused by 2019 novel coronavirus infection.
The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 0.001 to 99 wt %, preferably a ratio of 0.1 wt % to 90 wt % of the total weight of the compound of formula (A) as the active ingredient, and the rest is pharmaceutically acceptable carrier, diluent or solution or salt solution.
When necessary, one or more pharmaceutically acceptable carriers can also be added to the medicament of the present invention. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, and the like in the pharmaceutical field.
The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents and sterilization equipment suitable for injection or drip.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit measurement of the formulation generally contains 0.05-400 mg of the compound of formula A, preferably, the unit measurement of the formulation contains 1 mg-500 mg of the compound of formula A.
The compound and pharmaceutical composition of the present invention can be used clinically in mammals, including humans and animals, and can be administered through oral, nasal, skin, lung, gastrointestinal tract, etc. It is most preferably administered orally. The most preferred daily dose is 0.01-400 mg/kg (body weight) in a single dose, or 0.01-200 mg/kg (body weight) in divided doses. Regardless of the method of administration, the individual's optimal dosage should be determined based on the specific treatment. Normally, start with a small dose and gradually increase the dose until the most suitable dose is found.
The drugs or inhibitors of the present invention may be administered in a variety of different ways, for example, by injection, spray, nasal drops, eye drops, permeation, absorption, physical or chemically mediated introduction into the body such as intramuscular, intradermal, subcutaneous, intravenous, mucosal tissues; or introducing into the body by mixing or coating with other substances.
The main advantages of the invention include:
(a) The compounds of the present invention can efficiently inhibit the 2019-nCoV 3CL protease, and the IC50 value of some compounds reaches about 2.4 μM.
(b) The compound of the present invention can efficiently inhibit human cathepsin L, and the IC50 value of some compounds reaches about 0.45 nM.
(c) The compound of the present invention has a better inhibition rate against 2019-nCoV at the viral level than the positive control CQ, showing a better anti-2019-nCoV potential, and the EC50 value of some compounds reaches about 0.3 μM.
(d) The compound of the present invention has low toxic and side effects and good druggability.
The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacture's instructions. Unless indicated otherwise, percentage and parts are calculated by weight.
The analysis data of the sample were determined by the following instruments: nuclear magnetic resonance was determined by GEMINI-300, Bruker AMX-400 and INVOA-600 nuclear magnetic resonance instruments, TMS (tetramethylsilane) was as the internal standard, the chemical shift unit was ppm, and the coupling constant unit was Hz; Mass spectrometry was determined by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
200-300 mesh silica gel for column chromatography (produced by Qingdao Ocean Chemical Plant); TLC silica gel plate is HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Plant; petroleum ether boiling range is 60-90° C.; UV lamp is used, the iodine cylinder shows color. Unless otherwise stated, the conventional reagents and medicines used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were treated according to the specific conditions of the reaction.
Under the protection of argon, N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6 g, 21.8 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and a solution of LiHMDS (1M in THF) in tetrahydrofuran (47mL, 47 mmol) was slowly dropped at −78° C., and the temperature was kept stable at −78° C. during the dripping process for about 1 hour. After dripping, the reaction solution was stirred at −78° C. for 1 hour. Bromoacetonitrile (2.79 g, 23.3 mmol) was dissolved in 20 ml of tetrahydrofuran, and then the solution was slowly dropped into the reaction system. The dropping process was lasted for 1 to 2 hours. The temperature was controlled at −78° C. and the reaction was continued for 3 hours. When TLC monitoring (alkaline potassium permanganate color development) indicated the reaction was completed, NH4Cl solution was added to the reaction solution to quench the reaction, stirred for 10 min, and then warmed to room temperature. 40 mL of saturated sodium chloride solution was poured in and stirred well, and the reaction system appeared to separate into layers. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (EA). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (Flash, PE:EA=1:5) to obtain a pale yellow oil (1-2 3.9 g, the yield was 58%).
1-2 (1 g, 3.15 mmol) was dissolved in 25 mL of anhydrous methanol, stirred to 0° C. under an ice bath, then cobalt dichloride hexahydrate (450 mg, 1.89 mmol) was added. After 10 min, a small amount of sodium borohydride (715 mg, 18.9 mmol) was added in batches and the reaction solution continued to react under an ice bath for 1 h and then reacted at room temperature. After 15 h, the reaction was quenched with 5 mL of saturated NH4Cl solution, continued stirring for 10 min, and evaporated the filtrate after filtering the solid. The mixture was extracted with 20 mL of water and 30×3 mL of ethyl acetate. The combined organic phases was dried over anhydrous Na2SO4 for 1 h, concentrated under reduced pressure, and separated by column chromatography[PE:EA=1:2] to obtain 460 mg of white powdered solid with a yield of 51%.
Compound 1-3 (2.6 g) was dissolved in trifluoroacetic acid in dichloromethane solution (1/1, v/v), stirred at room temperature for 1 hour, 100 ml of dichloromethane was added after concentration, and washed with saturated sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain oily substance 1-4 (2.7 g) with a yield of 99%.
Boc-cyclohexylalanine (1.26 g, 5 mmol), EDCI (1.36 g, 6 mmol) and HOBt (0.822 g, 6 mmol) were added to 80 ml dichloromethane solution, and stirred at room temperature for 30 min. Subsequently, compound 1-4 (0.896 g, 5 mmol) was added, 1.2 equivalent of triethylamine was added dropwise, and the mixture was stirred at room temperature. When TLC monitoring (UV) indicated the reaction was complete, extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, the organic layers were combined and dried over anhydrous sodium sulfate, and concentrated to obtain 1.2 g of white viscous solid, the yield is 60%.
Compound 1-5 (2.5 g) was dissolved in trifluoroacetic acid in dichloromethane solution (1/1, v/v), stirred at room temperature for 1 hour, 100 ml of dichloromethane was added after concentration, and washed with saturated sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain oily substance 1-6 (2.61 g) with a yield of 99%.
Indole 2-formic acid (0.795 g, 5 mmol), EDCI (1.36 g, 6 mmol), and HOBt (0.822 g, 6 mmol) were added to 80 ml of dichloromethane solution, and stirred at room temperature for 30 min. Subsequently, compound 1-6 (2.2 g, 5 mmol) was added, 1.2 equivalent of triethylamine was added dropwise, and the mixture was stirred at room temperature. When TLC monitoring (UV) indicated the reaction was complete, extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, the organic layers were combined and dried over anhydrous sodium sulfate, and concentrated to obtain 1.3 g of white viscous solid, the yield is 60%.
1-7 (243 mg, 0.51 mmol) was dissolved in 20 ml of methanol, sodium borohydride (107 mg, 2.9 mmol) was slowly added in batches, and stirred at room temperature for about 2 hours to complete the reaction. After the reaction was completed, about 20 ml of saturated brine was added to quench the reaction, concentrated the reaction system to remove methanol, and dichloromethane was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid substance 1-8, which can be directly used in the next reaction.
Intermediate 1-8 (129 mg, 0.29 mmol) was dissolved in 20 ml of dichloromethane, and Dess-Martin oxidant (147 mg, 0.35 mmol) and sodium bicarbonate solid (29 mg, 0.35 mmol) were added, stirred at room temperature. When TLC monitoring (UV) indicated the reaction was completed, the reaction system was suction filtered, the filtrate obtained was extracted with saturated sodium bicarbonate, and the organic layer was subjected to wash with saturated salt water, dried over anhydrous sodium sulfate and concentrated. After separation and purification by flash column chromatography (CH2Cl2:MeOH=20:1), 77 mg of white solid powder compound 1 was obtained, with a yield of 60%.
Compound 1-9 (129 mg, 0.29 mmol) was dissolved in dichloromethane solvent, acetic acid (19.2 mg,0.32 mmol) and benzyl isocyanate (37.6 mg,0.32 mmol) were added to react to obtain compound 1-10, which was separated and purified by rapid column chromatography (CH2Cl2:MeOH=20:1) to obtain a total of 126 mg of white solid powder compound 1-10 with a yield of 70%.
Compound 1-10 (187 mg, 0.3 mmol) was dissolved in methanol solvent, and LiOH (0.6 mmol) was added to and stirred to obtain compound 1-11, which was separated and purified by rapid column chromatography (CH2Cl2:MeOH=20:1) to obtain a total of 148 mg of white solid powder compound 1-11 with a yield of 85%.
Compound 1-11 (174 mg, 0.3 mmol) was dissolved in dichloromethane solvent, Dess-Martin oxidant (152 mg, 0.36 mmol) was added, sodium bicarbonate (30 mg, 0.36 mmol) was added, and stirred to obtain the compound as a white solid powder compound 1-12 (140 mg in total, yield 80%).
1H NMR (500 MHz, Chloroform) δ 9.76 (s, 1H), 7.73 (s, 1H), 7.39 (s, 1H), 7.32-7.26 (m, 2H), 7.22 (s, 1H), 7.20-7.10 (m, 3H), 7.01 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 6.14 (s, 1H), 5.57 (s, 1H), 5.43 (s, 1H), 4.38 (s, 1H), 4.32 (d, J=19.2 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 3.06 (s, 1H), 2.20 (dd, J=15.4, 2.3 Hz, 4H), 2.12-2.03 (m, 2H), 1.92 (s, 1H), 1.77 (s, 1H), 1.73-1.67 (m, 3H), 1.66-1.53 (m, 6H), 1.37 (s, 1H).
Examples 2-310 was synthesized using the method similar to Example 1.
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 7.51 (d, J=18.0 Hz, 2H), 7.38 (s, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 6.26 (s, 1H), 6.04 (s, 1H), 5.80 (s, 1H), 5.25 (s, 1H), 4.81 (s, 1H), 4.67 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.55 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.96-1.91 (m, 3H), 1.73-1.52 (m, 5H), 1.40-1.36 (m, 2H), 1.35-1.29 (m, 10H), 1.20-1.09 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 8.28 (s, 1H), 7.48 (d, J=1.2 Hz, 2H), 7.34 (s, 1H), 7.10 (d, J=1.0 Hz, 2H), 7.03 (s, 1H), 6.05 (s, 1H), 5.59 (s, 1H), 5.30 (s, 1H), 4.63 (s, 1H), 4.45 (s, 1H), 3.58 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.95 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.98-1.90 (m, 3H), 1.73-1.67 (m, 3H), 1.65-1.61 (m, 2H), 1.51 (dtd, J=12.9, 8.9, 1.3 Hz, 13H), 1.45-1.39 (m, 3H), 1.38-1.34 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 1H), 7.53 (d, J=3.4 Hz, 2H), 7.40 (d, J=17.1 Hz, 2H), 7.12 (s, 1H), 7.06 (s, 1H), 6.16 (d, J=14.3 Hz, 2H), 5.65 (s, 1H), 5.23 (s, 1H), 4.44 (s, 1H), 3.44 (d, J=11.4 Hz, 2H), 3.35 (s, 1H), 3.09 (s, 1H), 2.97 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.75-1.68 (m, 4H), 1.62 (s, 1H), 1.48 (dt, J=16.0 , 8.0 Hz, 5H), 1.37-1.31 (m, 2H), 1.28 (s, 1H), 1.09-1.05 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.22 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.29-7.24 (m, 4H), 7.17 (d, J=29.6 Hz, 2H), 7.07 (s, 1H), 6.54 (s, 1H), 5.74 (s, 1H), 5.27 (s, 1H), 5.06 (s, 1H), 4.49 (s, 1H), 4.41 (s, 1H), 4.31 (s, 1H), 3.24 (d, J=17.4 Hz, 2H), 2.56 (s, 1H), 2.08-2.04 (m, 2H), 1.95-1.88 (m, 2H), 1.78 (d, J=6.9 Hz, 2H), 1.69 (dt, J=6.3 , 3.5 Hz, 7H), 1.51 (s, 1H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.15-1.11 (m, 2H), 1.08 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.30 (s, 2H), 7.48 (s, 2H), 7.43 (s, 2H), 7.35 (s, 2H), 7.10 (s, 2H), 7.03 (s, 2H), 6.45 (s, 2H), 5.99 (s, 2H), 5.76 (s, 2H), 5.25 (s, 2H), 4.81 (s, 2H), 4.29 (s, 2H), 3.24 (d, J=17.1 Hz, 4H), 2.75 (s, 2H), 2.05 (t, J=8.9 Hz, 6H), 1.79 (s, 2H), 1.71 (t, J=2.5 Hz, 7H), 1.58-1.54 (m, 3H), 1.51-1.33 (m, 10H), 1.33-1.29 (m, 20H), 1.23 (s, 2H), 1.15-1.11 (m, 3H), 0.94-0.90 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.29 (s, 1H), 8.69 (s, 1H), 7.52 (s, 1H), 7.43 (d, J=15.1 Hz, 2H), 7.13 (s, 1H), 7.06 (s, 1H), 5.93 (s, 1H), 5.59 (d, J=3.5 Hz, 2H), 5.11 (s, 1H), 4.51 (s, 1H), 3.41 (s, 1H), 3.24 (d, J=16.6 Hz, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.08-2.04 (m, 2H), 2.01-1.89 (m, 2H), 1.89-1.77 (m, 4H), 1.73-1.61 (m, 7H), 1.55-1.50 (m, 3H), 1.48 (s, 1H), 1.44-1.39 (m, 2H), 1.39-1.35 (m, 2H), 1.31 (s, 1H), 1.09-0.99 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 4H), 7.50 (d, J=31.7 Hz, 8H), 7.46-7.46 (m, 1H), 7.39 (s, 5H), 7.13 (s, 4H), 7.06 (s, 4H), 6.01 (s, 4H), 5.44 (s, 4H), 5.40 (s, 4H), 5.23 (s, 4H), 4.89 (s, 4H), 4.47 (s, 4H), 3.30-3.20 (m, 12H), 3.13 (s, 4H), 2.30 (s, 4H), 2.10-2.02 (m, 8H), 1.97 (s, 3H), 1.81-1.76 (m, 11H), 1.71 (t, J=1.6 Hz, 11H), 1.69-1.63 (m, 13H), 1.50 (s, 3H), 1.39-1.35 (m, 7H), 1.31 (s, 4H), 1.14-1.05 (m, 44H), 1.02 (s, 3H).
1H NMR (500 MHz, Chloroform) δ 7.66 (s, 1H), 7.34-7.28 (m, 5H), 7.22 (d, J=7.1 Hz, 2H), 7.10 (s, 1H), 6.72 (s, 1H), 6.17 (s, 1H), 5.97 (s, 1H), 5.84 (s, 1H), 5.47 (s, 1H), 4.42 (s, 1H), 4.34 (d, J=9.3 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 3.22 (s, 1H), 2.64 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.92 (s, 1H), 1.75-1.66 (m, 4H), 1.66-1.55 (m, 6H), 1.36 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.59 (s, 1H), 8.31 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.40 (s, 1H), 5.82 (s, 1H), 4.81 (s, 1H), 4.64 (s, 1H), 3.97 (s, 1H), 3.35 (s, 1H), 2.69 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.94-1.88 (m, 3H), 1.76-1.66 (m, 2H), 1.66-1.48 (m, 3H), 1.36-1.32 (m, 11H), 1.28 (s, 1H), 1.20 (s, 1H), 0.99-0.95 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.63 (s, 4H), 7.47 (s, 4H), 7.36 (s, 4H), 7.26 (s, 4H), 7.21 (s, 4H), 7.14 (s, 4H), 5.98 (s, 4H), 5.77 (s, 4H), 5.16 (s, 4H), 4.60 (s, 4H), 4.32 (s, 4H), 3.53 (s, 3H), 3.45 (s, 4H), 3.35 (s, 3H), 2.58 (s, 3H), 2.19 (s, 3H), 2.09-2.05 (m, 8H), 1.95-1.88 (m, 11H), 1.74-1.68 (m, 27H), 1.65-1.61 (m, 6H), 1.61-1.47 (m, 31H), 1.44-1.39 (m, 8H), 1.35-1.31 (m, 6H), 1.24 (s, 3H).
1H NMR (500 MHz, Chloroform) δ 8.31 (s, 4H), 7.60 (s, 4H), 7.49 (s, 4H), 7.40 (s, 4H), 7.21 (s, 4H), 7.15 (s, 4H), 6.18 (s, 4H), 5.46 (s, 4H), 5.25 (s, 4H), 5.12 (s, 4H), 4.63 (s, 4H), 3.43 (d, J=18.9 Hz, 8H), 3.35 (s, 3H), 3.11 (s, 4H), 2.76 (s, 4H), 2.17 (s, 3H), 2.13-2.01 (m, 8H), 1.93 (s, 4H), 1.85-1.81 (m, 6H), 1.73-1.69 (m, 7H), 1.69-1.62 (m, 7H), 1.61-1.42 (m, 16H), 1.33-1.29 (m, 6H), 1.26 (s, 3H), 1.14-1.10 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 4H), 7.51 (d, J=1.4 Hz, 1H), 7.46 (d, J=36.6 Hz, 7H), 7.32-7.14 (m, 29H), 6.56 (s, 4H), 5.75 (s, 4H), 5.66 (s, 4H), 5.09 (s, 4H), 4.56 (s, 4H), 4.41 (s, 4H), 4.32 (s, 4H), 3.24 (d, J=17.0 Hz, 8H), 2.32 (s, 4H), 2.10-2.02 (m, 9H), 1.99 (s, 4H), 1.97-1.89 (m, 8H), 1.79 (s, 4H), 1.75-1.52 (m, 28H), 1.40-1.36 (m, 7H), 1.32 (s, 4H), 1.23-1.19 (m, 8H), 1.16 (s, 3H).
1H NMR (500 MHz, Chloroform) δ 7.63 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.25 (s, 1H), 6.08 (s, 1H), 5.76 (s, 1H), 4.70 (d, J=19.7 Hz, 2H), 3.24 (d, J=14.7 Hz, 2H), 2.83 (s, 1H), 2.08-2.04 (m, 2H), 2.01 (s, 1H), 1.90 (s, 1H), 1.85-1.78 (m, 3H), 1.75-1.64 (m, 5H), 1.56-1.41 (m, 6H), 1.32 (s, 1H), 1.25-1.21 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 9.45 (s, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.16 (s, 1H), 6.07 (s, 1H), 5.85 (s, 1H), 5.08 (s, 1H), 4.48 (s, 1H), 3.32 (s, 1H), 3.24 (d, J=16.1 Hz, 2H), 2.92 (s, 1H), 2.16-2.08 (m, 2H), 2.08-2.04 (m, 2H), 2.02 (s, 1H), 1.80 (s, 1H), 1.76-1.66 (m, 8H), 1.65 (s, 1H), 1.57 (s, 1H), 1.55-1.40 (m, 8H), 1.40-1.37 (m, 1H), 1.31 (s, 1H), 1.12 (s, 1H), 0.90-0.82 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.60 (s, 1H), 7.49 (s, 1H), 7.40 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 6.20 (s, 1H), 5.99 (s, 1H), 5.91 (s, 1H), 5.65 (s, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 3.30 (s, 1H), 3.24 (d, J=17.4 Hz, 2H), 2.92 (s, 1H), 2.65 (s, 1H), 2.08-2.04 (m, 2H), 2.01 (s, 1H), 1.90-1.84 (m, 2H), 1.82 (s, 1H), 1.77-1.65 (m, 5H), 1.60-1.53 (m, 4H), 1.52-1.48 (m, 2H), 1.40 (s, 1H), 1.34 (s, 1H), 1.07-1.03 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.13 (s, 5H), 7.89 (s, 5H), 7.65 (s, 5H), 7.28 (dd, J=7.5, 4.2 Hz, 20H), 7.21 (dd, J=4.2, 2.6 Hz, 2H), 7.20-7.08 (m, 13H), 6.14 (s, 5H), 5.53 (s, 5H), 5.37 (s, 5H), 4.39-4.32 (m, 15H), 4.24 (s, 5H), 3.45 (s, 5H), 3.35 (s, 4H), 3.24 (s, 5H), 2.94 (s, 4H), 2.19 (s, 4H), 2.09-2.05 (m, 10H), 1.92 (s, 4H), 1.80-1.67 (m, 25H), 1.59-1.49 (m, 15H), 1.46-1.38 (m, 19H), 1.23 (s, 5H).
1H NMR (500 MHz, Chloroform) δ 8.37 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.31 (d, J=1.5 Hz, 2H), 6.28 (s, 1H), 6.05 (s, 1H), 5.80 (s, 1H), 5.25 (s, 1H), 4.82 (s, 1H), 4.68 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.56 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.95-1.88 (m, 3H), 1.73-1.52 (m, 5H), 1.41-1.37 (m, 2H), 1.35-1.29 (m, 10H), 1.18-1.09 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 8.95 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=2.0 Hz, 2H), 5.94 (s, 1H), 4.69 (s, 1H), 4.53 (s, 1H), 3.44 (d, J=9.6 Hz, 2H), 3.35 (s, 1H), 2.95 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.91 (t, J=7.7 Hz, 3H), 1.75-1.68 (m, 5H), 1.68-1.63 (m, 2H), 1.62-1.58 (m, 2H), 1.58-1.46 (m, 8H), 1.45-1.40 (m, 2H), 1.22-1.14 (m, 2H), 1.07 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.36 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.30 (d, J=2.5 Hz, 2H), 6.53 (s, 1H), 6.04 (s, 1H), 5.82 (s, 1H), 5.52 (s, 1H), 4.68 (d, J=6.4 Hz, 2H), 3.45 (s, 1H), 3.35 (d, J=3.1 Hz, 2H), 2.90 (s, 1H), 2.43 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.91 (t, J=5.9 Hz, 3H), 1.74-1.65 (m, 4H), 1.60-1.51 (m, 6H), 1.34 (s, 1H), 1.08-1.04 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.31 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.34-7.23 (m, 6H), 7.20 (s, 1H), 6.76 (s, 1H), 5.59 (s, 1H), 5.49 (s, 1H), 5.08 (s, 1H), 4.52 (s, 1H), 4.42 (s, 1H), 4.34 (s, 1H), 3.24 (d, J=17.6 Hz, 2H), 2.68 (s, 1H), 2.08-2.04 (m, 2H), 1.74-1.67 (m, 5H), 1.64 (dd, J=2.9, 1.7 Hz, 4H), 1.36-1.32 (m, 2H), 1.30 (s, 1H), 1.26 (s, 1H), 1.17 (s, 1H), 1.13-1.05 (m, 2H), 0.98 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.34 (s, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.30 (d, J=1.5 Hz, 2H), 6.15 (s, 1H), 6.10 (s, 1H), 5.41 (s, 1H), 4.64 (d, J=11.7 Hz, 2H), 3.24 (d, J=14.8 Hz, 2H), 2.90 (s, 1H), 2.11-2.01 (m, 2H), 1.89-1.81 (m, 4H), 1.77 (s, 1H), 1.73-1.68 (m, 4H), 1.66-1.59 (m, 5H), 1.55-1.49 (m, 2H), 1.35 (s, 1H), 1.32-1.28 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.93 (s, 1H), 8.55 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.30 (d, J=2.6 Hz, 2H), 6.05 (s, 1H), 5.83 (s, 1H), 5.68 (s, 1H), 5.13 (s, 1H), 4.34 (s, 1H), 3.33 (s, 1H), 3.24 (d, J=15.0 Hz, 2H), 2.73 (s, 1H), 2.43 (s, 1H), 2.08-2.04 (m, 5H), 1.85 (s, 1H), 1.78 (s, 1H), 1.73-1.67 (m, 5H), 1.66-1.52 (m, 7H), 1.51 (s, 2H), 1.44-1.39 (m, 3H), 1.34-1.30 (m, 2H), 1.27 (s, 1H), 0.83-0.72 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.61 (s, 2H), 7.40-7.26 (m, 10H), 7.18 (dd, J=24.7, 8.9 Hz, 9H), 6.51 (s, 2H), 6.14 (s, 2H), 5.17 (s, 2H), 4.61 (s, 2H), 4.40 (s, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 3.60-3.56 (m, 6H), 3.52 (s, 2H), 3.45 (s, 2H), 3.35 (s, 2H), 2.87 (s, 2H), 2.18 (s, 2H), 2.09-2.05 (m, 4H), 1.92 (s, 2H), 1.73-1.69 (m, 4H), 1.60-1.50 (m, 11H), 1.36-1.32 (m, 3H), 1.18 (s, 2H), 1.07-1.03 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.40 (s, 1H), 7.27 (d, J=5.4 Hz, 2H), 7.18 (d, J=11.2 Hz, 2H), 6.05 (d, J=0.5 Hz, 2H), 5.79 (s, 1H), 5.25 (s, 1H), 4.80 (s, 1H), 4.65 (s, 1H), 3.88-3.84 (m, 3H), 3.45 (s, 1H), 3.35 (s, 1H), 2.58 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.95-1.91 (m, 3H), 1.73-1.52 (m, 5H), 1.41-1.37 (m, 2H), 1.35-1.29 (m, 10H), 1.19-1.09 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.24 (s, 1H), 7.17 (s, 1H), 7.12 (d, J=0.8 Hz, 2H), 7.05 (s, 1H), 6.01 (s, 1H), 5.68 (d, J=17.0 Hz, 2H), 4.92 (s, 1H), 4.81 (s, 1H), 3.98 (s, 1H), 3.81 (s, 1H), 3.74-3.70 (m, 3H), 3.35 (s, 1H), 2.62 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.95-1.91 (m, 3H), 1.90-1.77 (m, 4H), 1.73-1.69 (m, 2H), 1.66-1.54 (m, 13H), 1.39-1.35 (m, 2H), 1.33 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.43 (s, 1H), 7.38-7.24 (m, 7H), 7.20 (d, J=8.0 Hz, 2H), 5.93 (s, 1H), 5.87 (s, 1H), 5.57 (s, 1H), 5.47 (s, 1H), 4.73 (s, 1H), 4.55 (s, 1H), 4.39 (d, J=18.9 Hz, 2H), 3.61-3.57 (m, 3H), 3.23 (d, J=15.5 Hz, 2H), 2.08-2.04 (m, 2H), 1.96-1.92 (m, 3H), 1.85 (s, 1H), 1.73-1.64 (m, 6H), 1.61 (s, 1H), 1.41 (t, J=7.7 Hz, 3H), 1.32 (s, 1H), 1.24 (s, 1H), 1.14-1.07 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.46 (s, 47H), 7.26 (d, J=19.3 Hz, 98H), 7.17 (d, J=7.3 Hz, 95H), 6.39 (s, 47H), 5.92 (d, J=11.5 Hz, 95H), 5.44 (s, 47H), 4.71 (s, 46H), 4.53 (s, 46H), 3.74-3.70 (m, 141H), 3.24 (d, J=18.1 Hz, 90H), 2.77 (s, 44H), 2.11-2.01 (m, 97H), 1.91 (s, 34H), 1.81 (s, 43H), 1.77-1.69 (m, 222H), 1.66-1.62 (m, 70H), 1.61-1.42 (m, 241H), 1.49-1.42 (m, 10H), 1.40-1.36 (m, 70H), 1.32-1.22 (m, 478H).
1H NMR (500 MHz, Chloroform) δ 7.41 (s, 1H), 7.35-7.22 (m, 2H), 7.19 (d, J=7.5 Hz, 2H), 5.92 (s, 1H), 5.54 (s, 1H), 5.38 (s, 1H), 5.23 (s, 1H), 5.04 (s, 1H), 4.34 (s, 1H), 3.99-3.95 (m, 3H), 3.86 (s, 1H), 3.24 (d, J=15.7 Hz, 2H), 2.86 (s, 1H), 2.08-2.02 (m, 4H), 1.99 (s, 1H), 1.81 (s, 1H), 1.78-1.67 (m, 7H), 1.66-1.51 (m, 10H), 1.43 (s, 1H), 1.41-1.37 (m, 2H), 1.30 (s, 1H), 0.77-0.70 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.87 (s, 1H), 7.29 (t, J=9.9 Hz, 3H), 7.22-7.11 (m, 2H), 6.98 (s, 1H), 6.61 (s, 1H), 6.43 (s, 1H), 6.20 (s, 1H), 5.62 (s, 1H), 4.55 (s, 1H), 4.43 (d, J=15.9 Hz, 2H), 4.32 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.12 (s, 1H), 2.33 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.94-1.88 (m, 3H), 1.74-1.66 (m, 4H), 1.63-1.55 (m, 6H), 1.35 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.04 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 5.77 (s, 1H), 4.93 (s, 1H), 4.55 (s, 1H), 3.99 (s, 1H), 3.35 (s, 1H), 2.63 (s, 1H), 2.19 (s, 1H), 2.10-2.04 (m, 4H), 1.93 (s, 1H), 1.69 (dt, J=18.2, 9.1 Hz, 5H), 1.41-1.37 (m, 2H), 1.35-1.27 (m, 11H), 1.24 (s, 1H), 1.05-1.01 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.86 (s, 1H), 8.48 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.06 (s, 1H), 6.01 (s, 1H), 5.47 (s, 1H), 5.20 (s, 1H), 5.05 (s, 1H), 4.55 (s, 1H), 4.00 (s, 1H), 3.58 (s, 1H), 3.51 (s, 1H), 3.35 (s, 1H), 2.19 (s, 1H), 2.12-2.02 (m, 2H), 2.00-1.96 (m, 2H), 1.94-1.87 (m, 3H), 1.73-1.46 (m, 14H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.12-1.06 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 8.68 (s, 11H), 7.45 (s, 11H), 7.38 (s, 11H), 7.31-7.23 (m, 34H), 7.23-7.17 (m, 26H), 7.16 (s, 8H), 7.11 (s, 11H), 5.89 (s, 11H), 5.79 (s, 11H), 4.76 (s, 11H), 4.51 (s, 11H), 4.35 (s, 11H), 4.29 (s, 11H), 3.24 (d, J=17.5 Hz, 21H), 2.73 (s, 11H), 2.10-2.04 (m, 23H), 2.02 (s, 9H), 1.83 (s, 10H), 1.81-1.74 (m, 33H), 1.73-1.65 (m, 23H), 1.65-1.50 (m, 45H), 1.52 (d, J=5.6 Hz, 2H), 1.34-1.30 (m, 19H), 1.28 (s, 11H), 0.99-0.93 (m, 32H).
1H NMR (500 MHz, Chloroform) δ 8.35 (s, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 7.05 (s, 1H), 6.43 (s, 1H), 5.97 (s, 1H), 5.59 (s, 1H), 5.50 (d, J=15.7 Hz, 2H), 4.67 (s, 1H), 3.24 (d, J=17.3 Hz, 2H), 2.48 (s, 1H), 2.08-2.04 (m, 2H), 1.87 (t, J=9.6 Hz, 3H), 1.78 (s, 1H), 1.72 (dd, J=8.3, 4.2 Hz, 4H), 1.67 (s, 1H), 1.65-1.50 (m, 6H), 1.45 (s, 1H), 1.36-1.28 (m, 10H).
1H NMR (500 MHz, Chloroform) δ 8.51 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.42 (s, 1H), 7.07 (s, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 5.86 (s, 1H), 5.04 (s, 1H), 4.52 (s, 1H), 3.32 (s, 1H), 3.24 (d, J=16.6 Hz, 2H), 2.97 (s, 1H), 2.16-2.01 (m, 5H), 2.01-1.92 (m, 2H), 1.82 (s, 1H), 1.78-1.69 (m, 8H), 1.65 (d, J=15.4 Hz, 2H), 1.56-1.46 (m, 3H), 1.44-1.40 (m, 4H), 1.32 (s, 1H), 1.17 (s, 1H), 1.07-1.00 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.98 (s, 1H), 8.03 (d, J=1.1 Hz, 2H), 7.63 (d, J=5.1 Hz, 2H), 7.37-7.27 (m, 4H), 7.21 (s, 1H), 6.95 (s, 1H), 6.43 (s, 1H), 6.01 (s, 1H), 4.94 (s, 1H), 4.85 (s, 1H), 4.67 (s, 1H), 4.41 (s, 1H), 4.32 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.77 (s, 1H), 2.19 (s, 1H), 2.13-2.01 (m, 2H), 1.89 (s, 1H), 1.83-1.74 (m, 2H), 1.74-1.69 (m, 2H), 1.66 (d, J=5.7 Hz, 2H), 1.58-1.49 (m, 6H), 1.31 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.39 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.62 (d, J=3.2 Hz, 2H), 6.17 (d, J=6.0 Hz, 2H), 5.59 (s, 1H), 5.27 (s, 1H), 4.98 (s, 1H), 4.91 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.51 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.98-1.95 (m, 2H), 1.92 (s, 1H), 1.73-1.61 (m, 5H), 1.41-1.37 (m, 2H), 1.34-1.28 (m, 10H), 1.21-1.11 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, J=4.8 Hz, 2H), 7.61 (d, J=2.2 Hz, 2H), 6.41 (s, 1H), 6.06 (s, 1H), 5.27 (s, 1H), 5.20 (s, 1H), 4.45 (s, 1H), 3.72 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.73 (s, 1H), 2.39-2.31 (m, 2H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.76-1.56 (m, 15H), 1.55-1.45 (m, 6H), 1.30 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.55 (s, 1H), 9.32 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.64 (d, J=11.6 Hz, 2H), 7.29-7.22 (m, 4H), 7.19 (s, 1H), 6.56 (s, 1H), 6.06 (s, 1H), 5.63 (s, 1H), 5.02 (s, 1H), 4.71 (s, 1H), 4.41 (s, 1H), 4.31 (s, 1H), 3.24 (d, J=17.3 Hz, 2H), 2.37 (s, 1H), 2.10-2.02 (m, 2H), 2.02-1.96 (m, 3H), 1.82 (s, 1H), 1.72 (t, J=9.8 Hz, 3H), 1.69-1.57 (m, 3H), 1.53 (s, 1H), 1.38-1.34 (m, 2H), 1.31 (s, 1H), 1.13-1.04 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.29 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.65 (d, J=4.6 Hz, 2H), 7.22 (s, 1H), 5.87 (d, J=8.3 Hz, 2H), 5.65 (s, 1H), 4.94 (s, 1H), 4.46 (s, 1H), 3.24 (d, J=14.8 Hz, 2H), 2.72 (s, 1H), 2.11-2.01 (m, 2H), 1.79 (d, J=1.0 Hz, 2H), 1.76-1.62 (m, 5H), 1.59 (s, 1H), 1.49-1.42 (m, 4H), 1.35-1.28 (m, 11H), 1.25 (s, 1H), 1.21-1.15 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 9.64 (s, 4H), 8.11 (d, J=10.4 Hz, 8H), 7.65 (d, J=1.9 Hz, 8H), 6.00 (s, 4H), 5.76 (s, 4H), 5.70 (s, 4H), 5.64 (s, 4H), 5.04 (s, 4H), 4.45 (s, 4H), 3.86 (s, 4H), 3.24 (d, J=17.3 Hz, 8H), 2.85 (s, 4H), 2.11-2.01 (m, 9H), 1.99-1.91 (m, 12H), 1.91-1.80 (m, 9H), 1.75 (s, 2H), 1.75-1.53 (m, 62H), 1.55-1.53 (m, 1H), 1.51 (s, 3H), 1.38-1.34 (m, 7H), 1.30 (s, 4H), 1.06 (s, 3H), 1.03-0.99 (m, 8H).
1H NMR (500 MHz, Chloroform) δ 8.56 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.42-7.28 (m, 5H), 7.21 (s, 1H), 6.00 (d, J=2.7 Hz, 2H), 4.43 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 3.83 (d, J=3.7 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 3.25 (s, 1H), 2.15 (s, 1H), 2.09-2.05 (m, 2H), 1.91 (s, 1H), 1.73-1.69 (m, 2H), 1.62-1.55 (m, 3H), 1.36-1.27 (m, 6H), 1.23 (s, 1H), 1.20-1.14 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 9.34 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 5.96 (s, 1H), 5.84 (s, 1H), 5.40 (s, 1H), 5.22 (s, 1H), 4.77 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.83 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.94-1.81 (m, 3H), 1.73-1.63 (m, 5H), 1.40-1.36 (m, 2H), 1.36-1.27 (m, 10H), 1.18 (s, 1H), 1.14-1.10 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.47 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.43 (d, J=13.7 Hz, 2H), 6.58 (s, 1H), 6.06 (s, 1H), 5.40 (s, 1H), 5.20 (s, 1H), 4.45 (s, 1H), 3.73 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.72 (s, 1H), 2.34-2.30 (m, 2H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.77-1.56 (m, 15H), 1.55-1.46 (m, 6H), 1.30 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.42 (s, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.34-7.25 (m, 4H), 7.20 (s, 1H), 6.77 (s, 1H), 5.89 (s, 1H), 5.82 (s, 1H), 5.57 (d, J=7.5 Hz, 2H), 4.42 (d, J=5.7 Hz, 2H), 4.34 (s, 1H), 3.24 (d, J=19.0 Hz, 2H), 2.81 (s, 1H), 2.43 (s, 1H), 2.11-2.01 (m, 2H), 1.95 (s, 1H), 1.86 (s, 1H), 1.81-1.74 (m, 3H), 1.69 (dt, J=17.1, 8.6 Hz, 5H), 1.47 (s, 1H), 1.41-1.37 (m, 2H), 1.31 (s, 1H), 0.84-0.77 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 3H), 8.13 (s, 3H), 7.79 (s, 3H), 7.69 (d, J=0.8 Hz, 6H), 7.44 (d, J=32.8 Hz, 6H), 6.55 (s, 3H), 6.05 (s, 3H), 5.75 (s, 3H), 4.77 (d, J=2.1 Hz, 6H), 3.25 (s, 3H), 3.21 (s, 3H), 2.70 (s, 3H), 2.11-2.01 (m, 6H), 1.96-1.87 (m, 6H), 1.79 (d, J=13.1 Hz, 5H), 1.70 (dt, J=19.3, 3.5 Hz, 19H), 1.60-1.51 (m, 18H), 1.35-1.30 (m, 30H).
1H NMR (500 MHz, Chloroform) δ 9.06 (s, 3H), 8.44 (s, 3H), 8.15 (s, 3H), 7.79 (s, 3H), 7.75 (s, 3H), 7.70 (s, 3H), 7.48 (d, J=8.2 Hz, 6H), 7.38 (s, 3H), 5.73 (s, 3H), 4.96 (s, 3H), 4.57 (s, 3H), 3.90 (s, 3H), 3.24 (d, J=14.7 Hz, 6H), 2.92 (s, 3H), 2.15-2.11 (m, 5H), 2.11-2.01 (m, 9H), 1.99 (t, J=7.9 Hz, 7H), 1.80 (s, 2H), 1.76-1.65 (m, 18H), 1.65-1.58 (m, 24H), 1.45 (t, J=13.5 Hz, 10H), 1.36 (dd, J=21.5, 15.7 Hz, 2H), 1.33 (s, 3H), 1.20 (s, 2H), 1.11-1.04 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.36 (s, 1H), 7.55 (d, J=12.3 Hz, 2H), 7.34 (t, J=21.8 Hz, 3H), 7.30-7.17 (m, 9H), 7.15 (d, J=2.2 Hz, 2H), 7.09 (s, 1H), 6.35 (s, 1H), 6.01 (s, 1H), 5.67 (s, 1H), 5.03 (s, 1H), 4.88 (s, 1H), 4.37 (s, 1H), 4.30 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.15 (d, J=18.6 Hz, 2H), 2.94 (s, 1H), 2.19 (s, 1H), 2.10-2.04 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.26 (s, 1H), 7.46 (s, 1H), 7.32 (t, J=17.0 Hz, 3H), 7.20 (dd, J=7.8, 5.2 Hz, 4H), 7.12 (s, 1H), 7.06 (s, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 4.84 (s, 1H), 4.69 (s, 1H), 4.53 (s, 1H), 3.45 (s, 1H), 3.41 (s, 1H), 3.35 (s, 1H), 3.30 (s, 1H), 3.19 (s, 1H), 2.96 (s, 1H), 2.16 (s, 1H), 2.13-2.01 (m, 2H), 1.89 (s, 1H), 1.30-1.26 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.35 (s, 1H), 7.90 (s, 1H), 7.52 (d, J=25.5 Hz, 2H), 7.39 (s, 1H), 7.29-7.21 (m, 4H), 7.14 (d, J=3.6 Hz, 2H), 7.08 (s, 1H), 6.52 (s, 1H), 6.16 (s, 1H), 5.70 (s, 1H), 4.92 (s, 1H), 4.78 (s, 1H), 3.46 (d, J=5.2 Hz, 2H), 3.35 (s, 1H), 3.21 (s, 1H), 2.85 (d, J=4.0 Hz, 2H), 2.17 (s, 1H), 2.13-2.02 (m, 2H), 2.00-1.90 (m, 3H), 1.68 (s, 1H), 1.56-1.50 (m, 2H), 1.49-1.45 (m, 3H), 1.44-1.40 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.70 (s, 1H), 7.50 (s, 1H), 7.39-7.20 (m, 5H), 7.20-7.11 (m, 4H), 7.09 (d, J=4.4 Hz, 2H), 7.06-6.94 (m, 2H), 6.90 (s, 1H), 6.19 (s, 1H), 5.93 (s, 1H), 5.51 (s, 1H), 4.70 (s, 1H), 4.25 (d, J=17.1 Hz, 2H), 3.79 (d, J=9.5 Hz, 2H), 3.24 (t, J=8.3 Hz, 3H), 3.04 (s, 1H), 2.16 (s, 1H), 2.12-2.04 (m, 3H), 1.78 (s, 1H), 1.72 (s, 1H), 1.62 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.64 (d, J=17.0 Hz, 2H), 8.19 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.36-7.27 (m, 2H), 7.27-7.22 (m, 2H), 7.14 (d, J=12.9 Hz, 2H), 7.08 (s, 1H), 5.63 (s, 1H), 5.01 (d, J=14.2 Hz, 2H), 4.78 (d, J=1.3 Hz, 2H), 3.24 (d, J=18.2 Hz, 2H), 3.18 (s, 1H), 3.03 (s, 1H), 2.97 (s, 1H), 2.06 (t, J=3.5 Hz, 3H), 1.94 (s, 1H), 1.88 (s, 1H), 1.81 (s, 1H), 1.21-1.17 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.76 (s, 1H), 7.53 (s, 1H), 7.41 (d, J=25.5 Hz, 2H), 7.27-7.21 (m, 2H), 7.21-7.18 (m, 2H), 7.15 (d, J=7.6 Hz, 2H), 7.08 (s, 1H), 5.95 (s, 1H), 5.61 (s, 1H), 5.25 (s, 1H), 5.14 (s, 1H), 4.78 (s, 1H), 3.42 (s, 1H), 3.25 (t, J=12.6 Hz, 3H), 2.87 (s, 1H), 2.70 (s, 1H), 2.56 (s, 1H), 2.08-2.04 (m, 2H), 2.02-1.90 (m, 2H), 1.87 (s, 1H), 1.80 (s, 1H), 1.68 (d, J=3.3 Hz, 2H), 1.55-1.51 (m, 4H), 1.48 (s, 1H), 1.45-1.39 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.51 (d, J=8.2 Hz, 2H), 7.41 (s, 1H), 7.30-7.12 (m, 12H), 6.67 (s, 1H), 5.69-5.61 (m, 3H), 5.09 (s, 1H), 4.88 (s, 1H), 4.41 (s, 1H), 4.33 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.26 (s, 1H), 3.16 (s, 1H), 3.07 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.54 (s, 1H), 7.47 (d, J=17.7 Hz, 2H), 7.28-7.22 (m, 3H), 7.18 (dd, J=20.8, 5.2 Hz, 4H), 6.42 (s, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 5.27 (s, 1H), 4.98 (s, 1H), 4.85 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.19 (s, 1H), 2.96 (s, 1H), 2.61 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.34-1.30 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.77 (s, 2H), 8.67 (s, 2H), 7.56 (s, 1H), 7.50 (s, 3H), 7.41 (s, 2H), 7.28-7.19 (m, 6H), 7.16 (d, J=4.9 Hz, 4H), 7.13-7.04 (m, 4H), 6.04 (s, 2H), 5.93 (s, 2H), 5.05 (s, 2H), 4.66 (s, 2H), 3.70 (s, 2H), 3.45 (s, 2H), 3.35 (s, 1H), 3.25 (s, 2H), 3.05 (s, 2H), 2.88 (s, 2H), 2.19 (s, 2H), 2.09-2.05 (m, 4H), 1.97-1.91 (m, 5H), 1.68-1.64 (m, 3H), 1.64-1.43 (m, 13H).
N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-benzofuran-2-carboxamide (A57)
1H NMR (500 MHz, Chloroform) δ 7.48 (s, 1H), 7.29 (d, J=38.0 Hz, 2H), 7.25 (s, 1H), 7.27-7.19 (m, 3H), 7.19-7.05 (m, 10H), 6.97 (s, 1H), 6.43 (s, 1H), 6.07 (s, 1H), 5.18 (d, J=3.4 Hz, 2H), 4.73 (s, 1H), 4.63 (s, 1H), 4.36 (s, 1H), 4.29 (s, 1H), 3.24 (d, J=16.8 Hz, 2H), 3.10 (s, 1H), 2.86 (d, J=21.8 Hz, 2H), 2.43 (s, 1H), 2.08-2.04 (m, 2H), 1.85 (s, 1H), 1.79 (s, 1H), 1.64 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.35 (s, 5H), 7.60 (s, 5H), 7.48 (d, J=29.1 Hz, 10H), 7.28-7.18 (m, 27H), 7.16 (d, J=17.5 Hz, 8H), 5.86 (s, 5H), 5.55 (s, 5H), 4.94 (s, 5H), 4.69 (s, 5H), 3.24 (t, J=10.0 Hz, 14H), 2.90 (s, 5H), 2.66 (s, 5H), 2.09-2.02 (m, 10H), 1.92 (s, 4H), 1.84-1.80 (m, 8H), 1.76 (s, 4H), 1.30-1.26 (m, 44H).
1H NMR (500 MHz, Chloroform) δ 9.35 (s, 5H), 7.60 (s, 5H), 7.48 (d, J=29.1 Hz, 10H), 7.28-7.18 (m, 27H), 7.16 (d, J=17.5 Hz, 8H), 5.86 (s, 5H), 5.55 (s, 5H), 4.94 (s, 5H), 4.69 (s, 5H), 3.24 (t, J=10.0 Hz, 14H), 2.90 (s, 5H), 2.66 (s, 5H), 2.09-2.02 (m, 10H), 1.92 (s, 4H), 1.84-1.80 (m, 8H), 1.76 (s, 4H), 1.30-1.26 (m, 44H).
1H NMR (500 MHz, Chloroform) δ 8.40 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.33 (d, J=3.7 Hz, 2H), 7.32-7.16 (m, 10H), 7.13 (d, J=16.7 Hz, 2H), 6.27 (s, 1H), 5.97 (s, 1H), 5.64 (s, 1H), 5.03 (s, 1H), 4.89 (s, 1H), 4.34 (d, J=4.2 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 3.15-3.11 (m, 2H), 2.94 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.93 (s, 1H), 7.82 (d, J=4.4 Hz, 2H), 7.28 (dd, J=20.7, 7.2 Hz, 4H), 7.22-7.11 (m, 3H), 6.05 (s, 1H), 4.70 (s, 1H), 4.64 (s, 1H), 4.59 (s, 1H), 4.39 (s, 1H), 3.99 (s, 1H), 3.55 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.15 (s, 1H), 2.95 (s, 1H), 2.17 (s, 1H), 2.13-2.02 (m, 2H), 1.89 (s, 1H), 1.21-1.17 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.32 (d, J=1.5 Hz, 2H), 7.28-7.23 (m, 2H), 7.15 (s, 1H), 7.12-7.05 (m, 2H), 6.14 (s, 1H), 5.94 (s, 1H), 5.04 (s, 1H), 4.66 (s, 1H), 3.45 (d, J=3.2 Hz, 2H), 3.35 (s, 1H), 3.26 (s, 1H), 3.05 (s, 1H), 2.89 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.95-1.91 (m, 3H), 1.73-1.64 (m, 3H), 1.56-1.52 (m, 2H), 1.50 (s, 1H), 1.46-1.40 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.49 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 7.29 (dd, J=19.0, 2.9 Hz, 4H), 7.18-7.07 (m, 5H), 7.07-6.97 (m, 3H), 6.33 (s, 1H), 6.11 (s, 1H), 4.93-4.89 (m, 2H), 4.36 (d, J=9.1 Hz, 2H), 4.29 (s, 1H), 3.28-3.20 (m, 3H), 2.92 (s, 1H), 2.58 (s, 1H), 2.16 (s, 1H), 2.08-2.04 (m, 2H), 1.83 (s, 1H), 1.77 (s, 1H), 1.73 (s, 1H).
N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-benzothiophene-2-carboxamide (A64)
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.30 (dd, J=17.5, 1.0 Hz, 4H), 7.26-7.19 (m, 2H), 7.17 (s, 1H), 7.02 (s, 1H), 6.45 (s, 1H), 6.10 (s, 1H), 5.93 (s, 1H), 4.93 (s, 1H), 4.86 (s, 1H), 3.27-3.11 (m, 3H), 2.95 (s, 1H), 2.83 (s, 1H), 2.11-2.01 (m, 2H), 1.95 (s, 1H), 1.83 (s, 1H), 1.76 (s, 1H), 1.56 (s, 1H), 1.35-1.31 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.28 (s, 6H), 7.86 (s, 6H), 7.60 (s, 6H), 7.27 (dd, J=17.2, 1.6 Hz, 20H), 7.24-7.12 (m, 22H), 5.78 (s, 6H), 5.41 (s, 6H), 5.09 (s, 6H), 4.97 (s, 6H), 4.85 (s, 6H), 3.31-3.10 (m, 30H), 2.97 (s, 6H), 2.60 (s, 4H), 2.51 (s, 5H), 2.12-2.00 (m, 12H), 1.97-1.86 (m, 12H), 1.71 (t, J=16.5 Hz, 17H), 1.58-1.45 (m, 30H), 1.45-1.36 (m, 12H), 1.12 (s, 4H).
1H NMR (500 MHz, Chloroform) δ 8.78 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.34-7.13 (m, 12H), 7.13-7.05 (m, 2H), 6.10 (s, 1H), 5.99 (s, 1H), 5.07 (s, 1H), 4.69 (s, 1H), 4.36 (d, J=3.5 Hz, 2H), 3.78-3.74 (m, 3H), 3.45 (s, 1H), 3.35 (s, 1H), 3.24 (s, 1H), 3.06 (s, 1H), 2.88 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.38 (s, 1H), 7.29-7.13 (m, 9H), 6.07 (s, 1H), 5.82 (d, J=4.8 Hz, 2H), 5.28 (s, 1H), 4.94 (s, 1H), 4.87 (s, 1H), 3.67-3.63 (m, 3H), 3.45 (s, 1H), 3.35 (s, 1H), 3.19 (s, 1H), 2.93 (s, 1H), 2.68 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.94 (s, 1H), 1.34-1.30 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.49 (s, 3H), 7.34-7.20 (m, 23H), 7.20 (s, 3H), 7.15 (s, 2H), 6.73 (s, 3H), 6.27 (s, 3H), 5.73 (s, 3H), 5.11 (s, 3H), 4.83 (s, 3H), 3.98 (s, 2H), 3.76 (s, 3H), 3.58-3.54 (m, 9H), 3.35 (s, 2H), 3.22 (s, 3H), 2.88 (s, 3H), 2.63 (s, 3H), 2.19 (s, 2H), 2.09-2.05 (m, 6H), 1.95-1.91 (m, 7H), 1.76-1.66 (m, 7H), 1.66-1.55 (m, 20H).
1H NMR (500 MHz, Chloroform) δ 7.35-7.29 (m, 2H), 7.29-7.26 (m, 1H), 7.26-7.06 (m, 11H), 6.67 (s, 1H), 6.05 (d, J=11.7 Hz, 2H), 5.74 (s, 1H), 4.95 (s, 1H), 4.77 (s, 1H), 4.39 (s, 1H), 4.34 (s, 1H), 3.86-3.82 (m, 3H), 3.29-3.17 (m, 3H), 2.95 (s, 1H), 2.56 (s, 1H), 2.44 (s, 1H), 2.12-2.00 (m, 2H), 1.85 (s, 1H), 1.78 (s, 1H), 1.41 (s, 1H), 1.15 (s, 1H).
N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-1-methyl-1H-indole-2-carboxamide (A70)
1H NMR (500 MHz, Chloroform) δ 7.51 (s, 1H), 7.31 (s, 1H), 7.22 (ddd, J=42.8, 13.4, 8.7 Hz, 8H), 6.91 (s, 1H), 6.06 (s, 1H), 5.93 (s, 1H), 5.54 (s, 1H), 4.80 (s, 1H), 4.71 (s, 1H), 3.73-3.69 (m, 3H), 3.26 (t, J=14.0 Hz, 3H), 2.82 (d, J=27.3 Hz, 2H), 2.11-2.01 (m, 2H), 1.92 (s, 1H), 1.82 (s, 1H), 1.75 (s, 1H), 1.54 (s, 1H), 1.32-1.28 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.25 (s, 1H), 7.38 (s, 1H), 7.28 (dd, J=15.9, 3.4 Hz, 4H), 7.24-7.12 (m, 5H), 5.93 (s, 1H), 5.32 (s, 1H), 5.07 (s, 1H), 4.75 (s, 1H), 4.41 (s, 1H), 3.85-3.77 (m, 4H), 3.27-3.20 (m, 3H), 3.04 (s, 1H), 2.84 (s, 1H), 2.49 (s, 1H), 2.17-2.10 (m, 2H), 2.10-2.02 (m, 2H), 1.86-1.75 (m, 6H), 1.65 (s, 1H), 1.58-1.52 (m, 4H).
1H NMR (500 MHz, Chloroform) δ 8.55 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 7.32-7.27 (m, 4H), 7.27-7.12 (m, 8H), 7.10 (s, 1H), 6.00 (s, 1H), 5.04 (s, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 4.38 (s, 1H), 4.30 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.27 (s, 1H), 3.12 (s, 1H), 2.87 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.55 (s, 1H), 8.14 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.28-7.22 (m, 2H), 7.22-7.11 (m, 3H), 7.09 (s, 1H), 6.01 (s, 1H), 5.55 (s, 1H), 5.12 (s, 1H), 4.74 (s, 1H), 4.31 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.30 (s, 1H), 3.08 (s, 1H), 2.92 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.39-1.35 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.85 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.28-7.23 (m, 2H), 7.15 (s, 1H), 7.12-7.06 (m, 3H), 6.10 (s, 1H), 5.94 (s, 1H), 5.03 (s, 1H), 4.66 (s, 1H), 3.45 (d, J=5.0 Hz, 2H), 3.35 (s, 1H), 3.27 (s, 1H), 3.06 (s, 1H), 2.90 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.95-1.91 (m, 3H), 1.72-1.68 (m, 3H), 1.56-1.52 (m, 2H), 1.50 (s, 1H), 1.46-1.41 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.67 (s, 13H), 7.46 (s, 13H), 7.30-7.24 (m, 28H), 7.24-7.14 (m, 80H), 7.12-7.00 (m, 30H), 7.00 (s, 11H), 6.93 (d, J=12.0 Hz, 26H), 6.07 (s, 13H), 4.91 (s, 13H), 4.80 (s, 13H), 4.36 (s, 13H), 4.31 (s, 13H), 4.27 (s, 13H), 4.04 (s, 13H), 3.31 (d, J=52.2 Hz, 35H), 3.22 (s, 5H), 3.01 (s, 14H), 2.86 (s, 11H), 2.31 (s, 9H), 2.08-2.04 (m, 25H), 1.83 (s, 12H), 1.77 (s, 10H), 1.54 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.53 (s, 8H), 7.62 (s, 8H), 7.43 (s, 8H), 7.38 (s, 8H), 7.26-7.21 (m, 16H), 7.21-7.14 (m, 21H), 7.14-7.11 (m, 4H), 7.09 (s, 8H), 5.81 (s, 8H), 5.66 (s, 8H), 5.34 (s, 8H), 4.92 (s, 8H), 4.75 (s, 8H), 3.33-3.20 (m, 24H), 2.87 (s, 7H), 2.59 (s, 7H), 2.08-2.04 (m, 16H), 1.86 (s, 6H), 1.80 (s, 7H), 1.73 (s, 6H), 1.48 (s, 6H), 1.34-1.30 (m, 72H).
1H NMR (500 MHz, Chloroform) δ 9.14 (s, 1H), 9.09 (s, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.33-7.27 (m, 2H), 7.27-7.14 (m, 3H), 7.10 (s, 1H), 6.82 (s, 1H), 5.96 (s, 1H), 5.80 (s, 1H), 4.98 (s, 1H), 4.82 (s, 1H), 3.35 (s, 1H), 3.24 (d, J=14.7 Hz, 2H), 3.16 (s, 1H), 2.96 (s, 1H), 2.83 (s, 1H), 2.16-2.04 (m, 5H), 1.82 (s, 1H), 1.75 (dd, J=19.9, 8.6 Hz, 4H), 1.59-1.49 (m, 4H), 1.44-1.40 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 9.21 (s, 1H), 8.80 (s, 1H), 8.10 (d, J=21.9 Hz, 2H), 7.71 (s, 1H), 7.63 (d, J=6.0 Hz, 2H), 7.30-7.11 (m, 10H), 6.38 (s, 1H), 5.97 (s, 1H), 4.90 (s, 1H), 4.69 (s, 1H), 4.36 (d, J=4.9 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 3.16 (s, 1H), 2.95 (s, 1H), 2.86 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.43 (s, 1H), 9.01 (s, 1H), 8.10 (d, J=11.8 Hz, 2H), 7.68-7.64 (m, 2H), 7.25-7.19 (m, 1H), 7.19-7.09 (m, 4H), 6.12 (s, 1H), 6.04 (s, 1H), 5.51 (s, 1H), 5.09 (s, 1H), 4.74 (s, 1H), 3.45 (s, 1H), 3.35 (d, J=2.3 Hz, 2H), 3.11 (s, 1H), 2.89 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.39-1.35 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 9.46 (s, 1H), 8.10 (d, J=1.3 Hz, 2H), 7.64 (d, J=1.4 Hz, 2H), 7.29-7.21 (m, 4H), 7.15 (s, 1H), 6.17 (s, 1H), 5.60 (s, 1H), 5.41 (s, 1H), 5.16 (s, 1H), 4.42 (s, 1H), 3.77 (s, 1H), 3.45 (s, 1H), 3.35 (d, J=2.0 Hz, 2H), 2.94 (s, 1H), 2.49 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.81-1.74 (m, 6H), 1.74-1.70 (m, 2H), 1.57-1.51 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 9.04 (s, 1H), 8.07 (d, J=5.3 Hz, 2H), 7.62 (d, J=0.9 Hz, 2H), 7.30-7.20 (m, 5H), 7.20-7.12 (m, 5H), 7.10 (s, 1H), 6.69 (s, 1H), 5.68 (d, J=19.5 Hz, 2H), 5.14 (s, 1H), 5.08 (s, 1H), 4.42 (s, 1H), 4.34 (s, 1H), 3.37 (s, 1H), 3.24 (d, J=17.2 Hz, 2H), 2.95 (s, 1H), 2.15 (s, 1H), 2.09-2.03 (m, 2H), 1.76 (s, 1H), 1.70 (s, 1H), 1.63 (s, 1H), 1.43 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.37 (s, 1H), 8.11 (d, J=1.9 Hz, 2H), 7.64 (d, J=1.0 Hz, 2H), 7.32-7.26 (m, 2H), 7.26-7.13 (m, 3H), 6.08 (s, 1H), 5.93 (d, J=13.8 Hz, 2H), 5.60 (s, 1H), 4.97 (s, 1H), 4.83 (s, 1H), 3.24 (d, J=16.7 Hz, 2H), 3.18 (s, 1H), 2.93 (s, 1H), 2.70 (s, 1H), 2.11-2.01 (m, 2H), 1.98 (s, 1H), 1.78 (s, 1H), 1.71 (s, 1H), 1.42 (s, 1H), 1.35-1.31 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 9.67 (s, 6H), 8.12 (d, J=8.3 Hz, 12H), 7.66 (d, J=1.4 Hz, 12H), 7.26-7.16 (m, 25H), 7.14 (s, 6H), 6.12 (s, 6H), 5.79 (s, 6H), 5.56 (s, 6H), 5.33 (s, 6H), 5.10 (s, 6H), 4.95 (s, 6H), 3.84 (s, 6H), 3.27 (t, J=34.6 Hz, 16H), 3.21 (d, J=6.1 Hz, 2H), 3.02 (s, 6H), 2.83 (s, 6H), 2.11-2.01 (m, 13H), 2.01-1.94 (m, 18H), 1.75 (s, 4H), 1.71-1.55 (m, 59H).
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 1H), 8.12 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.31-7.24 (m, 4H), 7.24-7.14 (m, 4H), 7.12 (s, 2H), 5.72 (s, 1H), 5.54 (s, 1H), 5.14 (s, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 4.29 (d, J=9.5 Hz, 2H), 3.74 (s, 1H), 3.35 (s, 1H), 3.31 (s, 1H), 3.08 (s, 1H), 2.72 (s, 1H), 2.17 (s, 1H), 2.10-2.05 (m, 2H), 1.89 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.40 (d, J=39.3 Hz, 11H), 8.36-8.34 (m, 1H), 8.19 (s, 6H), 7.80 (s, 6H), 7.71 (s, 6H), 7.49 (d, J=5.7 Hz, 12H), 7.30-7.25 (m, 12H), 7.25-7.15 (m, 14H), 7.14 (s, 4H), 6.20 (s, 6H), 5.92 (s, 6H), 5.07 (s, 6H), 4.75 (s, 6H), 3.45 (s, 6H), 3.38 (d, J=25.1 Hz, 12H), 3.32 (s, 1H), 3.02 (s, 6H), 2.35 (s, 5H), 2.19 (s, 4H), 2.09-2.05 (m, 12H), 1.92 (s, 5H), 1.36-1.32 (m, 53H).
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.49 (d, J=7.1 Hz, 2H), 7.26-7.20 (m, 2H), 7.20-7.09 (m, 3H), 5.94 (d, J=1.5 Hz, 2H), 5.63 (s, 1H), 5.44 (s, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.89 (s, 1H), 3.45 (s, 1H), 3.34 (d, J=11.1 Hz, 2H), 3.01 (s, 1H), 2.19 (d, J=10.9 Hz, 2H), 2.14-2.04 (m, 4H), 1.92 (s, 1H), 1.65-1.49 (m, 8H).
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.26-7.11 (m, 10H), 6.86 (s, 1H), 5.98 (s, 1H), 5.89 (s, 1H), 5.56 (d, J =16.8 Hz, 2H), 4.75 (s, 1H), 4.44 (s, 1H), 4.32 (s, 1H), 3.44 (s, 1H), 3.23 (d, J=18.1 Hz, 2H), 2.84 (s, 1H), 2.72 (s, 1H), 2.11-2.01 (m, 2H), 1.98 (s, 1H), 1.63 (s, 1H), 1.56 (s, 1H), 1.25 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.50 (d, J=13.8 Hz, 2H), 8.17 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.28-7.24 (m, 1H), 7.24-7.11 (m, 4H), 6.95 (s, 1H), 6.17 (s, 1H), 5.50 (s, 1H), 5.00 (s, 1H), 4.79 (s, 1H), 3.24 (d, J=15.4 Hz, 2H), 3.08 (s, 1H), 2.90 (s, 1H), 2.69 (s, 1H), 2.11-2.01 (m, 2H), 1.90 (s, 1H), 1.84 (d, J=3.8 Hz, 2H), 1.78 (s, 1H), 1.29-1.25 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 9.70 (s, 4H), 8.44 (s, 4H), 8.18 (s, 4H), 7.80 (s, 4H), 7.69 (d, J=18.4 Hz, 8H), 7.48 (d, J=4.0 Hz, 8H), 7.32-7.26 (m, 8H), 7.23-7.13 (m, 12H), 6.67 (s, 4H), 5.84 (s, 4H), 4.95 (s, 4H), 4.88 (s, 4H), 3.90 (s, 4H), 3.31 (d, J=56.1 Hz, 10H), 3.22 (s, 2H), 2.99 (s, 4H), 2.86 (s, 4H), 2.11-2.04 (m, 8H), 2.01 (t, J=7.0 Hz, 12H), 1.81 (s, 3H), 1.74 (s, 3H), 1.67-1.60 (m, 35H), 1.45 (s, 3H).
1H NMR (500 MHz, Chloroform) δ 8.36 (s, 1H), 7.52 (d, J=19.2 Hz, 2H), 7.39 (s, 1H), 7.26-7.19 (m, 4H), 7.18 (s, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.32 (s, 1H), 6.24 (s, 1H), 6.05 (s, 1H), 5.47 (s, 1H), 5.27 (s, 1H), 4.61 (s, 1H), 4.41 (s, 1H), 4.32 (s, 1H), 3.59 (s, 1H), 3.45 (s, 1H), 2.17 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.73 (d, J=11.4 Hz, 2H), 1.63 (s, 1H), 1.55 (s, 1H), 1.12-0.99 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.33 (s, 1H), 8.28 (s, 1H), 7.46 (d, J=15.1 Hz, 2H), 7.35 (s, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 6.12 (s, 1H), 5.28 (s, 1H), 4.95 (s, 1H), 4.31 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.75 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.70 (d, J=19.2 Hz, 2H), 1.44 (s, 1H), 1.36-1.32 (m, 9H), 0.99-0.85 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 7.51 (d, J=17.6 Hz, 2H), 7.37 (s, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 6.50 (s, 1H), 6.00 (s, 1H), 5.60 (s, 1H), 5.50 (s, 1H), 5.00 (s, 1H), 4.68 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.29 (s, 1H), 2.71 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.97-1.91 (m, 3H), 1.70 (t, J=9.1 Hz, 3H), 1.59-1.55 (m, 2H), 1.50 (dd, J=10.4, 1.1 Hz, 4H), 1.43-1.38 (m, 2H), 1.13-1.00 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.63 (s, 1H), 7.56 (s, 1H), 7.46 (d, J=25.5 Hz, 2H), 7.29-7.24 (m, 2H), 7.24-7.17 (m, 3H), 7.17-7.06 (m, 3H), 6.14 (s, 1H), 5.63 (s, 1H), 5.02 (d, J=15.0 Hz, 2H), 4.43 (s, 1H), 4.37 (s, 1H), 4.30 (s, 1H), 3.24 (d, J=17.4 Hz, 2H), 2.81 (s, 1H), 2.21 (s, 1H), 2.08-2.04 (m, 2H), 1.85 (s, 1H), 1.77 (t, J=13.2 Hz, 3H), 1.51 (s, 1H), 1.41 (s, 1H), 1.04-0.90 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 8.13 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 5.95 (s, 1H), 5.30 (d, J=18.0 Hz, 2H), 4.86 (s, 1H), 4.51 (s, 1H), 3.23 (d, J=15.7 Hz, 2H), 2.45 (s, 1H), 2.19 (s, 1H), 2.08-2.04 (m, 2H), 1.96 (s, 1H), 1.75 (s, 1H), 1.69 (d, J=8.0 Hz, 2H), 1.51 (s, 1H), 1.36-1.27 (m, 10H), 1.12-0.99 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.04 (s, 1H), 8.28 (s, 1H), 7.50 (d, J=31.2 Hz, 2H), 7.38 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 6.19 (s, 1H), 5.81 (s, 1H), 5.63 (s, 1H), 4.78 (s, 1H), 4.59 (s, 1H), 3.94 (s, 1H), 3.24 (d, J=18.2 Hz, 2H), 2.35 (s, 1H), 2.13-2.04 (m, 4H), 2.00 (s, 1H), 1.83-1.60 (m, 8H), 1.57 (s, 1H), 1.52-1.46 (m, 2H), 1.45-1.41 (m, 2H), 1.33 (s, 1H), 1.13-1.01 (m, 6H).
N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-benzofuran-2-carboxamide (A96)
1H NMR (500 MHz, Chloroform) δ 7.74 (s, 1H), 7.42 (s, 1H), 7.36-7.26 (m, 4H), 7.23 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 6.96 (s, 1H), 6.46 (s, 1H), 6.22 (s, 1H), 5.75 (s, 1H), 5.06 (s, 1H), 4.63 (s, 1H), 4.46 (d, J=17.5 Hz, 2H), 4.34 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.28 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.67 (s, 1H), 1.55 (s, 1H), 1.19 (s, 1H), 1.07-0.94 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.17 (s, 1H), 7.45 (d, J=28.3 Hz, 2H), 7.22 (s, 1H), 7.15 (s, 1H), 6.41 (s, 1H), 6.00 (s, 1H), 5.96 (s, 1H), 4.94 (s, 1H), 4.55 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.53 (s, 1H), 2.18 (s, 1H), 2.13-2.02 (m, 2H), 1.93 (s, 1H), 1.76 (s, 1H), 1.65 (s, 1H), 1.35-1.31 (m, 9H), 1.25 (s, 1H), 1.07-0.94 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 4H), 7.55-7.39 (m, 12H), 7.22 (s, 4H), 7.15 (s, 4H), 6.04 (s, 4H), 5.94 (s, 4H), 5.89 (s, 4H), 4.87 (s, 4H), 4.48 (s, 4H), 3.80 (s, 4H), 3.45 (s, 4H), 3.35 (s, 3H), 2.58 (s, 4H), 2.18 (s, 4H), 2.11-2.04 (m, 8H), 1.95-1.88 (m, 19H), 1.87 (t, J=3.1 Hz, 4H), 1.75 (d, J=29.9 Hz, 6H), 1.71 (d, J=3.3 Hz, 2H), 1.69-1.64 (m, 8H), 1.62 (s, 3H), 1.59-1.51 (m, 8H), 1.06-0.93 (m, 24H).
1H NMR (500 MHz, Chloroform) δ 7.58 (s, 1H), 7.52 (d, J=13.8 Hz, 2H), 7.38-7.32 (m, 2H), 7.30 (s, 1H), 7.26 (s, 1H), 7.23-7.16 (m, 3H), 6.21 (s, 1H), 5.77 (s, 1H), 5.68 (s, 1H), 4.86 (s, 1H), 4.82 (s, 1H), 4.56 (s, 1H), 4.37 (s, 1H), 4.33 (s, 1H), 3.24 (d, J=17.0 Hz, 2H), 2.63 (s, 1H), 2.05 (t, J=5.4 Hz, 3H), 1.82 (s, 1H), 1.75 (s, 1H), 1.60 (d, J=3.4 Hz, 2H), 1.48 (s, 1H), 1.39 (s, 1H), 1.09-1.00 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.58 (s, 1H), 7.52 (d, J=13.8 Hz, 2H), 7.38-7.32 (m, 2H), 7.30 (s, 1H), 7.26 (s, 1H), 7.23-7.16 (m, 3H), 6.21 (s, 1H), 5.77 (s, 1H), 5.68 (s, 1H), 4.86 (s, 1H), 4.82 (s, 1H), 4.56 (s, 1H), 4.37 (s, 1H), 4.33 (s, 1H), 3.24 (d, J=17.0 Hz, 2H), 2.63 (s, 1H), 2.05 (t, J=5.4 Hz, 3H), 1.82 (s, 1H), 1.75 (s, 1H), 1.60 (d, J=3.4 Hz, 2H), 1.48 (s, 1H), 1.39 (s, 1H), 1.09-1.00 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 1H), 7.48 (d, J=9.6 Hz, 2H), 7.20 (s, 1H), 7.14 (s, 1H), 5.80 (s, 1H), 5.26 (s, 1H), 5.11 (d, J=5.2 Hz, 2H), 4.91 (s, 1H), 3.81 (s, 1H), 3.24 (d, J=17.3 Hz, 2H), 2.61 (s, 1H), 2.09-2.02 (m, 4H), 1.95-1.87 (m, 2H), 1.84 (s, 1H), 1.77 (s, 1H), 1.69 (s, 1H), 1.58 (d, J=5.5 Hz, 2H), 1.51-1.44 (m, 4H), 1.26-1.22 (m, 4H), 1.08-0.95 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.47 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.33 (d, J=6.1 Hz, 2H), 7.28-7.17 (m, 5H), 6.42 (s, 1H), 6.05 (s, 1H), 5.73 (s, 1H), 5.38 (s, 1H), 5.27 (s, 1H), 4.46 (s, 1H), 4.36 (d, J=16.9 Hz, 2H), 3.45 (s, 1H), 3.35 (s, 1H), 2.67 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.82 (s, 1H), 1.70 (s, 1H), 1.52 (s, 1H), 1.10-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.37 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.30 (d, J=2.2 Hz, 2H), 6.58 (s, 1H), 6.03 (s, 1H), 5.61 (s, 1H), 5.53 (s, 1H), 5.02 (s, 1H), 4.70 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.69 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.69 (d, J=8.4 Hz, 2H), 1.49 (s, 1H), 1.32-1.28 (m, 9H), 1.10-1.02 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.34-7.30 (m, 2H), 6.18 (d, J=11.5 Hz, 2H), 6.02 (s, 1H), 4.62 (s, 1H), 4.48 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.27 (s, 1H), 2.56 (s, 1H), 2.19 (s, 1H), 2.11-2.05 (m, 3H), 1.92 (s, 1H), 1.83-1.70 (m, 3H), 1.69 (s, 1H), 1.59-1.54 (m, 3H), 1.50 (t, J=6.7 Hz, 3H), 1.42-1.37 (m, 2H), 1.12-0.98 (m, 6H).
N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)but-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-benzothiophene-2-carboxamide (A105)
1H NMR (500 MHz, Chloroform) δ 8.43 (s, 1H), 7.93 (d, J=0.7 Hz, 2H), 7.74 (s, 1H), 7.33 (d, J=2.2 Hz, 2H), 7.30-7.25 (m, 4H), 7.20 (s, 1H), 6.65 (s, 1H), 6.05 (s, 1H), 5.58 (s, 1H), 4.71 (s, 1H), 4.52 (s, 1H), 4.40 (s, 1H), 4.30 (s, 1H), 3.23 (d, J=15.8 Hz, 2H), 2.73 (s, 1H), 2.16 (s, 1H), 2.08-2.04 (m, 2H), 1.80 (s, 1H), 1.69 (d, J=6.6 Hz, 2H), 1.63 (s, 1H), 1.44 (s, 1H), 1.35 (s, 1H), 1.12-0.99 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.39 (s, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.31 (d, J=2.6 Hz, 2H), 6.50 (s, 1H), 5.87 (s, 1H), 5.71 (s, 1H), 5.57 (s, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 3.23 (d, J=15.7 Hz, 2H), 2.64 (s, 1H), 2.08-2.04 (m, 2H), 1.87 (d, J=17.5 Hz, 2H), 1.68 (d, J=6.0 Hz, 2H), 1.61 (d, J=2.0 Hz, 2H), 1.37 (s, 1H), 1.32-1.28 (m, 9H), 1.10-0.97 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.30 (s, 15H), 8.25 (s, 15H), 7.87 (s, 15H), 7.71 (s, 15H), 7.30 (d, J=1.3 Hz, 30H), 6.03 (s, 15H), 5.58 (s, 15H), 5.39 (s, 15H), 5.03 (s, 15H), 4.37 (s, 15H), 3.85 (s, 15H), 3.24 (d, J=16.7 Hz, 29H), 2.67 (s, 11H), 2.57 (s, 13H), 2.08-2.04 (m, 30H), 1.96-1.90 (m, 46H), 1.86 (s, 15H), 1.79 (s, 12H), 1.76-1.53 (m, 169H), 1.58 (d, J=5.6 Hz, 3H), 1.05-0.92 (m, 93H).
1H NMR (500 MHz, Chloroform) δ 7.39 (d, J=5.1 Hz, 10H), 7.31-7.22 (m, 12H), 7.22-7.06 (m, 35H), 5.99 (s, 5H), 5.29 (s, 5H), 4.40 (d, J=4.6 Hz, 10H), 4.30 (d, J=5.3 Hz, 1H), 4.24 (d, J=52.5 Hz, 9H), 3.68-3.64 (m, 15H), 3.58 (s, 5H), 3.45 (s, 5H), 2.78 (s, 5H), 2.17 (s, 3H), 2.15-1.95 (m, 17H), 1.89 (s, 4H), 1.81 (s, 5H), 1.62 (s, 5H), 1.48 (s, 4H), 1.07-0.94 (m, 31H).
1H NMR (500 MHz, Chloroform) δ 8.20 (s, 1H), 7.48 (s, 1H), 7.27 (d, J=17.1 Hz, 2H), 7.18 (d, J=7.0 Hz, 2H), 6.13 (s, 1H), 5.90 (s, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 4.65 (s, 1H), 3.79-3.75 (m, 3H), 3.45 (s, 1H), 3.35 (s, 1H), 2.81 (s, 1H), 2.17 (s, 1H), 2.13-2.02 (m, 2H), 1.93 (s, 1H), 1.67 (s, 1H), 1.60 (s, 1H), 1.55 (s, 1H), 1.34-1.30 (m, 9H), 1.13-1.00 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.37 (s, 3H), 7.28 (d, J=4.7 Hz, 6H), 7.19 (d, J=11.4 Hz, 6H), 6.24 (s, 3H), 5.90 (s, 3H), 5.81 (s, 3H), 5.30 (s, 3H), 4.90 (s, 3H), 4.68 (s, 3H), 3.90-3.86 (m, 9H), 3.45 (s, 3H), 3.37-3.33 (m, 5H), 2.70 (s, 3H), 2.19 (s, 3H), 2.12-2.04 (m, 6H), 1.93 (s, 3H), 1.86-1.76 (m, 9H), 1.71-1.60 (m, 11H), 1.60-1.54 (m, 1H), 1.51 (dd, J=18.4, 1.5 Hz, 11H), 1.44-1.38 (m, 6H), 1.08-0.95 (m, 18H).
1H NMR (500 MHz, Chloroform) δ 7.62 (s, 1H), 7.34 (s, 1H), 7.30-7.17 (m, 8H), 6.58 (s, 1H), 6.10 (s, 1H), 5.61 (s, 1H), 5.41 (s, 1H), 4.83 (s, 1H), 4.48 (s, 1H), 4.37 (s, 1H), 4.32 (s, 1H), 3.76-3.72 (m, 3H), 3.24 (d, J=17.6 Hz, 2H), 2.57 (s, 1H), 2.08-2.04 (m, 2H), 1.80 (s, 1H), 1.76 (s, 1H), 1.71-1.65 (m, 2H), 1.56 (d, J=15.2 Hz, 2H), 1.21 (s, 1H), 1.10-0.97 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.57 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 7.18 (d, J=5.1 Hz, 2H), 5.92 (s, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 4.99 (s, 1H), 4.47 (s, 1H), 3.74-3.70 (m, 3H), 3.24 (d, J=16.8 Hz, 2H), 2.71 (s, 1H), 2.41 (s, 1H), 2.08-2.04 (m, 2H), 1.76 (dd, J=34.2, 16.8 Hz, 4H), 1.55 (s, 1H), 1.45 (s, 1H), 1.30-1.26 (m, 9H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.57 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 7.18 (d, J=5.1 Hz, 2H), 5.92 (s, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 4.99 (s, 1H), 4.47 (s, 1H), 3.74-3.70 (m, 3H), 3.24 (d, J=16.8 Hz, 2H), 2.71 (s, 1H), 2.41 (s, 1H), 2.08-2.04 (m, 2H), 1.76 (dd, J=34.2, 16.8 Hz, 4H), 1.55 (s, 1H), 1.45 (s, 1H), 1.30-1.26 (m, 9H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.48 (s, 5H), 7.69 (s, 5H), 7.37 (s, 5H), 7.29 (d, J=6.5 Hz, 3H), 7.28-7.15 (m, 23H), 7.06 (s, 5H), 6.19 (s, 5H), 5.64 (s, 5H), 5.49 (s, 5H), 5.18 (s, 5H), 4.42 (s, 5H), 4.35 (d, J=14.2 Hz, 10H), 3.45 (s, 5H), 3.35 (d, J=1.5 Hz, 9H), 3.05 (s, 5H), 2.19 (s, 4H), 2.09-2.05 (m, 10H), 1.92 (s, 4H), 1.68 (s, 5H), 1.58 (s, 5H), 1.52 (s, 5H), 1.02-0.89 (m, 31H).
N-((S)-14 (S)-4-(tert-butylamino)-3,4-dione-14 (S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxopentan-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A115)
1H NMR (500 MHz, Chloroform) δ 8.36 (s, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.06 (s, 1H), 6.45 (s, 1H), 6.04 (s, 1H), 5.52 (d, J=2.2 Hz, 2H), 4.99 (s, 1H), 4.68 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.72 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.70 (d, J=9.3 Hz, 2H), 1.49 (s, 1H), 1.32-1.28 (m, 9H), 1.11-1.02 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.33 (s, 1H), 8.27 (s, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.03 (s, 1H), 6.84 (s, 1H), 6.14 (s, 1H), 5.29 (s, 1H), 4.95 (s, 1H), 4.31 (s, 1H), 3.83 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.73 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 2.05-1.90 (m, 3H), 1.72 (s, 1H), 1.70-1.44 (m, 9H), 1.44 (d, J=5.3 Hz, 1H), 0.98-0.85 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.29-7.22 (m, 4H), 7.19 (s, 1H), 7.10 (d, J=11.4 Hz, 2H), 6.65 (s, 1H), 5.62 (s, 1H), 5.55 (s, 1H), 4.99 (s, 1H), 4.48 (s, 1H), 4.37 (s, 1H), 4.33 (s, 1H), 3.24 (d, J=16.8 Hz, 2H), 2.56 (s, 1H), 2.45 (s, 1H), 2.08-2.04 (m, 2H), 1.80 (d, J=3.6 Hz, 2H), 1.72 (d, J=14.6 Hz, 2H), 1.55 (s, 1H), 1.46 (s, 1H), 1.10-0.97 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.59 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.20 (s, 1H), 5.74 (s, 1H), 5.41 (s, 1H), 4.71 (s, 1H), 4.48 (s, 1H), 3.24 (d, J=17.3 Hz, 2H), 2.48 (s, 1H), 2.06 (t, J=2.1 Hz, 3H), 1.86-1.74 (m, 3H), 1.68 (s, 1H), 1.58 (s, 1H), 1.53 (s, 1H), 1.32-1.28 (m, 9H), 1.15-1.01 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.63 (s, 1H), 8.33 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.32 (s, 1H), 5.80 (s, 1H), 5.52 (s, 1H), 4.79 (s, 1H), 4.59 (s, 1H), 3.96 (s, 1H), 3.24 (d, J=17.9 Hz, 2H), 2.36 (s, 1H), 2.15-2.08 (m, 2H), 2.08-2.04 (m, 2H), 2.00 (s, 1H), 1.74-1.68 (m, 5H), 1.68-1.60 (m, 3H), 1.60-1.50 (m, 5H), 1.33 (s, 1H), 1.13-1.01 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.79 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.64 (d, J=1.5 Hz, 2H), 7.36-7.25 (m, 4H), 7.20 (s, 1H), 5.82 (s, 1H), 5.78 (s, 1H), 5.24 (s, 1H), 4.97 (s, 1H), 4.68 (s, 1H), 4.36 (s, 1H), 4.23 (s, 1H), 3.68 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.21 (s, 1H), 2.09-2.05 (m, 2H), 1.90 (d, J=15.7 Hz, 2H), 1.76 (s, 1H), 1.65 (s, 1H), 1.45 (s, 1H), 1.10-0.97 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.24 (s, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.85 (s, 1H), 7.65 (d, J=1.9 Hz, 2H), 6.22 (s, 1H), 6.11 (s, 1H), 5.66 (s, 1H), 4.77 (s, 1H), 4.62 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.79 (s, 1H), 2.17 (s, 1H), 2.13-2.02 (m, 2H), 1.92 (s, 1H), 1.67 (d, J=2.5 Hz, 2H), 1.51 (s, 1H), 1.34-1.30 (m, 9H), 1.11-1.02 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.29 (s, 1H), 8.09 (d, J=18.4 Hz, 2H), 7.60 (d, J=2.0 Hz, 2H), 6.27 (s, 1H), 6.23 (s, 1H), 5.90 (s, 1H), 5.24 (s, 1H), 4.80 (s, 1H), 4.70 (s, 1H), 3.45 (s, 1H), 3.35 (d, J=1.2 Hz, 2H), 2.58 (s, 1H), 2.18 (s, 1H), 2.11-2.03 (m, 2H), 1.93 (s, 1H), 1.86-1.71 (m, 3H), 1.71-1.60 (m, 4H), 1.55-1.46 (m, 4H), 1.44-1.39 (m, 2H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.35 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.64 (d, J=15.8 Hz, 2H), 7.33-7.26 (m, 3H), 7.26-7.21 (m, 2H), 6.55 (s, 1H), 6.29 (s, 1H), 5.62 (d, J=10.0 Hz, 2H), 4.84 (s, 1H), 4.54 (s, 1H), 4.16 (d, J=16.2 Hz, 2H), 3.24 (d, J=17.4 Hz, 2H), 2.98 (s, 1H), 2.32 (s, 1H), 2.10-2.04 (m, 3H), 1.85 (s, 1H), 1.78 (s, 1H), 1.71 (s, 1H), 1.59 (s, 1H), 1.45 (s, 1H), 1.13-1.00 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.23 (s, 1H), 8.12 (d, J=11.8 Hz, 2H), 7.65 (d, J=2.9 Hz, 2H), 6.31 (s, 1H), 6.08 (s, 1H), 5.70 (s, 1H), 5.63 (s, 1H), 4.89 (s, 1H), 4.62 (s, 1H), 3.24 (d, J=17.3 Hz, 2H), 2.62 (s, 1H), 2.04 (t, J=12.6 Hz, 3H), 1.80 (s, 1H), 1.76-1.69 (m, 3H), 1.51 (s, 1H), 1.40 (s, 1H), 1.33-1.29 (m, 9H), 1.12-0.99 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.32 (s, 1H), 8.97 (s, 1H), 8.11 (d, J=3.7 Hz, 2H), 7.65 (d, J=2.2 Hz, 2H), 5.73 (s, 1H), 5.60 (s, 1H), 5.56 (s, 1H), 4.72 (s, 1H), 4.51 (s, 1H), 3.31-3.20 (m, 3H), 2.59 (s, 1H), 2.08-2.00 (m, 5H), 1.81 (s, 1H), 1.69 (d, J=9.0 Hz, 2H), 1.62 (s, 1H), 1.60-1.54 (m, 3H), 1.53-1.42 (m, 3H), 1.39 (dd, J=11.3, 3.2 Hz, 4H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.47 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.30-7.26 (m, 1H), 7.26-7.17 (m, 5H), 6.50 (s, 1H), 6.42 (s, 1H), 6.10 (s, 1H), 5.27 (s, 1H), 4.65 (d, J=5.3 Hz, 2H), 4.40 (s, 1H), 4.32 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.65 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.69 (s, 1H), 1.59 (d, J=10.7 Hz, 2H), 1.13-1.00 (m, 7H).
1H NMR (500 MHz, Chloroform) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 6.02 (s, 1H), 5.67 (s, 1H), 4.93 (s, 1H), 4.61 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.63 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.73 (d, J=1.3 Hz, 2H), 1.52 (s, 1H), 1.33-1.29 (m, 9H), 1.09-1.03 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 9.46 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.47 (d, J=10.8 Hz, 2H), 5.88 (s, 1H), 5.82 (s, 1H), 5.18 (s, 1H), 4.96 (s, 1H), 4.52 (s, 1H), 3.74 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 2.64 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.95 (t, J=7.9 Hz, 3H), 1.71 (s, 1H), 1.57 (tt, J=16.6, 2.2 Hz, 9H), 1.44 (s, 1H), 1.11-0.98 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.47 (d, J=14.9 Hz, 2H), 7.29-7.21 (m, 4H), 7.19 (s, 1H), 6.66 (s, 1H), 6.36 (s, 1H), 5.90 (s, 1H), 5.60 (s, 1H), 5.00 (s, 1H), 4.50 (s, 1H), 4.34 (d, J=14.6 Hz, 2H), 3.24 (d, J=16.9 Hz, 2H), 2.47 (d, J=1.9 Hz, 2H), 2.08-2.04 (m, 2H), 1.80 (s, 1H), 1.77-1.69 (m, 3H), 1.55 (s, 1H), 1.46 (s, 1H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.48 (d, J=2.3 Hz, 2H), 5.90 (s, 1H), 5.74 (s, 1H), 5.54 (s, 1H), 5.27 (s, 1H), 5.13 (s, 1H), 4.51 (s, 1H), 3.24 (d, J=17.6 Hz, 2H), 2.61 (s, 1H), 2.08-2.04 (m, 2H), 1.89-1.64 (m, 5H), 1.48 (d, J=18.1 Hz, 2H), 1.33-1.29 (m, 9H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.49 (d, J=4.2 Hz, 2H), 6.05 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 5.39 (s, 1H), 5.11 (s, 1H), 4.52 (s, 1H), 3.30-3.20 (m, 3H), 2.61 (s, 1H), 2.08-2.04 (m, 2H), 2.02-1.90 (m, 2H), 1.87-1.77 (m, 3H), 1.75-1.68 (m, 5H), 1.55-1.44 (m, 5H), 1.44-1.39 (m, 2H), 1.09-0.96 (m, 6H).
1H NMR (500 MHz, Chloroform) δ 7.39-7.29 (m, 2H), 7.29-7.20 (m, 7H), 7.18 (s, 1H), 6.65 (s, 1H), 6.45 (d, J=4.2 Hz, 2H), 6.24 (s, 1H), 6.13 (d, J=3.8 Hz, 2H), 6.03 (s, 1H), 5.47 (s, 1H), 4.93 (d, J=16.9 Hz, 2H), 4.66 (s, 1H), 4.42 (s, 1H), 4.33 (s, 1H), 3.66 (s, 1H), 3.45 (s, 1H), 3.40-3.30 (m, 3H), 3.18 (s, 1H), 2.96 (d, J=11.1 Hz, 2H), 2.18 (s, 1H), 2.12-2.02 (m, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.27-7.21 (m, 2H), 7.21-7.11 (m, 3H), 7.10 (s, 1H), 6.49 (s, 1H), 6.31 (s, 1H), 6.20 (s, 1H), 6.13 (s, 1H), 5.96 (d, J=15.6 Hz, 2H), 5.67 (s, 1H), 4.90 (s, 1H), 4.85 (s, 1H), 4.66 (s, 1H), 4.14 (s, 1H), 3.69 (s, 1H), 3.42 (d, J=26.2 Hz, 2H), 3.33 (d, J=15.0 Hz, 2H), 3.23 (s, 1H), 2.83 (s, 1H), 2.68 (s, 1H), 2.17 (s, 1H), 2.09-2.05 (m, 2H), 1.91 (s, 1H), 1.36-1.32 (m, 10H).
1H NMR (500 MHz, Chloroform) δ 8.76 (s, 5H), 8.45 (s, 5H), 7.29-7.23 (m, 10H), 7.16 (s, 5H), 7.14-7.05 (m, 10H), 6.44 (s, 5H), 6.29 (s, 5H), 6.03 (s, 5H), 5.93 (d, J=10.5 Hz, 10H), 5.21 (s, 5H), 5.05 (s, 5H), 4.64 (d, J=18.2 Hz, 10H), 3.67 (s, 4H), 3.48-3.46 (m, 2H), 3.43 (t, J=11.4 Hz, 14H), 3.37 (dt, J=43.5, 18.6 Hz, 29H), 3.05 (s, 5H), 2.86 (s, 5H), 2.19 (s, 5H), 2.09-2.05 (m, 10H), 1.95-1.86 (m, 15H), 1.72-1.64 (m, 15H), 1.56-1.52 (m, 9H), 1.50 (s, 6H), 1.45-1.40 (m, 10H).
1H NMR (500 MHz, Chloroform) δ 7.82 (s, 1H), 7.30-7.22 (m, 4H), 7.21-7.07 (m, 6H), 6.48 (s, 1H), 6.29 (s, 1H), 6.16 (s, 1H), 6.09 (s, 1H), 5.96 (d, J=19.6 Hz, 2H), 5.31 (s, 1H), 4.94 (s, 1H), 4.66 (s, 1H), 4.61 (s, 1H), 4.41 (s, 1H), 4.33 (s, 1H), 3.72 (s, 1H), 3.51-3.12 (m, 5H), 3.24 (d, J=16.9 Hz, 2H), 3.24 (d, J=16.9 Hz, 2H), 2.96 (s, 1H), 2.43 (s, 1H), 2.19 (s, 1H), 2.08-2.03 (m, 2H), 1.80 (s, 1H), 1.73 (s, 1H), 1.55 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.32-7.26 (m, 2H), 7.18 (s, 1H), 7.15-7.08 (m, 2H), 6.45 (s, 1H), 6.28 (s, 1H), 6.02 (s, 1H), 5.94 (d, J=3.0 Hz, 2H), 5.80 (s, 1H), 5.63 (s, 1H), 5.14 (s, 1H), 4.66 (s, 1H), 4.55 (s, 1H), 3.91 (s, 1H), 3.65 (s, 1H), 3.49-3.10 (m, 5H), 3.25 (t, J=14.8 Hz, 3H), 3.25 (t, J=14.8 Hz, 3H), 3.01 (s, 1H), 2.53 (s, 1H), 2.08-2.04 (m, 2H), 1.94 (s, 1H), 1.80 (d, J=1.0 Hz, 2H), 1.73 (s, 1H), 1.34-1.30 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.30-7.26 (m, 1H), 7.26-7.14 (m, 4H), 6.52 (s, 1H), 6.47 (s, 1H), 6.14 (s, 1H), 6.04 (s, 1H), 5.96 (s, 1H), 5.87 (d, J=16.5 Hz, 2H), 5.02 (d, J=1.5 Hz, 2H), 4.66 (s, 1H), 4.48 (s, 1H), 3.68 (s, 1H), 3.51 (s, 1H), 3.40 (s, 1H), 3.31 (d, J=10.7 Hz, 2H), 3.24 (d, J=17.3 Hz, 2H), 3.01 (d, J=17.6 Hz, 2H), 2.12-2.04 (m, 5H), 1.96 (s, 1H), 1.82 (s, 1H), 1.75 (s, 1H), 1.71-1.64 (m, 3H), 1.56-1.52 (m, 2H), 1.48 (s, 1H), 1.45-1.40 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.52 (s, 1H), 7.43-7.23 (m, 8H), 7.23-7.19 (m, 3H), 7.16 (s, 1H), 6.92 (s, 1H), 6.04 (s, 1H), 5.92-5.88 (m, 2H), 5.21 (s, 1H), 4.83 (s, 1H), 4.75 (s, 1H), 4.44 (s, 1H), 4.38 (s, 1H), 3.45 (s, 1H), 3.36 (d, J=13.2 Hz, 2H), 2.95 (s, 1H), 2.80 (s, 1H), 2.18 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.48 (s, 1H), 7.32 (s, 1H), 7.29-7.23 (m, 2H), 7.23-7.14 (m, 3H), 6.91 (s, 1H), 5.95 (s, 1H), 5.92-5.88 (m, 2H), 4.76 (d, J=1.1 Hz, 2H), 4.71 (s, 1H), 3.46 (d, J=12.3 Hz, 2H), 3.35 (s, 1H), 3.08 (s, 1H), 2.99 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.40-1.36 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.30 (dd, J=21.6, 15.7 Hz, 4H), 7.28-7.23 (m, 1H), 7.28-7.14 (m, 4H), 6.89 (s, 1H), 6.05 (s, 1H), 5.92-5.88 (m, 2H), 5.08 (s, 1H), 4.75 (d, J=16.1 Hz, 2H), 3.59 (s, 1H), 3.45 (d, J=2.5 Hz, 2H), 3.35 (s, 1H), 3.12 (s, 1H), 2.99 (s, 1H), 2.19 (s, 1H), 2.10-2.04 (m, 4H), 1.93 (s, 1H), 1.81-1.70 (m, 3H), 1.58-1.54 (m, 2H), 1.51 (s, 1H), 1.47-1.42 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.41 (s, 1H), 7.36 (s, 1H), 10.00-7.08 (m, 14H), 6.54 (s, 1H), 6.07 (s, 1H), 5.92-5.88 (m, 2H), 5.10 (s, 1H), 4.42 (s, 1H), 4.37 (d, J=6.5 Hz, 2H), 4.30 (s, 1H), 3.60 (s, 1H), 3.25 (t, J=13.9 Hz, 3H), 3.03 (s, 1H), 2.73 (s, 1H), 2.09-2.03 (m, 2H), 1.79 (d, J=5.2 Hz, 2H), 1.73 (s, 1H), 1.57 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 28H), 7.44 (s, 29H), 7.30-7.23 (m, 86H), 7.23-7.15 (m, 82H), 7.15 (d, J=1.8 Hz, 4H), 6.98 (s, 29H), 5.92-5.85 (m, 85H), 5.21 (s, 28H), 5.00 (s, 27H), 4.81 (s, 28H), 4.66 (s, 28H), 3.26 (t, J=21.5 Hz, 87H), 2.91 (s, 30H), 2.78 (s, 26H), 2.21 (s, 20H), 2.11-2.02 (m, 61H), 2.00 (s, 21H), 1.83 (s, 25H), 1.77 (s, 21H), 1.32-1.28 (m, 251H).
1H NMR (500 MHz, Chloroform) δ 8.29 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.28-7.23 (m, 2H), 7.23-7.11 (m, 3H), 6.94 (s, 1H), 6.09 (s, 1H), 5.92-5.88 (m, 2H), 5.06 (s, 1H), 4.91 (s, 1H), 4.73 (s, 1H), 4.38 (s, 1H), 3.36 (s, 1H), 3.31-3.20 (m, 3H), 3.07 (s, 1H), 2.85 (s, 1H), 2.08-2.03 (m, 4H), 1.88 (s, 1H), 1.81 (s, 1H), 1.78-1.69 (m, 3H), 1.67 (s, 1H), 1.58 (s, 1H), 1.51 (t, J=7.6 Hz, 3H), 1.43-1.39 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.29 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.28-7.23 (m, 2H), 7.23-7.11 (m, 3H), 6.94 (s, 1H), 6.09 (s, 1H), 5.92-5.88 (m, 2H), 5.06 (s, 1H), 4.91 (s, 1H), 4.73 (s, 1H), 4.38 (s, 1H), 3.36 (s, 1H), 3.31-3.20 (m, 3H), 3.07 (s, 1H), 2.85 (s, 1H), 2.08-2.03 (m, 4H), 1.88 (s, 1H), 1.81 (s, 1H), 1.78-1.69 (m, 3H), 1.67 (s, 1H), 1.58 (s, 1H), 1.51 (t, J=7.6 Hz, 3H), 1.43-1.39 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.60 (d, J=2.3 Hz, 2H), 7.83 (s, 1H), 7.23 (d, J=6.4 Hz, 1H), 7.22-7.08 (m, 5H), 5.97 (s, 1H), 5.48 (s, 1H), 4.88 (s, 1H), 4.38 (s, 1H), 4.01 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.26 (s, 1H), 2.96 (s, 1H), 2.69 (s, 1H), 2.40 (s, 1H), 2.16 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.32-1.28 (m, 10H).
1H NMR (500 MHz, Chloroform) δ 8.82 (s, 1H), 8.50 (s, 1H), 7.89 (s, 1H), 7.31-7.24 (m, 4H), 7.17 (s, 1H), 6.22 (s, 1H), 5.95 (s, 1H), 5.47 (s, 1H), 5.14 (s, 1H), 4.38 (s, 1H), 3.45 (s, 1H), 3.37 (d, J=16.6 Hz, 2H), 3.29 (s, 1H), 2.86 (s, 1H), 2.47 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.93 (s, 1H), 1.91-1.79 (m, 2H), 1.70 (s, 1H), 1.58-1.51 (m, 4H), 1.50 (s, 1H), 1.45-1.40 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.80 (s, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.41-7.32 (m, 2H), 7.32-7.18 (m, 6H), 7.16 (s, 1H), 7.09 (s, 1H), 6.51 (s, 1H), 6.23 (s, 1H), 5.85 (s, 1H), 4.87 (s, 1H), 4.36 (s, 1H), 4.30 (d, J=5.9 Hz, 2H), 3.24 (d, J=15.2 Hz, 2H), 3.09 (s, 1H), 2.82 (s, 1H), 2.57 (s, 1H), 2.08-2.04 (m, 2H), 1.98 (s, 1H), 1.82 (s, 1H), 1.76 (s, 1H), 1.65 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.82 (s, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.30-7.22 (m, 4H), 7.15 (s, 1H), 6.03 (s, 1H), 5.79 (s, 1H), 5.01 (s, 1H), 4.84 (s, 1H), 4.27 (s, 1H), 3.36 (s, 1H), 3.24 (d, J=14.9 Hz, 2H), 2.95 (s, 1H), 2.72 (s, 1H), 2.07 (t, J=5.5 Hz, 3H), 1.85 (s, 1H), 1.78 (s, 1H), 1.70 (s, 1H), 1.32-1.28 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.86 (s, 7H), 8.52 (s, 7H), 7.93 (s, 7H), 7.42 (s, 7H), 7.24-7.19 (m, 14H), 7.14 (s, 7H), 7.12-7.04 (m, 14H), 6.15 (d, J=16.5 Hz, 14H), 5.79 (s, 7H), 4.89 (s, 7H), 4.62 (s, 7H), 3.87 (s, 7H), 3.27 (t, J=22.0 Hz, 22H), 3.17 (t, J=12.5 Hz, 1H), 3.11 (d, J=17.0 Hz, 14H), 2.12 (s, 5H), 2.10-2.01 (m, 16H), 2.01-1.94 (m, 14H), 1.87 (s, 5H), 1.80 (s, 5H), 1.67-1.58 (m, 67H).
1H NMR (500 MHz, Chloroform) δ 7.52 (s, 5H), 7.32-7.14 (m, 55H), 7.13 (t, J=1.5 Hz, 1H), 7.07 (s, 5H), 6.09 (s, 5H), 6.01 (s, 5H), 5.64 (s, 5H), 5.02 (s, 5H), 4.84 (s, 5H), 4.36 (s, 5H), 4.29 (s, 5H), 3.89-3.85 (m, 15H), 3.45 (s, 5H), 3.35 (s, 4H), 3.17 (s, 4H), 3.11 (s, 5H), 2.93 (s, 5H), 2.19 (s, 4H), 2.10-2.04 (m, 10H), 1.92 (s, 4H).
1H NMR (500 MHz, Chloroform) δ 7.86 (s, 1H), 7.42 (s, 1H), 10.00-7.19 (m, 6H), 7.17 (s, 1H), 7.05 (s, 1H), 5.92 (d, J=15.2 Hz, 2H), 5.77 (s, 1H), 5.06 (s, 1H), 4.87 (s, 1H), 3.89-3.85 (m, 3H), 3.45 (s, 1H), 3.35 (s, 1H), 3.18 (s, 1H), 2.88 (d, J=18.2 Hz, 2H), 2.17 (s, 1H), 2.13-2.02 (m, 2H), 1.92 (s, 1H), 1.34-1.30 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.28-7.17 (m, 5H), 7.15 (s, 1H), 7.08 (s, 1H), 6.04 (s, 1H), 5.89 (s, 1H), 4.77 (s, 1H), 4.30 (s, 1H), 4.02-3.98 (m, 3H), 3.83 (s, 1H), 3.71 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.30 (s, 1H), 3.05 (s, 1H), 2.97 (s, 1H), 2.65 (s, 1H), 2.20 (s, 1H), 2.09-2.05 (m, 2H), 2.04-2.00 (m, 1H), 1.91 (s, 1H), 1.67-1.55 (m, 7H).
1H NMR (500 MHz, Chloroform) δ 8.58 (s, 7H), 8.29 (s, 7H), 7.42 (s, 7H), 7.32-7.24 (m, 28H), 7.18 (dt, J=57.0, 25.2 Hz, 40H), 7.08-7.07 (m, 2H), 6.51 (s, 7H), 6.01 (s, 7H), 5.10 (s, 7H), 4.81 (s, 7H), 4.38 (s, 7H), 4.32 (s, 7H), 3.93-3.89 (m, 21H), 3.30 (d, J=53.3 Hz, 17H), 3.21 (s, 3H), 3.21 (s, 6H), 2.99 (s, 7H), 2.17 (s, 6H), 2.11-2.01 (m, 14H), 1.76 (d, J=12.9 Hz, 12H), 1.68 (s, 5H), 1.42 (s, 6H).
1H NMR (500 MHz, Chloroform) δ 9.02 (s, 1H), 7.53 (s, 1H), 7.31-7.25 (m, 2H), 7.17 (dd, J=16.8, 9.4 Hz, 4H), 6.20 (s, 1H), 6.11 (s, 1H), 5.60 (s, 1H), 5.16 (s, 1H), 4.76 (s, 1H), 3.90-3.86 (m, 3H), 3.24 (d, J=15.4 Hz, 2H), 3.12 (s, 1H), 2.92 (d, J=17.7 Hz, 2H), 2.05 (t, J=4.4 Hz, 3H), 1.82 (s, 1H), 1.76 (s, 1H), 1.56 (s, 1H), 1.31-1.27 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.38 (s, 1H), 7.28-7.22 (m, 2H), 7.22-7.11 (m, 3H), 7.04 (s, 1H), 6.62 (s, 1H), 5.99 (s, 1H), 4.76 (s, 1H), 4.62 (s, 1H), 4.30 (s, 1H), 3.83-3.79 (m, 3H), 3.26 (dd, J=17.5, 12.1 Hz, 4H), 3.05 (s, 1H), 3.01 (s, 1H), 2.72 (s, 1H), 2.20-2.13 (m, 3H), 2.09-2.03 (m, 2H), 1.86 (s, 1H), 1.80 (s, 1H), 1.72-1.66 (m, 3H), 1.56 (t, J=5.2 Hz, 3H), 1.49 (s, 1H), 1.46-1.41 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.32-7.26 (m, 4H), 7.26-7.11 (m, 7H), 6.00 (s, 1H), 5.04 (s, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 4.38 (s, 1H), 4.30 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.27 (s, 1H), 3.11 (s, 1H), 2.85 (s, 1H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.80 (s, 1H), 8.37 (s, 1H), 7.69 (d, J=2.2 Hz, 2H), 7.59 (s, 1H), 7.28-7.21 (m, 2H), 7.21-7.11 (m, 3H), 6.78 (s, 1H), 5.98 (s, 1H), 5.45 (s, 1H), 4.93 (s, 1H), 4.66 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.22 (s, 1H), 2.96 (d, J=29.5 Hz, 2H), 2.19 (s, 1H), 2.09-2.05 (m, 2H), 1.92 (s, 1H), 1.34-1.30 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 8.39 (s, 1H), 7.69 (d, J=16.1 Hz, 2H), 7.60 (s, 1H), 7.36-7.20 (m, 9H), 7.19 (d, J=13.6 Hz, 2H), 6.50 (s, 1H), 6.28 (s, 1H), 6.16 (s, 1H), 6.10 (s, 1H), 4.75 (d, J=4.7 Hz, 2H), 4.39 (s, 1H), 4.30 (s, 1H), 3.24 (t, J=8.9 Hz, 3H), 3.01 (s, 1H), 2.72 (s, 1H), 2.11-2.01 (m, 2H), 1.84 (s, 1H), 1.80 (s, 1H), 1.73 (s, 1H), 1.36 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.79-7.57 (m, 3H), 7.27-7.21 (m, 2H), 7.21-7.10 (m, 3H), 6.09 (s, 1H), 5.52 (s, 1H), 5.08 (s, 1H), 4.74 (s, 1H), 4.45 (s, 1H), 3.25 (t, J=9.9 Hz, 3H), 3.01 (s, 1H), 2.85 (s, 1H), 2.10-2.02 (m, 2H), 1.88 (s, 1H), 1.81 (s, 1H), 1.68 (s, 1H), 1.60 (s, 1H), 1.35-1.31 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 9.87 (s, 1H), 8.26 (s, 1H), 7.68 (s, 1H), 7.57 (d, J=11.2 Hz, 2H), 7.27-7.21 (m, 2H), 7.21-7.10 (m, 3H), 6.07 (s, 1H), 4.94 (s, 1H), 4.78 (s, 1H), 4.51 (s, 1H), 3.54 (s, 1H), 3.45 (s, 1H), 3.24 (d, J=16.2 Hz, 2H), 3.17 (s, 1H), 2.97 (s, 1H), 2.92 (s, 1H), 2.28 (s, 1H), 2.09-2.04 (m, 4H), 1.81 (s, 1H), 1.74 (s, 1H), 1.70 (s, 1H), 1.59-1.52 (m, 4H), 1.49 (d, J=1.6 Hz, 2H), 1.47-1.41 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.62 (d, J=18.9 Hz, 2H), 7.34-7.23 (m, 9H), 7.23-7.12 (m, 3H), 6.92 (s, 1H), 6.17 (s, 1H), 5.35 (s, 1H), 5.03 (s, 1H), 4.70 (d, J=4.7 Hz, 2H), 4.38 (s, 1H), 4.33 (s, 1H), 4.03 (s, 1H), 3.35 (s, 1H), 3.27 (s, 1H), 3.04 (s, 1H), 2.82 (s, 1H), 2.17 (s, 1H), 2.12-2.03 (m, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.68 (s, 1H), 7.59 (s, 1H), 7.30-7.25 (m, 2H), 7.22-7.16 (m, 2H), 7.16-7.06 (m, 3H), 6.17 (s, 1H), 5.89 (s, 1H), 5.84 (s, 1H), 5.11 (s, 1H), 4.98 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.25 (s, 1H), 3.04 (s, 1H), 2.28 (s, 1H), 2.19 (s, 1H), 2.11-2.03 (m, 2H), 1.92 (s, 1H), 1.35-1.31 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.70 (s, 1H), 7.57 (d, J=4.5 Hz, 2H), 7.22 (dd, J=17.6, 7.1 Hz, 4H), 7.18-7.07 (m, 3H), 5.97 (s, 1H), 5.74 (s, 1H), 5.03 (s, 1H), 4.50 (d, J=11.0 Hz, 2H), 4.41 (s, 1H), 3.61 (s, 1H), 3.45 (s, 1H), 3.35 (s, 1H), 3.21 (s, 1H), 3.03 (s, 1H), 2.80 (s, 1H), 2.17 (s, 1H), 2.09-2.05 (m, 2H), 1.93-1.78 (m, 3H), 1.71 (s, 1H), 1.64-1.60 (m, 2H), 1.58-1.54 (m, 2H), 1.50 (s, 1H), 1.48-1.42 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 7.73 (s, 1H), 7.67 (s, 1H), 7.38 (t, J=17.9 Hz, 3H), 7.27-7.13 (m, 9H), 7.11 (s, 1H), 6.99 (s, 1H), 6.45 (s, 1H), 5.48 (s, 1H), 4.94 (d, J=7.2 Hz, 2H), 4.89 (s, 1H), 4.32 (s, 1H), 4.26 (s, 1H), 3.42 (s, 1H), 3.24 (d, J=18.2 Hz, 2H), 3.06 (s, 1H), 2.92 (s, 1H), 2.13 (s, 1H), 2.11-2.00 (m, 2H), 1.92 (s, 1H), 1.86 (s, 1H), 1.79 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 9.34 (s, 4H), 7.98 (s, 4H), 7.79 (s, 4H), 7.62 (s, 4H), 7.54 (s, 4H), 7.42-7.28 (m, 23H), 7.28-7.26 (m, 2H), 7.16 (s, 4H), 5.87 (s, 4H), 5.43 (s, 4H), 5.16 (s, 4H), 4.27 (s, 4H), 3.33-3.20 (m, 12H), 2.94 (s, 4H), 2.82 (s, 4H), 2.08-2.04 (m, 8H), 1.96 (s, 3H), 1.82 (s, 3H), 1.76 (s, 3H), 1.63 (s, 3H), 1.33-1.29 (m, 36H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 8.24 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.24 (dd, J=20.9, 2.1 Hz, 4H), 7.16-7.04 (m, 3H), 5.61 (s, 1H), 5.36 (s, 1H), 5.09 (s, 1H), 4.63 (s, 1H), 3.50 (s, 1H), 3.41 (s, 1H), 3.24 (d, J=15.7 Hz, 2H), 2.98 (s, 1H), 2.66 (s, 1H), 2.57 (s, 1H), 2.27-2.16 (m, 2H), 2.08-2.04 (m, 2H), 1.98 (s, 1H), 1.85 (s, 1H), 1.78 (s, 1H), 1.72 (s, 1H), 1.63-1.55 (m, 4H), 1.55-1.44 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.78 (s, 1H), 8.99 (s, 1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.49 (d, J=90.0 Hz, 2H), 7.40-7.38 (m, 4H), 7.30 (d, J=15.0 Hz, 5H), 7.19 (s, 34H), 7.14 (s, 4H), 7.07 (s, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.29 (s, 1H), 5.09 (s, 1H), 4.85 (s, 1H), 4.34 (s, 2H), 3.63 (s, 21H), 3.51 (s, 1H), 3.33 (s, 1H), 3.08 (s, 1H), 2.65 (s, 1H), 2.20 (s, 1H), 2.02 (s, 1H), 1.90 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.95 (s, 1H), 8.26 (d, J=60.3 Hz, 2H), 7.78 (s, 1H), 7.55 (s, 1H), 7.31-7.18 (m, 4H), 7.16 (s, 1H), 7.31-6.84 (m, 7H), 6.55 (d, J=16.4 Hz, 2H), 5.97 (s, 1H), 5.15 (s, 1H), 4.79 (s, 1H), 3.63 (s, 1H), 3.51 (s, 1H), 3.32 (s, 1H), 3.07 (s, 1H), 2.54 (s, 1H), 2.21 (s, 1H), 2.02 (s,1H), 1.91 (s, 1H), 1.26 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.98 (s, 13H), 8.34 (s, 13H), 8.22 (s, 14H), 7.80 (s, 13H), 7.57 (s, 14H), 7.37-7.20 (m, 2H), 7.18 (s, 14H), 7.37-6.87 (m, 82H), 6.56 (s, 13H), 6.49 (s, 13H), 5.99 (s, 13H), 5.17 (s, 7H), 4.95 (s, 5H), 4.79 (s, 7H), 3.64 (s, 6H), 3.52 (s, 6H), 3.33 (s, 15H), 3.08 (s, 14H), 2.55 (s, 5H), 2.20 (d, J=14.4 Hz, 31H), 2.02 (s, 14H), 1.88 (d, J=38.0 Hz, 37H), 1.80 (s, 5H), 1.62 (s, 9H), 1.37 (s, 27H), 1.31 (s, 11H), 1.20 (s, 23H).
1H NMR (500 MHz, Chloroform) δ 8.99 (s, 2H), 8.23 (s, 2H), 8.06 (s, 2H), 7.81 (s, 2H), 7.58 (s, 2H), 7.29 (d, J=15.0 Hz, 9H), 7.19 (s, 1H), 7.14 (s, 9H), 7.05 (d, J=24.0 Hz, 3H), 6.56 (s, 2H), 6.06 (s, 2H), 5.05 (s, 2H), 4.76 (s, 1H), 4.34 (s, 4H), 3.55-2.80 (m, 10H), 3.48-2.77 (m, 10H), 3.28-2.80 (m, 8H), 2.87-2.77 (m, 1H), 2.70 (s, 1H), 2.34 (s, 1H), 2.01 (s, 1H), 1.91 (d, J=2.6 Hz, 2H), 1.60 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.99 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.26-7.21 (m, 4H), 7.19 (s, 1H), 7.26-6.88 (m, 6H), 6.57 (d, J=15.1 Hz, 2H), 6.06 (s, 1H), 5.06 (s, 1H), 4.71 (s, 1H), 3.33 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.08 (s, 1H), 2.93 (s, 1H), 2.43 (s, 1H), 2.39 (s, 1H), 2.01 (s, 1H), 1.91 (d, J=1.1 Hz, 1H), 1.58 (s, 13H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.99 (s, 1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.26-7.21 (m, 7H), 7.19 (s, 1H), 7.26-6.88 (m, 6H), 6.53 (d, J=28.7 Hz, 2H), 6.50-6.48 (m, 5H), 6.08 (s, 1H), 5.06 (s, 1H), 4.95 (s, 1H), 4.70 (s, 1H), 3.33 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.08 (s, 1H), 2.94 (s, 1H), 2.44 (d, J=13.0 Hz, 2H), 2.19 (s, 2H), 2.03-1.73 (m, 5H), 1.84 (s, 3H), 1.84 (s, 2H), 1.60 (d, J=15.4 Hz, 2H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.75 (s, 2H), 8.14 (s, 2H), 7.54 (d, J=24.9 Hz, 4H), 7.37-7.24 (m, 13H), 7.17 (s, 1H), 7.11 (d, J=10.0 Hz, 11H), 6.85 (s, 2H), 6.14 (s, 2H), 5.18 (s, 2H), 4.86 (s, 1H), 4.33 (s, 4H), 3.65 (s, 1H), 3.53 (s, 1H), 3.28 (s, 4H), 3.03 (s, 1H), 2.54 (s, 2H), 2.22 (s, 2H), 2.02 (s, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 1H), 8.12 (s, 1H), 7.55 (d, J=25.0 Hz, 2H), 7.51 (s, 3H), 7.16 (dd, J=31.6, 6.6 Hz, 7H), 6.56 (s, 1H), 6.10 (s, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 3.65 (s, 1H), 3.54 (s, 1H)), 3.29 (s, 1H), 3.04 (s, 1H), 2.58 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 5H), 1.27 (s, 9H) .
1H NMR (500 MHz, Chloroform) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.55 (d, J=25.0 Hz, 2H), 7.51 (s, 3H), 7.19 (d, J=2.2 Hz, 2H), 7.13 (d, J=10.0 Hz, 5H), 6.44 (s, 1H), 6.11 (s, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 3.67 (d, J=15.7 Hz, 1H), 3.54 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.58 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.74 (s, 1H), 1.46 (t, J=12.5 Hz, 3H), 1.21 (s, 1H), 1.11 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.71 (s, 2H), 8.61 (s, 2H), 7.69 (s, 2H), 7.58 (s, 2H), 7.53 (s, 1H), 7.33-7.20 (m, 12H), 7.19 (s, 1H), 7.13 (d, J=10.0 Hz, 10H), 5.84 (s, 2H), 5.09 (s, 1H), 4.57 (s, 1H), 4.34 (s, 4H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 4H), 3.04 (s, 2H), 2.73 (s, 1H), 2.41 (s, 1H), 2.28 (s, 1H), 2.01 (s, 1H), 1.91 (d, J=4.5 Hz, 2H), 1.53 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.68 (s, 1H), 8.29 (s, 1H), 7.54 (d, J=25.0 Hz, 2H), 7.49 (s, 3H), 7.24 (s, 1H) , 7.17 (s, 1H), 7.11 (d, J=10.0 Hz, 5H), 6.61 (s, 1H), 5.90 (s, 1H), 5.05 (s, 1H), 4.68 (s, 1H), 3.28 (s, 1H), 3.22 (s, 1H), 3.11 (d, J=77.9 Hz, 2H), 2.85 (s, 1H), 2.33 (s, 1H), 2.13 (s, 1H), 2.01 (s, 1H), 1.89 (d, J=13.2 Hz, 11H), 1.53 (s, 5H), 1.27 (s, 9H). Example 178
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-5-fluoro-1H-indole-2-carboxamide (A178)
1H NMR (500 MHz, Chloroform) δ 8.69 (s,1H), 8.21 (s, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 7.13 (d, J=10.0 Hz, 5H), 6.53 (s, 1H), 5.93 (s, 1H), 5.07 (s, 1H), 4.95 (s, 1H), 4.67 (s,1H), 3.29 (s, 1H), 3.25-2.88 (m, 3H), 2.85 (s, 1H), 2.36 (s, 1H), 2.17 (d, J=18.2 Hz, 3H), 2.01 (s, 1H), 1.90 (d, J=11.3 Hz, 1H), 1.84 (s, 2H), 1.62 (s, 1H), 1.53 (s,1H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 1H), 8.13 (s, 1H), 7. 95 (s, 1H), 7.32-7.18 (m, 7H), 7.08 (d, J=49.9 Hz, 6H), 7.03 (s, 1H), 7.03 (s, 1H), 6.74 (s, 1H), 6.16 (s, 1H), 5.20 (s, 1H), 4.86 (s, 1H), 4.33 (s, 2H), 3.66 (s, 1H), 3.54 (s, 1H), 3.16 (d, J=124.8 Hz, 2H), 3.01 (d, J=6.4 Hz, 1H), 2.57 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H). Example 180
N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-6-fluoro-1H-indole-2-carboxamide (A180)
1H NMR (500 MHz, Chloroform) δ 8.71 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.46-6.88 (m, 8H), 7.04 (s, 1H), 7.04 (s, 1H), 6.57 (s, 1H), 6.10 (s, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 3.65 (s, 1H), 3.54 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.58 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.71 (s, 2H), 8.04 (s, 2H), 7.96 (s, 2H), 7.46-6.88 (m, 16H), 7.04 (s, 2H), 7.04 (s, 2H), 6.46 (s, 2H), 6.12 (s, 2H), 5.20 (s, 2H), 4.83 (s, 1H), 3.67 (d, J=17.5 Hz, 3H), 3.54 (s, 1H), 3.29 (s, 3H), 3.04 (s, 1H), 2.58 (s, 1H), 2.22 (s, 1H), 2.02 (s, 2H), 1.93 (s, 1H), 1.74 (s, 2H), 1.46 (t, J=12.5 Hz, 6H), 1.21 (s, 3H), 1.11 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.68 (s, 2H), 8.30 (s, 2H), 7.96 (s, 2H), 7.40 (s, 2H), 7.28 (t, J=11.5 Hz, 12H) , 7.15 (dd, J=57.0, 32.0 Hz, 15H), 7.04 (s, 2H), 7.04 (s, 2H), 5.92 (s, 2H), 5.05 (s, 1H), 4.71 (s, 1H)), 4.34 (s, 4H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 4H), 3.04 (s, 2H), 2.86 (s, 1H), 2.39 (s, 1H) , 2.18 (s, 1H), 2.01 (s, 1H), 1.90 (d, J=6.3 Hz, 4H), 1.54 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.68 (s, 1H), 8.30 (s, 11H), 7.96 (s, 1H), 7.45-6.97 (m, 8H), 7.04 (s, 1H), 7.04 (s, 1H), 6.62 (s, 1H), 5.92 (s, 1H), 5.06 (s, 1H), 4.69 (s, 1H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.85 (s, 1H), 2.33 (s, 1H), 2.13 (s, 1H), 2.01 (s, 1H), 1.90 (d, J=13.5 Hz, 1H), 1.53 (s, 1H), 1.27 (s, 9H). Example 184
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-6-fluoro-1H-indole-2-carboxamide (A184)
1H NMR (500 MHz, Chloroform) δ 8.67 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.45-6.89 (m, 8H), 7.14 (s, 4H), 7.09 (d, J=50.0 Hz, 5H), 7.04 (s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 5.07 (s, 1H), 4.95 (s, 1H), 4.67 (s, 1H), 3.29 (s, 1H), 3.25-2.88 (m, 3H), 2.85 (s, 1H), 2.35 (s, 1H), 2.17 (d, J=17.6 Hz, 3H), 2.01 (s, 1H), 1.90 (d, J=11.7 Hz, 1H), 1.84 (s, 1H), 1.62 (s, 1H), 1.53 (s, 1H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.92 (s, 2H), 8.83 (s, 2H), 7.84 (s, 2H), 7.49 (s, 2H), 7.33-7.26 (m, 11H), 7.22 (s, 2H), 7.02 (d, J=21.6 Hz, 6H), 6.97 (dd, J=5.6, 2.6 Hz, 1H), 6.77 (s, 2H), 6.28 (s, 2H), 5.16 (s, 2H), 4.91 (s, 1H), 4.34 (s, 4H), 3.67 (s, 1H), 3.55 (s, 1H), 3.29 (s, 3H), 3.04 (s, 1H), 2.61 (s, 1H), 2.23 (s, 2H), 2.02 (s, 2H), 1.93 (s, 1H). Example 186 N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-(3-fluorophenyl)-1-oxopropan-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A186)
1H NMR (500 MHz, Chloroform) δ 8.75 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.31-7.15 (m, 3H), 6.97 (d, J=7.1 Hz, 5H), 6.50 (s, 1H), 6.15 (s, 1H), 5.18 (s, 1H), 4.82 (s, 1H), 3.65 (s, 1H), 3.53 (s, 1H), 3.27 (s, 1H), 3.03 (s, 3H), 2.60 (s, 1H), 2.22 (s, 1H), 2.01 (s, 1H), 1.92 (s, 1H), 1.26 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.79 (s, 2H), 8.00 (s, 2H), 7.48 (s, 2H), 7.31 (d, J=14.5 Hz, 4H), 7.19 (s, 2H) , 7.01 (d, J=5.2 Hz, 5H), 6.40 (s, 2H), 6.18 (s, 2H), 5.20 (s, 2H), 4.85 (s, 1H), 3.68 (d, J=15.6 Hz, 3H), 3.55 (s, 1H), 3.29 (s, 1H), 3.04 (s, 3H), 2.61 (s, 2H), 2.23 (s, 1H), 2.02 (s, 2H), 1.93 (s, 1H), 1.74 (s, 2H), 1.46 (t, J=12.5 Hz, 6H), 1.21 (s, 3H), 1.11 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 9.00 (s, 4H), 8.91 (s, 4H), 7.70 (s, 4H), 7.49 (d, J=3.7 Hz, 8H), 7.29 (dd, J=9.6, 5.4 Hz, 26H), 7.21 (s, 5H), 7.00 (d, J=5.1 Hz, 11H), 6.69 (s, 4H), 4.96 (d, J=17.8 Hz, 6H), 4.33 (s, 8H), 3.29 (s, 3H), 3.21 (d, J=15.0 Hz, 8H), 2.96 (d, J=80.6 Hz, 8H), 2.85-2.81 (m, 1H), 2.48 (s, 4H), 2.27 (s, 4H), 2.00 (d, J=2.8 Hz, 4H), 1.91 (s, 6H), 1.53 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.57 (s, 1H), 7.45 (s, 1H), 7.32 (d, J=18.3 Hz, 2H), 7.20 (d, J=6.7 Hz, 2H) , 7.04 (s, 1H), 7.00 (s, 1H), 6.57 (s, 1H), 5.75 (s, 1H), 5.11 (s, 1H), 4.79 (s, 1H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.75 (s, 1H), 2.47 (s, 1H), 2.36 (s, 1H), 2.01 (s, 1H), 1.95 (s, 1H), 1.91 (s, 1H), 1.51 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.77 (s, 1H), 7.93 (s, 1H), 7.48 (s, 41H), 7.34-7.15 (m, 3H), 7.00 (s, 1H), 6.83 (s, 2H), 6.56 (s, 1H), 6.15 (s, 1H), 5.71 (s, 1H), 5.05 (s, 2H), 4.95 (s, 2H), 4.90 (s, 1H), 3.36-3.12 (m, 4H), 3.20 (s, 1H), 3.12 (d, J=78.0 Hz, 2H), 2.32 (s, 2H), 2.31-2.17 (m, 3H), 2.03-1.86 (m, 3H), 1.84 (s, 2H), 1.62 (s, 1H), 1.49 (s, 2H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.78 (s, 1H), 8.27 (s, 1H), 7.75-7.37 (m, 3H), 7.38 (s, 1H), 7.38 (s, 1H), 7.28 (d, J=15.0 Hz, 5H), 7.20-6.87 (m, 6H), 6.90 (s, 1H), 6.90 (s, 1H), 6.78 (s, 1H), 5.71 (s, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.63 (s, 1H), 3.50 (s, 1H), 3.29 (s, 2H), 3.04 (s, 1H), 2.54 (s, 1H), 2.22 (s, 1H), 2.02 (s, 2H), 1.91 (s, 1H).
IE NMR (500 MHz, Chloroform) δ 8.78 (s, 1H), 8.27 (s, 1H), 7.75-7.37 (m, 3H), 7.38 (s, 1H), 7.38 (s, 1H), 7.28 (d, J=15.0 Hz, 5H), 7.20-6.87 (m, 6H), 6.90 (s, 1H), 6.90 (s, 1H), 6.78 (s, 1H), 5.71 (s, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.63 (s, 1H), 3.50 (s, 1H), 3.29 (s, 2H), 3.04 (s, 1H), 2.54 (s, 1H), 2.22 (s, 1H), 2.02 (s, 2H), 1.91 (s, 1H), 1.27 (s, 9H). Example 193
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-5-methoxy-1H-indole-2-carboxamide (A193)
1H NMR (500 MHz, Chloroform) δ 8.68 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.16 (t, J=12.5 Hz, 6H) , 6.79 (s, 1H), 6.44 (s, 1H), 6.10 (s, 1H), 5.19 (s, 1H), 4.95 (s, 1H), 4.82 (s, 2H), 3.81 (s, 3H), 3.65 (s, 1H), 3.54 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.58 (s, 2H), 2.21 (d, J=16.4 Hz, 2H), 2.02 (s, 1H), 1.88 (d, J=41.9 Hz, 3H), 1.80 (s, 1H), 1.62 (s, 2H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.66 (s, 1H), 8.34 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.29 (d, J=15.0 Hz, 5H), 7.24-6.99 (m, 7H), 6.79 (s, 1H), 5.90 (s, 1H), 5.04 (s, 1H), 4.72 (s, 1H), 4.34 (s, 2H), 3.81 (s, 3H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.86 (s, 1H), 2.29 (s, 1H), 2.11 (s, 1H), 2.01 (s, 21H), 1.90 (d, J=11.7 Hz, 1H), 1.52 (s, 1H). Example 195
N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-5-methoxy-1H-indole-2-carboxamide (A195)
1H NMR (500 MHz, Chloroform) δ 8.46 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 7.12 (s, 4H), 7.00 (s, 1H) , 6.92 (s, 1H), 6.77 (s, 1H), 6.49 (s, 1H), 5.75 (s, 1H), 5.20 (s, 1H), 4.67 (s, 1H), 3.80 (s, 3H), 3.28 (s, 1H), 3.20 (d, J=15.0 Hz, 2H), 3.03 (s, 1H), 2.77 (s, 1H), 2.40 (s,1H), 2.30 (s, 1H), 2.00 (s, 1H), 1.94 (s, 41H), 1.90 (s, 1H), 1.51 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.61 (s, 1H), 8.10 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.19 (d, J=2.6 Hz, 2H), 7.14 (s, 4H), 6.72 (d, J=66.4 Hz, 2H), 5.95 (s, 1H), 5.05 (s, 1H), 4.95 (s, 1H), 4.71 (s, 1H), 3.81 (s, 3H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.86 (s, 1H), 2.37 (s, 61H), 2.21-2.17 (m, 2H), 2.01 (s, 1H), 1.90 (d, J=11.5 Hz, 1H), 1.84 (s, 2H), 1.62 (s, 1H), 1.54 (s, 1H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H). Example 197
N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide (A197)
1H NMR (500 MHz, Chloroform) δ 8.60 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.29 (d, J=15.0 Hz, 5H) , 7.16 (s, 1H), 7.10 (d, J=9.2 Hz, 2H), 6.97 (s, 1H), 6.16 (s, 1H), 4.87 (s, 1H), 4.67 (s, 1H), 4.34 (s, 2H), 3.65 (s, 1H), 3.54 (s, 1H), 2.61 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.76 (s, 1H), 1.11 (s, 1H), 0.60 (s, 1H), 0.35 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.59 (s, 1H), 7.98 (s, 1H), 7.61 (d, J=10.9 Hz, 2H), 7.12 (d, J=16.2 Hz, 2H) , 6.98 (s, 1H), 6.56 (s, 1H), 6.12 (s, 1H), 4.81 (s, 1H), 4.67 (s, 1H), 3.65 (s, 1H), 3.54 (s, 1H), 2.59 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.76 (s, 1H), 1.27 (s, 9H), 1.11 (s, 1H), 0.58 (s, 1H), 0.33 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.65 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.12 (d, J=24.7 Hz, 2H), 7.10-7.07 (m, 1H), 6.98 (s, 1H), 6.41 (s, 1H), 6.15 (s, 1H), 4.82 (s, 1H), 4.58 (s, 1H), 3.66 (d, J=5.6 Hz, 2H), 3.54 (s, 1H), 2.59 (s, 1H), 2.23 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H), 1.75 (d, J=10.0 Hz, 3H), 1.46 (t, J=12.5 Hz, 3H), 1.21 (s, 2H), 1.11 (d, J=0.5 Hz, 2H), 0.57 (s, 21H), 0.28 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.62 (s, 1H), 8.00 (d, J=20.6 Hz, 2H), 7.60 (s, 1H), 7.30 (d, J=15.0 Hz, 5H) , 7.18 (d, J=6.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.09 (s, 1H), 4.85 (s, 1H), 4.33 (d, J=13.7 Hz, 3H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.62 (s, 1H), 2.54 (s, 1H), 2.01 (s, 1H), 1.92 (d, J=12.0 Hz, 1H), 1.76 (s, 2H), 1.59 (s, 1H), 1.11 (s, 1H), 0.45 (s, 1H), 0.13 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.98 (s, 1H), 7.60 (s, 1H), 7.29 (d, J=15.0 Hz, 5H), 7.10 (s, 1H), 6.98 (s, 1H), 4.34 (s, 2H), 2.75 (s, 1H), 2.67 (s, 1H), 2.09 (s, 1H), 2.03 (d, J=6.8 Hz, 4H), 1.94 (s, 1H), 1.92-1.82 (m, 3H), 1.76 (s, 1H), 1.66 (d, J=10.0 Hz, 2H), 1.61 (s, 1H), 0.45 (s, 1H),
1H NMR (500 MHz, Chloroform) δ 7.98 (s, 1H), 7.60 (s, 1H), 7.29 (m, 3H), 7.10 (s, 1H), 6.98 (s, 1H), 6.29 (m, 3H), 2.75 (s, 1H), 2.67 (s, 1H), 2.09 (s, 2H), 2.03 (d, J=6.8 Hz, 3H), 1.94 (s, 1H), 1.92-1.82 (m, 3H), 1.76 (s, 1H), 1.66 (d, J=10.0 Hz, 2H), 1.61 (s, 1H), 1.27 (s, 9H), 0.45 (s, 1H)
1H NMR (500 MHz, Chloroform) δ 7.98 (s, 1H), 7.60 (s, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 4.95 (s, 1H), 2.74 (s, 1H) , 2.66 (s, 1H), 2.19 (s, 2H), 2.09 (s, 1H), 2.03 (d, J=6.9 Hz, 2H), 1.94 (s, 1H), 1.86 (dd, J=18.2, 10.2 Hz, 5H), 1.76 (s, 2H), 1.64 (dd, J=22.9, 7.1 Hz, 3H), 1.37 (s, 1H), 1.31 (s, 2H), 1.20 (s, 2H), 0.45 (s , 1H) Example 204
N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-cyclobutyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide (A204)
1H NMR (500 MHz, Chloroform) δ 7.98 (s, 1H), 7.60 (s, 1H), 7.29 (d, J=15.0 Hz, 4H), 7.10 (s, 1H), 6.98 (s, 1H), 6.05(m, 2H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.09 (s, 1H), 2.06-1.69 (m, 9H), 1.76 (s, 2H), 1.76 (s, 2H), 1.65 (s, 1H), 1.61 (s, 1H), 0.53 (s, 1H), 0.39 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.62 (s, 1H), 8.00 (d, J=20.6 Hz, 2H), 7.60 (s, 1H), 7.30 (d, J=15.0 Hz, 5H) , 7.18 (d, J=6.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.09 (s, 1H), 4.85 (s, 1H), 4.33 (d, J=13.7 Hz, 3H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.62 (s, 1H), 2.54 (s, 1H), 2.01 (s, 1H), 1.92 (d, J=12.0 Hz, 1H), 1.76 (s, 2H), 1.59 (s, 1H), 1.27(s,9H), 1.11 (s, 3H), 0.45 (s, 1H), 0.13 (s, 1H). Example 206
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-cyclobutyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide (A206)
1H NMR (500 MHz, Chloroform) δ 8.62 (s, 1H), 8.00 (d, J=20.6 Hz, 2H), 7.60 (s, 1H), 7.30 (d, J=15.0 Hz, 5H) , 7.18 (d, J=6.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.09 (s, 1H), 4.85 (s, 1H), 4.33 (d, J=13.7 Hz, 3H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.62 (s, 1H), 2.54 (s, 1H), 2.01 (s, 1H), 1.92 (d, J=12.0 Hz, 1H), 1.76 (s, 2H), 1.59 (s, 1H), 1.11 (s, 1H), 0.45 (s, 21H), 0.13 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.57 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=15.0 Hz, 5H), 7.13-7.07 (m, 2H), 6.98 (d, J=4.1 Hz, 2H), 6.13 (s, 1H), 4.81 (d, J=3.3 Hz, 1H), 4.34 (s,2H), 3.65 (s, 1H), 3.55 (s, 1H), 2.60 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 3H), 1.76 (s, 3H), 1.66 (d, J=4.7 Hz, 3H), 1.36 (s, 1H), 1.23 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.60 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.11 (d, J=5.1 Hz, 82H) , 6.98 (s, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 4.83 (s, 1H), 4.61 (s, 1H), 3.66 (s, 1H), 3.54 (s, 1H), 2.59 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H), 1.76 (s, 3H), 1.65 (d, J=11.9 Hz, 5H), 1.34 (s, 4H), 1.26 (d, J=8.6 Hz, 9H).
1H NMR (500 MHz, Chloroform) δ 8.54 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 7.08 (d, J=16.5 Hz, 2H) , 6.98 (s, 1H), 6.46 (s, 1H), 6.14 (s, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 3.64 (d, J=19.8 Hz, 2H), 3.54 (s, 1H), 2.59 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H), 1.75 (d, J=10.0 Hz, 6H), 1.65 (d, J=6.5 Hz, 63H), 1.46 (t, J=12.5 Hz, 4H), 1.35 (s, 3H), 1.27 (s, 1H), 1.21 (s, 2H), 1.11 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.51 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.30 (d, J=15.0 Hz, 5H), 7.24 (s, 1H) , 7.09 (d, J=13.7 Hz, 2H), 6.98 (s, 1H), 6.89 (s, 1H), 6.11 (s, 1H), 4.79 (s, 1H), 4.65 (s, 11H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.50 (d, J=13.8 Hz, 2H), 2.01 (s, 1H), 1.92 (d, J=5.3 Hz, 1H), 1.76 (s, 3H), 1.65 (d, J=5.8 Hz, 3H), 1.58 (s, 1H), 1.36 (s, 1H), 1.23 (s, 1H). Example 211
N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-cyclopentyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide (A211)
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.10 (s, 1H), 7.00 (d, J=18.5 Hz, 2H), 6.89 (s, 1H), 6.53 (s, 1H), 6.10 (s, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 2.90 (s, 1H), 2.49 (d, J=13.5 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=1.6 Hz, 1H), 1.76 (s, 3H), 1.63 (t, J=21.9 Hz, 4H), 1.55-1.52 (m, 1H), 1.37 (s, 1H), 1.27 (s, 9H), 1.22 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.45 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.10 (s, 1H), 7.00 (d, J=19.1 Hz, 42H), 6.88 (s, 1H), 6.44 (s, 1H), 6.10 (s, 1H), 4.95 (s, 1H), 4.77 (s, 1H), 4.64 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 2.90 (s, 1H), 2.49 (d, J=19.3 Hz, 2H), 2.19 (s, 2H), 2.01 (s, 1H), 1.93-1.89 (m, 1H), 1.84 (s, 2H), 1.76 (s, 3H), 1.73-1.60 (m, 6H), 1.57 (s, 1H), 1.37 (d, J=2.4 Hz, 3H), 1.31 (s, 1H), 1.21 (d, J=13.0 Hz, 2H).
1H NMR (500 MHz, Chloroform) δ 7.97 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.55-7.23 (m, 6H), 7.55-6.98 (m, 8H), 6.13 (s, 1H), 4.86 (s, 1H), 4.49 (s, 1H), 4.34 (s, 2H), 3.66 (s, 1H), 3.54 (s, 1H), 2.59 (s, 1H), 2.23 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H), 1.80 (s, 3H), 1.69 (d, J=10.0 Hz, 3H), 1.31 (s, 1H), 1.26 (s, 1H), 1.11 (s, 1H), 1.03 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.73 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.16 (s, 1H), 6.52 (s, 1H), 6.13 (s, 1H), 4.83 (s, 1H), 4.55 (s, 1H), 3.66 (s, 1H), 3.54 (s, 1H), 2.58 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.93 (s, 1H), 1.80 (s, 2H), 1.58 (s, 1H), 1.51 (d, J=15.0 Hz, 3H), 1.48-1.41 (m, 4H), 1.28 (d, J=5.4 Hz, 9H).
1H NMR (500 MHz, Chloroform) δ 7.55 (d, J=60.0 Hz, 2H), 7.16 (d, J=2.8 Hz, 2H), 6.45 (s, 1H), 6.14 (s, 1H) , 4.95 (s, 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.66 (s, 1H), 3.54 (s, 1H), 2.58 (s, 1H), 2.21 (d, J=17.0 Hz, 2H), 2.02 (s, 1H), 1.92 (s, 1H), 1.84 (s, 2H), 1.80 (s, 1H), 1.64 (d, J=16.1 Hz, 3H), 1.51 (d, J=15.0 Hz, 2H), 1.44 (dd, J=12.8, 7.8 Hz, 6H), 1.37 (s, 3H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 7.55 (d, J=60.0 Hz, 2H), 7.46-7.26 (m, 6H), 7.16 (s, 1H), 7.09 (s, 1H), 6.08 (s, 1H), 4.79 (s, 1H), 4.41 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.85 (s, 1H), 2.53 (d, J=12.1 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=3.6 Hz, 1H), 1.80 (s, 1H), 1.72 (s, 1H), 1.58 (s, 1H), 1.52 (d, J=15.0 Hz, 2H), 1.48-1.41 (m, 4H), 1.34 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.61 (s, 2H), 7.49 (s,2H), 7.16 (s,2H), 6.89 (s, 2H), 6.53 (s, 2H), 6.09 (s, 2H), 4.76 (s, 1H), 4.44 (s, 1H), 3.21 (d, J=15.0 Hz, 4H), 2.88 (s, 2H), 2.49 (d, J=3.0 Hz, 4H), 2.01 (s, 1H), 1.93-1.89 (m, 2H), 1.80 (s, 3H), 1.69 (d, J=10.0 Hz, 2H), 1.57 (s, 1H), 1.31 (d, J=4.8 Hz, 2H), 1.27 (s, 9H), 1.11 (s, 1H), 1.03 (s, 3H).
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)-2,2-difluorobenzo[d][1,3]dioxo1-5-carboxamide (A218) 1H NMR (500 MHz, Chloroform) δ 7.58 (s, 1H), 7.46 (s, 1H), 7.13 (s, 1H), 6.47 (d, J=5.5 Hz, 2H), 5.81 (s, 1H) , 4.93 (d, J=6.0 Hz, 2H), 4.37 (s, 1H), 3.34 (s, 1H), 3.20 (d, J=15.0 Hz, 2H), 2.37 (d, J=18.2 Hz, 2H), 2.18 (s, 2H), 2.00 (s, 1H), 1.90 (d, J=0.5 Hz, 1H), 1.81 (d, J=19.9 Hz, 6H), 1.69 (s, 2H), 1.64 (d, J=29.9 Hz, 3H), 1.51 (s, 1H), 1.37 (s, 3H), 1.31 (s, 2H), 1.18 (d, J=16.6 Hz, 3H), 1.11 (s, 1H), 1.03 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 7.58 (s, 1H), 7.46 (s, 1H), 7.13 (s, 1H), 6.47 (d, J=5.5 Hz, 2H), 5.81 (s, 1H), 4.93 (d, J=6.0 Hz, 2H), 4.37 (s, 1H), 3.34 (s, 1H), 3.20 (d, J=15.0 Hz, 2H), 2.37 (d, J=18.2 Hz, 2H), 2.18 (s, 2H), 2.00 (s, 1H), 1.90 (d, J=0.5 Hz, 1H), 1.81 (d, J=19.9 Hz, 6H), 1.69 (s, 2H), 1.64 (d, J=29.9 Hz, 3H), 1.51 (s, 1H), 1.37 (s, 3H), 1.31 (s, 2H), 1.18 (d, J=16.6 Hz, 3H), 1.11 (s, 1H), 1.03 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 9.90 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 7.30 (d, J=15.0 Hz, 5H), 7.23-7.03 (m, 6H), 6.71 (s, 1H), 6.26 (s, 1H), 5.98 (s, 1H), 5.15 (s, 1H), 4.87 (s, 1H), 4.34 (s, 2H), 3.79 (s, 6H), 3.64 (s, 1H), 3.52 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.52 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.60 (s, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 7.17 (d, J=25.0 Hz, 5H), 6.69 (s, 1H), 6.58 (s, 1H), 6.23 (s, 1H), 6.00 (s, 1H), 5.18 (s, 1H), 4.81 (s, 1H), 3.79 (s, 6H), 3.64 (s, 1H), 3.53 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.55 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.27 (s , 9H). Example 222
N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A222)
1H NMR (500 MHz, Chloroform) δ 8.59 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 7.15 (d, J=25.0 Hz, 5H), 6.67 (s, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 6.07 (s, 1H), 5.18 (s, 1H), 4.94 (s, 1H), 4.80 (s, 1H), 3.78 (s, 6H), 3.64 (s, 1H), 3.53 (s, 1H), 3.28 (s, 1H), 3.03 (s, 1H), 2.56 (s, 1H), 2.20 (d, J=16.3 Hz, 3H), 2.02 (s, 1H)), 1.88 (d, J=41.4 Hz, 3H), 1.80 (s, 1H), 1.62 (s, 1H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.65 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.27 (d, J=15.0 Hz, 5H), 7.14 (d, J=24.9 Hz , 5H), 6.92 (s, 1H), 6.59 (s, 1H), 6.20 (s, 1H), 6.08 (s, 1H), 5.01 (s, 1H), 4.76 (s, 1H), 4.33 (s, 2H), 3.78 (s, 6H), 3.28 (s, 1H), 3.20 (d, J=15.0 Hz, 2H), 3.03 (s, 1H), 2.85 (d, J=1.0 Hz, 2H), 2.32 (s, 1H), 2.00 (s, 1H), 1.90 (d, J=1.3 Hz, 1H), 1.61 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.80 (d, J=11.2 Hz, 2H), 7.09 (t, J=61.7 Hz, 6H), 6.94 (s, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 5.04 (d, J=1.0 Hz, 2H), 4.99 (s, 1H), 3.79 (s, 6H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 3H), 2.93 (d, J=106.3 Hz, 2H), 2.79-2.70 (m, 1H), 2.40 (s, 1H), 2.27 (s, 1H), 2.01 (s, 1H), 1.92 (d, J=8.4 Hz, 1H), 1.46 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.67 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.08 (t, J=67.3 Hz, 6H), 6.91 (s, 1H), 6.91 (s, 1H), 6.55 (s, 1H), 6.49 (s, 1H), 6.07 (s, 1H), 5.09 (s, 1H), 4.95 (s, 1H), 4.69 (s, 1H), 3.79 (s, 6H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.93 (s, 1H), 2.42 (d, J=15.8 Hz, 2H), 2.19 (s, 2H), 2.03-1.73 (m, 5H), 1.84 (s, 3H), 1.84 (s, 2H), 1.60 (d, J=16.9 Hz, 2H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.76 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.29 (d, J=15.0 Hz, 5H), 7.19 (d, J=17.1 Hz, 2H), 7.10 (d, J=2.2 Hz, 2H), 6.99 (d, J=15.0 Hz, 2H), 6.31 (s, 1H), 5.05 (s, 1H), 4.91 (s, 1H), 4.34 (s, 2H), 3.67 (s, 1H), 3.56 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.70 (s, 1H), 2.23 (s, 1H), 2.02 (s, 2H), 1.93 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.72 (s,1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.25 (s, 1H), 7.16 (s, 1H) , 7.09 (d, J=2.1 Hz, 2H), 6.98 (d, J=15.0 Hz, 2H), 6.60 (s, 1H), 5.97 (s, 1H), 5.12 (s, 1H), 4.82 (s, 1H), 3.64 (s, 1H), 3.52 (s, 1H), 3.28 (s, 1H), 3.03 (s, 1H), 2.54 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.69 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.23 (s,1H), 7.13 (s, 1H) , 7.06 (d, J=0.9 Hz, 2H), 6.96 (d, J=14.9 Hz, 2H), 6.65 (s, 1H), 5.95 (s, 1H), 5.11 (s, 1H), 4.92 (s, 1H), 4.81 (s, 1H), 3.63 (s, 1H), 3.51 (s, 1H), 3.27 (s, 1H), 3.02 (s, 1H), 2.53 (s, 1H), 2.19 (d, J=14.6 Hz, 2H), 2.01 (s, 1H), 1.87 (d, J=40.1 Hz, 3H), 1.79 (s, 1H), 1.61 (s, 1H), 1.36 (s, 2H), 1.30 (s, 1H), 1.19 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.69 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.27 (d, J=15.0 Hz, 5H), 7.14 (s, 1H), 7.07 (s, 1H), 6.97 (d, J=15.0 Hz, 2H), 6.82 (s, 1H), 6.58 (s, 1H), 6.04 (s, 1H), 5.01 (s, 21H), 4.83 (s, 1H), 4.32 (s, 2H), 3.28 (s, 1H), 3.20 (d, J=15.0 Hz, 2H), 3.03 (s, 1H), 2.89 (s, 1H), 2.70 (s, 1H), 2.25 (s, 1H), 2.00 (s, 1H), 1.90 (d, J=2.9 Hz, 1H), 1.60 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.74 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.60 (s,1H), 7.17 (s, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.03-6.90 (m, 3H), 6.53 (s, 1H), 5.75 (s, 1H), 5.12 (s, 1H), 4.72 (s, 1H), 3.29 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.04 (s, 1H), 2.75 (s, 1H), 2.43 (s, 1H), 2.33 (s, 1H), 2.01 (s, 1H), 1.96 (s, 1H), 1.91 (s, 1H), 1.52 (s, 1H), 1.27 (s, 9H).
1H NMR (500 MHz, Chloroform) δ 8.72 (s, 1H), 7.99 (d, J=25.5 Hz, 2H), 7.59 (s, 1H), 7.16 (s,1H), 7.09 (d, J=4.0 Hz, 2H), 6.97 (t, J=11.7 Hz, 3H), 6.45 (s, 1H), 6.07 (s, 1H), 5.09 (s, 1H), 4.94 (s, 1H), 4.68 (s, 1H), 3.28 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 3.03 (s, 1H), 2.95 (s, 1H), 2.44 (d, J=17.0 Hz, 2H), 2.19 (s, 2H), 2.03-1.73 (m, 5H), 1.84 (s, 2H), 1.84 (s, 2H), 1.60 (d, J=13.6 Hz, 2H), 1.37 (s, 2H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.26 (d, J=14.9 Hz,4H), 7.16-7.03 (m, 3H), 6.95 (s, 1H), 6.45 (s, 1H), 5.67 (s, 1H), 4.95 (s, 1H), 4.48 (s, 1H), 4.32 (s,2H), 3.79 (s, 1H), 2.20 (s, 1H), 2.15 (s, 1H), 2.04 (s, 2H), 1.77 (d, J=19.9 Hz, 3H), 1.68 (d, J=10.0 Hz, 4H), 1.37 (s, 1H), 1.30 (s, 1H), 1.11 (s, 1H), 1.01 (d, J=14.9 Hz, 6H).
1H NMR (500 MHz, Chloroform) δ 8.85 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.29 (d, J=15.0 Hz, 5H), 7.20 (d, J=16.0 Hz, 2H), 7.12 (d, J=20.0 Hz, 5H), 6.98 (s, 1H), 6.69 (s, 1H), 5.05 (s, 1H), 5.01 (s, 1H) , 4.74 (s, 1H), 4.34 (s, 2H), 3.81 (s, 1H), 3.29 (s, 2H), 3.04 (s, 1H), 2.21 (d, J=5.4 Hz, 2H), 2.05 (s, 2H), 1.00 (s, 6H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H) , 7.12 (d, J=20.0 Hz, 5H), 7.07 (s, 1H), 6.98 (s, 1H), 6.53 (s, 1H), 5.87 (s, 1H), 5.64 (s, 1H), 4.92 (s, 1H), 4.86 (s, 1H), 3.81 (s, 1H), 3.29 (s, 3H), 3.02 (d, J=18.8 Hz, 3H), 2.19 (d, J=11.4 Hz, 2H), 2.05 (s, 2H), 1.80 (s, 1H), 1.69 (d, J=10.0 Hz, 3H), 1.58 (s, 1H), 1.31 (s, 1H), 1.11 (s, 1H), 1.01 (d , J=15.0 Hz, 8H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 1H), 8.14 (s,1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 7.12 (d, J=20.0 Hz, 5H), 6.98 (s, 1H), 6.56 (s, 1H), 5.90 (s, 1H), 5.63 (s, 1H), 4.93 (d, J=16.9 Hz, 2H), 4.86 (s, 1H), 3.29 (s, 1H), 3.02 (d, J=18.8 Hz, 3H), 2.23-2.14 (m, 4H), 2.05 (s, 2H), 1.82 (d, J=20.0 Hz, 4H), 1.69 (d, J=10.0 Hz, 3H), 1.62 (s, 1H), 1.37 (d, J=0.9 Hz, 3H), 1.31 (s, 3H), 1.20 (s, 2H), 1.11 (s, 1H), 1.03 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 9.45 (s, 1H), 7.80 (s, 2H), 7.67 (s, 2H), 7.35-7.26 (m, 6H), 7.11 (s, 1H), 6.67 (s, 1H), 5.75 (s, 1H), 5.11 (s, 1H), 4.33 (d, J=6.4 Hz, 3H), 3.81 (s, 1H), 2.16 (d, J=10.5 Hz, 2H), 2.05 (s, 1H), 1.76 (s, 1H), 1.60 (s, 1H), 1.51 (d, J=15.0 Hz, 2H), 1.48-1.41 (m, 4H), 1.32 (s, 1H), 1.00 (s, 6H).
1H NMR (500 MHz, Chloroform)6 9.32 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.66 (d, J=4.6 Hz, 2H), 7.33-7.27 (m, 4H), 7.19 (s, 1H), 5.70 (s, 1H), 4.93 (s, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 4.03 (s, 1H), 3.98 (s, 1H), 3.24 (s, 1H), 3.02-2.98 (m, 3H), 2.30-2.26 (m, 2H), 2.18 (s, 1H), 2.10 (s, 1H), 1.82-1.75 (m, 2H), 1.75-1.71 (m, 2H), 1.67 (s, 1H), 1.45-1.41 (m, 2H), 1.33 (s, 1H), 1.30-1.20 (m, 6H), 1.14-1.07 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.34 (s, 1H), 8.08 (d, J=10.7 Hz, 2H), 7.62 (d, J=0.9 Hz, 2H), 7.30-7.21 (m, 8H), 7.19 (s, 1H), 7.14 (s, 1H), 6.23 (s, 1H), 6.03 (s, 1H), 5.22 (s, 1H), 5.08 (s, 1H), 4.95 (s, 1H), 4.88 (s, 1H), 4.33 (s, 1H), 4.28 (s, 1H), 3.96 (s, 1H), 3.22 (s, 1H), 2.99 (s, 1H), 2.38-2.34 (m, 2H), 2.21 (s, 1H), 2.16 (s, 1H), 1.33-1.20 (m, 6H). Example 239
N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(cyclohexylamino)-2-yl)amino)-3-(phenyl)-1-oxopropan-2-yl)-quinoxaline-2-carboxamide (A239)
1H NMR (500 MHz, Chloroform) δ 9.31 (s, 1H), 8.12 (d, J=31.2 Hz, 2H), 7.73 (s, 1H), 7.63 (d, J=6.0 Hz, 2H), 7.36-7.24 (m, 8H), 7.17 (d, J=11.8 Hz, 2H), 6.32 (s, 1H), 5.10 (s, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 4.36 (s, 1H), 4.30 (d, J=18.6 Hz, 2H), 4.12 (s, 1H), 3.24 (s, 1H), 2.97 (s, 1H), 2.31-2.27 (m, 2H), 2.12 (d, J=3.2 Hz, 2H), 1.94-1.87 (m, 2H), 1.73-1.63 (m, 4H), 1.61-1.55 (m, 4H).
1H NMR (500 MHz, Chloroform) δ 8.12 (s, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.36-7.25 (m, 4H), 7.20 (d, J=7.7 Hz, 2H), 6.84 (s, 1H), 6.18 (s, 1H), 5.49 (d, J=11.0 Hz, 2H), 4.70 (s, 1H), 4.39 (d, J=17.7 Hz, 2H), 4.08 (s, 1H), 3.24 (d, J=17.5 Hz, 2H), 2.54 (s, 1H), 2.08-2.04 (m, 2H), 1.82 (s, 1H), 1.78-1.67 (m, 6H), 1.66-1.62 (m, 2H), 1.58 (dd, J=9.5, 3.3 Hz, 5H), 1.44 (s, 1H), 1.37-1.27 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.33-7.27 (m, 4H), 7.23 (s, 1H), 6.79 (d, J=13.7 Hz, 2H), 6.29 (s, 1H), 6.09 (s, 1H), 5.05 (s, 1H), 4.99 (d, J=9.8 Hz, 2H), 4.41 (s, 1H), 4.34 (s, 1H), 3.24 (d, J=14.9 Hz, 2H), 2.92 (s, 1H), 2.36-2.32 (m, 3H), 2.08-2.04 (m, 2H), 1.85 (s, 1H), 1.79 (s, 1H), 1.74-1.55 (m, 11H), 1.48 (s, 1H), 1.46-1.23 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.33-7.30 (m, 22H), 7.28 (t, J=15.0 Hz, 33H), 6.83 (s, 9H), 6.14 (s, 9H), 6.09 (s, 9H), 5.94 (s, 9H), 5.19 (s, 9H), 5.01 (s, 9H), 4.36 (d, J=0.5 Hz, 18H), 3.45 (s, 9H), 3.35 (s, 7H), 2.59 (s, 9H), 2.38-2.34 (m, 27H), 2.18 (s, 8H), 2.09-2.05 (m, 18H), 1.96-1.88 (m, 24H), 1.88 (s, 3H), 1.73-1.60 (m, 46H), 1.40-1.36 (m, 16H), 1.32 (s, 9H), 1.15 (s, 7H), 1.12-1.08 (m, 17H).
1H NMR (500 MHz, Chloroform) δ 7.54 (s, 6H), 7.45 (s, 6H), 7.29-7.18 (m, 30H), 6.96 (s, 6H), 6.49 (s, 6H), 6.01 (s, 6H), 5.92-5.88 (m, 12H), 5.58 (s, 6H), 5.11 (s, 6H), 4.93 (s, 6H), 4.63 (s, 6H), 4.29 (s, 6H), 4.24 (s, 6H), 3.24 (d, J=17.5 Hz, 11H), 2.86 (s, 6H), 2.05 (t, J=4.2 Hz, 18H), 1.95-1.87 (m, 12H), 1.84 (s, 6H), 1.76 (t, J=4.8 Hz, 17H), 1.63 (dd, J=40.8, 34.9 Hz, 22H), 1.51 (dd, J=4.6, 1.3 Hz, 1H), 1.40-1.36 (m, 10H), 1.32 (s, 6H), 1.17-1.09 (m, 17H).
1H NMR (500 MHz, Chloroform) δ 7.84 (s, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.38 (s, 1H), 7.31-7.23 (m, 6H), 7.16 (s, 1H), 6.17 (s, 1H), 5.59 (s, 1H), 5.10 (s, 1H), 4.75 (s, 1H), 4.53 (s, 1H), 4.36 (d, J=17.3 Hz, 2H), 3.24 (d, J=17.5 Hz, 2H), 2.88 (s, 1H), 2.06 (t, J=2.7 Hz, 3H), 1.96-1.81 (m, 3H), 1.77 (s, 1H), 1.73-1.60 (m, 5H), 1.53 (s, 1H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.22-1.15 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.60 (s, 8H), 7.34-7.22 (m, 33H), 7.15 (d, J=10.0 Hz, 16H), 7.06 (s, 8H), 6.81 (s, 8H), 6.54 (s, 8H), 6.22 (s, 8H), 5.59 (s, 8H), 5.08 (s, 8H), 4.92 (s, 8H), 4.63 (s, 8H), 4.32 (d, J=1.1 Hz, 16H), 3.89-3.85 (m, 24H), 3.24 (d, J=17.4 Hz, 15H), 2.94 (s, 8H), 2.07 (t, J=5.1 Hz, 23H), 1.93-1.85 (m, 18H), 1.84 (s, 6H), 1.78 (s, 6H), 1.73-1.51 (m, 49H), 1.51 (d, J=5.5 Hz, 1H), 1.40-1.36 (m, 14H), 1.32 (s, 8H), 1.16-1.07 (m, 23H).
1H NMR (500 MHz, Chloroform) δ 7.60-7.40 (m, 3H), 7.32-7.18 (m, 7H), 6.67 (s, 1H), 5.57 (s, 1H), 5.15 (s, 1H), 4.67 (s, 1H), 4.55 (s, 1H), 4.30 (d, J=14.7 Hz, 2H), 3.24 (d, J=17.3 Hz, 2H), 2.73 (s, 1H), 2.15-2.10 (m, 4H), 2.08-2.04 (m, 2H), 1.88-1.81 (m, 3H), 1.77 (s, 1H), 1.73-1.59 (m, 5H), 1.55 (s, 1H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.14-1.05 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.50-7.34 (m, 3H), 7.32-7.26 (m, 4H), 7.23 (s, 1H), 7.11 (s, 1H), 6.68 (s, 1H), 5.57 (s, 1H), 5.15 (s, 1H), 4.69 (s, 1H), 4.55 (s, 1H), 4.30 (d, J=14.8 Hz, 2H), 3.24 (d, J=17.3 Hz, 2H), 2.73 (s, 1H), 2.45-2.41 (m, 3H), 2.15-2.10 (m, 4H), 2.08-2.04 (m, 2H), 1.88-1.81 (m, 3H), 1.77 (s, 1H), 1.73-1.59 (m, 5H), 1.55 (s, 1H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.14-1.05 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 1H), 7.34-7.27 (m, 2H), 7.27-7.22 (m, 2H), 7.10 (s, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 6.32 (s, 1H), 5.56 (s, 1H), 5.35 (s, 1H), 4.66 (d, J=18.6 Hz, 2H), 4.28 (s, 1H), 4.17 (s, 1H), 3.91-3.87 (m, 3H), 3.85-3.81 (m, 3H), 3.24 (d, J=17.8 Hz, 2H), 3.06 (s, 1H), 2.05 (t, J=6.8 Hz, 3H), 1.96-1.88 (m, 2H), 1.84 (s, 1H), 1.77 (s, 1H), 1.73-1.54 (m, 5H), 1.52 (s, 1H), 1.40-1.36 (m, 2H), 1.32 (s, 1H), 1.17-1.08 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 8.07 (s, 91H), 7.62 (s, 92H), 7.58 (s, 94H), 7.47 (s, 94H), 7.27 (dd, J=9.9 , 8.1 Hz, 379H), 7.20 (t, J=5.8 Hz, 274H), 6.24 (s, 91H), 5.61 (s, 91H), 5.16 (s, 90H), 4.93 (s, 91H), 4.52 (s, 89H), 4.32 (d, J=0.6 Hz, 182H), 3.24 (d, J=17.5 Hz, 174H), 2.89 (s, 93H), 2.06 (t, J=2.7 Hz, 257H), 1.92-1.80 (m, 277H), 1.81 (s, 7H), 1.77 (s, 70H), 1.73-1.51 (m, 541H), 1.51 (d, J=1.8 Hz, 6H), 1.40-1.36 (m, 160H), 1.32 (s, 86H), 1.22-1.16 (m, 264H).
1H NMR (500 MHz, Chloroform) δ 8.16 (s, 1H), 7.32 (s, 1H), 7.32-7.24 (m, 4H), 7.23-7.09 (m, 3H), 6.84 (s, 1H), 6.05 (s, 1H), 5.64 (s, 1H), 5.33 (s, 1H), 5.06-5.02 (m, 2H), 4.50 (d, J=9.3 Hz, 2H), 4.39 (s, 1H), 4.32 (s, 1H), 3.24 (d, J=17.4 Hz, 2H), 2.99 (s, 1H), 2.15 (s, 1H), 2.08-2.04 (m, 2H), 1.85 (s, 1H), 1.79 (s, 1H), 1.73-1.69 (m, 2H), 1.69-1.62 (m, 5H), 1.55 (s, 1H), 1.39-1.35 (m, 2H), 1.31 (s, 1H), 1.23-1.19 (m, 2H), 1.17 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 8.51 (s, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.11 (s, 1H), 5.40 (s, 1H), 5.16 (s, 1H), 4.65 (s, 1H), 4.52 (s, 1H), 4.38-4.34 (m, 4H), 3.45 (s, 1H), 3.36 (d, J=13.4 Hz, 2H), 2.68 (s, 1H), 2.18 (s, 1H), 2.11-2.02 (m, 2H), 1.99-1.84 (m, 3H), 1.78-1.72 (m, 2H), 1.71-1.62 (m, 5H), 1.58 (dd, J=9.0, 3.3 Hz, 5H), 1.55-1.50 (m, 2H), 1.48 (s, 1H), 1.43-1.39 (m, 4H), 1.37-1.29 (m, 3H).
1H NMR (500 MHz, Chloroform) δ 9.01 (s, 1H), 7.52 (s, 1H), 7.29-7.23 (m, 2H), 7.23-7.17 (m, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.92 (s, 1H), 6.21 (s, 1H), 5.12 (s, 1H), 5.05 (s, 1H), 4.87 (s, 1H), 4.52 (s, 1H), 4.38-4.34 (m, 4H), 3.44 (d, J=12.5 Hz, 2H), 3.37-3.20 (m, 3H), 2.98 (s, 1H), 2.19 (s, 1H), 2.12-2.04 (m, 2H), 1.92 (s, 1H), 1.85-1.78 (m, 2H), 1.66 (s, 1H), 1.56-1.52 (m, 2H), 1.48-1.39 (m, 3H), 1.23-1.11 (m, 2H).
1H NMR (500 MHz, Chloroform) δ 8.73 (s, 5H), 8.50 (s, 5H), 7.45 (s, 5H), 7.37 (s, 5H), 7.18 (s, 5H), 6.75 (s, 5H), 6.03 (s, 5H), 5.67 (s, 5H), 5.61 (s, 5H), 4.89 (s, 5H), 4.57 (s, 5H), 3.84-3.80 (m, 15H), 3.43 (d, J=16.9 Hz, 10H), 3.35 (s, 4H), 2.70 (s, 5H), 2.19 (s, 5H), 2.09-2.06 (m, 9H), 2.06-2.04 (m, 1H), 2.06-1.91 (m, 16H), 1.73-1.61 (m, 35H), 1.60-1.46 (m, 47H), 1.46-1.39 (m, 11H), 1.35-1.26 (m, 9H), 1.22 (s, 4H). Example 254 N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-4-fluorophenyl-1-oxopropan-2-yl)-5-methyl-benzofuran-2-carboxamide (A254)
1H NMR (500 MHz, Chloroform-d) δ 8.35 (d, J=9.7 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.60 (dd, J=2.7 , 1.8 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.35-7.22 (m, 7H), 7.22-7.17 (m, 1H), 7.07-7.00 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.75 (dt, J=9.7, 6.2 Hz, 1H), 4.54-4.46 (m, 1H), 4.50-4.45 (m, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.27-3.14 (m, 2H), 3.08 (ddt, J=6.2, 2.9, 1.1 Hz, 2H), 2.61 (tdd, J=8.9, 6.9, 4.3 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.81-1.61 (m, 4H).
1H NMR (500 MHz, Chloroform) δ 7.75 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=15.0 Hz, 6H), 7.21 (s, 1H), 6.10 (s, 1H), 4.78 (s, 1H), 4.52 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.53 (d, J=13.0 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=6.4 Hz, 1H), 1.76 (s, 1H), 1.64 (s, 1H), 1.58 (s, 1H), 1.55-1.37 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.66 (s, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 6.88 (s, 1H), 6.44 (s, 1H), 6.11 (s, 1H), 4.95 (s, 1H), 4.76 (s, 1H), 4.54 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 2.88 (s, 1H), 2.50 (d, J=13.5 Hz, 2H), 2.19 (s, 2H), 2.01 (s, 1H), 1.91 (d, J=0.5 Hz, 1H), 1.84 (s, 2H), 1.76 (s, 1H), 1.59 (dd, J=42.7, 19.7 Hz, 5H), 1.53 (s, 1H), 1.51 (d, J=15.0 Hz, 3H), 1.44 (dd, J=9.2, 5.8 Hz, 5H), 1.37 (s, 3H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 7.54 (t, J=2.6 Hz, 1H), 7.46 (d, J=71.6 Hz, 5H), 7.18 (s, 3H), 7.11 (d, J=2.3 Hz, 4H), 6.42 (s, 3H), 5.73 (s, 3H), 5.65 (s, 3H), 5.03 (s, 2H), 4.95 (s, 1H), 4.47 (s, 1H), 3.21 (d, J=15.0 Hz, 6H), 2.99 (s, 2H), 2.72 (s, 3H), 2.34 (s, 2H), 2.19 (s, 5H), 2.01 (s, 1H), 1.93 (d, J=16.1 Hz, 5H), 1.89-1.74 (m, 10H), 1.69 (d, J=10.0 Hz, 8H), 1.62 (s, 2H), 1.51 (s, 1H), 1.39 (d, J=6.9 Hz, 1H), 1.38-1.28 (m, 4H), 1.20 (s, 3H), 1.11 (s, 2H), 1.03 (s, 3H).
1H NMR (500 MHz, Chloroform) δ 8.58 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.29 (d, J=15.0 Hz, 4H), 7.22 (s, 1H), 7.05 (s, 1H), 6.30 (s, 1H), 5.77 (s, 1H), 4.90 (s, 1H), 4.45 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.97 (s, 1H), 2.67 (s, 1H), 2.13 (s, 1H), 2.01 (s, 1H), 1.93 (d, J=16.5 Hz, 2H), 1.78 (m, 2H), 1.75 (d, J=7.8 Hz, 1H), 1.57 (s, 1H), 1.46 (m, 9H).
1H NMR (500 MHz, Chloroform) δ 7.78-7.52 (m, 1H), 7.29 (d, J=15.0 Hz, 1H), 7.23 (d, J=10.0 Hz, 1H), 7.11 (s, 1H), 6.36 (s, 1H), 5.85 (s, 1H), 4.82 (s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 4.06 (s, 1H), 3.21 (d, J=15.0 Hz, 1H), 2.82 (s, 2H), 2.45 (d, J=1.0 Hz, 1H), 2.01 (s, 1H), 1.91 (s, 2H), 1.79-1.57 (m, 2H), 1.62-1.57 (m, 2H), 1.55-1.41 (m, 2H), 1.33 (d, J=7.5 Hz, 1H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 1H), 7.50 (d, J=5.0 Hz, 2H), 7.28 (s, 1H), 7.21 (d, J=5.0 Hz, 1H), 7.11 (d, J=1.5 Hz, 2H), 7.03 (s, 1H), 6.94 (s, 1H), 6.88 (s, 1H), 5.72 (s, 1H), 4.68 (s, 1H), 4.63 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.78 (s, 1H), 2.38-2.29 (m, 5H), 2.08-2.03 (m, 1H), 2.08-1.89 (m, 2H), 1.76 (s, 1H), 1.67 (s, 1H), 1.55-1.41 (m, 8H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 1H), 7.50 (s, 1H), 7.38 (d, J=2.0 Hz, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 6.12 (s, 1H), 4.80 (s, 1H), 4.53 (s, 1H), 4.34 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 2.91 (s, 1H), 2.51 (d, J=9.5 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=4.1 Hz, 1H), 1.76 (s, 1H), 1.65 (s, 1H), 1.58 (s, 1H), 1.51 (d, J=15.0 Hz, 2H), 1.44 (dd, J=8.0, 7.0 Hz, 6H).
1H NMR (500 MHz, Chloroform) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.29 (d, J=15.0 Hz, 5H), 7.19 (s, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 6.09 (s, 1H), 4.80 (s, 1H), 4.45 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.90 (s, 1H), 2.44 (d, J=5.0 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=1.4 Hz, 1H), 1.76 (s, 1H), 1.72 (s, 1H), 1.59-1.48 (m, 3H), 1.48-1.41 (m, 4H), 1.36 (s, 1H).
1H NMR (500 MHz, Chloroform) δ 7.59 (s, 1H), 7.50 (s, 1H), 7.38 (d, J=9.2 Hz, 5H), 7.28 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 6.12 (s, 1H), 4.80 (s, 1H), 4.53 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.92 (s, 1H), 2.51 (d, J=13.5 Hz, 2H), 2.01 (s, 1H), 1.91 (d, J=3.7 Hz, 1H), 1.76 (s, 1H), 1.65 (s, 1H), 1.58 (s, 1H), 1.51 (d, J=15.0 Hz, 2H), 1.44 (dd, J=8.3, 6.7 Hz, 6H).
1H NMR (500 MHz, Chloroform) δ 7.50 (d, J=32.8 Hz, 1H), 7.34-7.26 (m, 3H), 7.18 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 6.12 (s, 1H), 4.78 (s, 1H), 4.54 (s, 1H), 4.34 (s, 1H), 3.21 (d, J=15.0 Hz, 1H), 2.90 (s, 2H), 2.54 (d, J=18.2 Hz, 1H), 2.01 (s, 1H), 1.92 (d, J=6.0 Hz, 1H), 1.76 (s, 2H), 1.65 (s, 2H), 1.58 (s, 2H), 1.51 (d, J=15.0 Hz, 1H), 1.44 (dd, J=8.2, 6.8 Hz, 3H).
1H NMR (500 MHz, Chloroform) δ 7.53 (d, J=44.9 Hz, 1H), 7.34 (s, 1H), 7.28-7.12 (m, 2H), 7.05 (s, 1H), 6.84 (s, 1H), 6.11 (s, 1H), 4.79 (s, 1H), 4.53 (s, 1H), 4.33 (s, 1H), 3.21 (d, J=15.0 Hz, 1H), 2.92 (s, 1H), 2.50 (d, J=17.5 Hz, 1H), 2.01 (s, 1H), 1.91 (d, J=3.9 Hz, 2H), 1.76 (s, 1H), 1.65 (s, 1H), 1.58 (s, 1H), 1.55-1.41 (m, 4H).
1H NMR (500 MHz, Chloroform) δ 7.66 (s, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 6.88 (s, 1H), 6.44 (s, 1H), 6.11 (s, 1H), 4.95 (s, 1H), 4.76 (s, 1H), 4.54 (s, 1H), 3.21 (d, J=15.0 Hz, 2H), 2.88 (s, 1H), 2.50 (d, J=13.5 Hz, 1H), 2.19 (s, 2H), 2.01 (s, 1H), 1.91 (d, J=0.5 Hz, 1H), 1.84 (s, 1H), 1.76 (s, 1H), 1.59 (dd, J=42.7, 19.7 Hz, 5H), 1.53 (s, 1H), 1.51 (d, J=15.0 Hz, 3H), 1.44 (dd, J=9.2, 5.8 Hz, 5H), 1.37 (s, 3H), 1.31 (s, 1H), 1.20 (s, 2H).
1H NMR (500 MHz, Chloroform) δ 7.54 (s, 1H), 7.30-7.20 (m, 2H), 7.15 (s, 1H), 6.95-6.82 (m, 2H), 6.11 (s, 1H), 4.78 (s, 1H), 4.53 (s, 1H), 4.23 (s, 1H), 3.72 (s, 1H), 3.21 (d, J=15.0 Hz, 1H), 2.89 (s, 1H), 2.55 (d, J=18.5 Hz, 1H), 2.01 (s, 1H), 1.91 (d, J=5.9 Hz, 1H), 1.76 (s, 1H), 1.65 (s, 1H), 1.58 (s, 1H), 1.55-1.35 (m, 4H).
1H NMR (500 MHz, Chloroform) δ 9.81 (s, 1H), 8.52 (s, 1H), 7.99 (s, 1H), 7.33-7.26 (m, 6H), 6.71 (s, 1H), 6.06 (s, 1H), 4.75 (s, 1H), 4.45 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.83 (s, 1H), 2.65 (s, 1H), 2.52 (s, 1H), 2.01 (s, 1H), 1.90 (d, J=8.1 Hz, 1H), 1.76 (s, 1H), 1.65-1.28 (m, 9H), 1.39-1.28 (m, 1H).
1H NMR (500 MHz, Chloroform) δ 8.49 (s, 1H), 7.33-7.26 (m, 7H), 7.20 (s, 2H), 7.10 (s, 1H), 6.87 (s, 1H), 6.11 (s, 1H), 4.78 (s, 1H), 4.52 (s, 1H), 4.34 (s, 2H), 3.21 (d, J=15.0 Hz, 2H), 2.92 (s, 1H), 2.54 (d, J=17.0 Hz, 3H), 2.01 (s, 1H), 1.92 (d, J=8.4 Hz, 2H), 1.76 (s, 1H), 1.64 (s, 1H), 1.58 (s, 1H), 1.51 (d, J=15.0 Hz, 4H), 1.44 (dd, J=9.9, 5.2 Hz, 6H).
1H NMR (500 MHz, Chloroform) δ 7.54 (d, J=45.0 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.15 (s, 2H), 6.85 (d, J=1.8 Hz, 5H), 6.79 (s, 1H), 6.11 (s, 2H), 4.79 (s, 1H), 4.53 (s, 1H), 4.33 (s, 3H), 3.21 (d, J=15.0 Hz, 4H), 2.91 (s, 1H), 2.52 (s, 2H), 2.48 (s, 2H), 2.01 (s, 1H), 1.91 (d, J=3.5 Hz, 2H), 1.76 (s, 2H), 1.65 (s, 2H), 1.58 (s, 2H), 1.55-1.41 (m, 7H).
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.19 (dt, J=8.4, 1.0 Hz, 2H), 6.87-6.82 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.50 (ddt, J=5.8, 3.7, 1.1 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.78 (s, 2H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 631.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 7.85 (d, J=9.7 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.14 (dt, J=8.0, 1.1 Hz, 2H), 7.10 (dq, J=7.3, 0.7 Hz, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.55-4.48 (m, 2H), 4.50-4.43 (m, 1H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.99 (s, 2H), 2.61 (tdd, J=8.7, 6.8, 4.1 Hz, 1H), 2.16 (ddd, J=15.0, 8.8, 7.6 Hz, 1H), 1.94 (ddd, J=15.0, 8.8, 7.6 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 629.33 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.21-8.13 (m, 3H), 8.10 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60 (q, J=1.1 Hz, 1H), 7.60-7.52 (m, 2H), 7.43-7.34 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.50 (ddt, J=5.6, 4.6, 0.9 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9 , 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.71 (m, 4H), 1.74-1.59 (m, 3H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 646.28 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.80-7.75 (m, 2H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 6.78 (s, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.50 (dd, J=6.0, 2.9 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9 , 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.23 (s, 2H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 643.34 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.62-7.49 (m, 5H), 7.48-7.41 (m, 2H), 7.43-7.34 (m, 3H), 7.30 (dt, J=8.4, 1.0 Hz, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.49 (ddt, J=5.7, 2.1, 1.0 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9 , 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 677.33 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.79-7.72 (m, 2H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.08 (dd, J=8.1, 7.1 Hz, 1H), 7.00-6.95 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.53-4.44 (m, 2H), 4.46-4.39 (m, 1H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 629.33 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.62-7.56 (m, 2H), 7.59-7.52 (m, 1H), 7.44-7.34 (m, 4H), 6.26 (t, J=4.0 Hz, 1H), 4.49 (ddt, J=5.7 , 2.1, 0.9 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9 , 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 626.29 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.23 (dt, J=8.3, 1.1 Hz, 2H), 7.17-7.11 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.50 (ddt, J=5.8, 3.6, 1.0 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9 , 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 685.27 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.23-8.16 (m, 2H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.64-7.58 (m, 1H), 7.61-7.52 (m, 1H), 7.43-7.32 (m, 5H), 6.26 (t, J=4.0 Hz, 1H), 4.56 (dd, J=5.7, 1.0 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 626.30 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.69 (dd, J=3.8, 1.8 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 8.28 (dt, J=7.3, 1.9 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.40-7.32 (m, 1H), 7.34-7.30 (m, 1H), 7.32-7.27 (m, 2H), 7.30-7.22 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.48 (t, J=1.0 Hz, 1H), 4.49-4.39 (m, 3H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 601.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19-8.08 (m, 2H), 7.89 (d, J=9.3 Hz, 1H), 7.83 (t, J=2.1 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 2.0 Hz, 1H), 7.35-7.22 (m, 5H), 6.26 (t, J=4.0 Hz, 1H), 4.50-4.39 (m, 3H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.74 (m, 3H), 1.77-1.59 (m, 4H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 635.26 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.16 (d, J=9.9 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.35-7.22 (m, 5H), 7.16 (t, J=2.0 Hz, 1H), 7.08 (dd, J=8.4, 1.8 Hz, 1H), 6.26 (t, J=4.0 Hz, 1H), 4.47 (dt, J=5.7, 1.0 Hz, 2H), 4.44 (dt, J=9.2, 7.4 Hz, 1H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.82 (s, 2H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.71 (m, 4H), 1.75-1.59 (m, 3H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 631.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=9.9 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.35-7.22 (m, 5H), 6.26 (t, J=4.0 Hz, 1H), 4.50-4.39 (m, 3H), 4.26 (dt, J=9.9, 6.7 Hz, 1H), 3.27-3.14 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.2 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.86-1.59 (m, 7H), 1.57-1.34 (m, 8H), 1.32-1.20 (m, 2H). ESI-MS m/z 601.29 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J=9.7 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.35-7.22 (m, 6H), 7.01 (td, J=7.8, 1.9 Hz, 2H), 6.96 (dtt, J=7.9, 1.9, 1.0 Hz, 1H), 6.26 (t, J=4.0 Hz, 1H), 4.78 (dt, J=9.7, 6.2 Hz, 1H), 4.54-4.46 (m, 1H), 4.48 (s, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.27-3.14 (m, 2H), 3.05-2.93 (m, 2H), 2.61 (tdd, J=8.9, 6.9, 4.3 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.81-1.61 (m, 4H). ESI-MS m/z 613.24 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 9.91 (s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.63 (dt, J=8.0, 2.5 Hz, 1H), 7.50 (dd, J=7.2, 5.0 Hz, 1H), 7.30-7.14 (m, 7H), 7.08 (ddd, J=8.1, 7.1, 2.7 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.78 (dt, J=8.1, 6.2 Hz, 1H), 4.44 (dt, J=9.3, 7.3 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.08-3.01 (m, 1H), 3.04-2.97 (m, 1H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.3 Hz, 1H). ESI-MS m/z 564.25 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 9.91 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.37-7.31 (m, 2H), 6.82 (dd, J=7.3, 2.4 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.49-4.36 (m, 2H), 3.83 (s, 2H), 3.67 (dp, J=8.2, 4.9 Hz, 1H), 3.33-3.22 (m, 2H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.33 (m, 21H), 1.31-1.20 (m, 2H). ESI-MS m/z 608.34 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.18 (d, J=7.7 Hz, 1H), 7.85-7.75 (m, 2H), 7.48 (d, J=8.2 Hz, 1H), 7.43 (dd, J=8.3, 1.2 Hz, 1H), 7.31-7.15 (m, 8H), 6.13 (t, J=3.1 Hz, 1H), 4.75 (dt, J=7.5, 6.2 Hz, 1H), 4.41 (dt, J=9.2, 7.4 Hz, 1H), 3.93 (s, 2H), 3.67 (dp, J=8.2, 4.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.02 (ddt, J=6.2, 3.2, 1.0 Hz, 2H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.3, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.3 Hz, 1H), 1.75-1.40 (m, 8H), 1.43-1.36 (m, 2H), 1.40-1.33 (m, 1H). ESI-MS m/z 586.29 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 9.91 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.63 (dt, J=7.9, 2.5 Hz, 1H), 7.53-7.46 (m, 2H), 7.30-7.14 (m, 5H), 7.08 (ddd, J=8.1, 7.1, 2.7 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.78 (dt, J=8.1, 6.2 Hz, 1H), 4.41 (dt, J=9.2, 7.4 Hz, 1H), 3.67 (dp, J=8.2, 4.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.02 (ddt, J=6.2, 3.2, 1.0 Hz, 2H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.3 Hz, 1H), 1.75-1.33 (m, 11H). ESI-MS m/z 590.27 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J=9.7 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.38-7.22 (m, 8H), 7.07-7.00 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.75 (dt, J=9.7, 6.2 Hz, 1H), 4.54-4.46 (m, 1H), 4.50-4.45 (m, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.27-3.14 (m, 2H), 3.08 (ddt, J=6.2, 2.9, 1.1 Hz, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.3 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.81-1.61 (m, 4H). ESI-MS m/z 613.24 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J=9.7 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.35-7.22 (m, 5H), 7.10-7.03 (m, 1H), 7.03-6.96 (m, 2H), 6.26 (t, J=4.0 Hz, 1H), 4.78 (dt, J=9.7 , 6.2 Hz, 1H), 4.54-4.46 (m, 1H), 4.50-4.45 (m, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.27-3.14 (m, 2H), 3.07-2.95 (m, 2H), 2.61 (tdd, J=8.9 , 6.9, 4.3 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.81-1.61 (m, 4H). ESI-MS m/z 631.23 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J=9.7 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.30-7.16 (m, 6H), 6.13 (t, J=3.1 Hz, 1H), 4.70 (dt, J=9.7 , 6.2 Hz, 1H), 4.44 (dt, J=9.3, 7.3 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.08-2.97 (m, 2H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.3 Hz, 1H). ESI-MS m/z 547.25 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 7.95-7.87 (m, 2H), 7.54-7.46 (m, 2H), 7.40 (d, J=2.1 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.40 (dt, J=9.3 , 7.3 Hz, 1H), 4.36-4.29 (m, 1H), 4.29 (dd, J=4.8, 2.4 Hz, 2H), 4.27 (ddd, J=4.7 , 3.0, 2.2 Hz, 2H), 3.67 (dp, J=8.2, 4.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.77 (m, 2H), 1.80-1.66 (m, 4H), 1.68-1.61 (m, 1H), 1.64-1.58 (m, 1H), 1.61-1.49 (m, 2H), 1.53-1.38 (m, 10H), 1.41-1.33 (m, 2H), 1.31-1.20 (m, 2H). ESI-MS m/z 597.33 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.8, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.32-7.22 (m, 4H), 6.13 (t, J=3.1 Hz, 1H), 5.01 (dtdd, J=8.4, 6.1, 5.1, 1.1 Hz, 1H), 4.48-4.37 (m, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.68 (m, 4H), 1.57-1.34 (m, 12H), 1.31-1.20 (m, 2H). ESI-MS m/z 612.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.07-8.01 (m, 1H), 7.94 (dt, J=8.0, 0.8 Hz, 1H), 7.84 (d, J=9.7 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.9, 1.2 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.52 (dt, J=9.7, 7.7 Hz, 1H), 4.41 (dt, J=9.3, 6.6 Hz, 1H), 3.71 (ddd, J=9.7, 6.3, 3.6 Hz, 4H), 3.63 (dd, J=6.4, 3.6 Hz, 2H), 3.55 (dd, J=6.4, 3.6 Hz, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.64 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.16 (dt, J=15.3, 7.6 Hz, 1H), 2.01 (dt, J=15.1, 7.7 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.80 (m, 1H), 1.82-1.77 (m, 1H), 1.80-1.75 (m, 1H), 1.77-1.68 (m, 1H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 578.29 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.8, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.32-7.22 (m, 4H), 6.13 (t, J=3.1 Hz, 1H), 5.03 (dqt, J=8.1, 6.1, 1.1 Hz, 1H), 4.48-4.37 (m, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.68 (m, 4H), 1.57-1.34 (m, 12H), 1.31-1.20 (m, 2H). ESI-MS m/z 612.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.85 (d, J=9.7 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.8, 1.2 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.52 (dt, J=9.7, 7.7 Hz, 1H), 4.41 (dt, J=9.3, 6.6 Hz, 1H), 3.45 (q, J=7.3 Hz, 4H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.67 (tdd, J=7.9, 5.7, 3.9 Hz, 1H), 2.17 (dt, J=15.3, 7.7 Hz, 1H), 2.01 (dt, J=15.1, 7.6 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.70 (m, 4H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H), 1.20 (t, J=7.3 Hz, 6H). ESI-MS m/z 564.31 [M+H]+.
N-((S)-14(S)-4-(4-fluorobenzylamino)-3,4-dione-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)-quinoline-2-carboxamide (A297)
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.2 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.7 , 1.1 Hz, 1H), 7.32 (ddt, J=7.5, 5.0, 1.0 Hz, 2H), 7.11-7.03 (m, 2H), 6.13 (t, J=3.1 Hz, 1H), 4.55-4.45 (m, 3H), 4.41 (dt, J=9.3, 6.6 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.77 (m, 2H), 1.80-1.75 (m, 1H), 1.77-1.68 (m, 1H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 616.28 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.39-8.32 (m, 2H), 8.20 (d, J=8.2 Hz, 1H), 8.13 (t, J=5.7 Hz, 1H), 8.07-8.01 (m, 1H), 7.94 (dt, J=8.0, 0.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.9, 1.2 Hz, 1H), 7.19 (dt, J=8.4, 1.0 Hz, 2H), 6.87-6.82 (m, 2H), 6.13 (t, J=3.1 Hz, 1H), 4.55-4.49 (m, 1H), 4.52-4.44 (m, 2H), 4.41 (dt, J=9.3, 6.6 Hz, 1H), 3.78 (s, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.07-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.86-1.68 (m, 4H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 628.31 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 9.03 (d, J=6.6 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 8.01 (t, J=1.6 Hz, 1H), 7.92 (dd, J=23.3 , 8.9 Hz, 2H), 7.79 (dd, J=7.4, 1.6 Hz, 1H), 7.44 (s, OH), 7.35-7.17 (m, 6H), 6.69 (dd, J=3.3 , 2.0 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.54-4.46 (m, 1H), 4.47 (dd, J=5.8, 0.9 Hz, 2H), 4.33 (dt, J=8.4, 6.7 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.69 (m, 4H), 1.57-1.34 (m, 9H), 1.31-1.20 (m, 2H). ESI-MS m/z 586.30 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.74-8.70 (m, 1H), 8.58 (d, J=9.3 Hz, 1H), 8.47 (s, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.52 (dd, J=8.8, 1.3 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.35-7.22 (m, 5H), 6.13 (t, J=3.1 Hz, 1H), 4.54-4.46 (m, 1H), 4.48 (d, J=0.9 Hz, 1H), 4.47 (t, J=0.9 Hz, 1H), 4.41 (dt, J=9.3 , 6.6 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.68 (m, 4H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 665.20 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.36-8.30 (m, 2H), 8.19 (d, J=2.1 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.94-7.86 (m, 2H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.35-7.22 (m, 5H), 6.13 (t, J=3.1 Hz, 1H), 4.54-4.45 (m, 3H), 4.41 (dt, J=9.3, 6.6 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.80 (m, 1H), 1.82-1.77 (m, 1H), 1.80-1.75 (m, 1H), 1.77-1.68 (m, 1H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 676.20 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.11 (t, J=5.8 Hz, 1H), 7.95-7.87 (m, 2H), 7.52 (dd, J=8.4, 2.2 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.35-7.22 (m, 5H), 6.89 (d, J=8.5 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.54-4.46 (m, 1H), 4.48 (d, J=0.9 Hz, 1H), 4.47 (t, J=0.9 Hz, 1H), 4.36-4.29 (m, 1H), 4.29 (dd, J=4.8, 2.4 Hz, 2H), 4.27 (ddd, J=4.7, 3.0, 2.2 Hz, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.69 (m, 4H), 1.57-1.34 (m, 9H), 1.31-1.20 (m, 2H). ESI-MS m/z 605.29 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.36 (d, J=9.3 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.35-7.22 (m, 5H), 6.50 (s, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.47 (dt, J=5.4, 0.9 Hz, 2H), 4.48-4.37 (m, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.52 (s, 2H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.02 (dt, J=15.0, 7.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.86-1.80 (m, 1H), 1.82-1.77 (m, 1H), 1.80-1.75 (m, 1H), 1.77-1.68 (m, 1H), 1.57-1.34 (m, 8H), 1.31-1.20 (m, 2H). ESI-MS m/z 552.27 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.43-8.32 (m, 2H), 8.20 (d, J=8.2 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 8.04 (dd, J=8.1, 1.2 Hz, 1H), 7.97-7.91 (m, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.7, 1.2 Hz, 1H), 7.36-7.15 (m, 7H), 7.10 (td, J=7.9, 1.2 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.80 (dt, J=9.2, 7.3 Hz, 1H), 4.54-4.46 (m, 1H), 4.47 (dd, J=5.8, 0.9 Hz, 2H), 3.33-3.22 (m, 2H), 3.21 (ddd, J=15.8, 7.4, 0.9 Hz, 1H), 3.09 (ddd, J=15.9, 7.3, 0.7 Hz, 1H), 2.68 (tdd, J=7.7 , 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.07-1.99 (m, 1H), 1.90 (dddd, J=12.1, 6.1, 3.8, 2.5 Hz, 1H), 1.82 (dtd, J=12.2, 3.7, 2.3 Hz, 1H). ESI-MS m/z 610.24 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.43 (d, J=9.1 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 8.04 (dd, J=8.1, 1.2 Hz, 1H), 7.97-7.91 (m, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9 , 1.1 Hz, 1H), 7.53 (td, J=7.7 , 1.2 Hz, 1H), 7.35-7.22 (m, 6H), 7.01 (td, J=7.8, 1.9 Hz, 2H), 6.96 (dtt, J=7.9, 1.9, 1.0 Hz, 1H), 6.13 (t, J=3.1 Hz, 1H), 4.80 (dt, J=9.3, 6.3 Hz, 1H), 4.54-4.46 (m, 1H), 4.47 (dd, J=5.8, 0.9 Hz, 2H), 3.33-3.22 (m, 2H), 3.05-2.93 (m, 2H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.07-1.99 (m, 1H), 1.90 (dddd, J=12.1, 6.1, 3.8, 2.4 Hz, 1H), 1.82 (dtd, J=12.3, 3.7, 2.3 Hz, 1H). ESI-MS m/z 610.23 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.43 (d, J=9.1 Hz, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.8, 1.2 Hz, 1H), 7.35-7.22 (m, 7H), 7.07-7.00 (m, 2H), 6.13 (t, J=3.1 Hz, 1H), 4.77 (dt, J=9.2, 6.2 Hz, 1H), 4.54-4.46 (m, 1H), 4.48 (d, J=0.9 Hz, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.13-3.01 (m, 2H), 2.67 (tdd, J=7.8, 5.7, 3.9 Hz, 1H), 2.13 (dt, J=15.2, 7.5 Hz, 1H), 2.07-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.2 Hz, 1H). ESI-MS m/z 610.24 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.43 (d, J=9.1 Hz, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.73 (td, J=7.9, 1.1 Hz, 1H), 7.53 (td, J=7.8, 1.2 Hz, 1H), 7.35-7.22 (m, 5H), 7.10-7.03 (m, 1H), 7.03-6.96 (m, 2H), 6.13 (t, J=3.1 Hz, 1H), 4.80 (dt, J=9.3, 6.3 Hz, 1H), 4.54-4.46 (m, 1H), 4.47 (dd, J=5.7, 0.9 Hz, 2H), 3.33-3.26 (m, 1H), 3.29-3.22 (m, 1H), 3.00 (ddt, J=6.2, 2.8, 1.0 Hz, 2H), 2.68 (tdd, J=7.7, 5.7, 3.9 Hz, 1H), 2.17-2.08 (m, 1H), 2.07-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.82 (dtd, J=12.2, 3.7, 2.2 Hz, 1H). ESI-MS m/z 628.23 [M+H]+.
1H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J=9.7 Hz, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.43-7.34 (m, 2H), 7.37-7.26 (m, 5H), 7.29-7.23 (m, 1H), 7.26-7.18 (m, 1H), 7.21-7.17 (m, 1H), 7.10 (td, J=7.9, 1.2 Hz, 1H), 6.26 (t, J=4.0 Hz, 1H), 4.77 (dt, J=9.7 , 7.3 Hz, 1H), 4.54-4.46 (m, 1H), 4.48 (s, 1H), 4.47 (t, J=0.9 Hz, 1H), 3.27-3.14 (m, 3H), 3.09 (ddd, J=15.9 , 7.3, 0.8 Hz, 1H), 2.61 (tdd, J=8.9, 6.9, 4.3 Hz, 1H), 2.13 (ddd, J=15.0, 8.8, 7.3 Hz, 1H), 1.99 (ddd, J=15.2, 8.8, 7.3 Hz, 1H), 1.81-1.61 (m, 4H). ESI-MS m/z 613.23 [M+H]+.
1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=5.1 Hz, 1H), 8.57 (t, J=8.4 Hz, 2H), 7.81-7.75 (m, 1H), 7.68 (dd, J=8.4, 1.0 Hz, 1H), 7.63 (d, J=1.0 Hz, 1H), 7.47 (m, 2H), 7.37-7.30 (m, 1H), 5.08 (m, 1H), 4.59 (m, 1H), 3.10 (m, 2H), 2.72 (m, 1H), 2.28 (m, 1H), 2.11 (m, 1H), 1.90 (m, 1H), 1.77-1.49 (m, 6H), 1.45-1.34 (m, 2H), 1.29-1.06 (m, 3H), 0.97-0.87 (m, 2H), 0.74-0.59 (m, 2H), 0.59-0.26 (m, 2H). ESI-MS m/z 551.27 [M+H]+.
1H NMR (500 MHz, DMSO-d6) δ 8.78-8.63 (m, 3H), 7.76 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.35 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 7.07 (t, J=8.4 Hz, 2H), 5.13 (m, 1H), 4.78 (m, 1H), 3.16-3.06 (m, 3H), 3.06-2.97 (m, 1H), 2.73 (m, 1H), 2.27 (m, 1H), 2.14 (m, 1H), 2.08-1.89 (m, 1H), 1.73 (m, 2H), 1.56 (m, 1H), 1.42 (m, 1H), 0.71-0.60 (m, 2H), 0.60-0.42 (m, 2H). ESI-MS m/z 563.22 [M+H]+.
To determine the inhibitory activity of the compound against 3CL protease of 2019 novel coronavirus (2019-nCoV 3CLpro): the enzyme level inhibitory activity of inhibitors against 3CL protease was determined by fluorescence resonance energy transfer (FRET) technology. In a 96-well plate, 27.5 μL of buffer (20mM Tris, 100mM NaCl, 1mM EDTA, pH 7.4) was added to each well, 2.5 μL compounds (final concentrations were 211M, 4 μM, 6 μM, 8 μM, 10 μM, 12 μM, 14 μM, 16 μM, 18 μM, 20 μM, respectively) and 5 μL EV713Cpro (final concentration was 3 μM) were added at the same time. Incubated at 37° C. for 15 min. Then 15 μL fluorescent substrate diluted with buffer (final concentration was 20 μM) was added. The fluorescence parameters were determined by Ge n5 fluorescence spectrophotometer. The excitation wavelength and emission wavelength were 340 nm and 490 nm respectively, kept at 37° C., and the data were read after 10 min. A negative control was used, in which no compound was added to the control, and the rest was the same. The obtained data was processed by software GraphPad Prism 5, and the experimental results are shown in Table 1.
The experimental results show that most compounds have good inhibitory activity on 2019-nCoV 3CL protease, and the inhibitory activity IC50 of compounds A13 (DC403113) and A42 (DC404001) against 2019-nCoV 3CL protease reach 2.4 μM and 3.0 μM.
To determine the inhibitory activity of the compound against human cathepsin L (CatL): the enzyme level inhibitory activity against cathepsin L was determined by fluorescence resonance energy transfer (FRET) technique. In a 96-well plate, 10 μL buffer (50 mM CH3COONa, pH 5.5, 1 mM DTT, 2 mM EDTA) was added to each well, while 0.2 μL of compound (final concentrations were 100 nM, 10 nM, 1 nM, 0.1 nM and 0.01 nM, respectively) and 10 pL cathepsin L were added, and incubated at 25° C. for 15 min. Then 10 pL fluorescent substrate (Z-Phe-Arg-AMC, final concentration was 20 μM) diluted with buffer was added. The fluorescence parameters were determined by Tecan Infinite 200pro fluorescence spectrophotometer. The excitation wavelength and emission wavelength were 360 nm and 465 nm respectively, kept at 25° C., and the data were read after 30 min. A negative control was used, in which no compound was added to the control, and the rest was the same. The obtained data was processed by software GraphPad Prism 8.0, and the experimental results are shown in Table 2.
The experimental results show that the test compounds have excellent inhibitory activity against human cathepsin L, and the IC50 is in nanomolar level, even less than 1 nM (such as compounds A5, A284, A289, A290, A309, and A310).
To determine the inhibitory activity of the compound on replication of each 2019 novel coronavirus (2019-nCov): in a 96 well plate, 100 μL/well gradient compound was added, then 50 μL/well virus buffer was added, then well-cultured RD cells (rhabdomyosarcoma cells) were immediately added at 50 μL/well. The mixture was incubated at 37° C. for 3-4 days, until the maximum cytopathic effect was observed. The medium was aspirated, 75 μl of 5% MTS phenol red medium was added, and the wells were incubated at 37° C. with 5% CO2 for 1.5 h. The fluorescence values of each well were measured at 498 nM, and a graph of compound concentration versus cell response was drawn. The EC50 of compound inhibiting virus was calculated by using the software customized by Accelrys company.
The test results are shown in
At present, the positive compound against 2019-nCoV is CQ, and its inhibition rate of 2019-nCoV virus replication EC50=1.13 μM. The results showed that CQ was used as positive control to test the patented compounds under different concentration gradients. Compounds A13 (3113, DC403113), A42 (4001, DC404001), A289 (6009, DC406009) all have excellent virus inhibitory activity. Among them, the EC50 for 3113 is 9237 nM, and the EC50 for 6009 and 4001 are 296.5 nM and 580.5 nM respectively. The inhibition rate of 6009 and 4001 against 2019-nCoV at virus level is better than that of positive control CQ, showing excellent anti-2019-nCoV potential (
The purpose of this experiment is to observe the potential toxicity of SD rats after intravenous DC406009 for 7 consecutive days and to determine the possible toxic target organs. To provide non-toxic dose and/or toxic dose for the subsequent toxicity test design and clinical trial protocol design. To assess the level of drug exposure in vivo, a toxicokinetic evaluation is accompanied.
36 SD rats were divided into 8 groups (3 in toxicity test group/gender/group, a total of 5 groups; 1 in toxic satellite group/gender/group, 3 groups), intravenous injection of solvent (5% DMSO/5% EtOH/40% PEG300/50% NaCl), 0.9% sodium chloride injection and DC406009 (5, 15, 30 mg/kg/day), once a day for 7 consecutive days, all animals were euthanized on Day 8. During the test, the following indicators were evaluated: toxicology (only samples were collected), clinical observation, body weight, food consumption, clinical pathology (hematology, hemagglutination, plasma biochemistry) and anatomical macroscopic morphological observation.
The results showed that under the experimental conditions, SD rats were given DC406009(5, 15, 30 mg/kg/day) intravenously once a day for 7 consecutive days, animals can tolerate, and the maximum tolerated dose (MTD) was greater than 30 mg/kg/day, indicating that the compound DC406009 has good safety.
All literatures mentioned in the present invention are incorporated by reference herein, as though individually incorporated by reference. Additionally, it should be understood that after reading the above teaching, many variations and modifications may be made by the skilled in the art, and these equivalents also fall within the scope as defined by the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202010077723.7 | Jan 2020 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/074228 | 1/28/2021 | WO |
