CECHETTO, Jonathan (Unit 505, Daerim Arvill Apartment House,Hannam-dong, Yongsan-gu, Seoul 140-210, KR)
NO, Zaesung (Dongmun Goodmorning Hill Apt, Dongcheon-dong, Susi-gu, Yongin-si, Gyeonggi-do 448-710, 504-2201, KR)
CHRISTOPHE, Thierry (21 Rue Ampere, Pontarlier, F-25300, FR)
KIM, Taehee (704 Hangunbriang A.p.t. 338-20, Chunho2dong Kangdong-gu, Seoul 134-868, KR)
NAM, Ji, Youn (305-103 Jungheung-maeul, Yongam-dongSangdang-gu, Cheongju 360-734, KR)
SO, Wonyoung (475-22, Wonseong-dong Donganm-gu,Cheonan-si, Chungcheongnam-do 330-070, KR)
JO, Mina (721-1 Gaja-dong, Jinju-si, Gyeongsangnam-do 660-300, KR)
OK, Taedong (1905 Ho 101 Dong, City GukdongApartment, 509 Pungnap-dong, Songpa-gu, Seoul 130-040, KR)
PARK, Changmin (101 No, Hansung Housing 532-3, Uman-dong,,Paldal-gu, Suwon-si, Gyeonggi-do 442-819, KR)
SEO, Min, Jung (One-town 406-ho, 260-8 Woncheon-dong,Yeongtong-gu, Suwon-si, Gyeonggi-do 443-380, KR)
SOHN, Jeong-Hun (C1602 Intellege Ii, 24 Jeongja-dong,Boondang-gu, Seongnam-si, Kyeonggi-do 463-841, KR)
SOMMER, Peter (#301 Pacific Mansion Gold, 352,Itaewon-dong, Yongsan-gu, Seoul 140-202, KR)
BOESE, Annette, Sophia (#301 Pacific Mansion Gold, 352,Itaewon-dong, Yongsan-gu, Seoul 140-202, KR)
HAN, Sung-Jun (Youngdengpo Purgio Apt, Youngdengpo-dong, Youngdengpo-gu, Seoul 150-797, 103-1004, KR)
PARK, Young, Sam (Samik Apt 104-906 Poongdukchun-dong, Suji-gu, Yong In Gyeonggi 448-170, KR)
KIM, Hwa, Pyung (1048-34 Hwagok-dong, Gangseo-gu, Seoul 157-992, KR)
KIM, Junwon (Gyeonggi-do, Suwon-si Yeongtong-gu,,Lotte Apartment, Yeongtong-dong 971-1, 942-1502, KR)
CECHETTO, Jonathan (Unit 505, Daerim Arvill Apartment House,Hannam-dong, Yongsan-gu, Seoul 140-210, KR)
NO, Zaesung (Dongmun Goodmorning Hill Apt, Dongcheon-dong, Susi-gu, Yongin-si, Gyeonggi-do 448-710, 504-2201, KR)
CHRISTOPHE, Thierry (21 Rue Ampere, Pontarlier, F-25300, FR)
KIM, Taehee (704 Hangunbriang A.p.t. 338-20, Chunho2dong Kangdong-gu, Seoul 134-868, KR)
NAM, Ji, Youn (305-103 Jungheung-maeul, Yongam-dongSangdang-gu, Cheongju 360-734, KR)
SO, Wonyoung (475-22, Wonseong-dong Donganm-gu,Cheonan-si, Chungcheongnam-do 330-070, KR)
JO, Mina (721-1 Gaja-dong, Jinju-si, Gyeongsangnam-do 660-300, KR)
OK, Taedong (1905 Ho 101 Dong, City GukdongApartment, 509 Pungnap-dong, Songpa-gu, Seoul 130-040, KR)
PARK, Changmin (101 No, Hansung Housing 532-3, Uman-dong,,Paldal-gu, Suwon-si, Gyeonggi-do 442-819, KR)
SEO, Min, Jung (One-town 406-ho, 260-8 Woncheon-dong,Yeongtong-gu, Suwon-si, Gyeonggi-do 443-380, KR)
SOHN, Jeong-Hun (C1602 Intellege Ii, 24 Jeongja-dong,Boondang-gu, Seongnam-si, Kyeonggi-do 463-841, KR)
SOMMER, Peter (#301 Pacific Mansion Gold, 352,Itaewon-dong, Yongsan-gu, Seoul 140-202, KR)
BOESE, Annette, Sophia (#301 Pacific Mansion Gold, 352,Itaewon-dong, Yongsan-gu, Seoul 140-202, KR)
HAN, Sung-Jun (Youngdengpo Purgio Apt, Youngdengpo-dong, Youngdengpo-gu, Seoul 150-797, 103-1004, KR)
PARK, Young, Sam (Samik Apt 104-906 Poongdukchun-dong, Suji-gu, Yong In Gyeonggi 448-170, KR)
KIM, Hwa, Pyung (1048-34 Hwagok-dong, Gangseo-gu, Seoul 157-992, KR)
| Claims
1. A compound of the formula II:
II
wherein, m is 1, 2, 3, or 4; n is 1, 2, or 3; o is 1, 2, or 3;
A is C 5 -C 12 aryl or C 5 -Ci 2 heteroaryl;
B, C, D and E are each independently selected from the group consisting of C(R 2 ), C(O), C(S),
N, or N oxide; each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, C 1 -C 5 alkyl, C 1 -C 3 haloalkyl, , C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 3 , -C(O)N(R 3 ) 2 , aryl, oxo, -OH, -OR 3 , -OCH 2 R 3 , -R 4 CN, -NO 2 , -
N(R 3 )C(O)R 3 , -N(R 3 ) 2 , aryl, benzyl, or heteroaryl; each R 2 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl,
Ci-C 3 haloalkyl, C 3 -C 7 cycloalkyl, -OH, -OR 3 , -CN, -NO 2 , -N(R 3 ) 2 , aryl, benzyl, or heteroaryl; each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkylaryl, aryl, benzyl, or; heteroaryl; each R 4 is independently selected from the group consisting of Ci-C 6 alkyl, C 1 -C 8 alkylene,
C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
X and Y are each independently selected from the group consisting of -C(R 5 R 6 )-, -N(R 5 )-, -
0-, -S-, -S(O) 2 -, or -C(O)-;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen,
Ci-C 8 alkyl, aryl, or C(O)R 1 ;
Z is selected from the group consisting of:
Aryl is C 4 -C 12 aryl and is optionally substituted;
HetA and heteroaryl are C 3 -C 10 heteroaryl and are optionally substituted,
R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, C 1 -Ci 0 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, hydroxyl, oxo, -OR 11 , -C(O)OR 11 , -
C(O)R 11 , -C(O)N(R 1 %, -CN, -NO 2 , -NH 2 , -N(R 1 *) 2 , -OR 4 HetA, -OR 4 N(R 1 ^ 2 , -
C(O)N(R n )HetA, -C(O)HetA, -C(O)N(R 1 ^R 4 S(O) 2 R 11 ; -S(O) 2 N(R 11 ^, -S(O) 2 R 11 , -
N(R 1 ^C(O)R 4 SR 11 , -N(R 1 ^R 4 S(O) 2 R 11 , or -N(R 1 ^S(O) 2 R 11 , aryl, benzyl, or heterocyclyl; R 11 is each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl optionally substituted with at least one hydroxyl or halogen; C 3 -C 7 cycloalkyl, aryl; benzyl, or heterocyclyl.
2. The compound according to claim 1, which is one of the formulas 324-650 as shown in Table 1 as well as shown in Example 3 including
450
3. A compound having the general formula I:
wherein
A is selected from the group consisting of;
X is selected from the group consisting of NR 4 , O, or S;
Y and Z are independently selected from the group consisting of NR 4 , C, O, or S;
R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 1O cycloalkyl,
C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -Ci 0 alkynyl, C 1 -C 10 haloalkyl, -OH, -OR 5 , C 1 -C 10 alkoxy, C 3 -C 10 cycloalkoxy, C 3 -C 15 cycloalkylalkoxy, C 3 -C 15 cycloalkylalkyl, -CN, -NO 2 , -
NH 2 , -N(R 5 ) 2 , -C(O)R 5 , -C(O)OR 5 , -C(O)N(R 5 ) 2 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ),, aryl, benzyl, heteroaryl, or heterocyclyl;
R 2 is each independently selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, hydroxyl, -OR 5 , -CN, -NO 2 , -NH 2 , -N(R 5 )C(O)R 5 , -C(O)R 5 , -
C(O)OR 5 , -C(O)N(R 5 ) 2; -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, heterocyclyl or two groups of R are connected each other to make five or six membered cyclic and heterocyclic rings; each R 3 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, hydroxyl, -OR 5 , -CN, -NO 2 , -NH 2 , -N(R 5 )C(O)R 5 , -C(O)R 5 , -
C(O)OR 5 , -C(O)N(R 5 X S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, heterocyclyl, or two groups of R 3 are connected each other to make five or six membered cyclic and heterocyclic rings;
R 4 is independently selected from the group consisting from hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -Ci 0 alkynyl, C 1 -C 10 haloalkyl, -C(O)R 5 , -
C(O)OR 5 , -C(O)N(R 5 ) 2, -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, or heterocyclyl;
R 5 is independently selected from the group consisting from hydrogen, Ci-Ci 0 alkyl, C 3 -Ci 0 cycloalkyl, C 2 -Ci 0 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, C 1 -Ci 0 haloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl.
4. The compound according to claim 3 having one of the formulas 1-323 as shown in Table 1 as well as shown in Example 3 including
5. A use of a compound according to any of claims 1-4 for manufacturing a pharmaceutical composition for treatment of a viral infection.
6. The use according to claim 5, in which the viral infection is human immunodeficiency virus (HIV) infection.
7. A pharmaceutical composition comprising a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier.
8. A method of treatment of a viral infection, comprising administering an effective amount of a compound according to any of claims 1-4 to a subject in need thereof.
9. The method according to claim 8, wherein the viral infection is human immunodeficiency virus (HIV) infection. |
Anti Viral Compounds
This application claims benefit of patent application Nos. 61/107,448 filed October 22, 2008, 61/109,028 filed October 28, 2008, and 61/228,837 filed July 27, 2009, contents of which are incorporated by reference in their entirety.
There is provided small molecule anti-human immunodeficiency virus (anti-HIV) compounds as well as a phenotypic cell-based high throughput screening (HTS) assay for their identification.
Background of the Invention
Almost 30 years after it was first identified [1], HIV continues to be a serious worldwide health problem. Despite many years and billions of dollars invested in research and development aimed at finding a cure for HIV, people continue to be infected with HIV and die due to AIDS. In 2007 alone 2.5 million people were infected with HIV and 2.1 million people died. HIV remains a serious public health problem as there were 33.2 million people living with HIV in 2007 [2]. However, it is not all bad news as global rates of HIV infection have leveled off, and the number of deaths due to AIDS has decreased over the past few years [2]. This decrease coincides with the greater availability of antiretro viral therapy, particularly in sub-Saharan Africa where the highest rates of HIV infection and AIDS is found [2]. HIV belongs to the retrovirus family, which contain genetic information in the form of RNA. There are two types of HIV, HIV-I and HIV-2. HIV-I is much more prevalent and is thought to have arisen from cross-species transmission of a chimpanzee virus to humans [3-5]. HIV infects T cells that express CD4 on their surface. HIV infection requires a fusion of viral and cellular membranes. This process is accomplished by viral envelope glycoprotein (gpl20, gp41) and receptors (CD4 and coreceptors, such as CXCR4 or CCR5) on the target cell. After
the virus enters the cell, its RNA is reverse - transcribed to the DNA by a viral enzyme, reverse transcriptase (RT). The viral DNA enters the nucleus, where it is integrated to the genetic material of the cell by the viral enzyme, integrase. When the cell receives a signal to become active, the provirus creates the mRNA through the transcription and then it is translated into viral proteins. The viral enzyme, protease is required to cut a viral polyprotein precursor into individual mature proteins. The HIV proteins and HIVs RNA genetic material assemble at the cell surface into new virions, which then bud from the cell and are released to infect another cell [6,7].
Current antiretroviral therapy is suppressive and cannot cure an individual of HIV infection. Furthermore, shortly after introduction of the first anti-HIV drug, azidothymidine (AZT), HIV-I demonstrated its ability to rapidly generate drug-resistant mutants. In order to overcome the problem of resistance when using one anti-viral agent, combination HAART (highly active antiretroviral therapy) is now widely used [2,8]. While effective, HAART requires a strict adherence to the treatment protocol and can have severe side-effects [2]. Current anti-HIV drugs are active on only a few targets and stages of the HIV life cycle. Many current drugs act at the stages of viral fusion, reverse transcription and viral maturation. Novel anti-viral compounds that affect other stages of the viral life cycle would be a valuable addition to the anti-HIV armamentarium.
Most the anti-HIV drug discovery performed to date has been focused on identifying inhibitors of known HIV targets (eg. reverse transcriptase, protease) [9]. In this manner, only a few of a potentially large number of targets can be interrogated for their effect on HIV infection.
It was an object of the present invention to develop a phenotypic cell-based assay suitable for high throughput screening that allows for the search of compounds that would prevent HIV infection and replication regardless of the target.
There is provided a high throughput, fully infectious HIV-I cell based assay used to screen a diverse small molecule library. The cell based assay has the advantage of opening up every step of the HIV-I life cycle, and allows for identification of compounds that may inhibit viral and host cell proteins involved in HIV-I infection and replication.
It was another object of the present invention to identify compounds that would prevent HIV infection and replication.
A number of compounds that inhibit HIV-I infection of host cells were identified. These compounds belong to two structural classes, and their anti -HIV-I activity was confirmed and/or determined by dose response and p24 secondary assay.
Detailed Description
According to one aspect, there is provided compounds having the general formula I:
wherein
A is selected from the group consisting of;
X is selected from the group consisting of NR 4 , O, or S;
Y and Z are independently selected from the group consisting of NR 4 , C, O, or S; R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -Ci 0 alkynyl, C 1 -C 10 haloalkyl, -OH, -OR 5 , C 1 -C 10 alkoxy, C 3 -Ci 0 cycloalkoxy, C 3 -Ci 5 cycloalkylalkoxy, C 3 -Ci 5 cycloalkylalkyl, -CN, -NO 2 , - NH 2 , -N(R 5 ) 2 , -C(O)R 5 , -C(O)OR 5 , -C(O)N(R 5 ) 2 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ),, aryl, benzyl, heteroaryl, or heterocyclyl;
R 2 is each independently selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 0 cycloalkyl, hydroxyl, -OR 5 , -CN, -NO 2 , -NH 2 , -N(R 5 )C(O)R 5 , -C(O)R 5 , - C(O)OR 5 , -C(O)N(R 5 ) 2> -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, heterocyclyl or two groups of R 2 are connected each other to make five or six membered cyclic and heterocyclic rings; each R 3 is independently selected from the group consisting of hydrogen, halogen, Ci-C 10 alkyl, C 3 -Ci 0 cycloalkyl, hydroxyl, -OR 5 , -CN, -NO 2 , -NH 2 , -N(R 5 )C(O)R 5 , -C(O)R 5 , - C(O)OR 5 , ^C(O)N(R 5 ) 2, S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, heterocyclyl, or two groups of R 3 are connected each other to make five or six membered cyclic and heterocyclic rings;
R 4 is independently selected from the group consisting from hydrogen, Ci-C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, C 1 -Ci 0 haloalkyl, -C(O)R 5 , - C(O)OR 5 , -C(O)N(R 5 ) 2, -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, or heterocyclyl;
R 5 is independently selected from the group consisting from hydrogen, Ci-Ci 0 alkyl, C 3 -Ci 0 cycloalkyl, C 2 -Ci 0 alkenyl, C 3 -Cj 0 cycloalkenyl, C 2 -Ci 0 alkynyl, Ci-Ci 0 haloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl.
The term "optionally substituted" as used herein is meant to indicates that a hydrogen atom attached to a member atom within a group is possibly replaced by group, such as halogen including fluorine, Ci-Ci 0 alkyl, Ci-C 3 haloalkyl, C 3 -C 7 cycloalkyl, oxo, -OH, -OR 7 , -
OC(O)R 7 , -CN, -NO 2 , -N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -C(O)R 7 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -S(O)R 7 , -
S(O) 2 R 7 , -S(O) 2 N(R 7 ) 2 , phenyl, benzyl, or heterocyclyl;
R 7 is each independently selected from the group consisting of hydrogen, aryl, benzyl, heterocyclyl, Ci-C 8 alkyl, or C 3 -C 7 cycloalkyl;
R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, C 1 -Ci 0 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, hydroxyl, oxo, -OR 12 , -C(O)OR 12 , -
C(O)R 12 , -C(O)N(R I2 ) 2 , -CN, -NO 2 , -NH 2 , -N(R 12 ) 2 , -OR 4 HetA, -OR 4 N(R 12 ) 2 , -
C(O)N(R 12 )HetA, -C(O)HetA, -C(O)N(R 12 )R 4 S(O) 2 R 12 ; -S(O) 2 N(R 12 ) 2 , -S(O) 2 R 12 , -
N(R 12 )C(O)R 4 SR 12 , -N(R 12 )R 4 S(O) 2 R 12 , or -N(R 12 )S(O) 2 R 12 , aryl, benzyl, or heterocyclyl;
R 12 is each independently selected from the group consisting of hydrogen, Ci-C 8 alkyl optionally substituted with at least one hydroxyl or halogen; C 3 -C 7 cycloalkyl, aryl; phenyl, benzyl, or heterocyclyl;
The term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Ci-C 6 alkyl" refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl and methyl.
The term "alkoxy" means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e.,
C 1 -C 12 alkoxy), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-0-CH 3 or OMe), ethoxy (-OCH 2 CH 3 or -
OEt), t-butoxy (-O-C(CH 3 ) 3 or -OtBu) and the like.
The term "alkenyl" refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms in the specified range. Thus, for example, "C 2 -C 6 alkenyl" refers to all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2- propenyl, and ethenyl (or vinyl).
The term "alkynyl" refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon triple bond and having a number of carbon atoms in the specified range. Thus, for example, "C 2 -C 6 alkynyl" refers to all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-bytynyl, 1-propynyl, 2-propynyl, and ethynyl.
The term "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (- CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like. The term "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethenyl (-CH=CH-). The term "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CH 2 C≡C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C=CH-).
The term "cycloalkyl", alone or in combination with any other term, refers to a group, such as optionally substituted or non-substituted cyclic hydrocarbon, having from three to eight carbon atoms, unless otherwise defined. Thus, for example, "C 3 -C 8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "haloalkyl" refers to an alkyl group, as defined herein that is substituted with at least one halogen. Examples of straight or branched chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens. The term "haloalkyl" should be interpreted to include such substituents such as -CHF 2 , -CF 3 , -CH 2 -CH 2 -F, -CH 2 -CF 3 , and the like.
The term "heteroalkyl" refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3 , etc.), an amine (e.g., -NHCH 3 , -N(CH 3 ) 2 , etc.), or thioalkyl group (e.g., -SCH 3 , etc.). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a
heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH 3 , etc.), alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or thioalkyl ether (e.g., -CH 2 -S-CH 3 ).
The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
The term "aryl" refers to (i) optionally substituted phenyl, (ii) optionally substituted 9- or 10 membered bicyclic, fused carbocyclic ring systems in which at least one ring is aromatic, and (iii) optionally substituted 11- to 14-membered tricyclic, fused carbocyclic ring systems in which at least one ring is aromatic. Suitable aryls include, for example, phenyl, biphenyl, naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, anthracenyl, and fluorenyl. The term "phenyl" as used herein is meant to indicate that optionally substituted or non- substituted phenyl group.
The term "benzyl" as used herein is meant to indicate that optionally substituted or non- substituted benzyl group.
The term "heteroaryl" refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic, fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic, fused ring system contains from 1 to 4 heteroatoms independently selected from N, O, and S, where each N is optionally in the form of an oxide and each S in a ring which is not aromatic is optionally S(O) or S(O) 2 . Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9-and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[l,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3- dihydrobenzo- 1 ,4-dioxinyl.
The term "heterocyclyl" refers to (i) optionally substituted 4- to 8-membered, saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and from 1 to 4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing from 1 to 6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independent of fused to, or bridged with the other ring or rings and each ring is saturated or unsaturated but nonaromatic, and wherein each heteroatom in (i), (ii), and (iii) is
independently selected from N, O, and S, wherein each N is optionally in the form of an oxide and each S is optionally oxidized to S(O) or S(O) 2 . Suitable 4- to 8-membered saturated heterocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl. Suitable unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the above sentence in which a single bond is replaced with a double bond. It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs. These rings and ring systems are merely representative.
According to another aspect, there is provided compounds having the general formula II:
wherein, m is 1, 2, 3, or 4; n is 1, 2, or 3; o is 1, 2, or 3;
A is C 5 -C 12 aryl or C 5 -Ci 2 heteroaryl;
B, C, D and E are each independently selected from the group consisting of C(R 2 ), C(O), C(S),
N, or N oxide; each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, C 1 -C 5 alkyl, Cj-C 3 haloalkyl, , C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 3 , -C(O)N(R 3 ) 2 , aryl, oxo, -OH, -OR 3 , -OCH 2 R 3 , -R 4 CN, -NO 2 , -
N(R 3 )C(O)R 3 , -N(R 3 ) 2 , aryl, benzyl, or heteroaryl; each R 2 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl,
C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, -OH, -OR 3 , -CN, -NO 2 , -N(R 3 ) 2 , aryl, benzyl, or heteroaryl; each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkylaryl, aryl, benzyl, or; heteroaryl;
each R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 8 alkylene,
C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
X and Y are each independently selected from the group consisting of -C(R 5 R 6 )-, -N(R 5 )-, -
0-, -S-, -S(O) 2 -, or -C(O)-;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen,
Ci-C 8 alkyl, 8TyI 5 Or C(O)R 1 ;
Z is selected from the group consisting of:
Aryl is C 4 -C 12 aryl and is optionally substituted;
HetA and heteroaryl are C 3 -C 10 heteroaryl and are optionally substituted,
R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 10 alkyl, Cj-C 3 haloalkyl, C 3 -C 7 cycloalkyl, hydroxyl, oxo, -OR 11 , -C(O)OR 11 , -
C(O)R 11 , -C(O)N(R 1 %, -CN, -NO 2 , -NH 2 , -N(R 1 ') 2 , -OR 4 HetA, -OR 4 N(R 11 ^, -
C(O)N(R 1 ')HetA, -C(O)HetA, -C(O)N(R 1 ^R 4 S(O) 2 R 11 ; -S(O) 2 N(R 11 ^, -S(O) 2 R 11 , -
N(R 1 ^C(O)R 4 SR 11 , -N(R 1 ^R 4 S(O) 2 R 11 , or -N(R n )S(O) 2 R n , aryl, benzyl, or heterocyclyl;
R 11 is each independently selected from the group consisting of hydrogen, Ci-C 8 alkyl optionally substituted with at least one hydroxyl or halogen; C 3 -C 7 cycloalkyl, aryl; benzyl, or heterocyclyl.
The term "optionally substituted" has the same meaning as defined above.
The term "alkyl" has the same meaning as defined above.
The term "alkoxy" has the same meaning as defined above.
The term "alkenyl" has the same meaning as defined above.
The term "alkynyl" has the same meaning as defined above.
The term "Alkylene" has the same meaning as defined above.
The term "Alkenylene" has the same meaning as defined above.
The term "Alkynylene" has the same meaning as defined above.
The term "cycloalkyl", alone or in combination with any other term, has the same meaning as defined above.
The term "haloalkyl" has the same meaning as defined above.
The term "heteroalkyl" has the same meaning as defined above.
The term "halogen" has the same meaning as defined above.
The term "aryl" has the same meaning as defined above.
The term "phenyl" has the same meaning as defined above.
The term "benzyl" has the same meaning as defined above.
The term "heteroaryl" has the same meaning as defined above.
The term "heterocyclyl" has the same meaning as defined above.
The stereochemistry of general formula of I and II includes independently R or S as enantiomerically pure form or racemic mixtures.
Another embodiment of the present invention is compounds of general formula I and II, or pharmaceutically acceptable salts thereof.
According to one aspect, there is provided a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the treatment of viral infections.
According to one aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the treatment of human immunodeficiency virus (HIV).
According to another aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the manufacture of a medicament for the treatment of viral infections.
According to another aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the manufacture of a medicament for the treatment of human immunodeficiency virus (HIV).
According to one aspect, there is provided a compound listed in Figure 8 A-F or Table 1.
According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the inhibition of virus replication within and virus infection of host cells.
In one embodiment said virus is selected from HIV.
In one embodiment said host cells are T cells or B cells or a hybrid thereof.
According to one aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the treatment of viral infections.
According to one aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the treatment of human immunodeficiency virus (HIV).
According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of viral infections.
According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of human immunodeficiency virus (HIV).
According to an aspect, a pharmaceutical composition or combined preparation having synergistic effects against a viral infection and containing: (a) at least one compound listed in Figure 8 A-F or Table 1 , (b) (a) otionally one or more anti-viral agents, and (c) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers,for simultaneous, separate or sequential use in the treatment or prevention of a viral infection.
Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include, for instance, retroviral enzyme inhibitors belonging to categories well known in the art, such as HIV-I IN inhibitors, nucleoside reverse transcriptase inhibitors (e.g. zidovudine, lamivudine, didanosine, stavudine, zalcitabine and the like), non- nucleoside reverse transcriptase inhibitors (e.g. nevirapine, delavirdine and the like), other reverse transcriptase inhibitors (e.g. foscamet sodium and the like), and HIV-I protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir and the like). Other suitable antiviral agents include for instance acemannan, acyclovir, adefovir, alovudine, alvircept, amantadine, aranotin, arildone, atevirdine, pyridine, cidofovir, cipamfylline, cytarabine, desciclovir, disoxaril, edoxudine, enviradene, enviroxime, famciclovir, famotine, fiacitabine, fialuridine, floxuridine, fosarilate, fosfonet, ganciclovir, idoxuridine, kethoxal, lobucavir, memotine, methisazone, penciclovir, pirodavir, somantadine, sorivudine, tilorone, trifluridine, valaciclovir, vidarabine, viroxime, zinviroxime, moroxydine, podophyllotoxin, ribavirine, rimantadine, stallimycine, statolon, tromantadine and xenazoic acid, and their pharmaceutically acceptable salts.
Especially relevant to this aspect is the inhibition of the replication of HIV, in particular in human beings and other mammals such as primates.
Therefore, of particular relevance in the context of HIV prevention or treatment is coadministration with one or more other agents aiming at HIV inhibition well known in the art, such as but not limited to, nucleoside reverse transcriptase inhibitors (e.g, tenofovir, didanosine and the like), non-nucleoside reverse transcriptase inhibitors (e.g, efavirenz, delavirdine and the like), HIV-I protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir and the like), HIV-I integrase inhibitors (e.g, raltegravir and the like) and HIV-I entry inhibitors (e.g, maraviroc and the like). Synergistic activity of the pharmaceutical
compositions or combined preparations of this invention against viral infection may be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC). When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FlC x +FIC y ) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub-synergistic, and when it is lower than 0.5, the combination is by defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic. The pharmaceutical composition or combined preparation with synergistic activity against viral infection, especially HIV may contain at least one compound listed in Figure 8A-F or Table 1 over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the contents of the at least one compound listed in Figure 8 A-F or Table 1 in the pharamaceutical preparation is within the range of from 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from about 5 to 95% by weight.
The pharmaceutical compositions and combined preparations may be administered orally or in any other suitable fashion. Oral administration is preferred and the pharmaceutical composition or preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel. The dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like. Carrier materials and excipients are detailed hereinbelow and may include, inter alia, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like. The pharmaceutical composition or combined preparation of this invention may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium. Aqueous dispersions may comprise the biologically active composition or combined preparation in combination with a suspending agent, dispersing agent or wetting agent. Oil dispersions may comprise suspending agents such as a vegetable oil. Rectal administration is also applicable, for instance in the form of suppositories or gels. Injection (e.g. intramuscularly or intraperiteneously) is also applicable as a mode of administration, for instance in the form of
injectable solutions or dispersions, depending upon the disorder to be treated and the condition of the patient.
The term "pharmaceutically acceptable carrier or excipient" as used herein in relation to pharmaceutical compositions and combined preparations means any material or substance with which the active acomponent, , and optionally the additional antiviral agent, may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions or preparations of the present invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
The pharmaceutical compositions may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. They may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 μm, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active ingredient(s).
Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids
(C 10-22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates include, but are not limited to, the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl- naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphoshatidyl-choline and their mixtures.
Suitable non-ionic surfactants include, but are not limited to, polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non- ionic surfactants include, but are not limited to, water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino-polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts preferably contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants include, but are not limited to, nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts,
tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxy-polyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include, but are not limited to, quaternary ammonium salts, preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N- substituent at least one C 8-22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-C 1-4 alkyl radicals.
Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions and combined preparations of the invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).
Gelling agents which may be included into the pharmaceutical compositions and combined preparations of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents.
Other optional excipients which may be included in the pharmaceutical compositions and combined preparations of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as
citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densifϊcation agents such as magnesium salts; and mixtures thereof.
Additional ingredients may be included in order to control the duration of action of the biologically-active ingredient in the compositions and combined preparations of the invention. Control release compositions may thus be achieved by selecting appropriate pharmaceutically acceptable polymer carriers such as for example polyesters, polyamino-acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxy-methylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition or combined preparation of the invention may also require protective coatings.
Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof.
Other modes of local drug administration can also be used. For example, the selected active agent may be administered topically, in an ointment, gel or the like, or transdermally, using a conventional transdermal drug delivery system.
Since, in the case of combined preparations including at least at least one compound listed in Figure 8A-F or Table 1, and an additional antiviral agent, both active ingredients do not necessarily bring out their synergistic therapeutic effect directly at the same time in the patient to be treated, the said combined preparation may be in the form of a medical kit or package containing the two ingredients in separate but adjacent form. In the latter context, each ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral
formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
According to one aspect, there is provided a method of treatment of human immunodeficiency virus (HIV), comprising the application of an effective amount of a compound listed in Figure 8A-F or Table 1 to a person in need thereof.
According to the method for preventing or treating a viral infection or a pathologic condition associated therewith, including HIV in a patient, the patient may be a mammal such as a primate, more preferably a human being. The method consists of administering to the patient in need thereof a therapeutically effective amount of at least one compound listed in Figure 8A-F or Table 1, optionally together with an effective amount of another antiviral agent, or a pharmaceutical composition comprising the same, such as disclosed above in extensive details. The therapeutically effective amount is usually in the range of about 0.01 mg to 20 mg, preferably about 0.1 mg to 5 mg, per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated, the severity of infection, and the patient's condition, the said therapeutically effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. The patient to be treated may be any warm-blooded animal, preferably a mammal, more preferably a human being, suffering from said viral infection or associated pathologic condition.
According to another aspect, there is provided a screening method comprising the steps of
(a) adding compounds that are to be tested to a multi-well plate;
(b) seeding of host cells that express GFP upon infection by HIV-I;
(c) infection of said host cells with HIV-I virus into said multi-well plate containing said compounds;
(d) incubating said multi-well plate containing GFP expressing host cells infected with HIV-I virus and said compounds;
(e) analyzing said multi-well plate using automated confocal microscopy and fluorescent microplate readers.
The screening method provided is a phenotypic cell-based assay enabling the search for drugs that interfere with the infection or replication of HIV within host T or B cells or a hybrid thereof. The assay makes use of viral infection induced fluorescent protein expressing living cells infected with HIV-I (Bru) virus and uses automated confocal fluorescence microscopy
and fluorescence intensity to measure infection. The assay has been set-up for the high throughput screening (HTS) of large scale chemical libraries.
Figures and Tables
Reference is now made to the figures and tables, wherein
Figure 1: A plot of positive and negative controls from the primary screen of the Timtec compound library. The inhibition of HIV-I infection (%) is plotted. The T value of 0.54 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
Figure 2: A plot of the compound data from the primary screen of the Timtec compound library. Each circle represents one compound with 26,500 compounds tested in total. Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in dark gray are those considered active against HIV infection in the assay (1891 compounds), based upon a statistical cut off of 70% inhibition of activity (black line).
Figure 3: Quality control of the Timtec compound library primary screen. The location of active compounds was assessed based on the well location of the compound. Pie charts were constructed in order to identify any column (A) or row (B) bias in the assay. A trellis plot (C) indicates that the active compounds are distributed across different plates.
Figure 4: Identification of active compounds for further characterization. Compounds identified as active in the primary screen were re-tested in duplicate, at 3 different compound concentrations, 10 μM (A), 1 μM (B) and 0.1 μM (C). Compounds indicated in black are
those exhibiting 50% inhibition of infection at 1 μM. These compounds were selected for dose-response analysis.
Figure 5: Schematic of the process used to identify compounds active against HIV infection of CEMxI 74 cells. From a primary screen of 26,500 compounds, 1,891 compounds were identified as active from the primary screen (in singlet). Of these, 170 exhibited 50% inhibition of infection at a compound concentration of 1 uM. Of the 170 compounds, 7 were identified that showed activity against HIV infection while also exhibiting low toxicity against CEMxI 74 cells. These 7 compounds can be classified into 3 structural classes or scaffolds.
Figure 6: A plot of positive and negative controls from the primary screen of the ChemBridge and Cerep compound libraries. The inhibition of HIV-I infection (%) is plotted. The ε value of 0.56 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
Figure 7: Plots of the compound data from the primary screen of the ChemBridge (A) and Cerep (B) compound libraries. Each circle represents one compound with 30,480 compounds tested in total (20,000 ChemBridge compounds and 10,480 Cerep compounds). Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in light gray in the upper right corner of each plot are those considered active against HIV infection in the assay (496 compounds from ChemBridge and 286 compounds from Cerep), based upon a statistical cut off of activity of greater than 6 standard deviations from the mean of the average percentage inhibition of infection (bracket indicates bin of active compounds).
Figure 8: Identification of 6 compounds from the compounds libraries that are active against HIV-I infection of CEMx 174 cells while exhibiting low cellular toxicity. Activity of the compounds based on a decrease in fluorescence (RFU) is indicated in the dose-response curves on the left of each pair and the potency of each compound is indicated as a calculated EC 50 value. Curves on the right side of each pair indicate the effect of the compound on cell number (■) and cell viability, in the presence (A) and absence (•) of HIV-I infection. The 6 compounds can be identified as belonging to 2 distinct structural scaffolds, cyclic-urea containing (A-D; Scaffold I; Timtec compound library) and amino biphenyl containing (E-F; Scaffold II; ChemBridge compound library). Data for known anti-HIV agents is included (G; Nevirapine, AZT and Saquinavir).
Table 1: Summary of derivative activity data for Scaffolds I and II which exhibited anti-HIV- 1 activity. Derivatives 1 to 323 are based on Scaffold I and derivative compounds 324 to 650 are based on Scaffold II. The number allocated to each compound and its corresponding activity value(s) are indicated to the right of the compound.
Examples
The invention is now further described by reference to the following examples which are intended to illustrate, not to limit the scope of the invention.
Materials and Methods
Host cells
The HIV infection screening assay is based on the GFP expression under HIV infection using a LTR-GFP fusion stably expressed in CEM cells. Upon infection by HIV (Bru strain), the viral DNA is integrated and expressed, the viral protein TAT is expressed and promotes the expression of the gene controlled by LTR (i.e. GFP). CEMxI 74 cells were cultured in
RPMIl 640-Glutamax with 10% heat-inactivated fetal calf serum (Gibco), 100units/ml penicillin and streptomycin, 2mM sodium pyruvate, 2mM L-Glutamine at 37°C in 5% CO2.
To produce Bru virus, one million CEMxI 74 cells were infected with Bru virus (M.O.I, of 20) for 2 hr. After 24 hr incubation, the virus was transferred to a T-75 flask. After two weeks, ten million fresh cells were added to the flask. After a further two weeks 600 ml of virus- containing supernatant was collected, filtered and assayed for virus levels by a p24 assay. The virus is stocked and the cells are cultured in the same medium.
Chemical compounds
The small synthetic molecules from the screening libraries were resuspended in pure DMSO at an initial concentration of 1OmM (master plates) in 96 well polypropylene plates. To perform the primary screening, master plates of 96 well plates were reformatted to mother plates of the 384 well polypropylene plates (Greiner) and diluted to a final concentration of 2mM in pure DMSO. The compounds were kept frozen until use. For screening, the compound plates were thawed at room temperature. The compounds were directly added to the assay plates from the DMSO stock using an EVObird liquid handler (Evotec Technologies) which transfers 250nl of compound to achieve a dilution step of 1 :200. A fast mixing is performed to ensure complete diffusion of the small volume in the assay well.
Positive controls AZT, Nevirapine, and Saquinavir as well as negative control (DMSO) were added manually to each plate in columns 1-2 and 23-24.
During this study, a total of 56,980 compounds were tested. These compounds were sourced from Timtec (25,000 from the ActiProbe diverse library, 1,000 from the Kinase inhibitors ActiTargK library and 500 from the Protease inhibitors ActitargP library), ChemBridge
(20,000 from the NOVACore library) and Cerep (10,480 from the Odyssey II library). They were initially screened at one concentration (primary screen, concentration = lOuM). The "positives" identified from the primary screen were then confirmed either with a first step at 3 concentrations (10, 1 and 0.IuM) to identify the most active and/or by 10 concentration serial dilutions (from lOuM to 0.25nM).
Virus infection assay scale-up
Cells (4,000/well) were dispensed using a Wellmate (Matrix) into 384 well Evotec glass plates pre-dispensed with lOul of compound diluted in PBS and incubated for 1 hr at 37 degrees, 5% CO2. Cells were then infected with Bru virus at multiplicity of infection (MOI) 3.7 and incubated for 5 days at 37 degrees, 5% CO2. The plates were read for fluorescence detection using Victor3. Cells were then stained with SytoόO (Invitrogen) for Ih for imaging by an automated fluorescent confocal microscope OperaTM (Evotec Technologies).
Image acquisition and data analysis
Confocal images were recorded on an automated fluorescent confocal microscope OperaTM (Evotec Technologies) using 20X-water objective (NA 0.70), 488nm, 635nm lasers and 488/635 primary dichroic mirror. Each image was then processed using Accapella software (Evotec technologies). ActivityBase (IDBS) and DecisionSite (Tibco Spotfire) were used to store and analyze the screening data. IC 50 values were calculated in Prism (GraphPad software) from assay data using non-linear regression analysis and curve fitting to a sigmoidal dose-response (variable slope) model.
Example 1 : Development and validation of a visual, high-throughput HIV-I full replication
In order to develop a high-throughput HIV-I full replication assay, reporter cell lines harbouring an integrated HIV mini-genome encoding only the EGFP gene under the transcriptional control of the genuine HIV LTR promoter were constructed. Briefly, CEMx 174 [10] cells were stably transfected with TRIP-LTR-EGFP vector particles [11] and cloned. Cell lines were selected that expressed minimal levels of basal EGFP in an uninfected state, but responded to HIV-I infection with high levels of EGFP fluorescence. Individual clones were screened for high susceptibility to HIV-I infection and the cell line with the most desirable phenotype (named CEMx 174 #CG8) was chosen for further characterization. To facilitate effective screening under high-throughput conditions, optimized conditions for cell density (4,000 cells/well), the amount of virus used for infection (10 ng p24/well, M.O.I, of 3.7) and the incubation time (5 days) in 384-well plates were determined.
Example 2: High Throughput Screening
A 56,980 member small molecule library from Timtec, ChemBridge and Cerep was screened using CEMxl74 cells. This library is composed of a diverse 25,000 compound set (Timtec - ActiProbe-25K), a diverse 20,000 compounds set (ChemBridge - NOVACore), a diverse 10,480 compound set (Cerep - Odyssey II), a 1,000 compound kinase focused library (Timtec - ActiTarg-K) and a 500 compound protease focused library (Timtec - ActiTarg-P). The primary screen of the Timtec compounds was performed in singlet and was of high quality, with a ε of 0.45 for the entire screen (Figure 1). Based on a statistical cut off of 70% inhibition of infection, 1,891 compounds were identified as being active against HIV infection in CEMx 174 cells (Figure 2), an active rate of 7%. The plate and well locations of the active compounds were examined in order to identify any plate and/or well bias in the screen. The actives were found to be evenly distributed across the plates tested, except in the cases of structurally similar compounds that are grouped together on the plate (Figure 3). As the active rate is high, and only the most active compounds will be selected for further characterization,
a 3 step process was used to identify the most active and structurally interesting compounds. The overall process is shown in Figure 5. The active compounds were cherry picked from the compound library and re-screened at 3 concentrations (10, 1 and 0.1 uM) in order to filter out false positives and gain a first measure of active potency and toxicity. Image analysis was used to assess compound toxicity. Fluorescence intensity was also used to quantify compound activity, and a resazurin-based cell viability assay was used to complement the image based cell toxicity data. This active confirmation screen was performed in duplicate with both cell lines. Of the 1,891 compounds tested, 1,237 were active at the primary screening concentration of 10 uM, an active confirmation rate of 65% (Figure 4A). Compounds were selected for further characterization based on their ability to inhibit HIV infection by 50% at the intermediate concentration of 1 uM (Figure 4B). Although a number of these compounds exhibited some toxicity based on cell number quantification and resazurin-based cell viability, they were included for further analysis. Thus, 170 compounds were selected for a third round of characterization. Among the compounds identified were a number of known anti-HIV compounds. These included colchicine, an inhibitor of microtubule polymerization and weak inhibitor of HIV replication [12], and floxuridine and 5-fluorouridine, inhibitors of thymidylate synthase that suppress replication of multidrug-resistant HIV type 1 when used in combination with zidovudine or stavudine [13]. In the third round of active compound selection, compounds were tested in 10 point dose-response experiments, using CEMx 174 cells. Compound activity was measured by FI and compound toxicity was assessed by image analysis and resazurin-based cell viability in the presence and absence of HIV. As with the 3 concentration experiment, the compounds were tested in duplicate. A total of 7 compounds from the Timtec compound library were determined to be active with cell protection. These 7 compounds were grouped into three scaffolds, one of which, Scaffold I (4 compounds; 8A-D) is disclosed herein. These four compounds, Timtec I, II, III and IV were purchased as
required or Timtec II was also synthesized in-house and is also referred to as Compound 1 (Table 1) herein.
The primary screen of the ChemBridge and Cerep compounds was performed in duplicate and was of high quality, with a T of 0.56 for both replicates (Figure 6). Based on a statistical cut off of activity of greater than 6 standard deviations from the mean of the average percentage inhibition of infection, 782 compounds were identified as being active against HIV infection in CEMx 174 cells (Figure 7), an active rate of 3%. This lower hit rate as compared to the Timtec library is likely a result of screening in duplicate versus singlet, and the different chemical compositions of the libraries. Active compounds were tested in 10 point dose- response experiments using CEMx 174 cells. Compound activity was measured by FI and compound toxicity was assessed by image analysis and resazurin-based cell viability in the absence of HIV. Testing was performed in duplicate. A total of 7 compounds from the ChemBridge and Cerep compound libraries were determined to be active with cell protection. Two of these compounds were grouped as Scaffold II (ChemBridge compound library; 8E-F) which is disclosed herein. These two compounds, ChemBridge I and II were purchased from ChemBridge but were also synthesized in-house and are also referred to as Compound 278 and 280 respectively (Table 1) herein.
Based on the screening of the compound libraries mentioned herein, 4 Timtec (Scaffold I) and 2 ChemBridge (Scaffold II) compounds were identified that exhibited potent activity against HIV infection of CEMx 174 while also showing a cell protective effect, similar to that seen with HIV reference compounds (Figure 8G) and have additional structure activity relationship data disclosed herein.
To confirm that the 6 compounds are active against HIV infection and are not interfering with the fluorescence-based assay and are false positives, the activity of the compounds was assessed in a p24 activity assay. All 6 compounds showed a dose-dependent effect on the
amount of p24 core antigen (not shown), confirming the results of the GFP-based assay, and indicating that the 6 compounds are hits against HIV infection.
Example 3: Derivatization of anti -HIV-I Scaffolds I and II
Scaffolds I and II underwent derivatization according to the methods outlined below. Scaffold I derivatives correspond to compounds 1 to 323 and Scaffold II derivatives correspond to compounds 324 to 650. Resulting derivatives were examined for inhibitory activity using the assay(s) described above and the results are summarized in Table 1.
General procedure for Biginelli Reaction
A mixture Of Yb(OTf) 3 (0.05 mmol, 0.1 equiv), β-ketoester (0.5 mmol, 1.0 equiv), benzaldehyde (0.5 mmol, 1.0 equiv) and urea (0.5 mmol, 1.0 equiv) in THF (2 mL) was refluxed 20-30 h under Ar. After adding H 2 O (5 mL), the mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO 2 , n- Hexanes/EtOAc/AcOH, 50:50:0.5) to afford the desired pyrimidinone compound.
General procedure for transesterification
To a solution of β-keto ester (12.1 mmol, 1.0 equiv) and alcohol (14.5 mmol, 1.0 equiv) in toluene (24 mL) was added iodine (0.36 mmol, 0.03 equiv) at 25 0 C. The reaction was heated to reflux for 12 h at 120 °C. After the starting material disappeared on TLC, the mixture was cooled to 25 0 C and quenched by the addition of water (10 mL), sodium thiosulfate (20 mL) and extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with brine
(50 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for EDC coupling for the synthesis of β-keto ester
To a solution of β-keto ester (69.4 mmol, 1.0 equiv) in water (70 mL) was added NaOH (138.7 mmol, 2.0 equiv) at 25 °C and stirred for 12 h. After 12 h at 25 °C, the reaction mixture was acidified with 6 N HCl to set pH < 2 at 0 °C. The resulting solution was concentrated in vacuo at a temperature below 30-35 °C. The residue was rinsed with EtOAc and filtered. The filtrate was dried over Na 2 SO 4 . After filtration and concentration in vacuo, the crude β-keto acid was subjected to the following step without further purification.
To a 0 °C solution of β-keto acid (52.9 mmol, 1.2 equiv) and alcohol (44.1 mmol, 1.0 equiv) in CH 2 Cl 2 (88 mL) was added EDC (66.2 mmol, 1.5 equiv) and DMAP (66.2 mmol, 1.5 equiv) successively. The reaction mixture was warmed to 25 °C and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (50 mL). The phases were separated and the organic layer was washed with brine (100 mL), and then dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
Experimental procedure for Fractional Crystallization
The β-keto ester (1.0 g, .4.84 mmol), 3-hydroxybenzaldehyde (590 mg, 4.84 mmol), urea (290 mg, 4.84 mmol), and Yb(OTf) 3 (30 mg, 0.484 mmol) were dissolved in THF (9.6 mL) and stirred under Argon for 24 h at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (4 x 20 mL). The combined organic layers were dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , n- Hexanes/EtOAc/AcOH = 5:1 :0.5) to give Biginelli adduct (1.31 g, 77%) as a pale yellow solid.
To a solution of Biginelli adduct (1.30 g, 3.69 mmol) in DMF (19 mL) was added TBSCl (834 mg, 5.53 mmol) and imidazole (377 mg, 5.53 mmol) at 25 °C. After stirring for overnight at 25 °C, the reaction mixture was quenched by the addition of H 2 O (30 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , «-Hexanes/Et 2 O = 5:1 → n-Hexanes/EtOAc = 2: 1 to 1 : 1 → CH 2 Cl 2 MeOH = 20: 1) to give a TBS protected product with a quantitative yield as a white solid: 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, IH), 7.14-7.12 (m, 3H), 7.01- 6.98 (m, 3H), 6.70 (d, J= 7.2 Hz, IH), 6.61 (bs, IH), 6.60 (d, J= 8.4 Hz, IH), 5.48 (bs, IH), 5.21 (s, IH), 4.91 (s, 2H), 2.67-2.57 (m, 2H), 1.09-1.05 (m, 3H), 0.81 (s, 9H), 0.00 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.9, 156.1, 153.2, 152.5, 144.9, 136.0, 129.8, 128.4, 128.0, 127.9, 119.7, 119., 118.1, 99.9, 65.9, 55.4, 25.7, 25.3, 18.2, 12.5, -4.4; TLC R 1 (CH 2 Cl 2 MeOH 10:1) = 0.51.
To a solution of TBS protected product (721 mg, 1.545 mmol) in MeOH (16 mL) was added 10% Pd on carbon (72 mg) and Et 3 N (215 μL, 1.545 mmol) at room temperature. The reaction mixture was hydrogenated with H 2 gas (3 bar) for 3 h at 25 °C. The mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was resuspended in water (20 mL) and acidified with IN HCl (~3 mL, pH < 2). The resulting suspension was sonicated for 10 min and then filtered and washed with H 2 O. After freeze drying in vacuo, the resulting acid (white solid, 529 mg, 91%) was used in the following step without further purification. To a suspension of acid (1.00 g, 2.655 mmol) in MeOH (20 mL) was added cinchonine (782 mg, 2.655 mmol) at 76 ° C. The resulting suspension was treated with the slow addition of MeOH (10 mL) at 76 °C. The resulting clear solution was slowly cooled to room temperature followed by overnight storage at -20 °C. The next day, the salt was filtered and rinsed with
EtOH to give an acid/cinchonine salt (614 mg, 69%) as a white solid. The filtrate was concentrated in vacuo and the residue was resubjected to fractional crystallization in MeOH (10 mL) to give an additional acid/cinchonine salt (125 mg, 14%).
The salt above (80 mg) was resuspended in water (4 mL) and acidified with IN HCl (500 μL, pH < 2). The resulting suspension was sonicated for 10 min and then centrifuged to remove the upper layer. After repeating the same procedure one more time, the resulting solid was washed with H 2 O (3 x 4 mL) and freeze dried to give a salt-free acid (43 mg, 97%) as a white solid: 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.90 (s, IH), 7.47 (s, IH), 7.03 (t, J= 8.0 Hz, IH), 6.70 (d, J= 7.6 Hz, IH), 6.58 (s, IH), 6.55 (d, J= 8.0 Hz, IH), 4.90 (d, J= 3.6 Hz, IH), 2.50- 2.47 (m, 2H), 0.94 (t, J= 7.2 Hz, 3H), 0.77 (s, 9H), 0.00 (s, 6H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 167.5, 155.8, 153.4, 147.1, 130.1, 120.1, 119.2, 118.1, 54.2, 26.2, 24.6, 18.6,
13.8, -3.8; TLC R f (CH 2 Cl 2 : MeOH 10:1) = 0.31.
To a solution of acid (20 mg, 0.053 mmol) and alcohol (18 mg, 0.159 mmol) in DMF (5 mL) was added EDC (31 mg, 0.159 mmol) and DMAP (32 mg, 0.266 mmol) at room temperature. The resulting mixture was heated at 50°C overnight under Argon. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H 2 O (2 x 5 mL) and brine (5 mL) successively, and then dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via preparative TLC (SiO 2 , 0.5 mm, CH 2 Cl 2 /Me0H = 10:1) to give an ester with a quantitative yield as a colorless oil: 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (s, IH), 7.14 (t, J= 8.0 Hz, IH), 6.86 (d, J= 7.6 Hz, IH), 6.75-6.72 (m, IH), 6.71 (dd, J= 6.4, 1.6 Hz, IH), 5.59 (s, IH), 5.31 (d, J= 2.8 Hz, IH), 3.85-3.76 (m, 2H), 2.81-2.68 (m, 2H), 1.65-0.78 (m, 1 IH), 1.22 (t, J= 7.2 Hz, 3H), 0.94 (s, 9H), 0.14 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ D 157.9, 148.7, 145.8, 144.5, 137.6, 122.4, 112.3, 112.0, 110.7, 92.9, 62.0, 48.1, 29.8, 22.3,
18.9, 18.5, 18.3, 17.9, 10.8, 5.1; TLC R f (CH 2 Cl 2 MeOH 10:1) = 0.47.
To a 0 0 C solution of the above ester (0.053 mmol) in CH 2 Cl 2 (2 mL) was added dropwise TBAF (IM in THF, 64 μL, 0.064 mmol). After 10 min at 0 °C, the reaction was quenched by the addition of saturated aqueous NaHCO 3 (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via preparative TLC (SiO 2 , 0.5 mm, CH 2 Cl 2 MeOH = 10:1) to give a desilylated product 2a (17 mg, 86% over 2 steps) as a
white solid. The enantiomeric excess was determined to be 98% ee by chiral HPLC (Daicel Chiralcel AD column, 0.85 mL/min, rc-Hexanes/z-PrOH = 75:25).
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimid ine-5- carboxylate (1)
1 H NMR (400 MHz, CD 3 OD) δ 7.08 (t, J= 7.6 Hz, IH), 6.73 (d, J- 7.2 Hz, IH), 6.70 (s, IH), 6.63 (d, J= 6.8 Hz, IH), 5.19 (s, IH), 3.88 (dd, J= 10.4, 5.6 Hz 5 IH), 3.70 (dd, J= 10.4, 5.6 Hz, IH), 2.32 (s, 3H), 1.59-1.42 (m, 6H), 1.11-1.06 (m, 3H), 0.84-0.76 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in rø-Hexanes, 0.85 mL/min): Ia ( R — 15.0 min, Ib tβ = 20.0 min.
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 » 4-tetrahydropyrimidine-5- carboxylate (2)
1 U NMR (400 MHz, OMSO-d 6 ) δ 9.36 (s, IH), 9.15 (s, IH), 7.63 (s, IH), 7.09 (t, J= 8.0 Hz,
IH), 6.66-6.61 (m, 3H), 5.04 (d, J= 3.2 Hz, IH), 3.83 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J=
10.8, 6.0 Hz, IH), 2.76-2.68 (m, IH), 2.66-2.57 (m, IH), 1.61-1.41 (m, 6H), 1.40-1.00 (m,
6H), 0.87-0.75 (m, 2H);
13 C NMR (100 MHz, DMSO-^) δ 165.7, 158.1, 154.7, 152.9, 146.7, 129.9, 117.6, 114.8,
113.8, 98.8, 68.8, 54.6, 37.4, 29.72, 29.65, 26.4, 24.7, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in rø-Hexanes, 0.85 mL/min): 2a fø = 8.0 min, 2b fø= 15.0 min.
Cyclohexylmethyl 6-cyclopropyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (3)
1 H NMR (400 MHz, CDCl 3 ) δ 7.10 (t, J= 8.0 Hz, IH), 6.77-6.69 (m, 2H), 6.61 (s, IH), 6.17 (s, IH), 5.28 (d, J= 2.4 Hz, IH), 3.87 (dd, J= 10.8, 6.4 Hz, IH), 3.80 (dd, J= 10.8 , 6.4 Hz, IH), 2.99-2.94 (m, IH), 1.64-1.47 (m, 6H), 1.12-1.04 (m, 3H), 0.95-0.74 (m, 6H); 13 C NMR (100 MHz, DMSO-^) δ 171.1, 162.8, 158.2, 157.7, 151.4, 134.7, 122.3, 119.6, 118.5, 105.6, 73.6, 59.2, 42.2, 34.5, 34.4, 31.2, 30.7, 16.4, 12.7, 11.8.
Cyclohexylmethyl 4-(3-hydroxyphenyI)-2-oxo-6-((trimethylsilyl)ethynyl)-l,2,3) 4- tetrahydropyrimidine-5-carboxylate (4)
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (s, IH), 7.07 (t, J= 8.0 Hz, IH), 6.77 (d, J= 6.8 Hz, 2H), 6.69 (d, J= 7.6 Hz, IH), 6.37 (s, IH), 5.28 (d, J= 2.4 Hz, IH), 3.95 (dd, J= 10.8, 6.8 Hz, IH), 3.84 (dd, J= 10.8, 6.8 Hz, IH), 1.65-1.54 (m, 5H), 1.24-1.07 (m, 4H), 0.88-0.79 (m, 2H), 0.22 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.0, 157.2, 153.9, 144.2, 130.6, 128.0, 118.9, 116.2, 114.2, 110.2, 106.6, 97.1, 70.8, 55.8, 37.6, 30.3, 27.0, 26.3, 0.1, 0.0.
Cyclohexylmethyl 6-ethynyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimi dine-5- carboxylate (5)
4 (100 mg, 0.23 mmol), K 2 CO 3 (32 mg, 0.23 mmol) and anhydrous methanol (2 mL) was added to a 25 mL round-bottom flask. After stirring for 10 min at room temperature, the reaction mixture was diluted with ethyl acetate (10 mL), washed with aqueous 1 N HCl (2 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO 2 , «-Hexanes/EtOAc/AcOH = 50:50: 0.5) to give 60 (62 mg, 74%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (s, IH), 7.12 (t, J= 7.8 Hz, IH), 6.84-6.72 (m, 3H), 6.00 (s, IH), 5.34 (s, IH), 3.95 (dd, J= 10.2, 6.2 Hz, IH), 3.83 (dd, J= 10.2, 6.2 Hz, IH), 3.42 (s, IH), 1.65-1.52 (m, 5H), 1.16-1.05 (m, 4H), 0.86-0.83 (m, 2H).
6
CyclohexylmethyI 6-cyclopropyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyri midine- 5-carboxylate (6)
1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J- 8.4 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 6.78 (s, IH), 6.17 (s, IH), 5.48 (d, J= 3.2 Hz, IH), 3.89-3.81 (m, 2H), 3.10-3.03 (m, IH), 1.65-1.44 (m, 6H), 1.28-0.77 (m, 9H); 13 C NMR (IOO MHz, CDCl 3 ) δ 165.7, 152.9, 151.4, 150.6, 147.7, 127.7, 124.4, 101.3, 69.8, 55.4, 37.4, 31.8, 29.90, 29.88, 26.4, 25.79, 25.76, 22.9, 14.3, 12.0, 7.6, 7.0.
7
CyclohexylmethyI 4-(4-aminophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyri midine- 5-carboxylate (7)
1 H NMR (400 MHz, DMOS-J 6 ) δ 8.05 (s, IH), 7.53 (s, IH), 6.86 (d, J= 8.4 Hz, 2H), 6.47 (d, J= 8.4 Hz, 2H), 4.99 (s, IH), 4.98 (s, 2H), 3.81 (dd, J= 10.6, 6.2 Hz, IH), 3.74 (dd, J= 10.6, 6.2 Hz, IH), 3.13-3.06 (m, IH), 1.63-1.46 (m, 6H), 1.15-1.04 (m, 4H), 0.85-0.81 (m, 2H); 13 C
NMR (100 MHz, DMSO-^) δ 166.5, 153.1, 152.7, 148.6, 132.6, 127.6, 114.2, 101.6, 68.8, 54.2, 37.4, 29.78, 29.71, 26.5, 25.92, 25.91, 11.6, 7.8, 6.9.
Cyclohexylmethyl 6-cyclopropyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyri midine- 5-carboxylate (8)
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (m, 2H), 7.61 (d, J= 8.0 Hz, IH), 7.47 (t, J= 7.8 Hz, IH), 6.92 (s, IH), 6.36 (s, IH), 5.48 (d, J= 2.8 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.81 (dd, J = 10.8, 6.0 Hz, IH), 3.12-3.05 (m, IH), 1.73-1.43 (m, 6H), 1.28-0.76 (m, 9H); 13 C NMR (IOO MHz, CDCl 3 ) δ 165.7, 153.0, 151.7, 148.6, 146.0, 132.8, 130.1, 123.1, 122.0, 101.2, 69.8, 55.4, 37.3, 30.0, 26.4, 25.78, 25.77, 12.0, 7.6, 7.0.
Cyclohexylmethyl 4-(3-aminophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyri midine- 5-carboxylate (9)
1 U NMR (400 MHz, OMSO-d 6 ) δ 8.07 (s, IH), 7.59 (s, IH), 6.92 (t, J= 7.8 Hz, IH), 6.42- 6.67 (m, 3H), 5.02-5.00 (m, 3H), 3.82 (dd, J= 10.4, 6.0 Hz, IH), 3.75 (dd, J= 10.4, 6.0 Hz, IH), 3.13-3.06 (m, IH), 1.61-1.47 (m, 6H), 1.54-1.04 (m, 4H), 0.85-0.79 (m, 5H).
10
Cyclohexylmethyl 4-(3-nitrophenyI)-2-oxo-6-((trimethylsilyl)ethynyl)-l,2,3 » 4- tetrahydropy rimidine-5-carboxylate (10)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, IH), 8.11 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.6 Hz, IH), 7.48 (t, J= 8.0 Hz, IH), 7.21 (s, IH), 5.52 (d, J= 3.2 Hz, IH), 3.94 (dd, J= 10.6, 6.2 Hz, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 1.70-1.56 (m, 5H), 1.23-1.06 (m, 4H), 0.88-0.80 (m, 2H), 0.24 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.5, 152.9, 149.1, 145.2, 133.5, 130.6, 129.1, 123.9, 122.5, 108.9, 107.6, 96.7, 71.0, 55.7, 37.6, 30.4, 26.9, 26.2, 0.1, 0.0.
(£)-Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-(prop-l-enyl)-l,2,3 5 4- tetrahydropy rimidine-5-carboxylate (11)
To a mixture of ethylcyanoacetate (5.17 g, 45.7 mmol) in water (5.00 mL) was added HNO 3 (0.50 mL), and the resulting mixture was heated to 95-100 °C with stirring for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 2- cyanoacetic acid 11-a as a white solid (2.80 g, 72%): 1 H NMR (400 MHz, CD 3 OD) δ 3.68 (s, 2H).
To a mixture of cyclohexane methanol (1.34 g, 11.76 mmol) in CH 2 Cl 2 (20 mL) was added 11-a (1.00 g, 11.76 mmol), EDC (3.38 g, 17.6 mmol), and DMAP (0.72 g, 5.88 mmol) at 0 0 C. After stirring at 25 °C for 12 h, the mixture was diluted with CH 2 Cl 2 (30 mL), washed with water (20 mL), saturated aqueous NH 4 Cl (20 mL) and brine (20 mL), dried over Na 2 SO 4 ,
filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 11-b (1.94 g, 91%): 1 H NMR (400 MHz, CDCl 3 ) δ 4.00 (s, 2H), 3.43 (s, 2H), 1.68-1.73 (m, 6H), 1.12-1.29 (m, 3H), 0.92-0.98 (m, 2H).
To a mixture of zinc powder (430 mg, 6.64 mmol), cyclohexylmethyl 2-cyanoacetate (300 mg, 1.66 mmol) and allyl bromide (210 μL, 2.49 mmol) in dry THF (8.3 mL) was added AlCl 3 (88.5 mg, 0.66 mmol) at 0 0 C. The mixture was allowed to warm to room temperature and stir for 2 h. The resulting mixture was cooled to 0 0 C and aqueous 2 N HCl solution (20 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 24 h at room temperature. All organic volatiles were removed in vacuo and the remaining mixture was extracted with EtOAc. The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give β-keto ester 11-c (223 m, 60%): 1 H NMR (400 MHz, CDCl 3 ) δ 5.84-5.91 (m, IH), 5.13 (dd, J= 13.4, 7.8 Hz, 2H), 3.89 (d, J= 7.8 Hz, 2H), 3.27 (s, 2H), 3.26 (s, 2H), 1.59-1.71 (m, 6H), 0.94-1.23 (m, 3H), 0.88-1.13 (m, 2H).
A mixture of Yb(OTf) 3 (76.0 mg, 0.12 mmol), β-keto ester 11-c (184 mg, 0.82 mmol), 3- hydroxybenzaldehyde (100 mg, 0.82 mmol) and urea (49.0 mg, 0.82 mmol) in THF (1.5 mL) was refluxed for 30 h under Argon. After adding H 2 O (5 mL), the mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO 2 , n-Hexanes/EtOAc/AcOH, 50:50:0.5) to afford Biginelli adduct 11 (179 mg, 59%): 1 H NMR (400 MHz, CD 3 OD) δ 7.27 (d, J= 16.4 Hz, IH), 7.12 (t, J= 8.0 Hz, IH), 6.66-6.79 (m, 3H), 6.40-6.46 (m, IH), 5.28 (s, IH), 3.94 (dd, J= 10.8, 5.6 Hz, IH), 3.78 (dd, J= 10.6, 5.4 Hz, IH), 1.93 (d, J= 6.8 Hz, 3H), 1.06-1.78 (m, 12H), 0.80-0.89 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.3, 159.0, 155.3, 146.7, 145.9, 134.5, 130.8, 124.8, 118.9, 115.7, 114.5, 102.1, 70.5, 56.2, 38.7, 30.8, 30.7, 27.1, 27.0, 19.0.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in π-Hexanes, 0.8 mL/min): 11a ϊ R = 11.0 min, lib ϊ R = 21.5 min.
12
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-isopropyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine- 5-carboxylate (12)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.36 (s, IH), 8.82 (s, IH), 7.63 (s, IH), 7.09 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.04 (d, J= 3.2 Hz, IH), 4.21-4.14 (m, IH), 3.80 (dd, J= 10.8, 6.0 Hz, IH), 3.71 (dd, J= 10.8, 6.0 Hz, IH), 1.60-1.57 (m, 6H), 1.24-1.02 (m, 9H) 3 0.86-0.76 (m, 2H); 13 C NMR (100 MHz, DMSO-^) δ 166.0, 158.1, 157.2, 153,2, 146.5, 130.0, 117,6, 114.9, 113.8, 98.5, 68.9, 54.5, 37.4, 29.69, 29.61, 27.5, 26.4, 25.9, 19.87, 19.67.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-propyl-l,2,3,4-tetrahydropyrimid ine-5- carboxylate (13)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.31 (s, IH), 9.08 (s, IH), 7.59 (s, IH), 7.04 (t, J= 8.0 Hz, IH), 6.62-6.57 (m, 3H), 5.01 (d, J= 3.6 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J= 10.8, 6.0 Hz, IH), 2.64-2.56 (m, 2H), 1.54-1.40 (m, 8H), 1.13-0.99 (m, 3H), 0.89-0.74 (m, 5H); 13 C NMR (IOO MHZ, DMSO-^) δ 165.8, 158.1, 153.1, 152.9, 146.8, 129.9, 117.5, 114.8, 113.8, 99.4, 68.9, 54.6, 37.4, 33.0, 29.75, 29.69, 26.4, 25.9, 22.3, 14.4.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-phenyl-l,23,4-tetrahydropyrimidi ne-5- carboxylate (14)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.43 (s, IH), 9.23 (s, IH), 7.79 (s, IH), 7.41-7.38 (m, 3H), 7.33-7.31 (m, 2H), 7.15 (t, J= 7.6 Hz, IH), 6.83-6.81 (m, 2H), 6.66 (dd, J= 8.2, 1.8 Hz, IH), 5.15 (d, J= 3.2 Hz, IH), 3.56-3.47 (m, 2H), 1.51-1.49 (m, 3H), 1.22-0.97 (m, 6H), 0.58-0.52 (m, 2H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 165.9, 158.1, 152.7, 149.6, 146.4, 135.9, 130.1, 129.5, 129.0, 128.5, 117.6, 115.0, 100.9, 69.2, 54.7, 37.0, 29.47, 29.37, 26.3, 25.9.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-(2-(triisopropylsilyIoxy)ethyl)- l,2,3,4- tetrahydropyrimidine-5-carboxylate (15)
1 H NMR (400 MHz, CD 3 OD) δ 7.07 (t, J= 7.6 Hz, IH), 6.78-6.74 (m, 2H), 6.65 (d, J= 7.2 Hz, IH), 5.24 (s, IH), 3.99 (s, 2H), 3.89-3.87 (m, IH), 3.74-3.72 (m, IH), 3.19 (t, J= 6.8 Hz, IH), 2.92 (t, J= 6.4 Hz, IH), 1.60-1.44 (m, 8H), 1.07 (s, 21H), 0.91-0.80 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.9, 157.6, 153.6, 149.3, 145.6, 129.4, 117.5, 114.4, 113.5, 101.4, 69.0, 62.0, 55.2, 37.4, 34.1, 29.6, 26.2, 25.7, 17.4, 11.9; TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.68.
Cyclohexylmethyl 6-(2-hydroxyethyI)-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahy dro- pyrimidine-5-carboxylate (16)
1 H NMR (400 MHz, CD 3 OD) δ 7.07 (t, J= 7.6 Hz, IH), 6.77-6.74 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 5.23 (s, IH), 3.89 (dd, J= 10.4, 6.0 Hz, IH), 3.81 (t, J= 6.4 Hz, 2H), 3.71 (dd, J= 10.4, 6.0 Hz, IH), 3.02 (t, J= 6.4 Hz, 2H), 1.59-1.40 (m, 6H), 1.46-1.11 (m, 3H), 0.80-0.78 (m, 2H); 13 C NMR (IOO MHZ, CD 3 OD) δ 166.0, 157.6, 153.6, 149.2, 145.6, 129.5, 117.7,
114.5, 113.3, 101.4, 69.0, 60.3, 55.2, 37.4, 34.0, 29.4, 26.1, 25.6; TLC 2^(CH 2 Cl 2 MeOH 10:1) = 0.45.
Cyclohexylmethyl 6-(chloromethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydr opyri- midine-5-carboxylate (17)
1 H NMR (400 MHz 5 CD 3 OD) δ 7.12 (t, J= 7.6 Hz, IH), 6.77 (t, J= 7.6 Hz, 2H), 6.68 (d, J= 8.0 Hz, IH), 5.27 (s, IH), 4.72 (d, J= 11.2 Hz, IH), 3.97-3.94 (m, IH), 3.80-3.76 (m, IH), 1.62-1.46 (m, 6H), 1.28-1.09 (m, 3H), 0.89-0.80 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.0, 157.7, 153.6, 145.5, 144.9, 129.5, 117.5, 114.7, 113.4, 103.0, 69.5, 55.0, 38.3, 37.3, 29.4, 26.1, 25.7; TLC R 1 (CH 2 Cl 2 : MeOH 10:1) = 0.25.
CyclohexyImethyl 4-(3-hydroxyphenyl)-l,6-dimethyl-2-oxo-l,2,3,4- tetrahy dropyrimidine-5-carboxylate (18)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.65-6.74 (m, 3H), 3.94 (dd, J= 10.8, 5.8 Hz, IH), 3.80 (dd, J= 10.8, 5.6 Hz, IH), 3.20 (s, 3H), 2.67 (s, 3H), 1.48-1.67 (m, 6H), 1.10-1.23 (m, 3H), 0.83-0.88 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 167.8, 159.0, 151.7, 146.4, 130.8, 118.7, 115.7, 114.3, 105.5, 70.5, 54.6, 38.7, 30.6, 27.0, 16.6.
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-l-methyl-2-oxo-l,2,3 > 4- tetrahydropyrimidine-5-carboxylate (19)
1 U NMR (400 MHz, CDCl 3 ) δ 7.05 (t, J= 8.0 Hz, IH), 6.66-6.74 (m, 3H), 6.31-6.34 (m, IH), 5.22 (s, IH), 3.16 (s, 3H), 2.83-2.97 (m, 2H), 1.48-1.64 (m, 6H), 1.05-1.27 (m, 6H), 3.80-3.89 (m, 2H), 0.82-0.87 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.9, 156.8, 155.1, 154.6, 144.7, 129.9, 117.8, 115.0, 113.1, 103.8, 69.7, 53.2, 37.2, 29.7, 26.3, 25.7, 22.6, 14.2, 12.9.
Cyclohexylmethyl l-ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate (20)
1 H NMR (400 MHz, CD 3 OD) δ 7.08 (t, J= 7.8 Hz, IH), 6.66-6.74 (m, 3H), 6.61 (bs, IH), 5.71 (bs, IH), 5.24 (s, IH), 3.75 (m, 3H), 3.65-3.74 (m, IH), 2.49 (s, 3H), 1.48-1.67 (m, 6H), 1.05-1.19 (m, 6H), 0.80-0.86 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.4, 156.8, 154.1, 148.4, 144.9, 129.9, 117.9, 115.0, 113.2, 104.8, 69.7, 53.8, 38.0, 37.3, 29.8, 29.7, 26.3, 25.7, 16.0, 15.0.
Cyclohexylmethyl l,6-diethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine- 5-carboxylate (21)
1 H NMR (400 MHz, CDCl 3 ) δ 7.09 (t, J= 7.8 Hz, IH), 6.67-6.75 (m, 3H), 5.84 (bs IH), 5.22 (s, IH), 3.94 (dd, J= 14.0, 6.8 Hz, IH), 3.61 (dd, J= 14.0, 6.8 Hz, IH), 3.02-3.07 (m, IH), 2.77-2.82 (m, IH), 1.50-1.65 (m, 6H), 1.06-1.26 (m, 9H), 0.78-0.85 (m, 2H).
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l-propyl-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate (22)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.66-6.75 (m, 3H), 5.22 (s, IH), 3.93
(dd, J= 10.8, 5.6 Hz, IH), 3.81-3.89 (m, IH), 3.78 (dd, J= 10.8, 5.6 Hz, IH), 3.52-3.59 (m,
IH), 1.44-1.66 (m, 8H), 1.08-1.25 (m, 3H), 0.78-0.92 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.9, 158.9, 155.6, 150.9, 146.4, 130.7, 118.6, 115.6, 114.4, 105.5, 70.5, 54.6, 45.2, 38.7,
30.7, 27.4, 26.9, 24.2, 16.3, 11.4.
CyclohexylmethyI 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l-propyl-l,2,3 » 4- tetrahydropyrimidine-5-carboxylate (23)
1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (t, J= 7.8 Hz, IH), 6.66-6.75 (m, 3H), 5.84 (bs, IH), 5.22 (s, IH), 3.81-3.92 (m 3H), 3.36-3.42 (m, IH), 3.08-3.20 (m, IH), 2.62-2.66 (m, IH), 0.78- 1.65 (m, 18H).
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l-phenyl-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (24)
1 H NMR (400 MHz, CD 3 OD) δ 7.41-7.50 (m, 3H), 7.18-7.26 (m, 3H), 6.87-6.90 (m, 2H), 6.71-6.74 (m, IH), 5.35 (s. IH), 3.95 (dd, J= 10.6, 5.8 Hz, IH), 3.82 (dd, J= 10.6, 5.8 Hz, IH), 2.16 (s, 3H), 1.49-1.67 (m, 6H), 1.13-1.22 (m, 3H), 0.83-0.88 (m, 2H).
(S)-Cyclohexylmethyl 4-(3-acetoxyphenyl)-l-acetyl-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (25)
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (s, IH), 7.30 (t, J= 7.8 Hz, IH), 7.16 (d, J= 7.6 Hz, IH), 7.00-7.98 (m, 2H), 5.82 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 11.0, 6.2 Hz, IH), 3.78 (dd, J= 11.0, 6.2 Hz, IH), 2.83-2.78 (m, IH), 2.69-2.64 (m, IH), 2.26 (s, 3H), 1.66-1.44 (m, 6H), 1.22-1.06 (m, 6H), 0.87-0.77 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.5, 165.4, 153.4, 151.1, 145.5, 130.0, 124.1, 121.4, 120.0, 100.3, 69.7, 55.6, 37.3, 29.89, 29.87, 26.5, 25.9, 25.6, 21.4, 12.7.
Cyclohexylmethyl l-benzyI-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (26)
1 H NMR (400 MHz, CDCl 3 ) δ 7.21-7.30 (m, 3H), 7.10-7.15 (m, 3H), 6.69-6.77 (m, 3H), 5.31 (s, IH), 3.93 (dd, J= 10.8, 5.8 Hz, IH), 3.79 (dd, J= 10.8, 5.8 Hz, IH), 2.44 (s, 3H), 1.11- 1.65 (m, 9H), 0.80-0.84 (m, IH).
Cyclohexylmethyl l-benzyl-6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate (27)
1 H NMR (400 MHz, CDCl 3 ) δ 7.06-7.24 (m, 6H), 6.65-6.75 (m, 3H), 6.02 (bs, IH), 5.28 (s, IH), 5.23 (d, J= 16.2 Hz, IH), 4.74 (d, J= 16 Hz, IH), 3.80 (m 2H), 2.96-3.12 (m, IH), 2.65- 2.69 (m, IH), 0.93-1.64 (m, 12H), 0.80-0.85 (m, 2H).
28
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyl)-6-methyl-2-oxo-l ,2,3,4- tetrahydropyrimidine-5-carboxylate (28)
28
To a solution of 2,4-dimethoxybenzylamine hydrochloride (5.44 g, 26.7 mmol) in water (111 mL) was added urea (6.4 g, 1.07 mmol) and concentrated HCl (31 mL, 0.374 mmol) and the mixture was then refluxed for 6 h. The resulting mixture was cooled to room temperature and further cooled with ice. The precipitate formed was filtered off to give 2,4-
dimethoxybenzylurea as a white solid (2.58 g, 46%): 1 H NMR (400 MHz, OM&O-dβ) δ 7.11 (d, J= 8.8 Hz, IH), 6.57 (d, J= 2.0 Hz, IH), 6.50 (dd, J= 8.2, 2.0 Hz, IH), 6.14 (t. J= 5.8 Hz, IH), 5.50 (bs, 2H), 4.08 (d, J= 6.0 Hz, 2H), 2.12 (bs, IH).
A mixture of 3-methoxybenzaldehyde (863 mg, 6.34 mmol), β-ketoester (1.25 g, 6.34 mmol), 2,4-dimethoxybenzylurea (2.0 g, 9.51 mmol) and acetic acid (0.54 mL, 9.51 mmol) was heated with stirring at 90 °C for 12 h. The mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford Biginelli adduct 28 (2.28 g, 71%) as a white solid: 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (d, J= 8.0 Hz, IH), 6.92 (d, J= 8.2 Hz, IH), 6.68-6.72 (m, 3H), 6.37-6.38 (m, 2H), 5.25 (s, IH), 4.97 (d, J = 16.0 Hz, IH), 4.80 (d, J= 16.0 Hz, IH), 3.82-3.92 (m, 2H), 3.70 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H), 1.50-1.64 (m, 6H), 1.08-1.18 (m, 3H), 0.80-0.89 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.5, 160.2, 158.9, 157.8, 154.6, 150.3, 142.6, 129.6, 128.9, 119.2, 118.6, 113.0, 112.8, 104.2, 103.8, 98.4, 69.7, 55.5, 55.3, 55.2, 42.1, 37.3, 34.8, 30.0, 29.8, 25.9, 25.7, 16.1.
29
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyI)-3,6-dimethyl-2-o xo- l,2,3 ? 4-tetrahydropyrimidine-5-carboxylate (29)
1 H NMR (400 MHz, CDCl 3 ) δ 7.11 (d, J= 8.0 Hz, IH), 7.01 (d, J= 9.2 Hz, IH), 6.70-6.75 (m, 3H), 6.37-6.38 (m, 2H), 5.21 (s, IH), 4.95 (d, J= 16.4 Hz, IH), 4.84 (d, J= 16 Hz, IH), 3.84- 3.90 (m, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 2.92 (s, 3H), 2.43 (s, 3H), 1.55- 1.65 (m, 6H), 1.11-1.20 (m, 3H), 0.86-0.92 (m, 2H); 13 C NMR (400 MHz, CDCl 3 ) δ 166.5, 160.2, 159.9, 157.7, 153.8, 150.1, 142.6, 129.6, 129.1, 119.2, 118.6, 113.0, 112.8, 104.2, 103.8, 98.4, 69.7, 61.0, 55.5, 55.3, 55.2, 42.1, 37.3, 34.8, 30.0, 29.9, 25.9, 25.8, 16.5.
Cyclohexylmethyl 3-benzyl-l-(2,4-dimethoxyben2yl)-4-(3-methoxyphenyl)-6-methy l-2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (30)
1 H NMR (400 MHz, CDCl 3 ) δ 7.21-7.30 (m, 5H), 7.01- 7.19 (m, 2H), 6.62- 6.72 (m, 3H), 6.33- 6.37 (m, 2H), 5.32 (d, J= 15.2 Hz, IH), 5.17 (s, IH), 4.97 (d, J= 16 Hz, IH), 4.83 (d, J = 16 Hz, IH), 3.78- 3.83 (m, IH), 3.75 (s, 3H), 3.65- 3.70 (m, 3H), 3.64 (s, 3H), 3.60 (s, 3H), 2.43 (s, 3H), 1.56- 1.58 (m, 3H), 1.36- 1.44 (m, 3H), 1.03- 1.10 (3H), 0.69- 0.75 (m, 2H); 13 C NMR (400 MHz, CDCl 3 ) δ 166.0, 160.0, 159.6, 157.6, 153.9, 150.0, 142.4, 136.6, 129.4, 129.2, 128.0, 127.3, 118.9, 118.2, 112.7, 112.5, 103.9, 103.8, 98.2, 69.1, 56.4, 55.2, 54.9, 54.9, 48.9, 42.0, 36.9, 29.5, 29.4, 26.1, 25.7, 25.6, 16.1.
31
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l ,2,3,4- tetrahydropyrimidine-5-carboxyIate (31)
1 U NMR (400 MHz, CDCl 3 ) δ 7.16- 7.20 (m, IH), 6.89 (d, J= 8.0 Hz, IH), 6.79 (t, J= 7.8 Hz, 2H), 6.74 (s, IH), 6.47 (s, IH), 6.38 (d, J= 8.4 Hz, IH), 5.00 (d. J= 16 Hz, IH), 5.31 (s, IH), 4.76 (d, J= 16 Hz, IH), 3.81- 3.95 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 1.48- 1.65 (m, 6H), 1.07-1.19 (m, 3H), 0.81-0.90 (m, 2H); 13 C NMR (400 MHz, CDCl 3 ) δ 166.5, 160.6, 160.1, 157.9, 156.9, 150.6, 145.1, 129.4, 128.7, 118.4, 118.0, 112.5, 112.1, 104.1, 97.9, 69.2, 54.5, 54.3, 40.7, 37.4, 29.5, 29.4, 26.0, 25.6, 15.1.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-3,6-dimethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (32)
1 R NMR (400 MHz, CDCl 3 ) δ 7.07 (t, J= 7.8 Hz, IH), 6.81 (d, J= 8.0 Hz, IH), 6.67- 6.73
(m, 2H), 6.22-6.30 (m, IH), 5.19 (s IH), 3.93 (dd, J= 10.8, 6.4 Hz, IH), 3.79 (dd, J= 10.8,
5.6 Hz, IH), 2.92 (s, 3H), 2.49 (s, 3H), 1.48- 1.64 (m, 6H), 1.12- 1.22 (m 3H), 0.82- 0.88 (m,
2H).
Cyclohexylmethyl 3-benzyI-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate (33)
1 H NMR (400 MHz, CDCl 3 ) δ 7.19-7.29 (m, 5H), 6.97 (t, J= 7.4 Hz, IH), 6.85 (d, J=8.0 Hz, IH), 6.22-6.61 (m, 3H), 6.62 (m IH), 5.24 (d, J= 15.2 Hz, IH), 5.07 (s, IH), 3.74 (dd, J = 11.0, 6.2 Hz, IH), 3.68 (d, J= 15.2 Hz, IH), 3.63 (dd, J= 10.8, 6.0 Hz, IH), 2.47 (s, 3H), 1.53-1.60 (m, 3H), 1.32-1.41 (m, 3H), 0.96-1.07 (m, 3H), 0.63-0.72 (m, 2H).
34
CycIohexylmethyI 3-ethyl-l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyl)-6-methyl -2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (34)
1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (t, J= 8.0 Hz, IH), 6.98 (d, J= 9.2 Hz, IH), 6.69-6.74 (m, 3H), 6.34-6.37 (m, 2H), 5.34 (s, IH), 4.98 (d, J= 16.0 Hz, IH), 4.79 (d, J= 16.0 Hz, IH), 3.91 (d, J= 6.4 Hz, 2H), 3.77-3.84 (m, IH), 3.76 (s, 3H), 3.67 (s, 3H), 3.62 (s, 3H), 2.94-3.00 (m, IH), 2.42 (s, 3H), 1.57-1.70 (m, 7H), 1.08-1.27 (m, 8H), 0.86-0.90 (m, 3H).
CyclohexyImethyl 3-ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (35)
1 H NMR (400 MHz, CDCl 3 ) δ 7.05 (t, J= 7.8 Hz, IH), 6.65-6.78 (m. 4H), 6.20-6.30 (m, IH), 5.30 (s, IH), 3.94 (dd, J= 10.8, 6.0 Hz, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.65-3.72 (m, IH), 3.08-3.13 (m, IH), 2.46 (s, 3H), 1.27-1.68 (m, 6H), 1.16-1.22 (m, 3H), 1.10 (t, J= 7.0 Hz, 3H), 0.88-0.92 (m, 2H).
General procedure for nitrogen/sulfur containing derivatives
The β-keto ester (0.50 mmol, 1.0 equiv), aldehyde (0.45 mmol, 0.9 equiv), guanidine (0.54 mmol, 1.1 equiv), and NaHCO 3 (1.83 mmol, 3.7 equiv) were dissolved in DMF (1.0 mL) and stirred under Ar for 2-24 h at 70 0 C. After cooling to room temperature, the crude reaction mixture was poured into water and extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
The β-keto ester (0.82 mmol, 1.0 equiv), aldehyde (0.82 mmol, 1.0 equiv), thiourea (1.23 mmol, 1.5 equiv), and VCl 3 (0.082 mmol, 0.1 equiv) were dissolved in acetonitrile (2 mL) and stirred under Ar for 4 h at 90 °C. After cooling to room temperature, the crude reaction mixture was quenched with a saturated aqueous NaHCO 3 (2 mL), and then extracted with CH 2 Cl 2 (3 x 5 mL). The combined organic layers were washed with brine (5 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , «-Hexanes/EtOAc = 2:1) to give corresponding Biginelli adducts.
36
Cyclohexylmethyl 2-amino-6-(3-hydroxyphenyl)-4-methyl-l,6-dihydropyrimidine-5 - carboxylate acetate (36)
1 H NMR (400 MHz, CD 3 OD) δ 7.06 (t, J= 8.0 Hz, IH), 6.82-6.62 (m, 3H), 5.26 (s, IH), 3.88-3.83 (m, IH), 3.68-3.64 (m, IH), 2.35 (s, IH), 1.82 (s, IH), 1.55-1.52 (m, 3H), 1.44-1.39 (m, 3H), 1.06-1.03 (m, 4H), 0.74-0.69 (m, IH); 13 C NMR (100 MHz, CD 3 OD) δ 179.6, 165.1, 158.0, 151.5, 144.8, 143.6, 129.8, 117.5, 115.1, 113.3, 103.2, 69.3, 53.3, 37.3, 29.4, 26.1, 25.6, 22.8, 16.6; TLC R f (EtO Ac: MeOH: AcOH 9:1 :0.5) = 0.23.
37
CyclohexyImethyl 6-ethyl-4-(3-hydroxyphenyl)-2-(lH-pyrazol-l-yl)-l,4-dihydrop yrimi- dine-5-carboxylate (37)
1 H NMR (400 MHz, CD 3 OD) δ 7.64 (s, IH), 7.56 (s, IH), 7.06 (t, J= 7.6 Hz, IH), 6.82 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 6.42 (s, IH), 6.29 (s, IH), 5.55 (s, IH), 3.92-3.88 (m, IH), 3.76- 3.72 (m, IH), 2.92-2.83 (m, 2H), 1.63-1.03 (m, HH), 0.88-0.80 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 173.2, 169.3, 166.6, 157.6, 146.1, 142.4, 129.4, 128.2, 118.0, 114.5, 113.8, 108.7, 104.5, 102.2, 78.4, 63.7, 54.4, 37.4, 29.2, 26.5, 12.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.18.
CyclohexylmethyI 6-ethyl-4-(3-hydroxyphenyl)-2-(lH-pyrazol-l-yl)-l,4-dihydrop yrimi- dine-5-carboxylate (38)
1 H NMR (400 MHz, CD 3 OD) δ 7.64 (s, IH), 7.56 (s, IH), 7.06 (t, J= 7.6 Hz, IH), 6.82 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 6.42 (s, IH), 6.29 (s, IH), 5.55 (s, IH), 3.92-3.88 (m, IH), 3.76- 3.72 (m, IH), 2.92-2.83 (m, 2H), 1.63-1.03 (m, HH), 0.88-0.80 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 173.2, 169.3, 166.6, 157.6, 146.1, 142.4, 129.4, 128.2, 118.0, 114.5, 113.8, 108.7, 104.5, 102.2, 78.4, 63.7, 54.4, 37.4, 29.2, 26.5, 12.1; TLC J?/(ra-Hexanes:EtOAc 5:1) = 0.18.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-l,2,3,4-tetrahydropyri mi- dine-5-carboxylate (39)
1 U NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 4.0 Hz, IH), 6.75-6.66 (m, 3H), 5.46 (s IH), 3.94- 3.90 (m, IH), 3.76-3.72 (m, IH), 2.35 (s. 3H), 1.96-1.45 (m, 3H), 1.30-1.11 (m, 5H), 0.89-
0.78 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 174.6, 174.1, 166.2, 157.7, 144.9, 144.7, 129.6, 117.9, 114.8, 113.5, 101.7, 69.2, 55.3, 37.4, 29.5, 26.2, 25.7, 19.6, 16.6.
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-thioxo-l,2,3,4-tetrahydropyrim idine-5- carboxylate (40)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 8.0 Hz, IH), 6.75-6.66 (m, 3H), 5.21 (s, IH), 3.94-3.90 (m, IH), 3.77-3.73 (m, IH) 5 2.84-2.70 (m, 2H), 1.65-1.45 (m, 3H), 1.30-1.08 (m, 5H), 0.90-0.79 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 175.1, 165.7, 157.7, 150.5, 144.7, 129.5, 117.8, 114.7, 113.5, 100.8, 69.2, 55.2, 37.4, 31.5, 29.5, 25.9, 23.9, 22.5, 13.2, 12.0.
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2-dihydropyrimidine-5- carboxylate (41)
1 (50 mg, 0.15 mmol), NaHCO 3 (63 mg, 0.75 mmol) and acetone (1.50 mL) were added to a 50 mL round bottom flask containing a stir bar. To this suspension was added a solution of CAN (247 mg, 0.45 mmol) in water (0.20 mL), and the mixture was stirred for 1 h at -5 °C followed by overnight stirring at room temperature under Argon. The resulting mixture was diluted with CH 2 Cl 2 (10 mL) and filtered. The residue was washed with CH 2 Cl 2 (2 x 10 mL). The combined CH 2 Cl 2 layers were washed with saturated NH 4 Cl (10 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 41 (10 mg, 20%): 1 H NMR (400 MHz, CD 3 OD) δ 8.12 (d, J= 6.4 Hz, IH), 7.25 (s, IH) 7.11 (d, J= 8.0 Hz, IH), 6.94 (s, IH), 3.78-3.82 (m, 2H), 1.07-1.60 (m, 9H), 0.67-0.71 (m, 2H).
Ethyl 6-(4-methoxyphenyl)-2,4-dioxo-l ,2,3,4-tetrahy dropyrimidine-5-carboxyIate (42)
1 H NMR (400 MHz, CD 3 OD) δ 7 .42 (d, J= 8.8 Hz, 2H), 7.04 (d, J= 8.8 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.01 (t, J= 7.2 Hz, 3H).
Ethyl 6-(chIoromethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (43)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 7.6 Hz, IH), 6.77 (d, J= 8.0 Hz, IH), 6.76 (bs, IH), 6.67 (dd, J= 8.0, 2.0 Hz, IH), 5.27 (s, IH), 4.81 (d, J= 11.6 Hz, IH), 4.65 (d, J= 11.6 Hz, IH), 4.10-4.06 (m, 2H), 1.15 (t, J= 6.8 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.0, 157.6, 153.8, 145.1, 145.1, 129.6, 117.6, 114.7, 113.3, 103.4, 60.5, 55.0, 38.5, 13.2; TLC R 1 (CH 2 Cl 2 :Me0H 10:1) = 0.36.
4-(3-Hydroxyphenyl)-3,4-dihydrofuro[3,4-d]pyrimidine-2,5( l/ir,7H)-dione (44)
Biginelli adduct 43 (1.0 mmol) was heated neat in an oil bath at 210 °C (bath temperature) for approximately 6 min. The resulting solid was purified by recrystallization from MeOH to afford furopyrimidine 44: 1 K NMR (400 MHz, CD 3 OD) δ 7.14 (t, J= 8.0 Hz, IH), 6.82 (bd, J = 8.0 Hz, IH), 6.79 (bs, IH), 6.72-6.69 (m, IH), 5.23 (s, IH), 4.83-4.73 (m, 2H); 13 C NMR
(100 MHz, CD 3 OD) δ 171.4, 159.3, 157.7, 143.5, 129.7, 117.6, 115.1, 113.3, 98.4, 65.6, 53.5; TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.14.
Ethyl 4-(3-hydroxyphenyl)-2-oxo-6-(2-(triisopropylsilyloxy)ethyl)- l,2,3 > 4- tetrahydropyrimidine-5-carboxylate (45)
1. NaH 1 THF (COCI) 2 10 mol% SnCI 2
HO^^^OH
2. TIPSCI Tipscr "OH
DMSO, Et 3 N* TIPSO H N 2 ^CO 2 Et 92 % CH 2 CI 2
45-a 93% 45-b CH 2 CI 2
25 °C, 16 h
86%
45
Sodium hydride (60% dispersion in mineral oil, 1.66 g, 41.5 mmol) was suspended in THF (41 mL) and a solution of 1,3-propandiol (3 rnL, 41.5 mmol) in THF (20 mL plus 2 niL rinse) was added slowly via a cannula over 10 min at 25 °C. The white suspension was stirred for 45 min, and then a solution of triisopropylsilyl chloride (8.0 g, 41.5 mmol) in THF (20 mL) was added via a cannula over 5 min. The resulting white suspension was stirred for 7 h, and then quenched with a mixture of saturated aqueous NaHCO 3 (50 mL) and H 2 O (30 mL). The mixture was extracted with Et 2 O (3 x 100 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , n- Hexanes/Et 2 O = 10:1 -→ 2:1) to give compound 45-a (8.86 g, 92%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 ) δ 3.91 (t, J= 5.2 Hz, 2H), 3.81 (t, J= 5.6 Hz, 2H), 1.79-1.77 (m, 2H), 1.12-1.04 (m, 21H); 13 C NMR (100 MHz, CDCl 3 ) δ 63.7, 62.8, 34.1, 17.9, 11.8; TLC R 1 (rc-Hexanes:Et 2 O 5:1) = 0.11.
To a -78 0 C solution of oxalyl chloride (3.15 mL, 36.7 mmol) in CH 2 Cl 2 (240 mL) was added slowly dimethyl sulfoxide (5.21 mL, 73.4 mmol). Gas evolution was observed. After 15 min,
a solution of compound 45-a (7.11 g, 30.6 mmol) in CH 2 Cl 2 (50 mL plus 2 niL rinse) was added via a cannula over 8 min. The cloudy solution was stirred at -78 0 C for 30 min, and then Et 3 N (16.6 mL, 119.3 mmol) was added via a syringe over 7 min. The resulting solution was stirred at -78 °C for 50 min, and then warmed to 25 °C and stirred for an additional 30 min. The mixture was quenched at 25 °C with saturated aqueous NH 4 Cl (150 mL). The organic layer was washed with brine (100 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , n- Hexanes/Et 2 O = 10:1) to give aldehyde 45-b (6.55 g, 93%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 ) δ 9.82 (t, J= 1.6 Hz, IH), 4.08-4.04 (m, 2H), 2.61-2.57 (m, 2H), 1.10-0.98 (m, 21H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.2, 57.9, 46.7, 17.9, 11.9; TLC i?/(«-Hexanes:Et 2 O 5:1) - 0.42.
To a 0 "C suspension of aldehyde 45-b (2.0 g, 8.68 mmol) and tin (II) chloride (165 mg, 0.867 mmol) in CH 2 Cl 2 (87 mL) was added slowly ethyl diazoacetate (1.28 mL, 12.15 mmol) via a syringe over 15 min. Significant gas evolution was observed. The bright yellow suspension was stirred at 25 0 C for 16 h, and then additional ethyl diazoacetate (91 μL, 0.87 mmol) was added. Since no additional gas evolution was observed, the mixture was quenched by the addition of IN HCl (50 mL) and extracted with CH 2 Cl 2 (50 mL). The combined organic layers were washed with IN HCl (50 mL), and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , n- Hexanes only → n-Hexanes/Et 2 O = 10:1) to give β-keto ester 45-c (2.36 g, 86%) as a pale yellow oil: 1 H NMR (400 MHz, CDCl 3 ) δ 4.17 (q, J= 7.2 Hz, 2H), 3.97 (t, J= 6.4 Hz, 2H), 3.50 (s, 2H), 2.73 (t, J= 6.4 Hz, 2H), 1.25 (t, J= 7.2 Hz, 3H), 1.06-1.00 (m, 21H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.3, 167.2, 61.3, 59.1, 50.2, 46.0, 17.9, 14.1, 11.9; TLC R f (n- Hexanes:Et 2 O 2:1) = 0.59.
The β-keto ester 45-c (200 mg, 0.632 mmol), 3-hydroxybenzaldehyde (77 mg, 0.632 mmol), urea (57 mg, 0.948 mmol), and Yb(OTf) 3 (39 mg, 0.063 mmol) were dissolved in acetonitrile (1.6 mL) and stirred under Argon for 24 h at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (4 x 20 mL). The combined organic layers were dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , «-Hexanes/EtOAc = 5:1 → 1 :1 then CH 2 Cl 2 /Me0H = 20:1) to give Biginelli adduct 45 (164 mg, 56%) as a yellow solid: 1 U NMR (400 MHz, CD 3 OD) δ 7.88 (s,
IH), 7.01 (t, J= 7.6 Hz, IH), 6.76-6.73 (m, 2H), 6.64 (d, J= 8.0 Hz, IH), 6.39 (s, IH), 5.22 (s, IH), 4.04-3.94 (m, 4H), 3.07-2.97 (m, 2H), 1.12-1.02 (m, 24H); 13 C NMR (100 MHz, CD 3 OD) δ 165.7, 156.5, 153.1, 148.8, 144.9, 129.7, 117.8, 114.9, 113.7, 101.5, 62.0, 60.1, 55.1, 33.6, 17.9, 14.0; TLC ^ 7 (CH 2 Cl 2 MeOH 10:1) = 0.42.
Ethyl 6-(2-hydroxyethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3 » 4-tetrahydropyrimidine-5- carboxylate (46)
To a solution of 45 (110 mg, 0.237 mmol) in THF (2.4 niL) was added TBAF (1.0 M in THF, 476 μL, 0.476 mmol) at room temperature. After sitting overnight, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (5 mL) and extracted with CH 2 Cl 2 (3 χ lθ mL). The combined organic layers were dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2, CH 2 Cl 2 only → CH 2 Cl 2 MeOH = 10:1) to give 46 (58 mg, 80%) as a pale yellow oil: 1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 7.6 Hz, IH), 6.77 (d, J= 8.0 Hz, IH), 6.75 (d, J= 2.0 Hz, IH), 6.65 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 4.08-4.01 (m, 2H), 3.79 (t, J= 6.8 Hz, 2H), 3.03-2.94 (m, 2H), 1.13 (t, J= 6.8 Hz, 3H); D 13 C NMR (IOO MHz, CD 3 OD) δ 166.0, 157.6, 153.8, 148.7, 145.8, 129.4, 117.7, 114.5, 113.3, 101.7, 60.3, 60.0, 55.1, 34.1, 13.3; TLC R 1 (CH 2 Cl 2 :Me0H 10:1) = 0.30.
4-(3-Hydroxyphenyl)-3,4,7,8-tetrahydro-l//-pyraiio [4,3-</] pyrimidine-2,5-dione (47) Compound 46 (55 mg, 0.179 mmol) and dibutyltinoxide (58 mg, 0.233 mmol) were dissolved in MeOH (6 mL). The reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the reaction was concentrated in vacuo and then directly subjected to flash column chromatography (SiO 2 , CH 2 Cl 2 only → CH 2 Cl 2 MeOH = 10:1) to give lactone 47 (44
mg, 95%) as a white solid: 1 U NMR (400 MHz, CD 3 OD) δ 7.12 (t, J= 7.6 Hz, IH), 6.82-6.78 (m, 2H), 6.67 (ddd, J= 8.4, 2.4, 0.8 Hz, IH), 5.25 (s, IH), 4.39-4.34 (m, IH), 4.25 (dt, J= 11.2, 4.0 Hz, IH), 2.82-2.73 (m, IH), 2.48 (dt, J= 17.6, 4.0 Hz, IH); 13 C NMR (100 MHz, CD 3 OD) δ 166.1, 157.6, 152.9, 149.7, 145.3, 129.6, 117.4, 114.6, 113.1, 98.7, 64.6, 53.8, 24.9; TLC #/(CH 2 Cl 2 :Me0H 10:1) = 0.13.
Ethyl 6-(2-hydroxyethyI)-4-(3-hydroxyphenyl)-2-thioxo-l,2,3,4-tetr ahydropyrimidine-5- carboxylate (48)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.77-6.73 (m, 2H), 6.67 (d, J= 8.0 Hz, IH), 5.24 (s, IH), 4.08-4.03 (m, 2H), 3.78 (t, J= 8.0 Hz, 2H), 3.02-2.98 (m, 2H). 1.13 (t, J= 7.2 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 174.8, 165.8, 157.6, 145.7, 144.8, 129.6, 117.9, 114.8, 113.4, 102.8, 60.3, 60.2, 55.3, 33.4,. 13.3.
4-(3-hydroxyphenyl)-2-thioxo-3,4,7,8-tetrahydro-lH r -pyrano[4,3-<flpyrimidin-5(2H)-one (49)
1 H NMR (400 MHz, CD 3 OD) δ 7.15-7.09 (m, IH), 6.80-6.75 (m, 2H), 6.69-6.65 (m, IH), 5.24 (s, IH), 4.41-4.36 (m,lH), 4.29-4.22 (m, IH), 2.83-2.74 (m, IH), 2.56-2.50 (m, IH); 13 C NMR (100 MHz, CD 3 OD) δ 175.3, 166.0, 157.7, 146.1, 129.7, 117.6, 114.9, 113.3, 99.6, 64.6, 53.9, 24.4.
General procedure for lactam derivatives
To a solution of Biginelli adduct (0.16 mmol, 1.0 equiv) and amine (0.16 mmol, 1.0 equiv) in acetonitrile (800 μL) was added triethylamine (0.12 mmol, 0.75 equiv) at 25 0 C. The reaction temperature was warmed to 90 0 C and the resulting mixture was further stirred for 15 h. After the starting material disappeared, the reaction mixture was cooled to 25 °C and quenched by the addition of water (10 mL) and extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
Ethyl 6-((benzylamino)methyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3 » 4-tetrahydropyrimi- dine-5-carboxylate (50)
1 U NMR (400 MHz, CD 3 OD) δ 7.29-7.22 (m, 5H), 7.09 (t, J= 8.0 Hz, IH), 6.77-6.75 (m, 2H), 6.65 (d, J= 7.2 Hz, IH), 5.24 (s, IH), 4.05-4.00 (m, 2H), 3.85 (s, 2H), 3.72 (s, 2H), 1.18 (t, J= 6.8 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 169.8, 157.7, 153.5, 150.2, 144.4, 137.4, 129.5, 128.6, 127.6, 127.4, 117.6, 114.8, 113.3, 104.5, 53.9., 46.1, 45.3; TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.25.
6-Benzyl-4-(3-hydroxyphenyl)-3,4,6,7-tetrahydro-l/f-pyrro lo[3,4-</]pyriinidine-2,5-dione
(51)
1 H NMR (400 MHz, CD 3 OD) δ 7.29-7.10 (m, 6H), 6.83-6.79 (m, 2H), 6.68-6.66 (m, IH), 5.24 (s, IH), 4.53 (d, J= 15.2 Hz, IH), 4.42 (d, J= 15.2 Hz, IH), 3.91-3.84 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 169.8, 157.7, 153.5, 150.2, 144.4, 137.4, 129.5, 128.6, 127.6, 127.4, 117.6, 114.8, 113.3, 104.5, 53.9., 46.1, 45.3; TLC i?/ (CH 2 Cl 2 :MeOH 10:1) = 0.18.
6-(2,4-DimethoxybenzyI)-4-(3-hydroxyphenyl)-3,4,6,7-tetra hydro-lH-pyrrolo[3,4- rf]pyrimidine-2,5-dione (52)
1 H NMR (400 MHz, CD 3 OD) δ 7.13 (d, J= 7.6 Hz, IH), 7.03 (d, J= 8.4 Hz, IH), 6.85-6.80 (m, 2H), 6.70-6.68 (m, IH), 6.51 (d, J= 2.4 Hz, IH), 6.46-6.43 (m, IH), 5.24 (s, IH), 4.45- 4.44 (m, 2H), 3.87-3.75 (m, 6H); 13 C NMR (IOO MHz, CD 3 OD) δ 169.6, 165.9, 161.1, 158.7, 157.6, 153.6, 149.9, 145.8, 144.5, 130.4, 129.4, 117.6, 117.3, 114.7, 113.2, 104.6, 98.2, 54.6, 53.9, 40.2, 13.2; TLC R 1 (CH 2 Cl 2 :MeOH 10:1) = 0.43.
6-(Cyclohexylmethyl)-4-(3-hydroxyphenyI)-3,4,6,7-tetrahyd ro-liϊ-pyrrolo[3,4- </]pyrimidine-2,5-dione (53)
1 H NMR (400 MHz, CD 3 OD) δ 7.13 (t, J= 7.6 Hz, IH), 6.84-6.79 (m, 2H), 6.68-6.67 (m, IH), 5.23 (s, IH), 4.09-3.99 (m, 2H), 3.20-3.14 (m, 2H), 1.70-1.59 (m, 6H), 1.23-1.18 (m, 5H), 0.93-0.91 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 170.0, 157.6, 153.6, 149.8, 144.4, 129.4, 117.5, 114.7, 113.2, 104.7, 103.5, 53.8, 37.2, 30.6, 26.3, 25.6; TLC R f (CH 2 Cl 2 :MeOH 10:1) = 0.65.
General procedure for fused lactone analogs
The β-keto ester (1.50 mmol, 1.0 equiv), aldehyde (1.50 mmol, 1.0 equiv), urea (1.80 mmol, 1.2 equiv), and KHSO 4 (0.38 mmol, 0.25 equiv) were dissolved in glycol (6 mL) and stirred for 2 h at 100 0 C. After cooling to room temperature, the crude reaction mixture was poured into ice-water. The solids were filtered and washed with ice-water and 95% EtOH to give the pure Biginelli adducts.
4-(3-Methoxyphenyl)-3,4-dihy dro-l-fiT-chromeno [4,3-</] pyrimidine-2,5-dione (54)
1 H NMR (400 MHz, DMSO-^) δ 7.98 (d, J= 8.0 Hz, IH), 7.60 (t, J= 7.6 Hz, IH), 7.37-7.33 (m, 2H), 7.16 (t, J= 8.0 Hz, IH), 7.14-7.00 (m, IH), 6.81-6.80 (m, 2H) 5 6.75-6.73(m, IH), 6.37-6.35 (m, IH), 3.79 (s, 3H); 13 C NMR (IOO MHz, OMSO~d 6 ) δ 162.5, 161.8, 159.8, 152.9, 144.2, 133.0, 129.7, 124.8, 124.5, 118.8, 117.0, 116.8, 112.8, 111.8, 107.3, 55.6, 47.8.
4-(3-HydroxyphenyI)-3,4-dihydro-lH-chromeno[43-^pyrimidin e-2,5-dione (55)
1 H NMR (400 MHz, DMSO-^) δ 8.93 (s,lH), 7.82 (d, J= 8.0, IH), 7.34-7.31 (m,lH), 7.10- 7.02 (m, 2H), 6.93-6.89 (m, IH), 6.83-6.61 (m, 2H), 6.41 (d, J= 8.0, IH), 6.13(bs, IH), 5.72 (bs, IH).
General procedure for cyclic ketone analogs
The β-keto ester (1.50 mmol, 1.0 equiv), 3-methoxybenzaldehyde (1.50 mmol, 1.0 equiv), urea (2.25 mmol, 1.5 equiv), and H 3 BO 3 (0.30 mmol, 0.2 equiv) were dissolved in glacial acetic acid (3 niL) and stirred for 2 h at 100 °C. After cooling to room temperature, the reaction mixture was poured into ice-water. The solids were filtered and washed with ice- water and 95% EtOH to give Biginelli adducts.
4-(3-MethoxyphenyI)-3,4,7,8-tetrahydroquinazoline-2,5(lJH r ,6 J H r )-dione (56)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.43 (s, IH), 7.70 (s, IH), 7.18 (t, J= 8.0 Hz, IH), 6.77- 6.75 (m, 3H), 5.11 (s, IH), 3.68 (s, 3H), 2.47-2.41 (m, 2H), 2.22-2.17 (m, 2H), 1.92-1.86 (m, IH), 1.79-1.77 (m, IH).
4-(3-Hydroxyphenyl)-3,4,7,8-tetrahydroquinazoline-2,5(lH, 6fi)-dione (57)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.40 (s, IH), 9.28 (s, IH), 7.66 (s, IH), 7.03 (t, J= 8.0 Hz, IH), 6.65-6.63 (m, 2H), 6.55 (d, J= 8.0 Hz, IH), 5.04 (s, IH), 2.43-2.38 (m, 2H), 2.21-2.18 (m, 2H), 1.90-1.88 (m, IH), 1.88-1.86 (m, IH); 13 C NMR (IOO MHz, OMSO-d 6 ) δ 193.8, 157.9, 154.9, 152.6, 146.7, 129.9, 117.5, 114.6, 113.8, 109.3, 52.1, 37.0, 26.5, 21.4.
Dihydropyrimidine analogs at C-5 ester position.
Neopentyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (58)
1 H NMR (400 MHz, DMSO-tf*) δ 9.34 (s, IH), 9.18 (s, IH), 7.68 (s, IH), 7.09 (t, J= 7.6 Hz, IH), 6.68-6.63 (m, 2H), 6.61 (d, J= 6.8 Hz, IH), 5.08 (d, J= 3.2 Hz,lH), 3.64 (dd, J= 30.2, 10.6 Hz, 2H), 2.29 (s, 3H), 0.77 (s, 9H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 166.1, 158.1, 152.7, 149.5, 146.4, 130.0, 117.6, 114.9, 113.7, 99.4, 73.2, 55.6, 54.4, 39.5, 31.6, 26.9, 18.5.
Benzyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5-carboxylate
(59)
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (bs, IH), 7.24-7.26 (m, 3H), 7.09-7.12 (m, 2H), 7.01 (t, J = 7.8 Hz, IH), 6.36-6.71 (m, 3H), 6.36 (bs, IH), 5.21 (s, IH), 5.06 (d, J= 12.4 Hz, IH), 4.97 (d, J= 12.2 Hz, IH).
Benzyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5-carboxylate (60)
1 H NMR (400 MHz, CD 3 OD) δ 7.26 (s, 3H), 7.13-7.07 (m, 3H), 6.74-6.68 (m, 3H), 5.26 (s, IH), 5.06 (dd, J= 33.8, 12.6 Hz, 2H), 2.75 (m, 2H), 1.20 (t, J= 7.4 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 169.5, 161.6, 157.9, 157.8, 149.8, 140.4, 133.4, 132.1, 131.7, 121.7, 118.4, 117.2, 103.5, 69.5, 58.9, 28.4, 16.0.
Octyl 4-(3-hydroxyphenyI)-6-methyl-2-oxo-l,2,3 » 4-tetrahydropyrimidine-5-carboxyIate (61)
1 H NMR (400 MHz, DMSO-cfc) δ 9.34 (s, IH), 9.15 (s, IH), 7.67 (s, IH), 7.08 (t, J= 8.0 Hz, IH), 6.66-6.60 (m, 3H), 5.05 (d, J= 3.2 Hz, IH), 3.98-3.89 (m, 2H), 2.25 (s, 3H), 1.50-1.43 (m, 2H), 1.26-1.19 (m, 10H), 0.85 (t, J= 7.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 166.9, 158.9, 153.6, 149.8, 147.6, 130.7, 118.3, 115.6, 114.5, 100.6, 64.6, 55.3, 32.7, 30.1, 30.0, 29.7, 26.9, 23.6, 19.2, 15.4.
Adamantanemethyl ester (62)
1 H NMR (400 MHz, DMSO-^) δ 9.31 (s, IH), 9.14 (s, IH), 7.62 (s, IH), 7.06 (t, J= 7.8 Hz, IH), 6.64-6.57 (m, 3H), 5.03 (d, J= 3.2 Hz, IH), 3.61 (d, J= 10.8 Hz, IH), 3.39 (d, J= 10.4 Hz, IH), 2.26 (s, 3H), 1.80 (s, 3H), 1.52 (dd, J= 39.2, 11.6 Hz, 6H), 1.26 (dd, J= 24.0, 12.0
Hz, 6H); 13 C NMR (IOO MHZ, DMSO-J 6 ) δ 166.0, 158.2, 152.6, 149.6, 146.4, 130.0, 117.6, 114.8, 113.8, 99.3, 73.3, 54.6, 37.0, 33.4, 28.1, 18.4.
(l-Benzylpiperidin-4-yl)methyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate acetate (63)
1 H NMR (400 MHz, CD 3 OD) δ 7.37-7.40 (m, 5H), 7.11 (t, J= 7.8 Hz, IH), 6.77 (d, J= 7.6 Hz, IH), 6.74 (s, IH), 6.65 (d, J= 7.8 Hz, IH), 5.23 (s, IH), 3.98 (dd, J= 11.2, 6.8 Hz, IH), 3.87 (s, 2H), 3.82 (dd, J= 11.2, 6.0 Hz, IH), 3.06-3.13 (m, IH), 2.34-2.44 (m, 2H), 2.35 (s, 3H), 1.94 (s, 3H), 1.59-1.66 (m, 2H), 1.45-1.69 (m, IH), 1.21-1.35 (m, 2H).
(l-(BenzyloxycarbonyI)piperidin-4-yl)methyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (64)
To a stirred solution of 4-hydroxymethylpiperidine (1.0 g, 8.7 mmol, 1.0 equiv) in dry CH 2 Cl 2 (50 mL) was added Et 3 N (2.4 mL, 17.4 mmol, 2.0 equiv) and benzylchoroformate (1.85 niL, 17.4 mmol, 2.0 equiv) at 0 "C. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was washed with water (20 mL) and the aqueous phase was
extracted with CH 2 Cl 2 (2 x 25 mL). The combined organic phases were washed with brine (15mL), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford compound 64-a (1.95 g, 89%) as a clear oil: 1 H NMR (400 MHz, CDCl 3 ) δ 5.10 (s, 2H), 4.20 (br d, J= 11.2 Hz, 2H), 3.48 (d, J= 6.4 Hz, 2H), 2.77 (t, J= 12.8 Hz, 2H), 1.62-1.70 (m, 3H), 1.10-1.20 (m, 2H).
To a stirred mixture of compound 64-a (1.80 g, 7.22 mmol, 1.0 equiv) in CH 2 Cl 2 (14 mL) was added 3-oxobutanoic acid (0.81 g, 7.94 mmol, 1.1 equiv), EDC (2.08 g, 10.85 mmol, 1.5 equiv), and DMAP (0.44 g, 3.61 mmol, 0.5 equiv). After stirring for 12 h at 25 0 C, the mixture was diluted with CH 2 Cl 2 (50 mL), washed with water (20 mL), sat. NH 4 Cl (20 mL) and brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford β-ketoester 64-b (2.24 g, 93%): 1 H NMR (400 MHz, CDCl 3 ) δ 5.10 (s, 2H), 4.20 (bd, J= 9.2 Hz, 2H), 3.99 (d, J= 6.4 Hz, 2H), 3.44 (s, 2H), 2.76 (t, J= 12.2 Hz, 2H), 2.24 (s, 3H), 1.78-1.88 (m, IH), 1.69 (bd, J= 12.8 Hz, 2H), 1.13-1.25 (m, 2H).
A mixture of 3-hydroxybenzaldehyde (0.50 g, 4.09 mmol, 1.0 equiv), β-ketoester 64-b (1.36 g, 4.09 mmol, 1.0 equiv), urea (0.37 g, 6.14 mmol, 1.5 equiv) and acetic acid (0.35 mL) was heated with stirring at 90 °C for 12 h. The mixture was cooled to room temperature and water (7 mL) was added. The mixture was extracted with EtOAc (3 >< 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford Biginelli adduct 64 (1.47 g, 75%) as a white solid: 1 U NMR (400 MHz, CD 3 OD) δ 7.28-7.38 (m, 5H), 7.10 (t, J= 7.8 Hz, IH), 6.73-6.77 (m, 2H), 6.67 (d, J= 8.0 Hz, IH), 5.22 (s, IH), 3.99-4.07 (m, 3H), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.60-2.81 (m, 2H), 3.36 (s, 3H), 1.62-1.70 (m, IH), 1.22-1.46 (m, 2H), 0.90-1.03 (m, 2H).
Cycloheptylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 5 4-tetrahydropyriinidine-5- carboxylate (65)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.76-6.73 (m, 2H), 6.67-6.64 (m,
IH), 5.22 (s, IH), 3.90-3.85 (m, IH), 3.73-3.69 (m, IH), 2.79-2.73 (m, 2H), 1.66-1.32 (m,
1 IH), 1.22 (t, J= 8.0 Hz, 3H), 1.08-1.04 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.0,
157.7, 154.0, 153.7, 145.8, 129.5, 117.6, 114.4, 113.3, 99.6, 69.2, 55.0, 38.9, 30.8, 28.3, 28.2,
26.4, 26.4, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in rø-Hexanes, 0.85 mL/min): 65a ϊ R = 8.5 min, 65b ϊ R = 15.6 min.
2-Cyclohexylethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5- carboxylate (66)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.76-6.72 (m, 2H), 6.67-6.64 (m, IH), 5.21 (s, IH), 4.14-4.08 (m. IH), 3.99-3.93 (m, IH), 2.81-2.69 (m, 2H), 1.64-1.57 (m, 5H), 1.41-1.27 (m, 2H), 1.21 (t, J= 8.0 Hz, 3H), 1.17-1.05 (m, 3H), 0.85-0.77 (m, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 166.0, 157.7, 154.1, 153.5, 145.8, 129.5, 117.6, 114.5, 113.2, 99.7, 61.6, 55.0, 36.0, 34.1, 33.1, 32.8, 26.4, 26.0, 26.0, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 66a ( R = 7.7 min, 66b ϊ R = 15.3 min.
67
((R)-Tetrahydrofuran-2-yl)methyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydro-pyrimidine-5-carboxylate (67)
1 H NMR (400 MHz, CD 3 OD) δ 7.08 (t, J= 7.6 Hz, IH), 6.78-6.75 (m, 2H), 6.65 (d, J= 7.6 Hz, IH), 5.25 (s, IH), 4.07-3.93 (m, 3H), 3.73-3.65 (m, 2H), 2.75-2.70 (m, 2H), 1.82-1.74 (m, 3H), 1.44-1.40 (m, 3H), 1.20 (t, J- 7.2 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.6,
157.6, 154.1, 145.8, 129.5, 117.6, 114.4, 113.2, 99.6, 76.8, 68.0, 65.4, 54.8, 27.6, 27.4, 25.4, 19.7, 12.1; TLC i?/(«-Hexanes: EtOAc 1 :3) = 0.21.
((S)-T etrahydrofuran-2-yl)methyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 5 4-tetrahydro- pyrimidine-5-carboxylate (68)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.66-6.63 (m, IH), 5.25 (s, IH), 4.02-3.96 (m, 3H), 3.74-3.67 (m, 2H), 2.77-2.70 (m, 2H), 1.82-1.76 (m, 3H), 1.46-1.39 (m, IH), 1.22-1.18 (m, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.6, 157.6, 154.1, 145.7, 117.6, 114.4, 113.2, 99.4, 76.8, 68.0, 65.4, 65.1, 54.8, 27.6, 27.4, 25.4, 24.5, 12.0; TLC i?/(«-Hexanes:EtOAc 1 :3) = 0.21.
2-(Piperidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne- 5-carboxylate (69)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.67-6.64 (m, IH), 5.24 (s, IH), 4.17-4.12 (m, 2H), 2.75 (t, J= 8.0 Hz, 2H), 2.54 (t, J= 5.2 Hz, 2H), 2.33 (bs, 4H), 1.53-1.47 (m, 4H), 1.38 (d, J= 5.2 Hz, 2H), 1.22-1.19 (m, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.5, 157.6, 154.1, 154.0, 145.7, 129.5, 117.6, 114.5, 113.3, 99.3, 61.1, 56.9, 54.7, 54.3, 25.1, 24.5, 23.5, 12.1; TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.12. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 mL/min): 69a t R = 17.2 min, 69b t R = 32.5 min.
Phenethyl 6-ethyl-4-(3-hydroxyphenyI)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5-carboxy- late (70)
1 H NMR (400 MHz, CD 3 OD) δ 7.21-7.18 (m, 2H), 7.14-7.13 (m, IH), 7.08-7.05 (m, 3H),
6.74 (bs, IH), 6.67 (t, J= 8.0 Hz, 2H), 5.18 (s, IH), 4.23-4.19 (m, 2H), 2.79 (t, J= 4.0 Hz,
2H), 2.64-2.61 (m, 2H), 1.10 (t, J= 8.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.9,
157.6, 154.2, 153.5, 145.8, 129.5, 128.7, 126.3, 117.7, 114.5, 113.2, 99.8, 64.6, 54.8, 34.8,
24.5, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% /-
PrOH in n-Hexanes, 0.85 mL/min): 70a t R = 13.9 min, 70b t R = 20.7 min.
2-Morpholino-2-oxoethyl 4-(3-(te^-butyIdimethylsilyloxy)phenyl)-6-ethyI-2-oxo-l,2,3, 4- tetrahydropyrimidine-5-carboxylate (71)
1 H NMR (400 MHz, CD 3 OD) δ 6.99 (t, J= 8.0 Hz, IH), 6.77 (d, J= 7.6 Hz, IH), 6.67 (t, J= 2.0 Hz, IH), 6.56-6.54 (m, IH), 5.17 (s, IH), 4.65 (d, J= 14.4 Hz, IH), 4.49 (d, J= 14.4 Hz, IH), 3.44-3.40 (m, 8H), 2.66-2.58 (m, 2H), 1.05 (t, J= 8.0 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H); 13 C NMR (IOO MHZ, CD 3 OD) δ 166.7, 165.2, 156.1, 154.8, 154.1, 145.9, 129.5, 119.7, 119.3, 117.9, 99.3, 66.4, 66.3, 61.0, 54.4, 45.0, 42.2, 25.1, 25.0, 24.7, 17.9, 12.2, -5.3; TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.70.
2-Morpholino-2-oxoethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimi- dine-5-carboxylate (72)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.80-6.75 (m, 2H), 6.66-6.64 (m,
IH), 5.29 (s, IH), 4.80 (d, J= 14.4 Hz, IH), 4.65 (d, J= 14.4 Hz, IH), 3.61-3.50 (m, 8H),
2.79-2.70 (m, 2H), 1.21 (t, J= 8.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 166.9, 165.2,
157.6, 154.8, 154.1, 145.8, 129.5, 117.6, 114.4, 113.2, 99.2, 66.4, 66.2, 61.0, 54.6, 53.6, 45.1,
42.2, 24.6, 12.0.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in rc-Hexanes, 0.80 mL/min): 72a t R = 41.0 min, 72b t R = 52.9 min.
2-(Pyrrolidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 5 4-tetrahydropyrimi- dine-5-carboxylate (73)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.67-6.64 (m,
IH), 5.26 (s, IH), 4.16-4.12 (m, 2H), 2.77-2.71 (m, 2H), 2.68-2.64 (m, 2H), 2.44 (s, 4H), 1.70
(s, 4H), 1.03 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.6, 157.6, 154.1, 154.0,
145.7, 129.5, 117.6, 114.5, 113.3, 99.4, 62.4, 54.7, 54.2, 54.1, 24.4, 23.0, 12.0; TLC R 1
(CH 2 Cl 2 :Me0H 10:1) = 0.10.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i-
PrOH in rc-Hexanes, 0.80 mL/min): 73a t R = 17.7 min, 73b t R = 31.8 min.
(S)-(Tetrahydro-2H-pyran-4-yl)methyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (74a)
1 H NMR (400 MHz, CD 3 OD) δ 7.07 (t, J= 8.0 Hz, IH), 6.74-6.70 (m, 2H), 6.64-6.61 (m, 2H), 5.19 (s, IH), 3.82-3.72 (m. 3H), 3.30-3.21 (m, 2H), 2.77-2.68 (m, 2H), 1.70-1.68 (m, IH), 1.36-1.08 (m, 8H); 13 C NMR (100 MHz, CD 3 OD) δ 165.7, 157.6, 153.8, 145.9, 129.5, 117.6, 114.4, 113.3, 99.4, 68.0, 67.3, 55.0, 34.6, 29.3, 29.2, 24.2, 12.0; TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.45.
75
2-Oxo-2-(piperidin-l-yl)ethyl 4-(3-(te^-butyldimethylsilyloxy)phenyl)-6-ethyl-2-oxo- 1 ,2,3,4-tetrahydropyrimidine-5-carboxylate (75)
1 H NMR (400 MHz, CD 3 OD) δ 6.99 (t, J= 8.0 Hz, IH), 6.78-6.55 (m, IH), 6.56 (t, J= 1.2 Hz, IH), 5.54-5.31 (m, IH), 5.17 (s, IH), 4.65 (d, J= 14.4 Hz, IH), 4.47 (d, J= 14.4 Hz, IH), 3.32-3.31 (m, 2H), 3.12-3.11 (m, 2H), 2.62-2.58 (m, 2H), 1.49-1.44 (m, 2H), 1.40-1.32 (m, 4H), 1.05 (t, J= 8.0 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H); 13 C NMR (100 MHz, CD 3 OD) δ 166.2, 165.2, 156.1, 154.6, 145.9, 129.5, 119.7, 119.2, 117.9, 99.4, 54.4, 45.6, 43.0, 31.5, 26.0, 25.3 ,25.0, 24.6, 22.5, 17.9, 13.2, 12.1, -5.4.
(,S)-2-Oxo-2-(piperidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (76a)
1 U NMR (400 MHz, CD 3 OD) δ 7.08 (t, J= 6.0 Hz, IH), 6.80-6.76 (m, 2H), 6.66-6.63 (m, IH), 5.30 (s, IH), 4.79 (d, J= 14.4 Hz, IH), 4.62 (d, J= 14.4 Hz, IH), 3.47-3.44 (m, 2H), 3.25-3.22 (m, 2H), 2.80-2.70 (m, 2H), 1.61-1.53 (m, 2H), 1.50-1.48 (m, 4H), 1.21 (t, J= 4.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 166.3, 165.3, 157.6, 154.6, 154.2, 145.8, 129.5, 117.6, 114.4, 113.2, 99.4, 61.1, 54.6, 45.6, 43.0, 26.0, 25.3, 24.7, 24.1, 12.0.
2-(Cyclohexyloxy)ethyl 6-ethyl-4-(3-hydroxyphenyI)-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (77)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.79-6.75 (m, 2H), 6.66-6.63 (m,
IH), 5.25 (s, IH), 4.17-4.07 (m, 2H), 3.57 (t, J= 4.8 Hz, 2H), 3.21-3.19 (m, IH), 2.79-2.68
(m, 2H), 1.84-1.79 (m, 2H), 1.69-1.68 (m, 2H), 1.51-1.49 (m, IH), 1.27-1.19 (m, 9H); 13 C
NMR (IOO MHz, CD 3 OD) δ 165.9, 157.6, 154.3, 153.5, 145.9, 129.4, 117.6, 114.4, 113.2,
.99.9, 77.9, 65.7, 63.5, 54.8, 32.0, 32.0, 25.7, 24.6, 23.8, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 0.80 mL/min): 77a ^ = 11.8 min, 77b t R = 20.2 min.
2-Phenoxyethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (78)
1 H NMR (400 MHz, CD 3 OD) δ 7.24-7.01 (m, 2H), 6.99 (t, J= 8.0 Hz, IH), 6.90 (t, J= 8.0 Hz, IH), 6.86-6.84 (m, 2H), 6.77-6.74 (m, 2H), 6.63-6.61 (m, IH), 5.24 (s, IH), 4.33-4.30 (m, 2H), 4.07-4.03 (m, 2H), 2.74-2.67 (m, 2H), 1.17 (t, J= 8.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.8, 158.8, 157.6, 154.2, 153.6, 145.9, 129.3, 129.3, 120.8, 117.7, 114.5, 114.4, 113.10, 99.9, 65.8, 62.5, 54.9, 24.6, 12.0; TLC ^(π-Hexanes: EtOAc 1 :3) = 0.33. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 78a t R = 14.7 min, 78b t R = 26.0 min.
79
Cyclopentyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5- carboxylate (79)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.75-6.66 (m, 2H), 6.64 (d, J= 2.0 Hz, IH), 5.18 (s, IH), 5.09-5.06 (m, IH), 2.78-2.67 (m, 2H), 1.79-1.39 (m, 8H), 1.20 (t, J= 8.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 165.7, 157.6, 154.0, 153.1, 146.0, 129.4, 117.6, 114.4, 113.3, 100.1, 77.0, 55.2, 32.3, 24.5, 23.4, 23.2, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 79a t R = 8.6 min, 79b t R = 15.0 min.
80
Cyclohexyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 » 4-tetrahydropyrimidiiie-5-carboxy- late (80)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (d, J=8.0 Hz, IH), 6.77-6.66 (m, 2H), 6.66-6.64 (m, IH), 5.23 (s, IH), 4.71-4.67 (m, IH), 2.80-2.68 (m, 2H), 1.78-1.73 (m, IH), 1.66-1.55 (m, 3H), 1.45-1.32 (m, 4H), 1.30-1.19 (m, 5H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.4, 157.6, 154.1, 153.1, 145.9, 129.4, 117.7, 114.4, 113.3, 100.2, 72.2, 55.1, 31.4, 31.1, 25.3, 24.5, 23.3, 23.1, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 80a t R = 8.5 min, 80b t R = 14.7 min.
81
Cyclopentylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5- carboxylate (81)
1 H NMR (400 MHz, CD 3 OD) δ 7.09 (t, J =8.0 Hz, IH), 6.76-6.73 (m, 2H), 6.66-6.64 (m, IH),
5.22 (s, IH), 3.96-3.91 (m, IH), 3.88-3.83 (m, IH), 2.81-2.69 (m, 2H), 2.09-2.03 (m, IH),
1.64-1.47 (m, 5H), 1.23 (t, J =8.0 Hz, 3H), 1.19-1.07 (m, 3H); 13 C NMR (IOO MHZ 5 CD 3 OD) δ 166.1, 157.6, 154.1, 153.4, 145.8, 129.4, 117.6, 114.4, 113.3, 99.8, 57.7, 55.0, 38.8, 29.1,
25.1, 24.5, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in «-Hexanes, 0.85 mL/min): 81a t R = 8.6 min, 81b t R = 14.5 min.
82a
(4S)-1-Cyclohexylethyl 4-(3-(fer^butyldimethylsilyloxy)phenyI)-6-ethyl-2-oxo-l,2,3, 4- tetrahydropyrimidine-5-carboxylate (82a)
1 H NMR (400 MHz, CD 3 OD) δ 7.93 (bs, IH), 7.90 (bs, IH), 7.16-7.12 (m, IH), 6.84 (t, J= 6.2 Hz, IH), 6.75-6.70 (m, 2H), 5.70 (bs, IH), 5.31-5.28 (m, IH), 4.72-4.67 (m, IH), 2.85- 2.69 (m, 2H), 1.72-1.15 (m, 10H), 1.12 (d, J= 11.2 Hz, 3H), 0.94 (s, 9H), 0.87 (t, J= 6.8 Hz, 3H), 0.15 (s, 6H); 13 C NMR (100 MHz, CD 3 OD) δ 165.0, 164.9, 156.4, 156.2, 152.3, 145.3, 145.2, 129.9, 129.8, 119.8, 119.7, 119.6, 118.4, 118.3, 100.8, 100.3, 74.5, 55.8, 55.7, 42.8,
42.7, 31.8, 28.8, 28.7, 28.5, 28.3, 26.6, 26.4, 26.3, 26.2, 25.9, 25.4, 22.8, 18.4, 17.3, 16.8, 14.3,
12.8, -4.1, -4.2; TLC i?/(n-Hexanes:EtOAc 1:2) = 0.60.
83a
(4S)-l-Cyclohexylethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine- 5-carboxylate (83a)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 7.0 Hz, 2H), 6.76-6.73 (m, 4H), 6.65 (d, J- 8.0 Hz, 2H ), 5.22 (s, IH), 5.19 (s, IH), 4.68-4.63 (m, 2H), 3.03 (s, IH), 2.90 (s, IH), 2.82-2.70 (m, 4H), 1.71-0.90 (m, 32H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.6, 165.4, 157.7, 157.5, 153.9, 152.6, 145.9, 145.7, 129.5, 129.3, 117.8, 117.7, 114.4, 114.3, 113.5, 113.3, 100.3, 99.5, 74.3, 74.1, 55.2, 55.0, 42.9, 42.8, 28.7, 28.5, 28.3, 27.8, 26.3, 26.1, 26.0, 24.4, 24.3, 16.4, 15.9, 12.1, 12.0; TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.45.
4-(3-HydroxyphenyI)-6-methyI-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5-carboxylic acid
(84)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.80 (d, J= 8.0 Hz, IH), 6.78 (d, J- 1.2 Hz, IH), 6.66 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 2.33 (s, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 157.5, 147.1, 145.9, 129.3, 117.6, 114.3, 113.1, 101.5, 55.0, 16.9.
85
Allyl 4-(3-chloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydr opyrimidine-5- carboxylate (85)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (s, IH), 7.05 (d, J= 7.6 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.83-5.76 (m, IH), 5.12-5.08 (m, 2H), 4.55-4.44 (m, 2H), 2.73-2.72 (m, 2H), 1.07 (t, J= 11.4 Hz, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.4, 154.1, 153.7, 152.6, 136.8, 132.4, 128.2, 126.2, 126.1, 120.4, 117.1, 116.6, 99.7, 64.6, 54.2, 24.7, 12.4; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.31.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in rc-Hexanes, 4.0 mL/min): 85a t R = 42.2 min, 85b t R = 59.1 min.
86
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3 5 4-tetrahydropyrimidine-5-carboxylic acid (86)
Allyl ester (31 mg, 0.093 mmol), 5 mol% Pd(PPh 3 ) 4 (5 mg, 0.005 mmol), and piperidine (92 μL, 0.09 mmol) was added to a solution of THF (0.5 mL) and stirred for 5 h at 25 0 C. And then the reaction mixture was evaporated to dryness under reduced pressure and solid residue was treated with 0.5 M KOH solution (0.5 mL), vigorously stirred, and filtered. The filtrate was acidified by IN HCl till pH 2-3 and the resulting precipitates were collected by filtration. The product was white solid (18 mg, 66%): 1 H NMR (400 MHz, CD 3 OD) δ 7.01 (s, IH), 6.86 (d, J= 8.0 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 5.00 (s, IH), 2.59-2.47 (m, 2H), 1.00 (t, J= 7.4 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 167.7, 154.3, 153.2, 152.5, 136.9, 128.0, 125.9, 120.3, 116.4, 100.2, 54.1, 24.5, 12.1; TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.32.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.45 (s, IH), 7.50 (t, J= 5.4 Hz, IH), 7.36 (s, IH), 7.04 (t, J - 7.6 Hz, IH), 6.68 (s, IH), 6.61 (d, J= 6.8 Hz, 2H), 5.14 (s, IH), 3.42 (bs, IH), 2.92-2,86 (m, IH), 2.83-2.76 (m, IH), 1.96 (s, 3H), 1.56 (m, 4H), 1.31-1.25 (m, 2H), 1.05 (m, 3H), 0.73-0.70 (m, 2H); 13 C NMR (100 MHz, DMSO- d 6 ) δ 167.0, 158.4, 153.4, 146.4, 136.9, 129.6, 117.4, 114.8, 114.0, 106.1, 55.7, 45.6, 38.1, 31.1, 26.7, 26.1, 17.5.
6-Ethyl-4-(3-hydroxyphenyl)-iV-methoxy-λ L methyl-2-oxo-l,2,3,4-tetrahydropyriinidine- 5-carboxamide (88)
1 H NMR (400 MHz, CD 3 OD) δ 7.13 (t, J= 8.0 Hz, IH), 6.73 (bs, 2H), 6.68 (d, J= 8.0 Hz, 2H), 5.25 (s, IH), 3.40 (s, 3H), 3.01 (s, 3H), 2.25-2.07 (m, 2H), 0.98 (t, J= 7.2 Hz, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 167.7, 157.9, 154.7, 144.8, 139.1, 129.7, 117.3, 114.9, 113.1, 103.9, 60.3, 57.0, 32.9, 23.6, 11.3; TLC R 1 (CH 2 Cl 2 :MeOH 10:1) = 0.20.
General procedure for reduced Biginelli adducts
To a -78 °C solution of thiol ester (0.15 mmol, 1.0 equiv) in CH 2 Cl 2 (2 mL) was added DIBAL-H (1.0 M in CH 2 Cl 2 , 400 μL, 0.40 mmol, 2.7 equiv) under Argon. After 3 h at -78 0 C, the reaction was warmed to 25 "C and quenched by the addition of water (5 mL), saturated aqueous NH 4 Cl (5 mL) and extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with brine (5 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel to give reduced Biginelli adducts.
89 6-Ethyl-5-(hydroxymethyl)-4-(3-methoxyphenyl)-3,4-dihydropyr imidin-2(l//)-one (89)
1 H NMR (400 MHz, CD 3 OD) δ 7.22 (t, J= 8.0 Hz, IH), 6.90-6.86 (m, 2H), 6.82-6.80 (m, IH), 5.40 (s, IH), 4.15 (d, J= 12.0 Hz, IH), 3.75 (s, 3H), 3.57 (d, J= 12.4 Hz, IH), 2.24-2.17 (m, 2H), 1.13 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 160.3, 155.3, 145.6, 136.0, 129.5, 119.1, 133.0, 112.5, 106.9, 61.0, 56.9, 54.4, 21.9, 12.3; TLC R f (CH 2 Cl 2 MeOH 10:1) = 0.11.
90 6-Ethyl-5-(hydroxymethyl)-4-(3-hydroxyphenyl)-3,4-dihydropyr imidin-2(ljH)-one (90)
1 H NMR (400 MHz, CD 3 OD) δ 7.12 (t, J= 8.0 Hz, IH), 6.70-6.73 (m, 2H), 6.68-6.66 (m,
IH), 4.56 (s, IH), 3.95 (d, J = 11.6 Hz, IH), 3.75 (s, 3H), 3.53 (d, J= 11.6 Hz, IH), 2.24-2.22 (m, 2H), 1.12 (t, J= 7.6 Hz, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 157.7, 155.2, 145.4, 137.2, 129.4, 118.0, 114.6, 113.6, 104.1, 67.4, 57.2, 22.0, 12.2J TLC iJ 7 (CH 2 Cl 2 )MeOH 10:1) = 0.85.
General procedure for benzyl derivatives from Biginelli adducts
To a 0 °C solution of ketone (0.59 mmol, 1.0 equiv) and CeCl 3 7H 2 O (1.77 mmol, 3.0 equiv) in MeOH (5 niL) was added NaBH 4 (0.88 mmol, 1.5 equiv). The reaction temperature was warmed to 25 0 C and stirred overnight for 12 h. The reaction mixture was quenched by the addition of water (10 mL), NH 4 Cl (10 mL) and extracted with CH 2 Cl 2 (3 x 10 mL). The
combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give reduced alcohols.
To a solution of alcohol (0.059 mmol, 1.0 equiv) in EtOAc/MeOH (1 mL:l mL) added 10% Pd on carbon (72 mg) at room temperature. The reaction mixture was hydrogenated with H 2 gas (3 bar) for 1 h at 25 ° C. The resulting mixture was filtered through a pad of Celite and rinsed with EtOAc, and then concentrated in vacuo. The residue was purified via flash column chromatography (SiO 2 , EtOAc only) to give deoxygenated products.
91
6-EthyI-5-(hydroxy(phenyl)methyl)-4-(3-methoxyphenyl)-3,4 -dihydropyrimidin-2(l//)- one (91)
1 NMR (400 MHz, CD 3 OD) δ 7.09-7.06 (m, 2H), 6.96-6.88 (m, 4H), 6.58 (d, J= 7.6 Hz, IH), 6.57-6.51 (m, IH), 6.42 (t, J= 2.0 Hz, IH), 5.61 (s, IH), 4.86 (s, IH), 3.59 (s, 3H), 2.53-2.45 (m, 2H), 1.23 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 159.5, 156.1, 145.5, 142.2, 136.9, 128.9, 127.3, 126.3, 126.0, 119.1, 112.7, 112.1, 110.6, 69.5, 54.8, 54.2, 22.3, 12.3; TLC Rf (EtOAc only) = 0.10.
92 5-Benzyl-6-ethyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2( lH)-one (92)
1 H NMR (400 MHz, CD 3 OD) δ 7.26-7.09 (m, 6H), 6.82-6.79 (m, 2H), 6.57 (s, IH), 4.54 (s, IH), 3.73 (s, IH), 3.56 (d, J= 15.6 Hz, IH), 2.81 (d, J= 15.6 Hz, IH), 2.32-2.87 (m, 2H), 1.15 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 164.2, 159.2, 149.3, 143.3, 137.8,
133.5, 132.3, 132.2, 130.0, 123.1, 117.0, 116.4, 110.0, 62.0, 58.3, 37.0, 26.2, 15.9; TLC R 1 (EtOAc only) = 0.78.
93 5-Benzyl-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2( liϊ)-one (93)
1 H NMR (400 MHz, CD 3 OD) δ 7.27-7.24 (m, 2H), 7.18-7.09 (m, 4H), 6.70-6.67 (m, 3H), 4.48 (s, IH), 3.56 (d, J= 15.6 Hz, IH), 2.81 (d, J- 15.6 Hz, IH), 2.30-2.28 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 157.7, 155.3, 145.4, 139.4, 133.6, 129.4, 128.3, 128.2, 126.1, 11831, 114.6, 113.7, 106.2, 58.1, 33.0, 22.3, 12.0; TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.25.
Dihydropyrimidine analogs at C-4 phenyl position. General procedure for the deprotection of acetate group
Acetyl protected Biginelli product (9.8 μmol, 1.0 equiv) was suspended in MeOH (1 mL) and was added potassium carbonate (6.8 mg, 49 μmol, 5.0 equiv) and water (200 μL). The reaction was stirred at 25 °C for 30 min. The reaction was quenched with aqueous 2 N HCl and the mixture was extracted with CH 2 Cl 2 (3 x 5 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the crude residue was purified via flash column chromatography on silica gel.
Ethyl 6-methyl-2-oxo-4-phenyl-l ,2,3 > 4-tetrahy dropyrimidine-5-carboxylate (94)
1 U NMR (400 MHz, OMSO-Cl 6 ) δ 9.21 (bs, IH), 7.76 (bs, IH), 7.26-7.37 (m, 5H), 5.17 (s, IH), 4.01 (q, J= 7.2 Hz, 2H), 2.28 (s, 3H), 1.12 (t, J= 7.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 165.2, 152.1,148.3, 144.8, 128.3, 127.2, 126.2, 99.2, 59.1, 53.9, 17.7, 14.0.
95 Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5-carboxyIate
(95)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.18 (bs, IH), 7.65 (bs, IH), 7.18 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 8.4 Hz, 2H), 4.02 (q, J= 6.8 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.14 (t, J= 7.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 165.3, 158.4, 152.1 ,147.9, 137.0, 127.3, 113.6, 99.5, 59.1, 55.0, 53.3, 17.7, 14.0.
Ethyl 4-(3-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimid ine-5-carboxylate (96)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.21 (bs, IH), 7.76 (bs, IH), 7.28 (t, J= 7.8 Hz, IH), 6.01- 687 (m, 3H), 5.15 (s, IH), 4.04 (q, J= 7.2 Hz, 2H), 3.76 (s, 3H), 2.28 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); 13 C NMR (IOO MHZ, DMSO-J 6 ) δ 165.3, 159.1, 152.2, 148.4, 146.3, 129.5, 118.2, 112.3, 112., 99.1, 59.2, 54.9, 53.7, 17.7, 14.1.
Ethyl 4-(3-hydroxyphenyI)-6-methyl-2-oxo-l,2,3j4-tetrahydropyrimid ine-5-carboxylate
(97)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.35 (bs, IH), 9.14 (s, IH), 7.67 (s, IH), 7.09 (t, J= 8.0 Hz, IH), 6.68-6.60 (m, 3H), 5.06 (d, J= 3.6 Hz, IH), 3.99 (q, J= 6.8 Hz, 2H), 2.23 (s, 3H), 1.12 (t, J- 7.2 Hz, 3H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 165.4, 157.3, 152.2, 148.1, 146.3, 129.3, 116.9, 114.2, 113.1, 99.4, 59.2, 53.8, 17.8, 14.1.
Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5-carboxylate (98)
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.17 (d, J= 7.6 Hz, IH), 8.12 (s, IH), 7.93 (bs, IH), 7.67- 7.74 (m, 2H), 5.33 (s, IH), 4.00-4.07 (m, 2H), 2.31 (s, 3H), 1.13 (t, J= 7.0 Hz, 3H).
CyclohexyImethyl 6-methyl-2-oxo-4-phenyl-l,2,3,4-tetrahydropyrimidine-5-carbo xylate (99)
1 H NMR (400 MHz, CD 3 OD) δ 7.23-7.34 (m, 5H), 5.31 (s, IH), 3.89 (dd. J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.37 (s, 3H), 1.43-1.66 (m, 6H), 1.08-1.21 (m, 3H), 0.79- 0.87 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.6, 149.4, 145.6, 129.7, 128.8, 127.8, 101.7, 70.3, 56.7, 38.6, 30.8, 30.7, 27.4, 26.9, 18.2.
CycIohexylmethyl 4-(2-hydroxyphenyI)-6-methyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (100)
1 H NMR (400 MHz, CD 3 OD) δ 7.01 (d, J= 7.6 Hz, IH), 6.74-7.00 (m, 2H), 5.71 (bs, IH), 5.49 (s, IH), 3.90 (dd, J= 10.6, 5.8 Hz, IH), 3.68 (dd, J= 10.6, 5.8 Hz, IH), 2.40 (s, 3H), 1.57-1.62 (m, 3H), 1.29-1.44 (m, 3H), 1.02-1.18 (m, 3H), 0.69-0.79 (m, 2H).
Cyclohexylmethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimid ine-5- carboxylate (101)
1 H NMR (400 MHz, CD 3 OD) δ 7.11 (d, J= 6.8 Hz, 2H), 6.72 (d, J= 6.4 Hz, 2H), 5.22 (s, IH), 3.90 (dd, J= 10.6, 6.0 Hz, IH), 3.73 (dd, J= 10.6, 5.8 Hz, IH), 3.35 (s, IH), 2.33 (s, 3H), 1.44-1.68 (m, 6H), 1.10-1.21 (m, 3H), 0.80-0.86 (m, 2H).
Cyclohexylmethyl 4-(3-methoxyphenyl)-6-methyI-2-oxo-l,2,3 » 4-tetrahydropyrimidine-5- carboxylate (102)
1 H NMR (400 MHz, CD 3 OD) δ 7.23 (t, J= 7.8 H, IH) 6.81-6.89 (m, 2H), 5.28 (s, IH), 3.92 (dd, J= 10.8, 5.6 Hz, IH), 3.77 (s, 3H), 3.74 (dd, J= 10.8, 5.6 Hz, IH), 2.36 (s, 3H), 1.43- 1.66 (m, 6H), 1.11-1.20 (m, 3H), 0.79-0.85 (m, 2H).
Cyclohexylmethyl 6-methyl-2-oxo-4-(pyridin-3-yl)-l,2,3 > 4-tetrahydropyrimidine-5- carboxylate (103)
1 H NMR (400MHz, DMSO-J 6 ) δ 9.32 (s, IH), 8.46-8.44 (m, 2H), 7.78 (s, IH), 7.60 (d, J= 7.6 Hz, IH), 7.37 (dd, J= 7.8, 4.6 Hz, IH), 5.19 (d, J= 2.8 Hz, IH), 3.82 (dd, J= 10.6, 6.0 Hz, IH), 3.70 (dd, J= 10.6, 6.0 Hz, IH), 2.29 (s, 3H), 1.56-1.37 (m, 6H), 1.12-1.00 (m, 3H), 0.79-0.72 (m, 2H); 13 C NMR (100MHz, DMSO-J 6 ) δ 165.7, 152.4, 150.2, 149.3, 148.7, 134.6, 124.5, 98.6, 68.9, 52.8, 37.3, 29.69, 29.61, 26.4, 25.86, 25.85, 18.5.
3-(5-((CyclohexyImethoxy)carbonyl)-6-methyl-2-oxo-l,2,3,4 -tetrahydropyrimidiii-4- yl)pyridine 1-oxide (104)
1 H NMR (400 MHz, CD 3 OD) δ 8.16 (d, J= 4.0 Hz, 2H), 7.49-7.45 (m, 2H), 5.27 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J= 10.8, 6.0 Hz, IH), 2.28 (s, 3H), 1.61-1.37 (m, 6H), 1.19-1.02 (m, 3H), 0.82-0.76 (m, 2H).
105
Cyclohexylmethyl 6-ethyl-4-(4-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5- carboxylate (105)
1 H NMR (400 MHz, CD 3 OD) δ 7.12-7.09 (m, 2H), 6.74-6.70 (m, 2H), 5.22 (s, IH), 3.91 (dd, J= 11.0, 6.2 Hz, IH), 3.74 (dd, J= 11.0, 6.2 Hz, IH), 2.81-2.72 (m, 2H), 1.68-1.43 (m, 6H), 1.25-1.10 (m, 6H), 0.88-0.81 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 166.0, 157.0, 154.0, 153.2, 135.5, 127.7, 115.1, 100.1, 69.0, 54.6, 37.5, 29.51, 29.45, 26.2, 25.7, 24.4, 12.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 105a t R = 7.70 min, 105b t R = 14.51 min.
106a
(S)-Cyclohexylmethyl 4-(3-acetoxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidi ne-5- carboxylate (106a)
1 U NMR (400 MHz, CDCl 3 ) δ 7.84 (s, IH), 7.30 (t, J= 7.8 Hz, IH), 7.16 (d, J= 7.6 Hz, IH), 7.00-7.98 (m, 2H), 5.82 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 11.0, 6.2 Hz, IH), 3.78 (dd, J= 11.0, 6.2 Hz, IH), 2.83-2.78 (m, IH), 2.69-2.64 (m, IH), 2.26 (s, 3H), 1.66-1.44 (m, 6H), 1.22-1.06 (m, 6H), 0.87-0.77 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.5, 165.4, 153.4, 151.1, 145.5, 130.0, 124.1, 121.4, 120.0, 100.3, 69.7, 55.6, 37.3, 29.89, 29.87, 26.5, 25.9, 25.6, 21.4, 12.7.
107a
(S)-Cyclohexylmethyl 6-ethyl-2-oxo-4-(3-(pivaloyloxy)pb.enyl)-l,2,3 > 4- tetrahydropyrimidine-5-carboxylate (107a)
1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, IH), 7.30 (t, J= 8.0 Hz, IH), 7.14 (d, J= 8.0 Hz, IH), 6.96-6.94 (m, 2H), 5.77 (s, IH), 5.35 (d, J= 2.4 Hz, IH), 3.84-3.76 (m, 2H), 2.82-2.67 (m, 2H), 1.66-1.44 (m, 6H), 1.32 (s, 9H), 1.28-1.06 (m, 6H), 0.87-0.79 (m, 2H).
(S)-Cyclohexylmethyl 4-(3-(benzoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (108a)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J= 8.0 Hz, 2H), 7.80 (s, IH), 7.62 (t, J= 7.4 Hz, IH), 7.48 (t, J= 7.6 Hz, 2H), 7.36 (t, J= 7.8 Hz, IH), 7.20 (d, J= 8.0 Hz, IH), 7.14-7.11 (m, 2H), 5.88 (s, IH), 5.39 (d, J= 2.0 Hz, IH), 3.88 (dd, J= 11.0, 6.2 Hz, IH), 3.79 (dd, J= 11.0, 6.2 Hz, IH), 2.85-2.64 (m, 2H), 1.64-1.46 (m, 6H), 1.26-1.04 (m, 6H), 0.89-0.78 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 165.4, 165.2, 153.4, 152.3, 151.4, 145.6, 133.9, 130.4, 130.1, 129.7, 128.8, 124.2, 121.6, 120.3, 100.3, 69.7, 55.7, 37.3, 29.92, 29.88, 26.5, 25.9, 25.6, 12.7.
(S)-Cyclohexylmethyl 4-(4-acetoxyphenyl)-6-ethyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (109)
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (s, IH), 7.29 (d, J= 8.8 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 5.74 (s, IH), 5.37 (d, J= 2.4 Hz, IH), 3.87-3.78 (m, 2H), 2.81-2.67 (m, 2H), 2.27 (s, 3H), 1.68-1.44 (m, 6H), 1.23-1.06 (m, 6H), 0.87-0.78 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.6, 165.5, 153.5, 152.1, 150.5, 141.3, 127.9, 122.1, 100.6, 69.7, 55.4, 37.3, 29.9, 26.5, 25.85, 25.83, 25.6, 21.4, 12.7.
110a
(S)-CyclohexylmethyI 6-ethyl-2-oxo-4-(4-(pivaloyloxy)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (110a)
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, IH), 7.29 (d, J= 8.4 Hz, 2H), 6.99 (d, J= 8.4 Hz, 2H), 5.78 (s, IH), 5.37 (d, J= 2.0 Hz, IH), 3.81 (d, J= 6.0 Hz, 2H), 2.80-2.68 (m, 2H), 1.71-1.44 (m, 6H), 1.37-1.06 (m, 15H), 0.87-0.79 (m, 2H).
111a
(S)-Cyclohexylmethyl 4-(4-(benzoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3 j 4- tetrahydropy rimidine-5-carboxylate (Ilia)
1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J= 8.4 Hz, 2H), 7.57 (t, J= 6.8 Hz, IH), 7.44 (t, J= 7.6 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 Hz, 8.4), 5.52 (s, IH), 5.37 (s, IH), 3.84-3.77 (m, 2H), 2.77-2.66 (m, 2H), 1.67-1.47 (m, 6H), 1.21-1.03 (m, 6H), 0.82-0.76 (m, 2H).
(S)-Cyclohexylmethyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-6-ethyl-2-oxo-l,2,3 ? 4- tetrahy dropy rimidine-5-carboxylate (112a)
1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J= 8.4 Hz, 2H), 7.17-7.09 (m, 3H), 5.47 (s, IH), 5.38 (d, J= 2.4 Hz, IH), 3.87-3.78 (m, 2H), 2.81-2.68 (m, 2H), 1.74-1.45 (m, 15H), 1.24-1.03 (m, 6H), 0.86-0.78 (m, 2H).
(5)-CycIohexylmethyl 4-(4-((S)-2-(fer/-butoxycarbonylamino)propanoyloxy)phenyI)-6 - ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (113a)
1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, IH), 7.29 (d, J- 8.8 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 5.94 (s, IH), 5.36 (d, J= 2 Hz, IH), 5.13 (s, IH), 4.51 (s, IH), 3.86-3.76 (m, 2H), 2.80-2.64 (m, 2H), 1.65-1.34 (m, 18H), 1.27-1.02 (m, 6H), 0.90-0.76 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.5, 152.4, 150.3, 141.7, 127.9, 121.8, 100.4, 69.6, 55.3, 37.3, 29.9, 28.5, 26.5, 25.8, 25.5, 18.6, 12.8.
114a
(S)-Cyclohexylmethyl 4-(4-((S)-2-aminopropanoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (114a)
1 H NMR (400 MHz, CD 3 OD) δ 7.39 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 5.35 (s, IH), 4.39 (q, J= 7.2 Hz, IH), 3.90 (dd, J= 10.6, 5.8 Hz, IH), 3.78 (dd, J= 10.6, 5.8 Hz, IH), 2.85-2.71 (m, 2H), 1.71-1.45 (m, 9H), 1.26-1.10 (m, 6H), 0.90-0.82 (m, 2H); 13 C NMR (IOO
MHz, CD 3 OD) δ 168.7, 165.7, 154.1, 149.7, 143.1, 127.9, 121.3, 99.4, 69.1, 57.2, 37.4, 29.5, 26.2, 25.6, 24.5, 15.0, 12.1.
115a
(S)-Cyclohexylmethyl 6-ethyl-4-(4-(isonicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (115a)
1 U NMR (400 MHz, CDCl 3 ) δ 8.85 (bs, 2H), 8.00 (d, J= 9.2 Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 5.94 (s, IH), 5.42 (d, J= 2.4 Hz, IH), 3.89-3.79 (m, 2H), 2.83- 2.68 (m, 2H), 1.70-1.46 (m, 6H), 1.24-1.03 (m, 6H), 0.89-0.79 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.5, 163.5, 153.6, 152.4, 150.24, 150.20, 142.2, 137.7, 128.2, 123.8, 121.9, 100.4, 69.7, 55.3, 37.4, 29.9, 26.5, 25.9, 25.6, 128.
116a
(5)-CycIohexylmethyl 6-ethyl-4-(4-(nicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (116a)
1 H NMR (400 MHz, CDCl 3 ) δ 9.36 (s, IH), 8.85 (s, IH), 8.50 (d, J= 8.0 Hz, IH), 7.73 (s, IH), 7.53 (s, IH), 7.36 (d, J= 8.8 Hz, 2H), 7.15 (d, J= 8.8 Hz, 2H), 5.81 (s, IH), 5.40 (s, IH), 3.87-3.77 (m, 2H), 2.80-2.69 (m, 2H), 1.66-1.48 (m, 6H), 1.23-1.05 (m, 6H), 0.84 (m, 2H).
117
Cyclohexylmethyl 4-(3-acetoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimid ine-5- carboxylate (117)
1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, IH), 7.29 (t, J= 7.6 Hz, IH), 7.19 (dd, J= 27.4, 7.8 Hz, IH), 7.00-6.98 (m, 2H), 6.14 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 10.6, 6.2 Hz, IH), 2.33 (s, 3H), 2.26 (s, 3H), 1.65-1.44 (m, 6H), 1.25-1.05 (m, 3H), 0.86-0.77 (m, 2H).
Cyclohexylmethyl 4-(3-(benzoyloxy)phenyl)-6-methyl-2-oxo-l,2,3 » 4- tetrahydropyrimidine-5-carboxylate (118)
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, IH), 8.17 (d, J= 8.4 Hz, 2H), 7.64-7.60 (m, IH), 7.49 (t, J= 7.8 Hz, 2H), 7.35 (t, J= 7.8 Hz, IH), 7.26-7.11 (m, 3H), 6.37 (s, IH), 5.40 (d, J= 2.4 Hz, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 2.34 (s, 3H), 1.64- 1.49 (m, 6H), 1.65-1.05 (m, 3H), 0.88-0.80 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.9, 165.2, 154.0, 151.4, 147.3, 145.6, 133.9, 130.4, 130.1, 129.7, 129.3, 128.8, 128.5, 124.3, 121.6, 120.2, 101.0, 69.7, 55.5, 37.3, 29.9, 26.5, 25.9, 18.9.
119
Cyclohexylmethyl 6-methyl-2-oxo-4-(3-(pivaloyloxy)phenyl)-l,2,3j4- tetrahydropyrimidine-5-carboxylate (119)
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, IH), 7.30-7.22 (m, IH), 7.16-7.14 (m, IH), 6.96-6.93 (m, 2H), 6.25 (s, IH), 5.34 (d, J= 2.8 Hz, IH), 3.85 (dd, J- 10.6, 6.2 Hz, IH), 3.77 (dd, J = 10.6, 6.2 Hz, IH), 2.33 (s, 3H), 1.66-1.45 (m, 6H), 1.33-1.06 (m, 12H), 0.87-0.79 (m, 2H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 177.1, 165.8, 153.8, 151.4, 147.2, 145.5, 129.9, 124.0, 121.3, 120.0, 100.9, 69.6, 55.6, 39.3, 37.3, 29.91, 29.88, 27.4, 26.5, 25.9, 18.8.
120a
(S)-Cyclohexylmethyl 4-(3-(te^-butoxycarbonyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (120a)
To a mixture of 2a (10 mg, 0.028 mmol, 1.0 equiv) in CH 2 Cl 2 (0.5 mL) was added DIPEA (7.3 μL, 0.042 mmol, 2.0 equiv), (Boc) 2 O (7.3 mg, 0.034 mmol, 1.2 equiv), and DMAP (1.7 mg, 0.014 mmol, 0.5 equiv), and the reaction mixture was stirred for 3 h at 0 0 C. The mixture was diluted with CH 2 Cl 2 (5 mL), washed with water (1 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH/CH 2 Cl 2 ) to afford 120 (6.9mg, 54%): 1 H NMR (400 MHz, CD 3 OD) δ 7.33 (t, J = 8.0 Hz, IH), 7.18 (d, J = 7.6 Hz, IH), 7.03 (m, 2H), 5.30 (s, IH), 3.88 (dd, J= 10.8, 6.2 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 2.76 (q, J = 7.6 Hz, 2H), 1.66-1.43 (m, 15H), 1.27-1.11 (m, 6H), 0.93-0.81 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.1, 155.5, 155.2, 153.4, 153.0, 147.5, 130.9, 125.0, 121.7, 120.8, 100.7, 84.5, 70.5, 56.0, 38.7, 30.9, 28.0, 27.5, 27.0, 25.8, 13.4.
(5)-CyclohexyImethyl 6-ethyl-4-(3-(isonicotinoyloxy)phenyI)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (121a)
1 H NMR (400 MHz, CDCl 3 ) δ 8.85 (d, J = 5.2 Hz, 2H), 7.97 (d, J = 5.2 Hz, 2H), 7.56 (s, IH), 7.37 (t, J = 7.6 Hz, IH), 7.26 (s, IH), 7.15 (t, J = 7.2 Hz, 2H), 5.73 (s, IH), 5.41 (d, J = 2.8 Hz, IH), 3.89 (dd, J = 10.8, 6.0 Hz, IH), 3.81 (dd, J = 10.6, 6.2 Hz, IH), 2.83 (m, IH), 2.69 (m, IH), 1.65-1.50 (m, 6H), 1.55-1.03 (m, 6H), 0.86-0.80 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.4, 163.8, 153.1, 152.3, 151.1, 145.9, 137.0, 130.3, 124.7, 123.4, 121.2, 119.9, 100.3, 68.8, 55.7, .37.4, 29.92, 29.90, 26.5, 25.9, 25.7, 12.7.
(S)-Cyclohexylmethyl 6-ethyl-4-(3-(nicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (122a)
1 H NMR (400 MHz, CDCl 3 ) δ 9.38 (t, J = 1.0 Hz, IH), 8.86 (d, J = 5.2 Hz, IH), 8.43 (d, J = 8.0 Hz, IH), 7.77 (bs, IH), 7.47 (dd, J = 8.0, 4.8 Hz, IH), 7.40 (t, J = 7.8 Hz, IH), 7.25 (d, J = 8.0 Hz, IH), 7.17 (m, 2H), 5.85 (bs, IH), 5.42 (d, J = 2.8 Hz, IH), 3.90 (dd, J = 11, 6.2 Hz, IH), 3.82 (dd, J = 10.6, 6.2 Hz, IH), 2.83 (m, IH), 2.70 (m, IH), 1.67-1.51 (m, 6H), 1.31- 1.07 (m, 6H), 0.88-0.81 (m, 2H).
(5)-Cyclohexylmethyl 4-(3-((5)-2-(tert-butoxycarbonylamino)propanoyloxy)phenyl)-6 - ethyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5-carboxylate (123a)
To a mixture of 2a (20 mg, 0.056 mmol, 1.0 equiv) in CH 2 Cl 2 (0.5 niL) was added Boc-L- alanine (18 mg, 0.095mmol, 1.7 equiv), DIPEA (24.3 μL, 0.14mmol, 2.5 equiv), EDC (13.9 mg, 0.073mmol, 1.3 equiv), and DMAP (3.4 mg, 0.028mmol, 0.5 equiv), and the reaction mixture was stirred for 4 h at 35 °C. The resulting mixture was diluted with CH 2 Cl 2 (5 mL), washed with water (1 mL), dried over MgSO 4 , filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC (5% MeOH/ CH 2 Cl 2 ) to afford 123 (13.1 mg, 44%): 1 H NMR (400 MHz, CD 3 OD) δ 7.35 (t, J = 7.8 Hz, IH), 7.19 (d, J = 7.6 Hz, IH), 7.02 (t, J = 8.2 Hz, 2H), 5.30 (s, IH), 4.31 (q, J = 7.6 Hz, IH), 3.88 (dd, J = 10.4, 6.0 Hz, IH), 3.74 (dd, J = 10.4, 5.6 Hz, IH), 2.77 (m, 2H), 1.65-1.39 (m, 18H), 1.31-1.07 (m, 6H), 0.86-0.78 (m, 2H).
(S)-Cyclohexylmethyl 4-(3-((<S)-2-aminopropanoyloxy)phenyl)-6-ethyl-2-oxo-l,2, 3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (124a)
1 H NMR (400 MHz, CD 3 OD) δ 7.32 (t, J = 7.6 Hz, IH), 7.18 (d, J = 7.6 Hz, IH), 7.02 (d, J = 8.0 Hz, 2H), 5.26 (s, IH), 4.30 (q, J = 6.8 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J = 10.8, 6.0 Hz, IH), 2.73 (m, IH), 2.62 (m, IH), 1.64-1.36 (m, 9H), 1.22-0.99 (m, 6H), 0.79-0.72 (m, 2H).
Cyclohexylmethyl 6-ethyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine -5- carboxylate (125)
1 H NMR (400 MHz, CD 3 OD) δ 8.19 (d, J= 7.2 Hz, 2H), 7.53 (d, J= 7.2 Hz, 2H), 5.40 (s, IH), 3.88 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.6, 6.2 Hz, IH), 2.86-2.67 (m, 2H), 1.61- 1.39 (m, 6H), 1.26-1.05 (m, 6H), 0.84-0.75 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.5, 161.6, 154.7, 151.5, 148.2, 147.6, 127.8, 123.7, 98.6, 69.1, 54.6, 37.4, 29.52, 29.47, 26.1, 25.58, 25.54, 24.5, 12.1.
Cyclohexylmethyl 4-(4-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine -5- carboxylate hydrochloride (126)
1 H NMR (400 MHz, CD 3 OD) δ 7.46 (d, J= 11.2 Hz, 2H), 7.35 (d, J= 11.2 Hz, 2H), 5.35 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 2.84-2.68 (m, 2H), 1.68- 1.45 (m, 6H), 1.24-1.01 (m, 6H), 0.90-0.80 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.7, 154.4, 153.7, 145.7, 130.2, 128.4, 123.1, 99.1, 69.2, 54.4, 37.4, 29.57, 29.54, 26.2, 25.6, 24.5, 12.1.
127
Cyclohexylmethyl 4-(4-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine -5- carboxylate (127)
1 H NMR (400 MHz, CD 3 OD) δ 7.00 (d, J= 8.4 Hz, 2H), 6.64 (d, J= 8.4 Hz, 2H), 5.16 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.73 (dd, J= 10.8, 6.0 Hz, IH), 2.77-2.70 (m, 2H), 1.67- 1.45 (m, 6H), 1.22-1.09 (m, 6H), 0.88-0.81 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.1, 154.1, 152.9, 147.3, 142.1, 134.0, 127.4, 115.3, 100.2, 69.0, 57.1, 54.7, 37.4, 29.54, 29.51, 26.2, 25.7, 24.4, 17.2, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in fl-Hexanes, 0.85 mL/min): 127a t R = 20.0 min, 127b t R = 50.0 min.
128
CyclohexyImethyl 6-ethyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine -5- carboxylate (128)
1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, IH), 8.14 (s, IH), 8.11 (d, J= 8.4 Hz, IH), 7.63 (d, J= 7.6 Hz, IH), 7.48 (t, J= 7.6 Hz, IH), 6.37 (s, IH), 5.47 (s, IH), 3.82 (m, 2H), 2.55 (m, 2H), 1.62-1.44 (m, 6H), 1.24-1.03 (m, 6H), 0.85-0.76 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.2, 149.7, 149.3, 144.7, 142.0, 129.0, 126.2, 119.2 118.0, 95.7, 65.9, 51.3, 33.3, 26.0, 22.5, 21.8, 21.6, 8.9.
Cyclohexylmethyl 4-(3-aminophenyl)-6-ethyl-2-oxo-l,2,3 5 4-tetrahydropyrimidine-5- carboxylate hydrochloride (129)
1 H NMR (400 MHz, CD 3 OD) δ 7.50 (t, J= 7.8 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.36 (s, IH), 7.30 (d, J= 8.0 Hz, IH), 5.73 (s, IH), 4.08 (dd, J= 14.4, 7.2 Hz, IH), 3.83 (m, IH), 2.84 (m, IH), 2.69 (m, IH), 1.67-1.46 (m, 6H), 1.24-1.09 (m, 6H), 0.90-0.80 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 169.6, 158.4, 157.6, 151.2, 135.1, 134.4, 131.6, 126.2, 124.9, 103.0, 73.2, 58.5, 41.3, 33.52, 33.49, 30.1, 29.5, 28.5, 16.1.
130
Cyclohexylmethyl 4-(3-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine -5- carboxylate (130)
1 H NMR (400 MHz, CD 3 OD) δ 7.03 (t, J= 7.6 Hz, IH), 6.67-6.60 (m, 3H), 5.20 (s, IH), 3.89
(dd, J= 10.4, 6.0 Hz, IH), 3.75 (dd, J= 10.4, 6.0 Hz, IH), 2.84-2.68 (m, 2H), 1.67-1.49 (m,
6H), 1.29-1.10 (m, 6H), 0.90-0.85 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.0, 154.0,
153.4, 148.0, 145.1, 129.1, 116.3, 114.8, 113.4, 99.7, 69.0, 55.2, 37.4, 29.54, 29.49, 26.2,
25.7, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in n-Hexanes, 0.85 mL/min) : 130a t R = 16.93 min, 1303b t R = 40. ,77 min.
131
Cyclohexylmethyl 4-(3-aminophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyriinidi ne-5- carboxylate (131)
Cyclohexylmethyl 4-6-methyl-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidin e-5- carboxylate was synthesized by the Biginelli reaction: 1 H NMR (400 MHz, DMSO-^ 6 ) δ 9.41 (bs, IH), 8.19 (d, J= 7.2 Hz, IH), 8.11 (bs, IH), 7.89 (bs, lH)m 7.69-7.75 (m, 2H), 5.33 (d, J = 2.8 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J= 10.8, 6.0 Hz, IH), 2.34 (s, 3H), 1.37-1.60 (m, 6H), 1.00-1.15 (m, 3H), 0.72-0.83 (m, 2H); 13 C NMR (100 MHz, DMSO-<4) δ 164.6, 151.2, 149.5, 147.3, 146.5, 132.7, 130.0, 122.1, 120.8, 97.5, 67.9, 53.3, 38.5, 36.3, 28.7, 28.6, 25.3, 24.8, 24.7, 17.4.
To a mixture of the above nitro compounds (100 mg, 0.27 mmol) in MeOH (3 mL) was added 10% Pd on carbon (7 mg), and the reaction mixture was stirred for 3 h at room temperature under hydrogen balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to give 131 (86 mg, 93%) as a white solid: 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (bs, IH), 6.65 (d, J= 7.2 Hz), 6.59 (s, IH), 6.55 (d, J= 8.0 Hz, IH), 5.98 (bs, IH), 5.25 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 3.26 (bs, 2H), 2.31 (s, 3H), 1.03-1.64 (m, 9H), 0.81-0.85 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.9, 153.7, 146.6, 144.9, 129.7, 117.0, 114.9, 113.3, 101.1, 69.4, 55.6, 37.2, 28.8, 26.7, 26.4, 25.8, 18.7.
132
Cyclohexylmethyl 6-ethyl-4-(4-(methylamino)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (132)
1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (s, IH), 7.08 (d, J= 6.8 Hz, 2H), 6.54 (d, J= 6.8 Hz, 2H),
5.82 (s, IH), 5.25 (s, IH), 3.85-3.74 (m, 2H), 2.83 (s, 3H), 2.79-2.68 (m, 2H), 1.64-1.47 (m,
6H), 1.27-1.05 (m, 6H), 0.85-0.77 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.7, 154.0,
151.2, 148.7, 133.3, 127.8, 113.1, 101.2, 69.5, 55.5, 37.4, 31.2, 29.9, 26.5, 25.9, 25.4, 21.1,
12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in rc-Hexanes, 0.85 mL/min): 132a t R = 12.2 min, 132b t R = 27.2 min.
Cyclohexylmethyl 4-(4-(dimethylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (133)
1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (bs, IH), 7.14 (d, J= 8.4 Hz, 2H), 6.63 (d, J= 8.4 Hz, 2H), 5.44 (bs, IH), 5.27 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.90 (s, 6H), 2.68-2.79 (m, IH), 1.41-1.66 (m, 6H), 1.07-1.23 (m, 6H), 0.78-0.92 (m, 2H).
Cyclohexylmethyl 6-ethyl-4-(4-(ethylamino)phenyl)-2-oxo-l,2,3,4-tetrahydropyr imidine- 5-carboxylate (134)
1 U NMR (400 MHz, CDCl 3 ) δ 7.81 (s, IH), 7.07 (d, J= 8.4 Hz, 2H), 6.50 (d, J= 8.4 Hz, 2H), 5.55 (s, IH), 5.24 (d, J = 2.4 Hz, IH), 3.84 (dd, J= 11.0, 6.2 Hz, IH), 3.77 (dd, J= 11.0, 6.2 Hz, IH), 3.11 (q, J= 7.2 Hz, 2H), 2.77-2.66 (m, 2H), 1.66-1.44 (m, 6H), 1.28-1.06 (m, 9H), 0.88-0.78 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 165.8, 153.6, 151.3, 148.3, 132.8, 127.8, 112.9, 101.1, 69.4, 55.6, 38.7, 37.4, 29.9, 26.5, 25.92, 25.91, 25.5, 15.0, 12.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 134a t R = 9.9 min, 134b t R = 24.9 min.
135
Cyclohexylmethyl 6-ethyl-4-(3-(methylamino)phenyl)-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate (135)
To a stirred solution of 130 (50.0 mg, 0.14 mmol) in CH 2 C1 2 /DMF (3:1, 0.40 niL) were added /-Pr 2 NEt (24.0 μL, 0.14 mmol) and MeI (9.00 μL, 0.14 mmol) at 0 0 C. The mixture was allowed to warm to room temperature and stirred for 12 h. The resulting mixture was diluted with CH 2 Cl 2 (10 mL), washed with brine (3 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 135 (20.6 mg, 42%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (bs, IH), 7.10 (t, J- 7.6 Hz, IH), 6.61 (d, J= 7.2 Hz, IH) 5 6.46-6.50 (m, 2H), 5.68 (bs, IH), 5.28 (s, IH), 3.84 (dd. J= 10.8, 6.2 Hz, IH) 5 3.76 (dd, J= 10.8, 6.2 Hz, IH), 2.78 (s, 3H), 2.76 (q, J= 7.6 Hz, 2H), 1.46-1.66 (m, 6H), 1.02-1.64 (m, 8H), 0.81-0.86 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 0.8 mL/min): 135a t R = 16.0 min, 135b t R = 30.6 min.
Cyclohexylmethyl 6-ethyl-4-(3-(ethylamino)phenyl)-2-oxo-l,2,3 5 4-tetrahydropyrimidine- 5-carboxylate (136)
To a mixture of 130 (50.0 mg, 0.14 mmol), acetaldehyde (7.80 μL, 0.14 mmol) and AcOH (16.0 μL, 0.28 mmol) in CH 2 Cl 2 (0.5 mL) was added NaBH(OAc) 3 (41.5 mg, 1.4 mmol), and the resulting mixture was stirred at room temperature for 12 h under Argon. After quenching with saturated NaHCO 3 (5 mL), the mixture was extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 136 (42 mg, 78%) as a white solid: 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (bs, IH), 7.08 (t, J= 7.8 Hz, IH), 6.59 (d, J= 7.6 Hz, IH), 6.47 (d, J= 8.4 Hz, 2H), 5.74 (bs, IH), 5.28 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 3.10 (q, J= 10.6 Hz, 2H), 2.74 (q, J= 10.8 Hz, 2H), 2.00-2.04 (m, 2H), 1.05-1.64 (m, 13H), 0.76-0.90 (m, 4H).
Cyclohexylmethyl 6-ethyl-2-oxo-4-(3-(propylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (137)
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (bs, IH), 7.21 (bs, IH), 7.04 (t, J= 7.6 Hz, IH), 6.55 (d, J = 7.6 Hz, IH), 6.42-6.45 (m, 2H), 5.73 (bs, IH), 5.22 (s, IH) 3.82 (dd, J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.99 (t, J= 6.8 Hz, 2H), 2.64-2.72 (m, 2H), 1.45-1.59 (m, 6H), 1.02-1.21 (m, 9H), 0.93 (t, J= 7.4 Hz, 3H), 0.79-0.83 (m, 2H); 13 C NMR (100 MHz,
CDCl 3 ) δ 165.6, 153.8, 151.9, 128.9, 144.7, 129.7, 115.3, 112.1, 110.8, 100.3, 69.3, 55.9, 45.8, 37.3, 29.7, 26.4, 25.8, 25.3, 22.8, 12.7, 11.7.
138
Cyclohexylmethyl 4-(4-(diethylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (138)
1 U NMR (400 MHz, CDCl 3 ) δ 8.19 (s, IH), 7.10 (d, J= 8.4 Hz, 2H), 6.56 (d, J= 8.4 Hz, 2H), 5.75 (s, IH), 5.25 (d, J- 2.4 Hz, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 3.30 (q, J= 7.2 Hz, 2H), 2.78-2.67 (m, 2H), 1.65-1.45 (m, 6H), 1.23-1.05 (m, 12H), 0.87-0.79 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 172.2, 161.9, 150.1, 147.5, 143.7, 126.8, 123.9, 107.9, 97.1, 65.5, 51.4, 40.6, 33.5, 25.9, 22.6, 22.0, 21.5, 17.3, 8.9. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 0.80 mL/min): 138a t R = 7.2 min, 138b ^ = 13.0 min.
139
Cydohexylmethyl 6-ethyI-2-oxo-4-(4-(propylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (139)
1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (s, IH), 7.06 (d, J= 8.4 Hz, 2H), 6.52 (d, J= 8.4 Hz, 2H), 5.73 (s, IH), 5.24 (d, J= 2.8 Hz, IH), 3.84 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J = 10.8, 6.0 Hz, IH), 3.03 (t, J= 12 Hz, 2H), 2.77-2.66 (m, 2H), 1.65-1.45 (m, 8H), 1.28-1.06 (m, 6H), 0.98-0.78 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.8, 153.9, 151.5, 147.9, 133.1, 127.8, 113.2, 101.0, 69.4, 55.5, 46.3, 37.4, 31.8, 29.9, 26.5, 25.9, 25.5, 22.9, 22.8, 14.3, 12.8, 11.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10-30 % /-PrOH in rc-Hexanes gradient, 0.85-1.0 mL/min): 139a t R = 17.8 min, 139b t R = 33.3 min.
140
Cyclohexylmethyl 4-(4-(benzylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (140)
1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, IH), 7.33-7.24 (m, 5H), 7.07 (d, J= 7.6 Hz, 2H), 6.67 (d, J= 7.6 Hz, 2H), 5.82 (s, IH), 5.24 (d, J= 2.4 Hz, IH), 4.30 (s, 2H), 3.85-3.76 (m, 2H), 2.79-2.69 (m, 2H), 1.66-1.44 (m, 6H), 1.28-1.06 (m, 6H), 0.86-0.81 (m, 2H).
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-(pentylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (141)
1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (bs, IH), 7.06 (d, J= 8.0 Hz, 2H), 6.49 (d, J= 8.0 Hz, 2H), 5.55 (bs, IH), 5.28 (bs, IH), 5.23 (s, IH), 3.84 (dd, J= 10.6, 5.8 Hz, IH), 3.77 (dd, J = 10.8, 6.4 Hz, IH), 3.05 (t, J= 7.2 Hz, 2H), 2.67-2.78 (m, 2H), 0.82-1.65 (m, 23H).
142
Cyclohexylmethyl 6-ethyl-4-(4-(octylamino)phenyl)-2-oxo-l,2,3 ? 4-tetrahydropyrimidine- 5-carboxylate (142)
1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (bs, IH), 7.06 (d, J= 8,4 Hz, 2H), 6.49 (d, J= 8.4 Hz, 2H), 5.27 (bs, IH), 5.24 (s, IH), 3.84 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 3.05 (t, J= 7.2 H, 2H), 2.70-2.74 (m, 2H), 0.81-1.65 (m, 29H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.7, 153.8, 151.2, 148.4, 132.4, 127.7, 112.7, 101.3, 69.3, 55.4, 44.1, 37.3, 31.9, 29.8, 29.6, 29.5, 27.2, 26.4, 25.8, 25.3, 22.7, 14.2, 12.6.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 142a ϊ R = 5.4 min, 142b fø = 7.8 min. oc
143
Cyclohexylmethyl 4-(4-(5-(tert-butoxycarbonylamino)pentylamino)phenyl)-6-ethy l-2- oxo-1 ,2,3 5 4-tetrahy dropy rimidine-5-carboxylate (143)
1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (bs, IH), 7.04 (d, J= 8.0 Hz, 2H), 6.48 (d, J= 8.0 Hz, 2H), 5.93 (s, IH), 5.25 (s, IH), 4.59 (s, IH), 3.84-3.73 (m, 2H), 3.19-3.03 (m, 4H), 2.85-2.62 (m, 2H), 1.63-1.34 (m, 16H), 1.27-1.02 (m, 8H), 0.98-0.77 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.8, 156.3, 154.1, 151.7, 148.1, 133.0, 129.2, 128.4, 127.8, 125.5, 113.0, 100.9, 79.3, 69.4, 55.4, 44.1, 40.6, 37.4, 30.1, 29.9, 29.2, 28.6, 26.5, 25.9, 25.4, 24.5, 21.3, 14.3, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 40% z-PrOH in «-Hexanes gradient, 6.5 mL/min): 143a t R = 38.5 min, 143b t R = 69.2 min.
Cyclohexylmethyl 4-(4-(5-aminopentylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (144)
1 H NMR (400 MHz, CD 3 OD) δ 7.53 (d, J= 9.2 Hz, 4H), 5.38 (s, IH), 3.88 (dd, J- 10.8, 6.0 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.40 (t, J= 7.4 Hz, 2H), 2.95 (t, J= 7.0 Hz, 2H), 2.86-2.80 (m, IH), 2.77-2.70 (m, IH), 1.81-1.51 (m, 12H), 1.25-1.11 (m, 6H), 0.92-0.84 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.6, 154.5, 153.7, 146.4, 135.0, 128.6, 122.9, 99.0, 69.2, 54.4, 51.8, 39.2, 37.4, 29.58, 29.55, 26.8, 26.2, 25.6, 25.4, 24.5, 23.2, 12.2.
Cyclohexylmethyl 4-(4-acetamidophenyl)-6-ethyI-2-oxo-l,2,3,4-tetrahydropyrimi dine-5- carboxylate (145)
1 H NMR (400 MHz, CD 3 OD) δ 7.50 (d, J= 8.8 Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 5.27 (s, IH), 3.90 (dd, J= 10.8, 5.6 Hz, IH), 3.75 (dd, J= 10.8, 5.6 Hz, IH), 2.75-2.80 (m, 2H), 2.10 (s, 3H), 1.45-1.67 (m, 6H), 1.13-1.23 (m, 6H), 0.82-0.85 (m, 2H); 13 C NMR (I OO MHZ, CDCl 3 ) δ 171.7, 167.1, 155.2, 154.9, 141.4, 139.6, 128.2, 121.3, 100.9, 70.3, 55.9, 38.7, 30.7, 26.9, 25.7, 23.9, 13.4.
146
Cyclohexylmethyl 4-(4-butyramidophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrim idine- 5-carboxyIate (146)
1 H NMR (400 MHz, CD 3 OD) δ 7.52 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 5.27 (s, IH), 3.92 (dd, J= 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.74-2.80 (m, 2H), 2.33
(t, J= 7.4 Hz, 2H), 1.43-1.74 (m, 4H), 1.23 (t, J= 7.4 Hz, 3H), 1.11-1.19 (m 3H), 0.99 (t, J= 7.4 Hz, 3H), 0.80-0.84 (m, 2H).
147
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-propionamidophenyl)-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate(147)
To a stirred solution of 127 (50 mg, 0.14 mmol, 1.0 equiv) in CH 2 Cl 2 (0.3 ml) was added i- Pr 2 NEt (27.0 μL, 0.15 mmol, 1.07 equiv) and propionyl chloride (9.0 μL, 0.154 mmol, 1.1 equiv) at 0 0 C. After stirring for 1 h at 0 °C, the mixture was diluted with CH 2 Cl 2 (30 mL), washed with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 147 (52.6 mg, 99 %): 1 H NMR (400 MHz, CD 3 OD) δ 7.51 (d, J= 8.8 Hz, 2H), 7.24 (d, J= 8.8 Hz, 2H), 5.27 (s, IH), 3.90 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.73-2.81 (m, 2H), 2.37 (q, J= 8.0 Hz, 2H), 1.44-1.66 (m, 6H), 1.09-1.25 (m, 9H), 0.80-0.85 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% i-PrOH in «-Hexanes gradient, 0.8 niL/min): 147a t R = 1st band, 147b t R = 2nd band.
148
CyclohexyImethyl 6-ethyl-2-oxo-4-(4-pentanamidophenyl)-l,2,3,4-tetrahydropyri midine- 5-carboxylate (148)
1 H NMR (400 MHz, DMSO-J 6 ) δ 10.00 (s, IH), 9.16 (s, IH), 7.64 (s, IH), 7.54 (d, J= 8.4 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 5.07 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.6, 6.2 Hz, IH), 3.70 (dd, J= 10.6, 6.2 Hz, IH), 2.73-2.60 (m, 2H), 2.29 (t, J= 7.4 Hz, 2H), 1.58-0.98 (m, 16H), 0.92-0.76 (m, 5H); 13 C NMR (100 MHz, DMSO-J 15 ) δ 171.9, 165.6, 154.7, 152.9, 139.9, 139.2, 127.2, 119.6, 98.9, 68.8, 54.2, 37.4, 36.7, 29.71, 29.65, 28.0, 26.4, 25.9, 24.7, 22.4, 14.4, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% /-PrOH in n-Hexanes gradient, 0.8 mL/min): 148a t R = 1st band, 148b t R = 2nd band.
149
Cyclohexylmethyl 6-ethyl-4-(4-octanamidophenyl)-2-oxo-l,2,3,4-tetrahydropyrim idine- 5-carboxylate (149)
1 H NMR (400 MHz, DMS-J 15 ) δ 9.84 (s, IH), 9.15 (s,lH), 7.62 (s, IH), 7.51 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 5.07 (d, J= 3.2 Hz, IH), 3.81 (dd, J= 10.6, 6.2 Hz, IH), 3.70 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.60 (m, 2H), 2.26 (t, J= 7.4 Hz, 2H), 1.56-1.01 (m, 22H), 0.99-0.73 (m, 5H); 13 C NMR (IOO MHz, DMSO-J 6 ) δ 171.8, 165.6, 154.7, 152.9, 139.9, 139.2, 127.2, 119.6, 98.8, 68.8, 54.3, 37.4, 37.0, 31.9, 29.71, 29.65, 29.3, 29.1, 26.5, 25.9, 25.8, 24.7, 22.7, 14.6, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% i-PrOH in rc-Hexanes gradient, 0.8 mL/min): 149a t R = 1st band, 149b t R = 2nd band.
Cyclohexylmethyl 4-benzyl-6-ethyI-2-oxo-l,2,3 > 4-tetrahydropyrimidine-5-carboxylate (150)
1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, IH), 7.30-7.15 (m, 5H), 5.40 (s, IH), 4.47-4.44 (m, IH), 3.97 (d, J= 6.0 Hz, 2H), 2.93 (dd, J= 13.2, 3.2 Hz, IH), 2.75-2.69 (m, 2H), 2.64-2.57 (m, IH), 1.79-1.65 (m, 6H), 1.33-0.86 (m, 8H); 13 C NMR (IOOMHZ, CDCl 3 ) δ 165.8, 154.6, 153.1, 137.1, 130.0, 128.9, 127.1, 100.5, 69.8, 53.7, 43.3, 37.7, 30.31, 30.27, 26.7, 26.0, 25.5, 12.8.
151
Cyclohexylmethyl 4-(4-cyanophenyI)-6-ethyl-2-oxo-l,2,3 5 4-tetrahydropyrimidine-5- carboxylate (151)
1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (bs, IH), 7.60 (d, J= 8.4Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 6.58 (bs, IH), 5.42 (d, J= 3.2 Hz, IH), 3.88 (dd, J= 10.6, 6.2 Hz, IH), 3.82 (dd, J= 10.6, 6.2Hz, IH), 2.80 (m, IH), 2.67 (m, IH), 1.65-1.47 (m, 6H), 1.27-1.07 (m, 6H), 0.83 (m, 2H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 165.2, 153.9, 153.1, 148.8, 132.8, 127.5, 118.6, 111.9, 99.5, 69.7, 55.3, 37.2, 29.8, 26.3, 25.7, 25.4, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 15% /-PrOH in «-Hexanes, 6.5 mL/min): 151a fa = 22.1 min, 151b fa = 26.9 min.
4-(5-((Cyclohexylmethoxy)carbonyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidin-4- yl)benzoic acid (152)
To a solution of benzyl ester 156 (100 mg, 0.21 mmol, 1.0 equiv) in MeOH (3 mL) was added 10% Pd on carbon (10 mg) at room temperature. The reaction mixture was hydrogenated with H 2 gas (3 bar) for 3 h at 25 °C. The mixture was filtered through a plug of Celite and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
to give acid 152 (70 mg, 86%) as a white solid: 1 H NMR (400 MHz, OMSO-d 6 ) δ 9.29 (bs, IH), 7.92 (d, J= 8.0 Hz, 2H), 7.79 (bs, IH), 7.32 (d, J= 8.0 Hz, 2H), 5.21 (s, IH), 3.87 (dd, J = 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.77-2.82 (m, IH), 2.63-2.68 (m, IH), 1.42-1.61 (m, 6H), 1.08-1.19 (m, 6H), 0.80-0.83 (m, 2H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 164.7, 154.7, 152.0, 149.1, 129.6, 126.4, 97.5, 68.2, 53.8, 36.6, 29.0, 28.9, 25.7, 25.1, 24.0, 13.0.
Cyclohexylmethyl 6-ethyl-4-(4-(methoxycarbonyl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (153)
1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 5.37 (s, IH), 3.90 (s, 3H), 3.31-3.89 (m. 2H), 2.81-2.83 (m, IH), 2.73-2.75 (m, IH), 1.43-1.65 (m, 6H), 1.24 (t, J= 7.6 Hz, 3H), 1.10-1.23 (m, 3H), 0.79-0.82 (m 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.3, 166.9, 155.6, 154.9, 150.8, 131.1, 130.7, 128.0, 100.3, 79.6, 79.3, 78.9, 70.4, 56.1, 52.7, 38.6, 30.8, 30.7, 27.4, 26.9, 26.8, 25.8, 13.4.
Cyclohexylmethyl 4-(4-(ethoxycarbonyl)phenyl)-6-ethyl-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxyIate (154)
1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J= 8.0 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.01 (bs, IH), 5.41 (s, IH), 4.34 (q, J= 6.8 Hz, 2H), 3.75-3.84 (m, 2H), 2.69-2.78 (m, 2H), 1.04-1.60 (m, 15H), 0.77-0.81 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.3, 165.2, 153.5, 152.5, 148.4, 130.2, 126.6, 99.9, 69.5, 61.1, 55.5, 37.2, 29.7, 26.3, 25.7, 25.4, 14.4, 12.6.
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-(propoxycarbonyl)phenyl)-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate (155)
1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J= 8.0 Hz, 2H), 7.24 (d, J= 8.0 Hz, 2H), 5.28 (s, IH), 3.91 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.72-2.83 (m, 2H) , 2.37 (q, J = 7.6 Hz, 2H), 1.53 -1.64 (m, 7H), 1.09-1.48 (m, HH), 0.78-0.90 (m, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 175.4, 167.2, 154.9, 155.1, 154.9, 141.3, 139.7, 128.2, 121.3, 101.0, 70.3, 55.9, 38.7, 31.1, 30.9, 30.8, 27.4, 26.9, 25.7, 13.4, 10.3.
Cyclohexylmethyl 4-(4-(benzyloxycarbonyl)phenyl)-6-ethyl-2-oxo-l,2,3 > 4- tetrahydropyrimidine-5-carboxylate (156)
1 H NMR (400 MHz, CDCl 3 ) 5 8.01 (d, J= 8.0 Hz, 2H), 7.86 (bs, IH), 7.31-7.41 (m, 7H), 5.81 (bs, IH), 5.41 (s, IH), 5.33 (s, 2H), 3.78-3.83 (m, 2H), 2.72-2.76 (m, 2H), 1.42-1.60 (m, 3H), 1.21 (t, J= 6.8 Hz, 3H), 1.07-1.18 (m, 3H), 0.76-0.81 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 166.0, 165.2, 153.2, 152.4, 148.6, 136.1, 130.4, 129.9, 128.7, 128.2, 126.7, 99.9, 69.5, 66.8, 55.6, 37.2, 29.7, 26.3, 25.7, 25.4, 12.6.
Cyclohexylmethyl 6-ethyl-4-(3-(methoxycarbonyl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (157)
1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, IH), 7.94-7.90 (m, 2H), 7.48 (dd, J= 4.6, 3.4 Hz, IH), 7.37 (t, J= 7.8, IH), 5.96 (s, IH), 5.41 (d, J= 2.4 Hz, IH), 3.82 (dd, J= 10.6, 6.2 Hz, IH), 3.75 (dd, J= 11.0, 6.2 Hz, IH), 2.82-2.70 (m, 2H), 1.62-1.40 (m, 6H), 1.24-1.02 (m, 6H), 0.81-0.72 (m, 2H); 13 C NMR (100MHz, CDCl 3 ) δ 166.9, 165.3, 153.5, 152.8, 144.3, 131.3, 130.8, 129.4, 129.2, 128.1, 100.0, 69.6, 55.7, 52.4, 37.3, 29.8, 26.4, 25.8, 25.5, 12.7.
3-(5-((Cyclohexylmethoxy)carbonyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidin-4- yl)benzoic acid (158)
1 U NMR (400 MHz, CD 3 OD) δ 8.00 (s, IH), 7.93 (d, J= 7.6 Hz, IH), 7.55 (d, J= 7.6 Hz, IH), 7.45 (t, J= 7.8 Hz, IH), 5.37 (s, IH), 3.91 (dd, J= 10.6, 6.2 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.84-2.77 (m, 2H), 1.65-1.42 (m, 6H), 1.39-1.07 (m, 6H), 0.9-0.78 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 167.0, 155.6, 155.1, 146.3, 132.50, 132.46, 130.2, 130.1, 129.4, 100.6, 70.4, 56.3, 48.7, 48.5, 38.7, 30.85, 30.82, 27.5, 26.9, 25.8, 13.4; TLC R 1 (CH 2 Cl 2 :Et0Ac + 0.5% MeOH 1 :1) = 0.54.
Cyclohexylmethyl 6-ethyl-4-(4-fluorophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidin e-5- carboxylate (159)
1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, IH), 7.25-7.21 (m, 2H), 7.00-6.99 (m, 2H), 6.16 (s, IH), 5.34 (s, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.65 (m, 2H), 1.65-1.41 (m, 6H), 1.30-1.04 (m, 6H), 0.86-0.74 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.5, 163.8, 161.3, 153.9, 152.3, 139.82, 139.78, 128.5, 128.4, 115.9, 115.7, 100.4, 69.6, 55.2, 37.3, 29.8, 26.4, 25.82, 25.81, 25.4, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in π-Hexanes, 6.5 mL/min): 159a t R = 12 A min, 159b t R = 21.4 min.
160
Cyclohexylmethyl 4-(4-chIorophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin e-5- carboxylate (160)
1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (s, IH), 7.20 (m, 4H), 6.55 (s, IH), 5.30 (s, IH), 3.84 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.2, 6.6 Hz, IH), 2.76-2.61 (m, 2H), 1.64-1.43 (m, 6H), 1.33-1.00 (m, 6H), 0.80-0.74 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.4, 154.2, 152.6, 142.4, 133.8, 129.0, 128.1, 100.1, 69.6, 55.0, 37.3, 29.8, 26.4, 25.8, 25.8, 25.4, 12.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 160a fø = 12.5 min, 160b t R = 22.5 min.
CycIohexylmethyl 6-ethyl-4-(3-fluorophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidin e-5- carboxylate (161)
1 H NMR (400 MHz, CD 3 OD) δ 7.35 (dd, J = 13.8, 7.8 Hz, IH), 7.11 (d, J = 7.6 Hz, IH), 6.96 (m, 2H), 5.30 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.74 (dd, J = 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.65-1.43 (m, 6H), 1.26-1.06 (m, 6H), 0.88-0.78 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 170.0, 155.5, 148.5, 131.7, 123.6, 115.6, 115.4, 114.7, 114.5, 100.5, 70.4, 55.9, 38.7, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in rø-Hexanes, 6.5 mL/min): 161a ϊ R = 14.8 min, 161b ϊ R = 22.2 min.
Cyclohexylmethyl 4-(3-chlorophenyl)-6-ethyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidme-5- carboxylate (162)
1 H NMR (400 MHz, CD 3 OD) δ 7.30-7.21 (m, 4H), 5.28 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.64-1.48 (m, 6H), 1.45-1.07 (m, 6H), 0.86-0.76 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.9, 155.6, 155.1, 148.0, 135.5, 131.5, 128.9, 128.2, 126.1, 100.4, 70.4, 56.0, 38.7, 30.9, 30.8, 27.5, 27.0, 25.8, 13.5. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 162a ϊ R = 17.0 min, 162b ϊ R = 23.0 min.
Cyclohexylmethyl 4-(2-chlorophenyI)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin e-5- carboxylate (163)
1 K NMR (400 MHz, CD 3 OD) δ 7.39-7.21 (m, 4H), 5.82 (s, IH), 3.84 (dd, J = 10.8, 6.0 Hz, IH), 3.65 (dd, J = 10.6, 5.6 Hz, IH), 2.82 (m, 2H), 1.58-1.02 (m, 12H), 0.78-0.65 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 166.7, 156.5, 154.9, 142.1, 134.0, 131.1, 130.5, 129.5, 128.9, 99.3, 70.3, 53.2, 38.7, 30.7, 30.6, 27.4, 27.03, 37.01, 25.7, 13.4.
Cyclohexylmethyl 4-(3-bromophenyl)-6-ethyl-2-oxo-l,2,3j4-tetrahydropyrimidine -5- carboxylate (164)
1 H NMR (400 MHz, CD 3 OD) δ 7.40 (m, 2H), 7.25 (m, 2H), 5.26 (s, IH), 3.91 (dd, J = 10.8, 6.2 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, 2H), 1.66-1.42 (m, 6H), 1.27-1.10 (m, 6H), 0.83-0.78 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 166.9, 155.7, 155.0, 148.3, 131.9, 131.8, 131.2, 126.6, 123.6, 100.4, 70.4, 56.0, 38.8, 30.90, 30.86, 27.5, 27.0, 25.8, 13.4.
Cyclohexylmethyl 4-(4-chloro-3-hydroxyphenyl)-6-ethyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (165)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (d, J = 8.4H, IH), 6.86 (d, J = 1.6 Hz, IH), 6.74 (dd, J = 8.4, 1.8 Hz, IH), 5.20 (s, IH), 3.92 (dd, J = 10.8, 6.2 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, 2H), 1.61-1.41 (m, 6H), 1.26-1.06 (m, 6H), 0.81-0.78 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.1, 155.1, 154.6, 145.9, 131.2, 121.0, 119.9, 116.0, 100.7, 70.4, 56.0, 38.8, 30.9, 30.8, 27.5, 26.98, 26.96, 25.8, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in ra-Hexanes, 0.80 mL/min): 165a t R = 11.22 min, 165b t R = 20.97 min.
Cyclohexylmethyl 4-(3-chloro-4-hydroxyphenyI)-6-ethyl-2-oxo-l,2,3,4- tetrahydropy rimidine-5-carboxylate (166)
1 H NMR (400 MHz, DMSO-J 6 ) δ 10.10 (s, IH), 9.19 (s, IH), 7.62 (s, IH)), 7.12 (s, IH), 6.99-6.90 (m, 2H), 5.02 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 3.69 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.60 (m, 2H), 1.58-1.41 (m, 6H), 1.18-1.02 (m, 6H), 0.85-0.74 (m, 2H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 165.5, 154.9, 152.9, 152.7, 137.3, 128.6, 126.5, 119.9, 117.3, 98.6, 68.8, 53.8, 37.4, 29.73, 29.65, 26.4, 25.9, 24.6, 13.7. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 166a fø = 6.86 min, 166b fø = 9.14 min.
Cyclohexylmethyl 4-(2-chloro-4-hydroxyphenyl)-6-ethyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (167)
1 K NMR (400 MHz, CD 3 OD) δ 7.08 (d, J = 8.4 Hz, IH), 6.80 (d, J = 2.0 Hz, IH), 6.66 (dd, J = 8.4, 2.0 Hz, IH), 5.70 (s, IH), 3.88 (dd, J = 10.8, 6.0 Hz, IH), 3.64 (dd, J = 10.8, 6.0 Hz,
IH), 2.79 (m, 2H), 1.59 (m, 3H), 1.42 (m, 6H), 1.24 (t, J = 7.4 Hz, 3H), 0.73 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.2, 152.8, 152.4, 134.7, 134.2, 133.7, 115.3, 113.9, 112.5, 98.9, 68.1, 53.9, 36.7, 29.11, 29.08, 25.8, 25.24, 25.22, 24.0, 13.1
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 0.85 mL/min) : 167a t R = 16.40 min, 167b t R = 26.61 min.
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-5-hydroxyphenyl)-2-oxo-l,2,3 > 4- tetrahydropyrimidine-5-carboxyIate (168)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.32 (s, IH), 9.23 (s, IH), 7.63 (s, IH), 6.93 (t, J= 10.0 Hz, IH), 6.64-6.60 (m, 2H), 5.36 (d, J= 3.2 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.66 (dd, J= 10.8, 6.0 Hz, IH), 2.74-2.66 (m, 2H), 1.57-1.36 (m, 6H), 1.63-1.05 (m, 6H), 0.79-0.73 (m, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 165.3, 155.5, 154.4, 154.27, 154.25, 152.5, 152.0, 132.6, 132.5, 116.6, 116.4, 116.0, 115.9, 114.63, 114.59, 97.2, 68.8, 48.6, 37.4, 29.60, 29.50, 26.4, 25.9, 24.6, 13.7.
169
CyclohexylmethyL 4-(4-acetoxy-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxylate (169)
To a solution of phenol 166 (50 mg, 0.13mmol, 1.0 equiv) in CH 2 Cl 2 (0.5 mL) was added acetic anhydride (14.4 μl, 0.15 mmol, 1.15 equiv) and DMAP (7.8 mg, 0.06 mmol, 0.5 equiv), and the resulting mixture was stirred for 4 h at 0 °C. The mixture was diluted with CH 2 Cl 2 (10 mL), washed with water (2 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOHZCH 2 Cl 2 ) to afford 169 (32 mg, 57%): 1 H NMR (400 MHz, CD 3 OD) δ 7.37 (d, J = 2.0 Hz, IH), 7.26 (dd, J = 8.4, 2.0
Hz, IH), 7.15 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 3.92 (dd, J = 10.8, 6.0 Hz, IH) 3.75 (dd, J = 10.8, 5.6 Hz, IH), 2.82 (m, IH), 2.72 (m, IH), 2.29 (s, 3H), 1.66-1.43 (m, 6H), 1.31-1.08 (m, 6H), 0.90-0.80 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in n-Hexanes, 0.85 mL/min): 169a t R = 10.19 min, 169b t R = 15.15 min.
170
Cyclohexylmethyl 4-(3-acetoxy-4-chlorophenyl)-6-ethyI-2-oxo-l,2,3 ? 4- tetrahy dropy rimidine-5-carboxyIate (170)
1 H NMR (400 MHz, CD 3 OD) δ 7.43 (d, J = 8.4 Hz, IH), 7.18 (dd, J = 8.4, 1.6 Hz, IH), 7.10 (d, J = 1.6 Hz, IH), 5.29 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.75 (dd, J = 10.8, 5.6 Hz, IH), 2.80 (m, IH), 2.69 (m, IH), 2.29 (s, 3H), 1.63-1.43 (m, 6H), 1.30-1.04 (m, 6H), 0.90- 0.78 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 169.9, 166.9, 155.7, 155.0, 148.7, 146.4, 131.5, 127.2, 126.6, 123.5, 100.3, 70.5, 55.6, 38.7, 30.91, 30.89 , 27.5, 26.9, 25.8, 20.5, 13.4. Enantiomeric pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in o-Hexanes, 0.85 mL/min): 170a t R = 14.81 min, 170b t R = 21.80 min.
(S)-Cyclohexylmethyl 4-(4-((5)-2-(te/Y-butoxycarbonylamino)propanoyloxy)-3- chlorophenyl)-6-etb.yl-2-oxo-l,2,3j4-tetrab.ydropyrimidine-5 -carboxylate (171a)
1 H NMR (400 MHz, CD 3 OD) δ 7.38 (s, IH), 7.27 (d, J = 8.4 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 4.38 (q, J = 7.6 Hz, IH), 3.92 (dd, J = 10.6, 6.2 Hz, IH), 3.74 (dd, J = 10.6, 5.8 Hz, IH), 2.80 (m, IH), 2.71 (m, IH), 1.65-1.41 (m, 18H), 1.32-1.07 (m, 6H), 0.88-
0.76 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 172.7, 166.9, 155.8, 155.0, 147.8, 145.5, 129.8, 127.9, 127.5, 125.4, 100.3, 70.5, 55.6, 51.0, 38.8, 30.93, 30.89, 28.9, 27.5, 27.0, 25.8, 17.7, 13.4.
(S)-Cyclohexylmethyl 4-(4-((5)-2-aminopropanoyIoxy)-3-chIorophenyI)-6-ethyl-2-oxo - l,2,3 ? 4-tetrahydropyrimidine-5-carboxylate hydrochloride (172a)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.28 (bs, IH), 8.65 (bs, 3H), 7.74 (bs, IH), 7.33 (t, J= 9.2 Hz, 2H), 7.24 (d, J= 8.0Hz, IH), 5.13 (s, IH), 4.44 (m, IH), 3.81 (dd, J= 10.4, 5.2 Hz, IH), 3.66 (dd, J= 10.2, 5.0 Hz, IH), 2.72 (m, IH), 2.57 (m, IH), 1.58-1.54 (m, 6H), 1.44-1.31 (m, 3H), 1.15-0.95 (m, 6H), 0.81-0.71 (m, 2H).
(S)-Cyclohexylmethyl 4-(4-acetoxy-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (173a)
1 H NMR (400 MHz, CD 3 OD) δ 7.37 (s, IH), 7.25 (d, J= 8.4 Hz, IH), 7.15 (d, J= 8.8 Hz, IH), 5.28 (s, IH), 3.92 (dd, J= 10.4, 6.0 Hz, IH), 3.74 (dd, J= 10.4, 5.6Hz, IH), 2.81(m, IH), 2.72 (m, IH), 2.29 (s, 3H), 1.63-1.45 (m, 6H), 1.36-1.05 (m, 6H), 0.88-0.77 (m, 2H).
(S)-Cyclohexylmethyl 4-(4-(benzoyloxy)-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3 ? 4- tetrahy dropy rimidine-5-carboxylate (174a)
1 H NMR (400 MHz, CD 3 OD) δ 8.09 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 6.8 Hz, IH), 7.61 (t, J = 7.6 Hz, IH), 7.47 (t, J = 8.0 Hz, 2H), 7.38 (s, IH), 7.28 (t, J = 7.6 Hz, IH), 5.25 (s, IH), 3.86 (dd, J = 10.4, 5.6 Hz, IH), 3.70 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, IH), 2.65 (m, IH), 1.59- 142 (m, 6H), 1.23-1.03 (m, 6H), 0.81-0.77 (m, 2H).
175a
(S)-CyclohexylmethyI 4-(3-chloro-4-(pivaloyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (175a)
1 H NMR (400 MHz, CD 3 OD) δ 7.37 (d, J = 2.0 Hz, IH), 7.26 (dd, J = 8.4, 2.0 Hz, IH), 7.10 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 3.91 (dd, J = 10.8, 6.0 Hz, IH), 3.75 (dd, J - 10.8, 6.0 Hz, IH), 2.82 (m, IH), 2.70 (m, IH), 1.63-1.46 (m, 6H), 1.38-1.12 (m, 15H), 0.88-0.79 (m, 2H).
176a
(S)-Cyclohexylmethyl 4-(3-chloro-4-(isonicotinoyloxy)phenyI)-6-ethyl-2-oxo-l,2,3 > 4- tetrahydropy rimidine-5-carboxylate (176a)
To a mixture of 166a (6.0 mg, 15.2 μmol, 1.0 equiv) in THF was added isonicotinoyl chloride hydrochloride (3.5 mg, 19.7 μmol, 1.3 equiv), and DIPEA (9.3 μL, 53.4 μmol, 3.5 equiv), and the reaction mixture was allowed to stir overnight at room temperature. The mixture was subjected to preparative TLC (5% MeOH/CH 2 Cl 2 ) to afford 176a (6.4 mg, 85%): 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (dd, J = 4.4, 1.6 Hz, 2H), 8.01 (dd, J = 4.4, 1.6 Hz, 2H), 7.44 (s, IH), 7.29 (m, 2H), 7.15 (s, IH), 5.59 (s, IH), 5.41 (s, IH), 3.91 (dd, J = 10.6, 5.8 Hz, IH), 3.84 (dd, J = 10.2, 5.8 Hz, IH), 2.85 (m, IH), 2.71 (m, IH), 1.70-1.42 (m, 6H), 1.27-1.09 (m, 6H), 0.92-0.87 (m, 2H).
177a
(S)-Cyclohexylmethyl 4-(3-chloro-4-(nicotinoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3 5 4- tetrahy dropyrimidine-5-carboxyIate (177a)
1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (d, J = 2.0 Hz, IH), 8.88 (dd, J = 4.8 Hz, 1.2 Hz, IH), 8.47 (dd, J = 8.4, 2.0 Hz, IH), 7.69 (s, IH), 7.52-7.45 (m, 2H), 7.38-7.25 (m, 2H), 5.85 (s, IH), 5.42 (s, IH), 3.92 (dd, J = 10.8, 6.0 Hz, IH), 3.85 (dd, J = 10.8, 6.0 Hz, IH), 2.86 (m, IH), 2.71 (m, IH), 1.71-1.43 (m, 6H), 1.34-1.07 (m, 6H), 0.93-0.84 (m, 2H).
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-hydroxyphenyl)-2-oxo-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate (178)
1 H NMR (400 MHz, CD 3 OD) δ 6.92 (ddd, J= 15.4, 10.2, 2.0 Hz, 2H), 6.83 (t, J= 8.4 Hz, IH), 5.19 (s, IH), 3.91 (dd, J= 10.8, 6.4Hz, IH), 3.73 (dd, J= 10.6, 5.8 Hz, IH), 2.76 (m, 2H), 1.64(m, 3H), 1.47 (m, 3H), 1.21-1.08 (m, 6H), 0.82 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.2, 155.1, 154.1, 151.7, 145.9, 137.8, 123.8, 118.9, 115.4, 101.0, 70.4, 55.6, 38.8, 30.9, 30.8, 27.5, 27.00, 26.98, 25.8, 13.4.
Enantiomeric pure forms were obtained by chiral HPLC (OD-H preparative column, 10% i- PrOH in «-Hexanes, 6.5 mL/min): 178a t R = 32.0 min, 178b t R = 48.7 min.
Cyclohexylmethyl 4-(4-acetoxy-2-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (179)
1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (bs, IH), 7.21 (t, J= 8.6Hz, IH), 6.86 (t, J= 8.6Hz, 2H), 5.72 (s, 2H), 3.86 (dd, J= 10.8, 5.6Hz, IH), 3.77 (dd, J= 10.6, 5.8Hz, IH), 2.85 (m, 2H), 2.29 (s, 3H), 1.63 (m, 3H), 1.45 (m, 3H), 1.28-1.04 (m, 6H), 0.80 (m, 2H); 13 C NMR(IOOMHz, CDCl 3 ) δ 169.0, 165.1, 161.5, 159.0, 154.1, 153.5, 128.6, 127.6, 117.9, 110.1, 97.7, 69.5, 49.13, 49.10, 37.3, 29.73, 29.70, 26.4, 25.8, 25.4, 21.3, 12.8. Enantiomeric pure forms were obtained by chiral HPLC (OD-H preparative column, 10% i- PrOH in w-Hexanes, 6.5 mL/min): 179a t R = 19.6 min, 179b t R = 28.4 min.
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-4-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (180)
Enantiomerically pure forms were obtained from 179a/179b by hydrolysis using K 2 CO 3 in MeOH.
1 H NMR (400 MHz, CD 3 OD) δ 7.03 (t, J= 8.8 Hz, IH), 6.49 (ddd, J= 23.0, 10.2, 2.4 Hz, 2H), 5.52 (s, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J= 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.62 (m, 3H), 1.44 (m, 3H), 1.23-1.07 (m, 6H), 0.79 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.0, 163.5, 161.1, 160.2, 155.4, 130.2, 123.1, 112.6, 103.8, 99.4, 70.3, 50.03, 50.00, 38.8, 30.8, 30.7, 27.5, 27.0, 25.7, 13.4.
Cyclohexylmethyl 6-ethyl-4-(3-hydroxy-4-methoxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (181)
1 K NMR (400 MHz, CD 3 OD) δ 6.84 (d, J= 9.6 Hz, IH), 6.78 (s, IH), 6.76 (d, J= 10.8 Hz, IH), 5.20 (s, IH), 3.92 (dd, J= 10.8, 5.6Hz, IH), 3.81 (s, 3H), 3.73 (dd, J= 10.8, 5.6 Hz, IH), 2.73-2.81 (m, 2H), 1.45-1.67 (m, 6H), 10.9-1.25 (m, 6H), 0.80-0.86 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in π-Hexanes, 0.85 mL/min): 181a t R = 14.67 min, 181b t R = 65.58 min.
182
Cyclohexylmethyl 6-ethyl-4-(4-hydroxy-3-methoxyphenyl)-2-oxo-l,2,3 » 4- tetrahy dropy rimidine-5-carboxy late (182)
1 H NMR (400 MHz, CD 3 OD) δ 6.85 (s, IH), 6.73 (s, 2H), 5.23 (s, IH), 3.93 (dd, J= 10.6, 5.4 Hz, IH), 3.82 (s, 3H), 3.74 (dd, J= 10.6, 5.4 Hz, IH), 2.71-2.86 (m, 2H), 1.43-1.66 (m, 6H), 1.05-1.34 (m, 6H), 0.80-0.86 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in «-Hexanes, 0.85 mL/min): 182a t R = 15.59 min, 182b t R = 39.79 min.
Cyclohexylmethyl 6-ethyl-4-(4-fluoro-3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (183)
1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, IH), 6.94-6.90 (m, 2H), 6.73-6.70 (m, IH), 6.10 (s, IH), 5.27 (d, J= 1.6 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.63 (m, 2H), 1.66-1.41 (m, 6H), 1.19-1.06 (m, 6H), 0.84-0.78 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.5, 153.9, 152.3, 151.8, 149.9, 144.4, 144.3, 140.4, 118.8, 116.1, 115.9, 115.7, 100.8, 69.8, 55.3, 37.3, 29.86, 29.84, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in n-Hexanes, 0.8 mL/min): 183a t R = 14.12 min, 183b t R = 24.70 min.
CyclohexylmethyM^benzoIdUl^ldioxol-S-y^-o-ethyl-l-oxo-l^^ ^- tetrahy dropyrimidine-5-carboxylate (184)
1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (bs, IH), 6.69 (m, 3H), 5.91 (s, 2H), 5.75 (bs, IH), 5.27 (s, IH), 3.87 (dd, J= 10.4, 6.0 Hz, IH), 3.77 (dd, J= 10.4, 6.0 Hz, IH), 2.68-2.78 (m, 2H), 1.47-1.65 (m, 6H), 1.21 (t, J= 7.4 Hz, 3H), 1.06-1.14 (m, 3H), 0.79-0.84 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.4, 153.4, 151.9, 148.1, 147.3, 137.9, 120.1, 108.3, 107.1, 101.2, 100.4, 69.4, 55.7, 37.3, 29.8, 29.7, 26.4, 25.8, 25.7, 25.4, 12.6.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in n-Hexanes, 8.0 mL/min): 184a t R = 11.4 min, 184b t R = 17.5 min.
185
Cyclohexylmethyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3, 4- tetrahy dropyrimidine-5-carboxylate (185)
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (s, IH), 6.96 (d, J= 8.0 Hz, IH), 6.91 (d, J= 2.0 Hz, IH), 6.72 (dd, J= 8.2, 1.8 Hz, IH), 6.45 (t, J= 74.2 Hz, IH), 6.36 (s, IH), 5.25 (d, J = 2.8 Hz, IH), 3.87 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 11.0, 5.8 Hz, IH), 2.77-2.72 (m, IH), 2.64-2.59 (m, IH), 1.64-1.44 (m, 6H), 1.25-1.04 (m, 6H), 0.86-0.78 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.6, 154.2, 152.2, 148.2, 142.4, 138.24, 138.22, 138.19, 121.1, 119.0, 118.7, 115.3, 100.5, 69.8, 55.1, 37.3, 29.83, 29.81, 26.4, 25.8, 25.5, 12.7; TLC £/(Hexanes:EtOAc + 0.5% MeOH 1 :1) = 0.12.
Cyclohexylmethyl 4-(4-(benzyloxy)-3-hydroxyphenyI)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropyrimidine-5-carboxylate (186)
1 R NMR (400 MHz, CDCl 3 ) δ 8.13 (bs, IH), 7.38 (s, 5H), 6.90 (s, IH), 6.83 (d, J= 8.0Hz, IH), 6.75 (d, J= 8.4 Hz, IH), 5.82 (d, J= 17.2 Hz, 2H), 5.28 (s, IH), 5.06 (s, 2H), 3.87 (dd, J =10.4, 6.0 Hz, IH), 3.78 (dd, J= 11.2, 5.2 Hz, IH), 2.78 (m, IH), 2.69 (m, IH), 1.63-1.48 (m, 6H), 1.26-1.07 (m, 6H), 0.85 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 165.6, 153.7, 152.1, 146.3, 145.7, 137.8, 136.5, 128.9, 128.6, 128.0, 118.4, 113.3, 112.4, 100.4, 71.4, 69.4, 55.5, 37.4, 29.84, 29.82, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 50% /-PrOH in «-Hexanes, 6.5 mL/min): 186a t R = 37.1 min, 186b t R = 75.0 min.
Cyclohexylmethyl 4-(3,4-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyri midine- 5-carboxylate (187)
1 H NMR (400 MHz, CDCl 3 ) δ 6.75 (s, IH), 6.72 (d, J- 17.2 Hz, IH), 6.62 (d, J= 8.4 Hz, IH), 5.17 (s, IH), 3.92 (dd, J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.71-2.82 (m, 2H), 1.45-1.68 (m, 6H), 1.10-1.25 (m, 6H), 0.81-0.90 (m, 2H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 167.4, 155.3, 154.3, 146.6, 146.1, 137.4, 119.3, 116.3, 114.9, 101.4, 70.2, 56.1, 38.8, 30.8, 30.7, 27.4, 27.0, 25.7, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25- 30% /-PrOH in «-Hexanes, 0.85 mL/min): 187a t R = 9.5 min, 187b t R = 38.1 min.
CycIohexylmethyI 6-ethyI-4-(3-hydroxy-4-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (188)
1 U NMR (400 MHz, CD 3 OD) δ 8.03 (d, J = 8.8 Hz, IH), 7.04 (d, J = 2.0 Hz, IH), 6.96 (dd, J = 8.4, 2.0 Hz, IH), 5.30 (s, IH), 3.91 (dd, J = 10.6, 6.2 Hz, IH), 3.76 (dd, J = 10.8, 6.0 Hz, IH), 2.81 (m IH), 2.70 (m, IH), 1.65-1.43 (m, 6H), 1.27-1.07 (m, 6H), 0.89-0.77 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.5, 154.8, 154.6, 153.7, 153.6, 133.8, 125.7, 118.2, 117.6, 98.4, 69.2, 54.5, 37.4, 29.6, 29.5, 26.1, 25.61, 25.59, 24.5, 12.1.
CyclohexyImethyl 4-(4-amino-3-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (189)
To a mixture of 188 (65.6 mg, O.lόmmol, 1.0 equiv) in MeOH (2 niL) was added Pd/C (10%, 7 mg), and the reaction mixture was stirred for 3 h at room temperature under hydrogen balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (3% MeOH/Et 2 O) to afford 189 (26 mg, 73%): 1 H NMR (400 MHz, CD 3 OD) δ 6.67 (m, 2H), 6.58 (d, J = 7.6 Hz, IH), 5.13 (s, IH), 3.87 (dd, J = 10.8, 6.0 Hz, IH), 3.73 (dd, J = 10.8, 6.0 Hz, IH), 2.72 (m, 2H), 1.67-1.50 (m, 6H), 1.48-1.12 (m, 6H), 10.9-0.78 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 167.5, 155.4, 154.1, 146.8, 136.7, 136.1, 119.6, 117.2, 114.0, 101.6, 70.3, 56.2, 38.8, 30.92, 30.86, 27.5, 27.0, 25.7, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 niL/min): 189a t R = 15.45 min, 189b t R = 31.49 min.
190
Cyclohexylmethyl 4-(4-chloro-3-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (190)
1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (s, IH), 7.79 (s, IH), 7.50-7.44 (m, 2H), 6.20 (s, IH), 5.42 (d, J= 2.8 Hz, IH), 3.88 (dd, J= 10.8, 6.4 Hz, IH), 3.82 (dd, J= 10.8, 6.4 Hz, IH), 2.84-2.77 (m, IH), 2.72-2.65 (m, IH), 1.70-1.47 (m, 6H), 1.28-1.05 (m, 6H), 0.88-0.78 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.0, 153.23, 153.12, 148.1, 144.2, 132.6, 131.4, 126.7, 124.1, 99.6, 70.0, 54.8, 37.3, 31.8, 29.97, 29.93, 26.4, 25.77, 25.75, 25.69, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 190a t R = 16.57 min, 190b t R = 22.63 min.
Cyclohexylmethyl 4-(3-amino-4-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (191)
190 (100 mg, 0.24 mmol, 1.0 equiv), Zn (93 mg, 1.42 mmol, 5.9 equiv), AcOH (0.9 mL) and concentrated HCl (0.1 mL) was added to a 20 mL round-bottom flask. After stirring at 80 °C for 1 h, the reaction mixture was cooled to 0 0 C and aqueous saturated K 2 CO 3 (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (n-Hexanes/EtOAc/AcOH = 50:50:0.5) to afford 191 (82 mg, 88%): 1 H NMR (400 MHz, CD 3 OD) δ 7.13 (d, J= 8.0 Hz, IH), 6.77 (s, IH), 6.57 (dd, J= 8.0, 1.6 Hz, IH), 5.19 (s, IH), 3.94 (dd, J= 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.86-2.79 (m, IH), 2.74-2.67 (m, IH), 1.67-1.44 (m, 6H), 1.30-1.09 (m, 6H), 0.88-0.78 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.9, 153.8, 153.7, 144.4, 144.1, 129.1, 117.9, 116.3, 114.0, 99.4, 69.0, 54.8, 37.5, 29.54, 29.45, 26.2, 25.67, 25.65, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 191a t R = 10.0 min, 191b t R = 23.1 min.
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-nitrophenyl)-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (192)
1 U NMR (400 MHz, CD 3 OD) δ 8.10 (t, J= 8.4 Hz, IH), 7.35-7.31 (m, 2H), 5.40 (s, IH), 3.95 (dd, J= 10.8, 6.4 Hz, IH), 3.80 (dd, J= 10.8, 6.4 Hz, IH), 2.89-2.82 (m, IH), 2.75-2.68 (m, IH), 1.69-1.45 (m, 6H), 1.26-1.10 (m, 6H), 0.89-0.80 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.4, 156.8, 155.1, 154.2, 153.36, 153.31, 153.24, 126.60, 126.58, 122.84, 122.80, 116.4, 116.2, 98.2, 69.3, 54.4, 37.4, 29.58, 29.50, 26.1, 25.58, 25.55, 24.55, 12.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 192a t R = 18.5 min, 192b t R = 24.8 min.
Cyclohexylmethyl 4-(4-amino-3-fluoropheiiyl)-6-ethyl-2-oxo-l,2,3 ? 4- tetrahydropyrimidine-5-carboxylate (193)
1 K NMR (400 MHz, CD 3 OD) δ 6.89-6.84 (m, 2H), 6.77 (t, J= 8.6 Hz, IH), 5.18 (s, IH), 3.92 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.72 (m, 2H), 1.70-1.46 (m, 6H), 1.25-1.11 (m, 6H), 0.91-0.83 (m, 2H); 13 C NMR (IOO MHZ, CD 3 OD) δ 166.0, 154.0, 153.4, 152.9, 150.5, 135.3, 135.1, 134.5, 134.4, 122.49, 122.46, 116.91, 116.88, 113.2, 113.0, 99.8, 69.0, 54.3, 37.5, 29.55, 29.48, 26.2, 25.66, 25.64, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 193a t R = 13.3 min, 193b t R = 22.0 min.
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-5-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (194)
1 H NMR (400 MHz, DMSO-^) δ 9.46 (s, IH), 8.26-8.22 (m, IH), 8.09-8.07 (m, IH), 7.83 (s, IH), 7.52 (t, J= 9.2 Hz, IH), 5.51 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.8, 6.4 Hz, IH), 3.66 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.66 (m, 2H), 1.59-1.21 (m, 6H), 1.17-0.95 (m, 6H), 0.77-
0.66 (m, 2H); 13 C NMR (IOO MHz, DMSO-J 6 ) δ 164.5, 164.3, 161.9, 155.8, 151.4, 143.93, 143.9, 133.3, 133.1, 125.5, 125.4, 124.5, 124.4, 117.7, 117.4, 95.3, 68.3, 49.0, 36.6, 29.0, 28.9, 25.7, 25.2, 25.1, 24.0, 13.0.
Cyclohexylmethyl 4-(5-amino-2-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (195)
1 H NMR(400 MHz, CD 3 OD) δ 6.82 (t, J= 9.2 Hz, IH), 6.66-6.59 (m, 2H), 5.57 (s, IH), 3.89 (dd, J= 10.4, 6.0 Hz, IH), 3.71 (dd, J= 10.8, 5.6 Hz, IH), 2.91-2.84 (m, IH), 2.76-2.70 (m, IH), 1.66-1.43 (m, 6H), 1.35-1.09 (m, 6H), 0.88-0.75 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.0, 156.0, 155.9, 155.1, 153.7, 145.49, 145.47, 132.4, 132.2, 117.3, 117.2, 117.0, 116.8, 115.9, 115.8, 99.1, 70.3, 38.7, 30.8, 30.7, 27.5, 27.0, 25.7, 13.4.
CyclohexylmethyI 6-ethyl-4-(4-fluoro-3-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (196)
1 H NMR (400 MHz, CDCl 3 ) δ 7.99-7.95 (m, 2H), 7.60-7.56 (m, IH), 7.26-7.21 (m, IH), 6.22 (s, IH), 5.44 (d, J= 3.2 Hz, IH), 3.89-3.80 (m, 2H), 2.84-2.77 (m, IH), 2.74-2.67 (m, IH), 1.70-1.48 (m, 6H), 1.30-1.06 (m, 6H), 0.88-0.79 (m,2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.1, 156.5, 153.9, 153.3, 153.1, 141.1, 141.0, 133.9, 133.8, 124.62, 124.59, 119.3, 119.1, 99.8, 70.0, 54.8, 37.3, 31.8, 30.0, 29.9, 26.4, 25.78, 25.76, 25.68, 22.9, 14.3, 12.8.
197
Cyclohexylmethyl 4-(3-amino-4-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxyIate (197)
1 E NMR(400 MHz, CD 3 OD) δ 6.90-6.85 (m, IH), 6.79 (d, J= 8.8 Hz, IH), 6.58-6.55 (m, IH), 5.20 (s, IH), 3.92 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.6, 5.8 Hz, IH), 2.85-2.75 (m, IH), 2.73-2.68 (m, IH), 1.68-1.44 (m, 6H), 1.29-1.09 (m, 6H), 0.90-0.79 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.3, 155.2, 154.8, 153.9, 151.5, 142.0, 141,98, 137.2, 137.0, 117.23, 117.17, 116.6, 116.5, 116.1, 115.9, 101.0, 70.4, 56.1, 38.8, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 25% z-PrOH in «-Hexanes, 6.5 mL/min): 197a t R = 25.5 min, 197b t R = 43.4 min.
198
Cyclohexylmethyl 4-(3-chloro-4-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (198)
1 H NMR (400 MHz, CD 3 OD) δ 7.92 (d, J = 8.4 Hz, IH), 7.52 (d, J = 1.2 Hz, IH), 7.43 (dd, J = 8.4, 1.6 Hz, IH), 5.36 (s, IH), 3.94 (dd, J = 10.8, 6.0 Hz, IH), 3.74 (dd, J = 10.8, 5.6 Hz, IH), 2.83 (m, IH), 2.71 (m, IH), 1.63 (m, 3H), 1.53-1.39 (m, 3H), 1.30-1.07 (m, 6H), 0.89- 0.76 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 166.6, 156.5, 154.7, 151.9, 148.8, 131.3, 127.7, 127.5, 127.4, 99.5, 70.6, 55.7, 38.8, 30.94, 30.87, 27.5, 27.0, 25.9, 13.4.
Cyclohexylmethyl 4-(4-amino-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (199)
1 U NMR (400 MHz, CD 3 OD) δ 7.09 (d, J = 2.0 Hz, IH), 6.96 (dd, J = 8.4 Hz, 2.0 Hz, IH), 6.75 (d, J = 8.4 Hz, IH), 5.14 (s, IH), 3.91 (dd, J = 10.6, 6.2 Hz, IH), 3.72 (dd, J = 10.6, 5.8 Hz, IH), 2.75 (m, 2H), 1.67-1.42 (m, 6H), 1.27-1.08 (m, 6H), 0.88-0.78 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 30% /-PrOH in rc-Hexanes, 6.5 mL/min): 199a t R = 1st band, 199b t R = 2nd band.
Cyclohexylmethyl 4-(2-chloro-5-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (200)
1
U NMR (400MHz,
Cyclohexylmethyl 4-(5-amino-2-chloropheiiyl)-6-ethyl-2-ox()-l,2,3,4- tetrahydropyrimidine-5-carboxylate (201)
1 H NMR(400 MHz, CD 3 OD) δ 7.08 (d, J= 8.4 Hz, IH), 6.67 (d, J= 2.8 Hz, IH), 6.59 (dd, J = 8.4, 2.8 Hz, IH), 5.72 (s, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.67 (dd, J= 10.8, 5.2 Hz, IH), 2.98-2.93 (m, IH), 2.74-2.69 (m, IH), 1.63-1.34 (m, 6H), 1.30-1.07 (m, 6H), 0.82-0.72 (m, 2H); 13 C NMR (IOO MHZ, CD 3 OD) δ 166.7, 156.0, 154.8, 148.9, 142.0, 131.1, 121.5, 117.0, 115.4, 99.2, 70.1, 53.0, 38.5, 30.5, 30.4, 27.2, 26.88, 26.87, 25.4, 13.2. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 20% /-PrOH in n-Hexanes, 6.5 mL/min): 201a t R = 53.8 min, 201b t R = 59.9 min.
Cyclohexylmethyl 4-(3,4-dinitrophenyl)-6-ethyl-2-oxo-l,2,3 5 4-tetrahydropyrimidiiie-5- carboxylate (202)
1 H NMR (400 MHz, CD 3 OD) δ 8.06 (d, J = 8.4 Hz, IH), 7.93 (d, J = 1.6 Hz, IH), 7.79 (dd, J = 8.4, 1.6 Hz, IH), 5.46 (s, IH), 3.94 (dd, J = 10.8, 6.4 Hz, IH), 3.77 (dd, J = 10.8, 6.0 Hz, IH), 2.86 (m, IH), 2.69 (m, IH), 1.65 (m, 3H), 1.51 (m, 3H), 1.22 (m, 6H), 0.90-0.76 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 165.2, 155.6, 153.1, 151.5, 131.7, 126.0, 123.6, 97.9, 69.3, 54.3, 37.3, 29.59, 29.56, 26.1, 25.55, 25.52, 24.6, 12.1.
Cyclohexylmethyl 4-(3,4-diaminophenyl)-6-ethyI-2-oxo-l,2,3 5 4-tetrahydropyrimidine-5- carboxylate (203)
To a mixture of 202 (33 mg, 0.076 mmol, 1.0 equiv) in MeOH (2 mL) was added 10% Pd/C (7 mg), and the reaction mixture was stirred for 2 h at room temperature under hydrogen
balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative. TLC (3% MeOHTEt 2 O) to afford 203 (26 mg, 73%): 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.92 (d, J = 1.2 Hz, IH), 7.36 (t, J = 2.4 Hz, IH), 6.35 (m, 2H), 6.22 (dd, J = 8.0, 2.0 Hz, IH), 4.86 (d, J = 3.2 Hz, IH), 4.36 (s, 2H), 4.32 (s, 2H), 3.72 (m, 2H), 2.68 (m, IH), 2.54 (m, IH), 1.60-1.42 (m, 6H), 1.20-1.02 (m, 6H), 0.85 (m, 2H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 165.2, 152.8, 152.4, 134.7, 134.2, 133.7, 115.3, 113.9, 112.5, 98.9, 68.1, 53.9, 36.7, 29.11, 29.08, 25.8, 25.24, 25.22, 24.0, 13.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 35% i- PrOH in π-Hexanes, 0.85 mL/min): 203a t R = 21.36 min, 203b t R = 56.14 min.
204
Cyclohexylmethyl 4-(3,4-difluorophenyl)-6-ethyI-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (204)
1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (s, IH), 7.10-6.98 (m, 3H), 6.40 (s, IH), 5.32 (s, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.73 (m, IH), 2.70-2.61 (m, IH), 1.69-1.43 (m, 6H), 1.26-1.02 (m, 6H), 0.87-0.76 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 154.0, 152.7, 151.9, 151.7, 151.4, 151.3, 149.4, 149.3, 148.9, 148.8, 140.95, 140.92, 140.87, 122.72, 122.69, 122.66, 122.62, 117.8, 117.6, 115.9, 115.7, 100.1, 69.7, 54.9, 37.3, 29.9, 26.4, 25.80, 25.77, 25.5, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 204a t R = 8.8 min, 204b t R = 18.1 min.
Cyclohexylmethyl 4-(3,5-bis(trifluoromethyl)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (205)
1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (s, IH), 7.77 (s, IH), 7.72 (s, 2H), 6.21 (s, IH), 5.51 (d, J = 2.4 Hz, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.8, 6.0 Hz, IH), 2.83-2.72 (m, 2H), 1.62-1.42 (m, 6H), 1.24-1.03 (m, 6H), 0.86-0.74 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.9, 153.5, 153.2, 146.3, 132.9, 132.6, 132.2, 131.9, 127.4, 127.1, 124.7, 122.3, 122.0, 99.3, 69.9, 55.3, 37.2, 29.9, 29.8, 26.4, 25.7, 25.6, 12.7.
206
Cyclohexylmethyl 4-(3,5-dibromophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimi dine-5- carboxylate (206)
1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, IH), 7.52 (s, IH), 7.24 (s, IH), 6.48 (s, IH), 5.27 (d, J = 2.8 Hz, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.85-2.78 (m, IH), 2.66-2.59 (m, IH), 1.67-1.45 (m, 6H), 1.23-1.03 (m, 6H), 0.86-0.76 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.1, 153.8, 153.4, 147.5, 133.8, 128.8, 123.5, 99.3, 69.8, 55.0, 37.3, 29.96, 29.92, 26.5, 25.9, 25.5, 12.8.
Cyclohexylmethyl 4-(3,5-difluorophenyl)-6-ethyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidine-5- carboxylate (207)
1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, IH), 6.80 (t, J= 6.2 Hz, 2H), 6.70-6.65 (m, IH), 6.39 (s, IH), 5.33 (d, J- 2.8 Hz, IH), 3.89 (dd, J= 10.6, 6.2 Hz, IH), 3.79 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.75 (m, IH), 2.70-2.63 (m, IH), 1.65-1.44 (m, 6H), 1.21-1.02 (m, 6H), 0.87-0.76 (m, 2H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 165.2, 164.7, 164.6, 162.2, 162.1, 153.9, 153.1,
147.6, 109.76, 109.70, 109.58, 109,51, 103.8, 103.6, 103.3, 99.6, 69.8, 55.1, 37.4, 29.9, 29.9, 26.4, 25.82, 25.81, 25.5, 12.8.
Cyclohexylmethyl 4-(3,4-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrim idine-5- carboxylate (208)
1 H NMR (400 MHz, CDCl 3 ) δ 8.44, 7.35-7.33 (m, 2H), 7.12-7.09 (m, IH), 6.47 (s, IH), 5.30 (d, J= 2.8 Hz, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.80-2.73 (m, IH), 2.69-2.62 (m, IH), 1.66-1.44 (m, 6H), 1.27-1.05 (m, 6H), 0.85-0.76 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.2, 153.9, 152.9, 144.1, 132.9, 132.2, 131.0, 128.9, 126.1, 99.8, 69.8, 54.9, 37.4, 29.9, 26.4, 25.84, 25.82, 25.5, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% /-PrOH in w-Hexanes gradient, 0.8 mL/min): 208a t R = 1st band, 208b t R = 2nd band.
Cyclohexylmethyl 4-(4-acetoxy-3,5-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (209)
1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (bs, IH), 7.30 (s, 2H), 6.03 (bs, IH), 5.36 (s, IH), 3.93 (dd, J= 10.8, 6.0 Hz, IH), 3.83 (dd, J= 10.8, 6.0 Hz, IH), 2.88 (m, IH), 2.68 (m, IH), 2.38 (s, 3H), 1.71-1.54 (m, 6H), 1.43-1.07 (m, 6H), 0.88 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.4, 165.1, 153.3, 153.0, 143.8, 143.4, 129.3, 127.1, 99.7, 70.0, 55.0, 37.3, 30.01, 29.99, 26.5, 25.8, 25.6, 20.4, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 15% /-PrOH in «-Hexanes, 6.5 mL/min): 209a t R = 15.3 min, 209b t R = 21.3 min.
Cyclohexylmethyl 4-(3,5-dichloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (210)
Enantiomeric pure forms were obtained from 209a/209b by hydrolysis using K 2 CO 3 in
MeOH.
1 H NMR (400 MHz, CD 3 OD) δ 7.16 (s, 2H), 5.18 (s, IH), 3.95 (dd, J= 10.6, 5.8 Hz, IH),
3.71 (dd, J= 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.62-1.42 (m, 6H), 1.26-1.07 (m, 6H), 0.80 (m,
2H); 13 C NMR (IOO MHZ, CD 3 OD) δ 166.9, 155.6, 154.9, 150.4, 138.5, 128.0, 123.6, 100.3,
70.4, 55.3, 38.8, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4.
211
Cyclohexylmethyl 4-(3-chloro-4,5-dihydroxyphenyI)-6-ethyl-2-oxo-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate (211)
1 H NMR (400 MHz, DMSO-sfc) δ 9.17 (bs, IH), 7.59 (bs, IH), 6.67 (s, IH), 6.65 (s, IH), 5.00 (s, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.73 (dd, J= 10.8, 6.0 Hz, IH), 3.22 (bs, 2H), 2.72- 2.79 (m, IH), 2.62-2.68 (m, IH), 1.46-1.66 (m, 6H), 1.11-1.23 (m, 6H), 0.81-0.89 (m, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 164.7, 153.8, 152.0, 146.3, 147.9, 135.9, 119.4, 117.8, 111.7, 97.9, 68.0, 53.3, 38.8, 36.6, 29.0, 28.8, 25.7, 25.1, 23.9, 12.9.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.8 mL/min): 211a t R = 19.0 min, 211b t R = 25.3 min.
212
Cyclohexylmethyl 6-ethyI-4-(3-fluoro-4,5-dihydroxyphenyl)-2-oxo-l,2,3)4- tetrahydropyrimidine-5-carboxylate (212)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.46 (bs, IH), 9.16 (s, IH), 8.91 (bs, IH), 7.60 (s, IH), 6.51 (d, J= 1.6 Hz, IH), 6.41 (dd, J= 11.4, 2.2 Hz, IH), 4.96 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.71 (dd, J- 10.8, 6.0 Hz, IH), 2.74-2.59 (m, 2H), 1.61-1.40 (m, 6H), 1.18-1.03 (m, 6H), 0.87-0.78 (m, 2H); 13 C NMR (IOO MHz, DMSO-J 15 ) δ 165.6, 154.7, 153.4, 152.9, 151.1, 148.14, 148.08, 135.83, 135.77, 133.06, 132.9, 109.8, 105.3, 105.1, 98.7, 68.8, 54.0, 37.5, 29.74, 29.65, 26.4, 25.93, 25.91, 24.6, 13.7.
Enantiomeric pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.8 mL/min): 212a t R = 18.2 min, 212b t R = 32.6 min.
213
Cyclohexylmethyl 6-ethyl-2-oxo-4-(3,4,5-trihydroxyphenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (213)
1 H NMR (400 MHz, CDCl 3 + DMSO-J 6 ) δ 6.29 (s, 2H), 5.10 (s, IH), 3.83 (dd, J= 10.8, 6.4 Hz, IH), 3.75 (dd, J= 10.8, 6.4 Hz, IH), 2.58-2.74 (m, 2H), 1.45-1.63 (m, 6H), 1.03-1.18 (m, 6H), 0.78-0.82 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 + DMSO-J 6 ) δ 166.0, 151.3, 145.1, 135.3, 105.6, 100.9, 69.6, 55.1, 37.2, 29.7, 26.3, 25.7, 25.2, 12.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 30% i- PrOH in n-Hexanes, 0.8 mL/min): 213a t R = 21.0 min, 213b t R = 36.9 min.
214
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-2-oxo-l,2,3 » 4- tetrahydropyrimidine-5-carboxylate (214)
1 H NMR (400 MHz, CD 3 OD) δ 6.70 (s, IH), 6.62 (d, J= 10.8 Hz, IH), 5.23 (s, IH), 3.96 (dd, J= 10.8, 5.6 Hz, IH), 3.84 (s, 3H), 3.75 (dd, J= 10.8, 5.6 Hz, IH), 2.72-2.85 (m, 2H), 1.46- 1.68 (m, 6H), 1.11-1.27 (m, 6H); 13 C NMR (IOO MHz, CD 3 OD) δ 167.1, 154.2, 151.1, 135.5, 135.4, 107.9, 106.9, 100.7, 70.3, 56.9, 55.9, 38.8, 30.7, 27.4, 27.0, 25.7, 13.5.
CycIohexylmethyl 4-(3-chloro-4,5-dimethoxyphenyl)-6-ethyl-2-oxo-l,2,3 5 4- tetrahydropyrimidine-5-carboxylate (215)
1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (bs, IH), 6.84 (s, IH), 6.71 (s, IH), 6.38 (bs, IH), 5.26 (s, IH), 3.87 (dd, J= 10.6, 5.8 Hz, IH), 3.78 (s, 3H), 3.76 (s, 3H), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.72 (q, J= 7.2 Hz, 2H), 1.45-1.62 (m, 6H), 1.02-1.25 (m, 6H), 0.79-0.81 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.2, 154.0, 153.8, 152.6, 145.0, 140.1, 128.4, 119.9, 109.2, 99.6, 69.5, 60.6, 56.0, 55.0, 37.2, 29.7, 26.3, 25.7, 25.2, 12.7.
216
Cyclohexylmethyl 4-(3-bromo-4,5-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxylate (216)
1 H NMR (400 MHz, DMSOd 6 ) δ 9.18 (s, IH), 7.60 (s, IH), 6.76 (d, J= 1.6 Hz, IH), 6.67 (d, J= 1.6 Hz, IH), 4.95 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.6, 5.8 Hz, IH), 3.69 (dd, J= 10.6, 5.8 Hz, IH), 2.74-2.59 (m, 2H), 1.62-1.41 (m, 6H), 1.14-1.03 (m, 6H), 0.87-0.76 (m, 2H); 13 C NMR (100 MHz, DMSOd 6 ) δ 164.9, 154.1, 152.1, 146.3, 142.2, 136.7, 120.9, 112.4, 109.1, 98.1, 68.2, 53.4, 36.8, 29.14, 29.08, 25.8, 25.3, 24.0, 13.1.
CyclohexyImethyl 6-ethyl-4-(2-fluoro-4,5-dihydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (217)
1 R NMR (400 MHz, DMSOd 6 ) δ 9.21 (bs, 2H), 8.89 (s, IH), 7.53 (s, IH), 6.57 (d, J= 7.6 Hz, IH), 6.46 (d, J= 11.2 Hz, IH), 5.30 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.6, 6.2 Hz, IH), 3.66 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.62 (m, 2H), 1.60-1.39 (m, 6H), 1.16-1.02 (m, 6H), 0.84-0.72 (m, 2H); 13 C NMR (IOO MHZ, DMSOd 6 ) δ 165.4, 154.9, 153.9, 152.7, 151.6, 146.3, 146.2, 142.26, 142.24, 121.9, 121.7, 114.4, 114.3, 103.5, 103.2, 97.7, 68.8, 48.1, 37.4, 29.6, 29.5, 26.4, 25.97, 25.94, 24.6, 13.7.
CyclohexyImethyI 4-(l-bromonaphthalen-2-yl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (218)
1 H NMR (400 MHz, DMSOd 6 ) δ 9.36 (s, IH), 8.28 (d, J= 8.4 Hz, IH), 7.96 (d, J= 8.8 Hz, IH), 7.73 (d, J= 8.0 Hz, IH), 7.74 (s, IH), 7.69 (t, J= 7.6 Hz, IH), 7.59 (t, J= 7.4 Hz, IH), 7.41 (d, J= 8.4 Hz, IH), 5.96 (d, J= 2.8 Hz, IH), 3.76 (dd, J= 10.8, 6.8 Hz, IH), 3.53 (dd, J
= 10.8, 6.8 Hz, IH), 2.82-2.72 (m, 2H), 1.35-1.13 (m, 9H), 0.94-0.63 (m, 3H), 0.54-0.42 (m, 2H); 13 C NMR (100 MHz, DMSO-J 15 ) δ 165.2, 156.1, 152.1, 141.8, 134.3, 132.3, 129.5, 128.8, 128.6, 127.9, 127.4, 125.6, 122.7, 97.7, 68.8, 55.7, 37.3, 29.6, 29.2, 26.2, 25.8, 25.6, 24.7, 13.7.
Cyclohexylmethyl 4-(4-(tert-butoxycarbonylamino)-3,5-dichlorophenyl)-6-ethyl- 2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (219)
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (bs, IH), 7.28 (s, 2H), 6.44 (bs, IH), 6.36 (bs, IH), 5.31
(d, J= 3.2 Hz, IH), 3.87 (m, 2H), 2.84 (dd, J= 13.2, 7.6 Hz, IH), 2.64(dd, J= 13.4, 7.4 Hz,
IH), 1.71-1.45 (m, 15H), 1.28-1.07 (m, 6H), 0.90 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ
D 165.2, 153.5, 153.3, 144.3, 134.1, 132.0, 126.8, 99.4, 81.4, 72.4, 54.8, 37.3, 30.02, 29.97,
28.4, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 5-
10% /-PrOH in rc-Hexanes, 6.5 mL/min): 219a t R = 49.8 min, 219b t R = 53.4 min.
Cyclohexylmethyl 4-(4-amino-3,5-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (220)
1 U NMR (400 MHz, CD 3 OD) δ 7.08 (s, 2H), 5.13 (s, IH), 3.96 (dd, J= 10.6, 6.2 Hz, IH), 3.71 (dd, J= 11.0, 5.8 Hz, IH), 2.77 (m, 2H), 1.66-1.43 (m, 6H), 1.27-1.08 (m, 6H), 0.84 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 167.0, 155.3, 155.0, 141.9, 135.5, 127.5, 120.3, 100.5, 70.4, 55.4, 38.8, 30.9, 30.8, 27.5, 27.0, 25.7, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in rc-Hexanes, 6.5 mL/min): 220a t R = 12.2 min, 220b t R = 15.5 min.
221
Cyclohexylmethyl 4-(2,3-dibromo-4,5-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (221)
1 H NMR (400 MHz, DMSO-J 6 ) δ 10.04 (bs, IH), 9.54 (bs, IH), 9.28 (s, IH), 7.49 (s, IH), 6.73 (s, IH), 5.56 (d, J= 2.8 Hz, IH), 3.83 (dd, J= 10.8, 6.4 Hz, IH), 3.57 (dd, J= 10.8, 6.4 Hz, IH), 2.83-2.26 (m, 2H), 1.53-1.22 (m, 6H), 1.20-0.95 (m, 6H), 0.72-0.60 (m, 2H); 13 C NMR (100 MHz, DMSO-^ 5 ) δ 164.6, 154.9, 151.6, 145.5, 144.3, 135.3, 114.0, 113.2, 113.1, 97.5, 68.1, 55.2, 54.9, 38.9, 36.8, 29.1, 28.7, 25.7, 25.4, 23.9, 13.0.
Dihydropyrimidine aryl ketone analogs at C-5 position.
General procedure for the synthesis of β-keto thiol esters
To a 0 0 C solution of diisopropylamine (707 μL, 5.00 mmol, 1.1 equiv) in THF (10 mL) was added n-BuLi (2.5 M in «-Hexanes, 2.0 mL, 5.00 mmol, 1.1 equiv) via a syringe under Ar. After 30 min at 0 0 C, the reaction was cooled to -78 °C and then treated with a solution of thiol ester (4.54 mmol, 1.0 equiv) in THF (2 mL) via a cannula. After 30 min at -78 °C, aldehyde (4.54 mmol, 1.0 equiv) was added dropwise, and the whole reaction mixture was allowed to stir at -78 °C for another 10 min. The reaction was then quenched by the addition of saturated aqueous NH 4 Cl (10 mL), and the reaction mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography (SiO 2 , π-Hexanes/Et 2 O = 5:1→ 2:1) to give β -hydroxy thiol esters.
To a 0 °C solution of the above β-hydroxy thiol ester (1.00 mmol, 1.0 equiv) and NaHCO 3 (253 mg, 3.00 mmol, 3.0 equiv) in CH 2 Cl 2 (10 mL) was added Dess-Martin periodinane solution (15% by wt in CH 2 Cl 2 , 2.5 mL, 1.20 mmol, 1.2 equiv). After 5 min at 0 0 C, the reaction was warmed to 25 ° C and then further stirred for 1 h. The resulting mixture was diluted with n-Hexanes (10 mL) and filtered through a pad of silica gel (rinsed with n- Hexanes/EtOAc = 2:1). After concentrated in vacuo, the residue was purified via flash column chromatography (SiO 2 , rø-Hexanes/Et 2 O = 15:1) to give β-keto thiol esters.
General procedure for Biginelli reaction with β-keto thiol esters
The β-keto thiol ester (0.573 mmol, 1.0 equiv), aldehyde (0.573 mmol, 1.0 equiv), urea (0.860 mmol, 1.5 equiv), and Yb(OTf) 3 (0.057 mmol, 0.1 equiv) were dissolved in THF (2 mL) and stirred under Ar for 16 h at 75 "C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (4 x 20 mL). The combined organic layers were dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give Biginelli adducts.
General procedure for ketone analogs using Pd-eatalvzed cross couplings
Thiol ester (0.13 mmol, 1.0 equiv), boronic acid (0.26 mmol, 2.0 equiv), CuTC (0.39 mmol, 3.0 equiv), Pd(OAc) 2 (10 mol%) and PPh 3 (20 mol%) were added to a sealed tube and flushed with Ar. Then anhydrous THF was added. The reaction mixture was heated for overnight at
75 °C. After cooling to 25 0 C, the reaction mixture was diluted with EtOAc and washed with 10% aqueous NH 3 , and then dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , CH 2 Cl 2 ZMeOH = 10:1) to give ketone analogs.
S-Ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3 5 4-tetrahydropyrimidine-5-carbothioate
(222)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.79-6.67 (m, 2H), 6.66-6.65 (m, IH), 5.36 (s, IH), 2.85-2.79 (m, 2H), 2.76-2.65 (m, 2H), 1.22 (t, J= 8.0 Hz, 3H), 1.15 (t, J= 8.0 Hz, 3H).
223
5-Benzoyl-6-ethyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2 (lJjT)-one (223) 1H NMR (400 MHz, CD 3 OD) δ 7.52-7.48 (m, 3H), 7.43-7.39 (m, 2H), 7.18 (t, J= 7.6 Hz, IH), 6.78 (t, J= 7.6 Hz, IH), 6.71 (s, IH), 5.43 (s, IH), 3.71 (s, 3H), 2.09 (q, J= 7.6 Hz, 2H), 1.04 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 196.5, 160.1, 154.3, 148.5, 145.1, 140.6, 131.9, 129.6, 128.4, 127.9, 118.3, 113.0, 111.8, 110.0, 56.6, 54.4 ,24.1, 11.9; TLC R f («-Hexanes:EtOAc 1 :1) = 0.27.
223 5-Benzoyl-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2 (ljF/)-one (224)
1 H NMR (400 MHz, CD 3 OD) δ 7.50-7.47 (m, 3H), 7.41-7.37 (m, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.38 (s, IH), 2.13-2.09 (m, 2H), 1.02 (t, J=8.0 Hz, 3H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 224a t R = 63.4 min, 224b t R = 86.9 min.
225 6-Ethyl-4-(3-hydroxyphenyl)-5-(4-methyIbenzoyl)-3,4-dihydrop yrimidin-2(lH)-one (225)
1 H NMR (400 MHz, CD 3 OD) δ 7.42 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.06 (t, J=
7.6 Hz, IH), 6.68-6.63 (m, 3H), 5.40 (s, IH), 2.36 (s, 3H), 2.15-2.00 (m, 2H), 1.03 (t, J= 7.6
Hz, 3H); 13 C NMR (IOO MHZ, CD 3 OD) δ 196.5, 157.6, 154.5, 146.8, 145.2, 143.2, 137.7,
129.5, 129.0, 128.3, 117.2, 114.5, 112.9, 110.3, 56.8, 24.0, 20.3, 11.8; TLC R 1 (EtO Ac only) =
0.18.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i-
PrOH in n-Hexanes, 0.80 mL/min): 225a t R = 50.9 min, 225b t R = 64.9 min.
226 6-Ethyl-5-(4-ethylbenzoyl)-4-(3-hydroxyphenyl)-3,4-dihydropy rimidin-2(l/7)-one (226)
1 U NMR (400 MHz, CD 3 OD) δ 7.43 (d, J= 8.4 Hz, 2H), 7.23 (d, J= 8.0 Hz, 2H), 7.04 (t, J= 7.6 Hz, IH), 6.67-6.60 (m, 3H), 5.38 (s, IH), 2.68-2.62 (m, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H), 1.01 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 196.6, 157.6, 154.5, 149.5, 146.8, 145.2, 137.9, 129.5, 128.4, 127.9, 117.2, 114.5, 112.9, 110.4, 56.8, 28.6, 24.0, 14.5, 11.8; TLC ^ 7 (EtOAc only) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 226a t R = 45.6 min, 226b t R = 58.2 min.
227 5-(3,5-Dimethylbenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihy dropyrimidin-2(ljBF)-oiie
(227)
1 H NMR (400 MHz, CD 3 OD) δ 7.23 (s, 2H), 7.14 (s, IH), 7.08-7.00 (m, IH), 6.66-6.63 (m,
3H), 5.32 (s, IH), 2.31 (s, 6H), 2.14-2.07 (m, 2H), 1.01 (t, J= 7.6 Hz, 3H); 13 C NMR (100
MHz, CD 3 OD) δ 197.1, 157.7, 154.5, 147.6, 145.2, 140.7, 138.3, 133.4, 129.5, 125.6, 117.2,
114.5, 112.9, 110.5, 56.6, 24.0 ,19.9, 11.6; TLC i?/(EtOAc only) = 0.15.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i-
PrOH in ra-Hexanes, 0.80 mL/min): 227a t R = 47.9 min, 227b t R = 59.3 min.
228 6-Ethyl-5-(4-fluorobenzoyl)-4-(3-hydroxyphenyl)-3,4-dihydrop yrimidin-2(lJH)-one (228)
1 H NMR (400 MHz, CD 3 OD) δ 7.60-7.54 (m, 2H), 7.15-7.10 (m, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.64-6.61 (m, 3H), 5.36 (s, IH), 2.17-2.10 (m, 2H), 1.04 (t, J= 8.0 Hz, 3H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 228a t R = 49.0 min, 228b t R = 71.8 min.
229 5-(4-Chlorobenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydrop yrimidin-2(lH)-one (229)
1 U NMR (400 MHz, CD 3 OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.64-6.61 (m, 3H),5.35 (s, IH), 2.16-2.10 (m, 2H), 1.04 (t, J= 8.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 195.1, 157.7, 154.3, 148.3, 145.1, 139.1, 138.1, 131.9, 131.8, 129.7, 129.6, 128.8, 128.7, 117.3, 114.6, 113.0, 109.9, 56.7, 24.2, 11.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in rc-Hexanes, 0.80 mL/min): 229a t R = 22.0 min, 229b t R = 31.9 min.
230
5-(4-tert-Butylbenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-d ihydropyrimidin-2(liϊ)-one
(230)
1 K NMR (400 MHz, CD 3 OD) δ 7.45 (bs, 4H), 7.05 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.38 (s, IH), 2.13-2.06 (m, 2H), 1.31 (s, 9H), 1.02 (t, J= 8.0 Hz, 3H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 230a t R = 33.7 min, 230b t R = 46.1 min.
231
6-Ethyl-4-(3-hydroxyphenyl)-5-(4-methoxybenzoyl)-3,4-dihy dropyrimidin-2(lJϊ)-one
(231)
1 H NMR (400 MHz, CD 3 OD) δ 7.53 (dd, J= 9.4, 2.0 Hz, 2H), 7.04 (t, J= 8.0 Hz, IH), 6.91 (dd, J= 9.4, 2.0 Hz, 2H), 6.67-6.60 (m, 3H), 5.37 (s, IH), 2.09-2.01 (m, 2H), 1.02 (t, J= 8.0 Hz, 3H).
Dihydropyrimidine aliphatic ketone analogs at C-5 position.
4-(3-Chloro-4-hydroxyphenyl)-5-(2-(cyclohexyIoxy)acetyl)- 6-ethyl-3,4- dihydropyrimidin-2(llϊ)-one (232)
1 H NMR (400 MHz, CD 3 OD) δ 7.12 (d, J= 2.4 Hz, IH), 7.06 (dd, J= 4.2, 2.0 Hz, IH), 6.83 (d, J= 8.4 Hz, IH), 5.58 (s, IH), 4.92-4.83 (m, 2H), 3.67-3.60 (m, IH), 2.70-2.60 (m, 2H), 1.85-1.01 (m, 10H), 0.99 (t, J= 7.2 Hz, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 210.0, 155.9, 153.8, 136.1, 131.2, 129.7, 128.8, 126.8, 121.8, 117.6, 113.2, 81.2, 53.9, 33.9, 33.5, 33.2, 26.7, 24.7, 24.6, 8.2; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.23.
233
4-(3-Chloro-4-hydroxyphenyl)-6-(cyclohexyloxymethyl)-5-pr opionyl-3,4- dihydropyrimidin-2(l//)-one (233)
1 H NMR (400 MHz, CD 3 OD) δ 7.23 (s, IH), 7.06 (d, J= 8.4 Hz, IH), 6.87 (d, J= 8.4 Hz, IH), 5.36 (s, IH), 4.70 s, 2H), 3.46-3.40 (m, IH), 2.56-2.47 (m, IH), 2.18-2.10 (m, IH), 1.98- 1.94 (m, 2H), 1.77-1.74 (m, 2H), 1.45-1.23 (m, 6H), 0.88 (t, J= 7.2 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 199.3, 153.3, 152.8, 148.5, 135.3, 128.4, 126.3, 120.9, 116.9 107.3, 78.6, 65.1, 54.4, 33.3, 31.9, 25.6, 23.7, 7.0; TLC i?/(n-Hexanes:EtOAc 1:2) = 0.35.
234
2-ChIoro-4-(5-(3-cyclopentylpropanoyl)-6-ethyl-2-oxo-l,2, 3,4-tetrahydropyrimidin-4- yl)phenyl acetate (234)
1 H NMR (400 MHz, CD 3 OD) δ 7.42 (d, J= 2.0 Hz, IH), 7.29 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.19 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.70 (m, 2H), 2.52 (m, IH), 2.31 (m, 4H), 1.65-1.36 (m, 9H), 1.26 (t, J= 7.6 Hz, 3H), 0.91 (m, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.64.
235
4-(3-Chloro-4-hydroxyphenyl)-5-(3-cycIopentylpropanoyl)-6 -ethyl-3,4- dihydropyrimidin-2(l/?)-oiie (235)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.4 Hz, 2.0Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.67 (q, J= 8.4 Hz, 2H), 2.43 (m, IH), 2.25 (m, IH), 1.61-1.33 (m, 10H), 1.23 (t, J= 7.4 Hz, 3H), 0.92 (m, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.25.
236
2-Chloro-4-(6-(2-cyclopentylethyl)-2-oxo-5-propionyI-l,2, 3,4-tetrahydropyrimidin-4- yl)phenyl acetate (236)
1 H NMR (400 MHz, CD 3 OD) δ 7.42 (d, J- 2.0 Hz, IH), 7.28 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.19 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.73 (m, 2H), 2.59 (m, IH), 2.28 (m, 4H), 1.86 (m, 3H), 1.67 (m, 3H), 1.56 (m, 2H), 1.25 (m, 3H), 0.96 (t, J= 7.2 Hz, 3H); TLC ^/(CH 2 Cl 2 :MeOH 19:1) = 0.64.
4-(3-Chloro-4-hydroxyphenyl)-6-(2-cyclopentylethyl)-5-pro pionyI-3,4- dihydropyrimidin-2(l//)-one (237)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.85 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.70 (m, 2H), 2.51 (dd, J= 17.2, 7.2 Hz, IH), 2.20 (dd, J = 17.2, 7.2 Hz, IH), 1.86 (m, 3H), 1.66-1.54 (m, 5H), 1.23 (m, 5H), 0.91 (t, J= 7.2 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.25.
238
4-(3-Chloro-4-hydroxyphenyI)-6-ethyl-5-(3-phenylpropanoyl )-3,4-dihydropyrimidin- 2(li7)-one (238)
1 U NMR(400MHz, CD 3 OD) δ 7.15 (m, 3H), 7.09 (d, J= 7.6 Hz, IH), 6.99 (m, 3H), 6.84 (d, J = 8.4 Hz, IH), 5.27 (s, IH), 2.78-2.62 (m, 5H), 2.59-2.51 (m, IH), 1.21 (t, J= 7.6 Hz, 3H); 13 C NMR(IOOMHZ, CD 3 OD) δ 197.8, 153.2, 152.9, 144.3, 141.0, 135.4, 128.1, 127.8, 127.8, 126.0, 125.4, 120.5, 116.5, 108.1, 54.0, 41.9, 29.9, 24.6, 11.7; TLC i?/(CH 2 Cl 2 :Me0H 95:5) =0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 40% i-PrOH in rc-Hexanes gradient, 4.0 mL/min): 238a t R = 89.1 min, 238b fø = 131.4 min.
4-(3-Chloro-4-hydroxyphenyl)-6-phenethyI-5-propionyl-3,4- dihydropyrimidin-2(lH)- one (239)
1 H NMR (400 MHz, CD 3 OD) δ 7.31-7.22 (m, 5H), 7.17 (t, J= 7.0 Hz, IH), 6.99 (dd, J= 2.0, 8.4 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.94 (m, 4H), 2.44 (m, IH), 2.14 (m, IH), 0.88 (t, J= 7.2 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 95:5) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 40% z-PrOH in rc-Hexanes gradient, 4.0 mL/min): 239a t R = 73.6 min, 239b t R = 115.2 min.
(S)-4-(3-Chloro-4-hydroxyphenyl)-5-(3-cyclohexylpropanoyl )-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (240a)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 1.6 Hz, IH), 7.06-7.04 (m, IH), 6.86 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.69-2.64 (m. 2H), 2.39-2.35 (m, IH), 2.30-2.26 (m, IH), 2.05-1.99 (m, IH), 1.62-1.51 (m, 2H), 1.48-0.98 (m, 10H), 0.88-0.71 (m, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 199.7, 153.5, 153.1, 152.8, 135.8, 128.4, 126.3, 120.7, 116.7, 108.4, 61.0, 54.4, 38.0, 37.3, 33.1, 32.8, 31.7, 26.4, 26.1, 24.9, 12.0; TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in rc-Hexanes, 0.80 mL/min): 240a ^ = 17.2 min.
(S)-4-(3-Chloro-4-hydroxyphenyl)-6-(2-cyclohexylethyI)-5- propionyl-3,4- dihydropyrimidin-2(lH)-one (241a)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (s, IH), 7.03 (d, J= 9.2 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.74-2.64 (m. 2H), 2.54-2.48 (m, IH), 2.23-2.17 (m, IH), 2.05-1.99 (m, IH), 1.81-1.64 (m, 2H), 1.54-0.96 (m, 10H), 0.92-0.86 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 199.5, 153.6, 153.5, 152.2, 135.6, 128.4, 126.1, 120.8, 116.7, 108.4, 61.0, 54.2, 38.1, 36.0, 33.8, 33.1, 33.0, 29.3, 26.5, 26.2, 7.4; TLC i?/(Hexanes: EtOAc 1:1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 niL/min): 241a tn = 15.3 min.
242a
(5)-2-Chloro-4-(5-(3-cycloheptylpropanoyl)-6-ethyl-2-oxo- l,2,3,4-tetrahydropyrimidin- 4-yl)phenyl acetate (242a)
1 U NMR (400 MHz, CD 3 OD) δ 7.42(d, J= 2.0 Hz, IH), 7.29 (dd, J= 8.4, 2.0 Hz, IH), 7.20 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.71 (m, 2H), 2.47 (m, IH), 2.31 (m, 4H), 1.55-1.24 (m, HH), 1.20-0.87 (m, 4H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.50.
243a
(S)-4-(3-Chloro-4-hydroxyphenyl)-5-(3-cycloheptylpropanoy l)-6-ethyI-3,4- dihydropyrimidin-2(lH)-one (243a)
1 H NMR (400 MHz, CD 3 OD) δ 7.22 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.4 Hz, 1.6 Hz, IH), 6.87 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.67 (q, J= 7.2 Hz, 2H), 2.38 (m, IH), 2.25 (m, IH), 1.52 (m, 8H), 1.32 (m, 8H), 1.05 (m, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.29.
(-S)-2-Chloro-4-(6-(2-cycIoheptylethyl)-2-oxo-5-propionyI -l,2,3j4-tetrahydropyrimidin-4- yl)phenyl acetate (244a)
1 H NMR (400 MHz, CD 3 OD) δ 7.42 (d, J= 2.0 Hz, IH), 7.28 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.18 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.74 (m, 2H), 2.60 (m, IH), 2.31 (s, 3H), 2.26 (m, IH), 1.82 (m, 2H), 1.69 (m, 2H), 1.56 (m, 5H), 1.31 (m, 3H), 0.96 (t, J= 7.2 Hz, 3H); TLC R f (CH 2 Cl 2 :Me0H 19:1) = 0.50.
(S)-4-(3-Chloro-4-hydroxyphenyl)-6-(2-cycloheptylethyl)-5 -propionyl-3,4- dihydropyrimidin-2(ljH)-one (245a)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.85 (d, J= 8.4Hz, IH), 5.30 (s, IH), 2.70 (m, 2H), 2.51 (m, IH), 2.19 (m, IH), 1.79 (m, 2H), 1.69 (m, 2H), 1.53 (m, 10H), 1.24 (m, 5H), 0.91 (t, J= 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc + 0.5% MeOH) = 0.29.
(S)-4-(3-Chloro-4-hydroxyphenyl)-5-(2-cyclopentylacetyl)- 6-ethyl-3,4- dihydropyrimidin-2(lH)-one (246a)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (d, J= 2.0 Hz, IH ), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.69-2.63 (m, 2H), 2.53-2.47 (m, IH), 2.25-2.11 (m, IH), 1.67-1.39 (m, 9H), 0.99 (t, J= 8.2 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 199.3, 156.2, 153.6, 153.1, 135.8, 128.4, 126.3, 120.7, 116.7, 108.8, 35.5, 54.4, 36.0, 32.3, 32.0, 24.9, 24.6, 24.5, 12.1; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.42.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in «-Hexanes, 0.80 mL/min): 246a t R = Yl 2 min.
(5)-4-(3-ChIoro-4-hydroxyphenyl)-6-ethyl-5-(2-phenylacety l)-3,4-dihydropyrimidin-
2(U2)-one (247a)
1 H NMR (400 MHz, CD 3 OD) δ 7.15-7.08 (m, 4H), 6.98 (dd, J= 8.4, 2 Hz, IH ), 6.89 (d, J=
7.2 Hz, 2H), 6.78 (d, J= 8.4 Hz, IH), 5.27 (s, IH), 3.68 (d, J= 15.6 Hz, IH ), 3.46 (d, J=
15.6 Hz, IH ), 2.60-2.58 (m, 2H), 1.13 (t, J= 7.4 Hz, 3H ); 13 C NMR (100 MHz, CD 3 OD) δ
196.7, 154.1, 153.4, 153.1, 135.5, 135.0, 129.0, 128.4, 128.3, 126.5, 126.3, 120.8, 116.8,
108.0, 54.2, 24.9, 24.0, 12.0; TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15%
/-PrOH in rc-Hexanes, 0.80 mL/min): 247a t R = 26.3 min.
(S)-6-Benzyl-4-(3-chloro-4-hydroxyphenyl)-5-propionyl-3,4 -dihydropyrimidin-2(lH)- one (248a)
1 H NMR (400 MHz, CD 3 OD) δ 7.26-7.19 (m, 4H), 7.15-7.13 (m, 2H), 6.96 (dd, J= 8.4, 2 Hz, IH ), 6.76 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 4.08-3.98 (m, 2H), 2.50-2.43 (m, IH), 2.17-2.06 (m IH), 0.81 (t, J= 7.2 Hz, 3H ); 13 C NMR (100 MHz, CD 3 OD) δ 199.7, 160.1, 153.1, 152.6, 148.4, 137.3, 135.7, 128.6, 128.0, 126.7, 126.6, 120.8, 116.7, 110.1, 54.3, 36.2, 33.9, 7.3; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in ra-Hexanes, 0.80 mL/min): 248a t R = 29.2 min.
4-(3-Chloro-4-hydroxyphenyl)-5-(2-cyclohexylacetyl)-6-eth yl-3,4-dihydropyrimidin- 2(LH)-OiIe (249)
1 H NMR (400 MHz, CD 3 OD) δ 7.19 (d, J= 2.4 Hz, IH), 7.04-7.02 (m, IH), 6.85 (d, J= 8.4 Hz, IH), 5.27 (s, IH), 2.67-2.62 (m. 2H), 2.34-2.23 (m, IH), 2.11-2.04 (m, IH), 1.68-1.03 (m, HH), 0.92-0.64 (m, 3H); 13 C NMR (IOO MHz, CD 3 OD) δ 199.1, 153.6, 153.0, 152.5, 135.7, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 34.5, 33.1, 32.9, 26.1, 26.0, 24.9, 12.1; TLC R f (n- Hexanes:EtOAc 1 :1) = 0.36.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% /- PrOH in «-Hexanes, 0.80 mL/min): 249a t R = 17.2 min, 249b t R = 30.8 min.
250
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methylcycloh exyl)acetyI)-3,4- dihydropyrimidin-2(l/f)-one (250)
1 H NMR (400 MHz, CD 3 OD) δ 7.22 (d, J= 2.4 Hz, IH), 7.07-7.05 (m, IH), 6.88 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.68 (q, J= 7.6 Hz, 2H), 2.37-2.32 (m, IH), 2.09 (dd, J= 15.6, 6.8 Hz, IH), 1.63-1.56 (m, 4H), 1.46-1.40 (m, IH), 1.34-1.14 (m, 6H), 0.94-0.71 (m, 5H); 13 C NMR (100 MHz, CD 3 OD) 6 200.4, 154.9, 154.3, 153.8, 137.0, 129.6, 127.5, 121.9, 117.9, 110.2, 55.5, 49.5, 36.2, 36.1, 35.6, 34.2, 34.1, 33.7, 31.8, 31.3, 30.4, 26.1, 23.0, 13.3; TLC R f (n- Hexanes:EtOAc 1:1 + 2% MeOH) = 0.24.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in n-Hexanes, 6.5 mL/min): 250a ϊ R = 18.1 min, 250b fø = 36.2 min.
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methylenecyc lohexyl)acetyl)-3,4- dihydropyrimidin-2(lH)-one (251)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (s, IH), 7.03 (d, J= 7.6 Hz, IH), 6.84 (d, J= 8.0 Hz, IH), 5.29 (s, IH), 4.55 (s, 2H), 2.64 (q, J= 6.8 Hz, 2H), 2.33 (dd, J= 15.4 Hz, 5.8 Hz, IH), 2.27-1.78 (m, 6H), 1.66 (d, J= 10.8 Hz, IH), 1.49 (d, J= 11.2 Hz, IH), 1.21 (t, J= 6.8 Hz, 3H), 0.90-0.70 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 198.7, 153.7, 153.0, 152.6, 148.9, 135.8, 128.4, 126.3, 120.8, 116.8, 109.0, 106.4, 54.3, 34.3, 34.2, 34.1, 33.9, 25.0, 12.2; TLC tf/(«-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.25.
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-ethylcyclohe xyl)acetyl)-3,4- dihydropyrimidin-2(lH)-one (252)
1 K NMR (400 MHz, CD 3 OD) δ 7.22 (d, J- 2.0 Hz, IH), 7.09-7.05 (m, IH), 6.88 (d, J= 8.8
Hz, IH), 5.30 (s, IH), 2.68 (q, J= 7.6 Hz, 2H), 2.37-2.32 (m, IH), 2.10 (dd, J= 15.4, 7.0 Hz,
IH), 1.72-1.58 (m, 4H), 1.48-1.45 (m, IH), 1.35-1.12 (m, 8H), 0.95-0.70 (m, 5H); 13 C NMR
(100 MHz, CD 3 OD) δ 200.2, 152.6, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 48.3, 39.5,
34.8, 33.1, 32.9, 32.6, 32.5, 29.8, 24.9, 12.1, 10.6; TLC i?/(«-Hexanes:EtOAc 1 :1 +2%
MeOH) = 0.23.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15%
Z-PrOH in rc-Hexanes, 6.5 mL/min): 252a t R = 20.0 min, 252b t R = 38.6 min.
253
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(3-methylcycloh exyl)acetyl)-3,4- dihydropyrimidin-2(l//)-oiie (253)
1 H NMR (400 MHz, CD 3 OD) δ 6.99 (s, IH), 6.83 (d, J= 8.0 Hz, IH), 6.65 (d, J= 8.4Hz, IH), 5.08 (s, IH), 2.45 (q, J= 7.2 Hz, 2H), 2.11 (m, IH), 1.89 (m, IH), 1.52-1.30 (m, 5H), 1.18- 1.00 (m, 8H), 0.92 (d, J= 6.0 Hz, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 199.2, 153.7, 153.1, 152.5, 135.8, 128.5, 126.4, 120.7, 116.7, 109.1, 54.4, 41.8, 34.8, 34.7, 32.7, 32.5, 26.0, 24.9, 22.0, 12.2; TLC R 1 (CH 2 Cl 2 : MeOH 95:5) = 0.12.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25- 40% /-PrOH in ra-Hexanes gradient, 4.0 mL/min): 253a t R = 29.7 min, 253b t R = 52.6 min.
254
4-(3-Chloro-4-hydroxyphenyI)-6-ethyl-5-(2-(4-(propan-2-yl idene)cyclohexyl)acetyl)-3,4- dihydropyrimidin-2(l/?)-one (254)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.2 Hz, 2.2 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.66 (q, J= 7.6 Hz, 2H), 2.56 (m, 2H), 2.33 (dd, J= 15.4, 6.2 Hz, IH), 2.10 (dd, J= 15.4, 7.0 Hz, IH), 1.81 (m, IH), 1.68-1.56 (m, 9H), 1.24 (t, J = 7.6 Hz, 3H), 0.83 (m, 3H); 13 C NMR (100 MHz, CD 3 OD) δ 198.8, 153.4, 152.8, 152.4, 135.6, 130.7, 128.2, 126.1, 120.5, 120.0, 116.5, 108.8, 54.1, 34.4, 33.8, 33.6, 28.9, 28.94, 28.86, 24.7, 18.7, 18.60, 18.58, 11.9; TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.50.
255
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-isopropylcyc lohexyl)acetyl)-3,4- dihydropyrimidin-2(l//)-one (255)
1 U NMR (400 MHz, CD 3 OD) δ 7.17 (d, J= 6.4 Hz, IH), 7.00 (d, J= 7.2 Hz, IH), 6.82 (d, J= 8.0 Hz, IH), 5.24 (s, IH), 2.61 (q, J= 7.6 Hz, 2H), 2.28 (dd, J= 15.2, 6.0 Hz, IH), 2.03 (dd, J = 15.0, 6.6 Hz, IH), 1.49 (m, 4H), 1.26 (m, 7H), 0.82 (m, 12H); 13 C NMR (100 MHz, CD 3 OD) δ 199.2, 153.7, 153.0, 152.6, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 44.0, 34.8, 33.2, 33.1, 32.8, 29.5, 29.4, 24.9, 19.0, 12.1; TLC i?/(n-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.15.
4-(3-Chloro-4-hydroxyphenyl)-5-(2-cycIoheptylacetyl)-6-et hyl-3,4-dihydropyrimidin- 2(lH)-one (256)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.05-7.03 (m, IH), 6.85 (d, J= 8.8 Hz, IH), 5.28 (s, IH), 2.68-2.62 (m, 2H), 2.35-2.30 (m, IH), 2.17-2.12 (m, IH), 1.59-1.31 (m, 14H), 1.29-0.90 (m, 2H); 13 C NMR (400 MHz, CD 3 OD) δ 199.2, 153.0, 152.5, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 60.3, 54.3, 35.8, 34.5, 34.2, 28.1, 26.2, 26.0, 24.9, 19.6, 13.2, 12.1; TLC i?/(«-Hexanes: EtOAc 1 :1) = 0.67.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 mL/min): 256a t R = 16.0 min, 256b t R = 35.9 min.
257
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-ethyIidenecy clohexyI)acetyl)-3,4- dihydropyrimidin-2(lH)-one (257)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.0 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.28 (s, IH), 2.65 (q, J= 7.6 Hz, 2H), 2.32 (dd, J= 15.2, 6.4 Hz, IH), 2.08 (dd, J= 15.2, 6.8 Hz, IH), 1.64 (m, 3H), 1.45 (m, IH), 1.23 (m, 3H), 1.14 (m, 2H), 0.96 (m, IH), 0.83 (m, 6H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.36.
258
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methoxycyclo hexyl)acetyl)-3,4- dihydropyrimidin-2(liϊ)-one (258)
1 HNMR (400 MHz, CD 3 OD) δ 7.21(d, J= 2.4 Hz, IH), 7.05 (dd, J= 8.4, 2.0 Hz, IH), 6.86 (d, J= 8.0 Hz, IH), 5.30 (s, IH), 3.29 (m, IH), 3.21 (s, 3H), 2.66 (q, J= 7.6 Hz, 2H), 2.34 (dd, J= 15.8, 6.6 Hz, IH), 2.12 (dd, J= 15.8, 7.0 Hz, IH), 1.72 (m, 3H), 1.38 (m, 4H), 1.21 (m, 5H); TLC ^(CH 2 Cl 2 IMeOH 19:1) = 0.07.
259
4-(3-Chloro-4-hydroxyphenyl)-6-((4-methoxycycIohexyl)meth yl)-5-propionyI-3,4- dihydropyrimidin-2(liϊ)-one (259)
1 U NMR (400 MHz, CD 3 OD) δ 7.21 (s, IH), 7.04 (d, J= 8.0 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.32 (s, IH), 3.26 (m, IH), 3.11 (s, 3H), 2.62 (m, 2H), 2.51 (m, IH), 2.20 (m, IH), 1.87- 1.24 (m, 9H), 0.90 (t, J= 7.2 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.07.
Dihydropyrimidine bioisostere analogs at C-5 position General procedure for oxazoline bioisosteres
CHO 25 0
C
Aldehyde (500 mg, 4.46 mmol, 1.0 equiv) was added to a stirred solution OfNaHSO 3 (1.02 g, 9.81 mmol, 2.2 equiv) in H 2 O (3.5 mL) at 25 °C to afford a white solid. The reaction mixture was stirred for 1 h. To the resulting suspension, was cooled at 0 0 C, a solution of KCN (0.64 g, 9.81 mmol, 2.2 equiv) in H 2 O (2.4 mL) was added dropwise. After stirring at 25 °C for 10 min, the reaction mixture was warmed to 25 °C. The precipitate gradually disappeared. The reaction mixture was extracted with Et 2 O (2 x 100 mL). The organic layer was washed with brine (100 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , n-Hexanes/EtOAc = 3:1) to give corresponding 2-cyclohexyl-2-hydroxyacetonitrile (620 mg, 99%): 1 H NMR (400 MHz, CDCl 3 ) 54.25 (d, J= 6.0 Hz, IH), 1.90-1.68 (m, 6H), 1.31-1.05 (m, 5H); 13 C NMR (IOO MHz, CDCl 3 ) δ 119.3, 66.6, 42.5, 28.3, 28.0, 26.1,25.7, 25.6; TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.33.
The solution of 2-cyclohexyl-2-hydroxyacetonitrile (0.6 g, 4.31 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise to a LiAlH 4 (0.36 g, 9.48 mmol, 2.2 equiv) in THF (20 mL) at 0 °C. After warmed to 25 0 C and stirred for 6 h, the reaction mixture was quenched with H 2 O until hydrogen evolution ceased. MgSO 4 was added and the reaction mixture filtered and the solvent removed in vacuo to give a white solid. Trituration with hexane gave the 2-amino-l- cyclohexylethanol (510 mg, 83%) as a white solid: 1 H NMR (400 MHz, CD 3 OD) δ 3.24 (m, IH), 2.71 (dd, J= 13.0, 3.0 Hz, IH), 2.53 (dd, J= 13.0, 8.6 Hz, IH), 1.96-1.64 (m, 6H), 1.38-
1.02 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) δ 76.2, 44.9, 42.1, 29.2, 28.8, 26.7, 26.4, 26.3; TLC i?/(n-Hexanes:EtOAc 5:1) = 0.02.
To a stirring (S)-4-(3-(tert-butyldimethylsilyloxy)phenyl)-6-ethyl-2-oxo-l ,2,3,4- tetrahydropyrimidine-5-carboxylic acid (100 mg, 0.27 mmol, 1.0 equiv) and 2-amino-l- cyclohexylethanol (76 mg, 0.54 mmol, 2.0 equiv) in DMF (1.0 mL) was added EDC (100 mg, 0.54 mmol, 2.0 equiv) and DMAP (65 mg, 0.54 mmol, 2.0 equiv) in one portion at 25 0 C. After stirred for overnight, the reaction mixture was extracted with EtOAc (2 x 100 mL). The organic layers were washed with brine (100 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO 2 , CH 2 Cl 2 /Me0H = 40:1 → 20:1) to give corresponding (S)-4-(3-(tert- butyldimethylsilyloxy)phenyl)-N-(2-cyclohexyl-2-hydroxyethyl )-6-ethyl-2-oxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide (127 mg, 95%): 1 H NMR (400 MHz, CD 3 OD) δ 7.24- 7.19 (m, IH), 6.93 (t, J= 6.2 Hz, IH), 6.84 (d, J= 2.0 Hz, IH), 6.76 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 3.41-3.36 (m, IH), 3.29-3.25 (m, IH), 3.17-2.99 (m, IH), 2.58-2.41 (m, 2H), 1.94-
1.52 (m, 6H), 1.29-1.10 (m, 6H), 1.04-0.95 (m, HH), 0.20 (s, 6H); 13 C NMR (IOO MHZ, CD 3 OD) δ 169.5, 157.5, 157.4, 155.7, 146.2, 146.1, 144.5, 143.7, 131.0, 130.9, 120.8, 120.8, 119.2, 106.4, 106.1, 75.5, 75.4, 57.5, 57.4, 44.2, 42.7, 42.6, 30.3, 28.9, 28.7, 27.3, 27.2, 27.1, 26.2, 24.9, 24.8, 19.1, 13.3, -4.2, -4.22; TLC £/(CH 2 Cl 2 :Me0H 40:1) = 0.16.
A solution of (<S)-4-(3-(tert-butyldimethylsilyloxy)phenyl)-N-(2-cycloh exyl-2-hydroxyethyl)- 6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide (120 mg, 0.24 mmol, 1.0 equiv) and Burgess reagent (85 mg, 0.36 mmol, 1.5 equiv) in dry THF (12 mL) was stirred at 70 0 C for 1 h. After concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , π-Hexanes/EtOAc + 2% MeOH = 1:1) to give corresponding (5)-4-(3- (tert-butyldimethylsilyloxy)phenyl)-5-((i?)-5-cyclohexyl-4,5 -dihydrooxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one 261-a (27 mg, 23%) and (5)-4-(3-(tert- butyldimethylsilyloxy)phenyl)-5-((5)-5-cyclohexyl-4,5-dihydr ooxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one 262-a (33 mg, 29%): 261-a 1 H NMR (400 MHz, CD 3 OD) δ 7.17 (t, J= 7.8 Hz, IH), 6.94 (d, J= 7.6 Hz, IH), 6.83 (t, J= 2.0 Hz, IH), 6.74-6.71 (m, IH), 5.28 (s, IH), 4.34-4.28 (m, IH), 3.80-3.74 (m, IH), 3.56-3.51 (m, IH), 2.76-2.65 (m, 2H), 1.74-
1.53 (m, 6H), 1.41-1.13 (m, 6H), 1.02-0.82 (m, HH), 0.19 (s, 6H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.1, 157.2, 155.9, 148.7, 146.4, 130.6, 121.0, 120.5, 119.2, 98.6, 85.1, 57.0, 56.4, 43.8, 29.4, 28.9, 27.4, 26.9, 26.8, 26.2, 25.5, 19.1, 13.6, -4.2; TLC i?/(Hexanes:EtOAc 1:1 +
2% MeOH) = 0.27; 262-a 1 H NMR (400 MHz, CD 3 OD) δ 7.17 (t, J= 7.8 Hz, IH), 6.94 (d, J = 7.6 Hz, IH), 6.83 (t, J= 2.0 Hz, IH), 6.74-6.71 (m, IH), 5.27 (s, IH), 4.38-4.32 (m, IH), 3.82-3.73 (m, IH), 3.48-3.42 (m, IH), 2.71-2.55 (m, 2H), 1.71-1.50 (m, 6H), 1.38-1.12 (m, 6H), 1.00-0.82 (m, HH), 0.18 (s, 6H); 13 C NMR (100 MHz, CD 3 OD) δ 165.4, 157.1, 155.9, 148.2, 146.4, 130.5, 121.1, 120.4, 119.2, 98.9, 85.3, 56.9, 56.6, 43.6, 29.3, 28.7, 27.4, 26.9, 26.8, 26.2, 25.7, 19.1, 13.7, -4.2; TLC i?/(Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.17.
260 iV-(2-CyclohexyI-2-hydroxyethyl)-6-ethyl-4-(3-hydroxyphenyl) -2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide (260)
1 H NMR (400 MHz, CD 3 OD) δ 7.15 (t, J= 7.8 Hz, IH), 6.80-6.78 (m, 2H), 6.70 (d, J= 7.2 Hz, IH), 5.23 (s, IH), 3.30-3.26 (m, IH), 3.16-3.09 (m, IH), 3.07-3.01 (m, IH), 2.61-2.52 (m, IH), 2.43-2.35 (m, IH), 1.82-1.52 (m, 6H), 1.27-1.11 (m, 6H), 1.07-0.87 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) δ 168.5, 157.9, 154.5, 144.9, 142.8, 129.7, 117.6, 114.8, 105.4, 105.0, 74.3, 56.6, 42.3, 41.3, 39.3, 29.15, 19.12, 27.7, 27.5, 26.3, 26.1, 26.0, 25.9, 23.7, 23.6, 12.0; TLC i?/(EtOAc:MeOH 15:1) = 0.55.
261
(S)-5-((i?)-5-cyclohexyl-4,5-dihydrooxazol-2-yI)-6-ethyl- 4-(3-hydroxyphenyl)-3,4- dihydropyrimidin-2(lH)-one (261)
To a solution of 261-a (27 mg, 0.056 mmol, 1.0 equiv) in THF (0.11 niL) was added TBAF (1.0 M in THF, 0.112 niL, 0.112 mmol, 2.0 equiv) at 0 0 C. After stirred at 25 0 C for 15 min, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , n-
Hexanes/EtOAc + 2% MeOH = 1 :1 → EtOAc/MeOH = 15:1) to give 261 (16 mg, 92%): 1 H NMR (400 MHz, CD 3 OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.81 (s, IH), 6.79-6.79-6.77 (m, IH), 6.68-6.65 (m, IH), 5.26 (s, IH), 4.34-4.28 (m, IH), 3.80-3.74 (m, IH), 3.55-3.50 (m, IH), 2.82-2.73 (m, IH), 2.66-2.58 (m, IH), 1.74-1.51 (m, 6H), 1.39-1.10 (m, 6H), 1.02-0.82 (m, 2H); 13 C NMR (IOO MHZ, CD 3 OD) δ 165.2, 158.8, 155.8, 148.5, 146.3, 130.6, 119.0, 115.7, 114.6, 98.6, 85.0, 56.9, 56.7, 43.8, 29.3, 28.9, 27.4, 26.9, 26.8, 25.5, 13.5; TLC R f (n- Hexanes:EtOAc + 2% MeOH 1 :1) = 0.52.
262
(»S)-5-((5)-5-cyclohexyl-4,5-dihydrooxazoI-2-yl)-6-ethyl -4-(3-hydroxyphenyl)-3,4- dihydropyrimidin-2(lH)-one (262)
1 H NMR (400 MHz, CD 3 OD) δ 7.10 (t, J= 7.8 Hz, IH), 6.78 (s, IH), 6.78-6.77 (m, IH), 6.67-6.65 (m, IH), 5.25 (s, IH), 4.37-4.31 (m, IH), 3.81-3.75 (m, IH), 3.49-3.43 (m, IH), 2.64-2.58 (m, 2H), 1.73-1.50 (m, 6H), 1.40-1.09 (m, 6H), 1.02-0.08 (m, 2H); 13 C NMR (IOO MHz, CD 3 OD) δ 165.5, 158.7, 155.9, 147.8, 146.3, 130.5, 118.9, 115.6, 114.6, 98.9, 85.2, 56.9, 56.8, 43.6, 29.2, 28.7, 27.4, 26.9, 26.8, 25.6, 13.6; TLC i?/(«-Hexanes:EtOAc + 2% MeOH 1 :1) = 0.50.
General procedure for oxazole/thiazole/imidazole bioisosteres
To a solution of PhI(OAc) 2 (2.0 g, 6.24 mmol, 1,5 equiv) in CH 3 CN (20 mL) was added slowly CF 3 SO 3 H (1.09 ml, 11.6 mmol, 1.9 equiv) at 25 0 C. The suspension was stirred at 25 °C for 30 min, and then a solution of acetophenone (0.50 g, 4.16 mmol, 1.0 equiv) in CH 3 CN (5 mL) added via cannula at 25 °C. The resulting solution was refiuxed for 4 h, and then quenched with a mixture of saturated aqueous Na 2 CO 3 (20 mL) and H 2 O (20 mL). The mixture was extracted with CH 2 Cl 2 (3 * 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of λζiV-diisopropylamine (0.88 ml, 6.25 mmol, 5.0 equiv) in THF (1 mL) was added slowly R-BuLi (2.5M in n-Hexanes, 2.5 ml, 6.25 mmol, 5.0 equiv) at 0 0 C. The suspension was stirred at 0 "C for 15 min, and then a solution of 2-methyl-5-phenyloxazole (0.20 g, 1.25 mmol, 1.0 equiv) in THF (1 mL) added via cannula at -78 0 C. The suspension was stirred at -78 "C for 30 min, and then a solution of ethyl propionate (0.21 ml, 1.875 mmol, 1.5 equiv) in THF (1 mL) added via cannula at -78 0 C, and the resulting solution was stirred at 25 0 C for 3 h, then quenched with a mixture of saturated aqueous NH 4 Cl (10 mL) solution and H 2 O (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for oxazole/thiazole/imidazole bioisosteres
In a sealed tube was added 2-bromo-l-cyclohexylethanone (1.0 equiv) and amide (3.0 equiv) and stirred at 130 0 C for 2 h. To the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous Na 2 CO 3 , brine, and then dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , «-Hexanes:EtOAc 19:1) to give cyclized products.
To a solution of acetamidine (5.0 equiv) in methanol was added sodium hydroxide (5.0 equiv) and stirred at 0 °C for 3 hours. After filtration and concentration in vacuo, the residue was dissolved in acetonitrile. To the reaction mixture was added potassium carbonate (2.0 equiv) in H 2 O and 2-bromo-l-cyclohexylethanone (1.0 equiv) in acetonitrile and stirred at room temperature for 12 h. To the reaction mixture was added water and extracted with methylene chloride (x 3). The organic layer was washed with brine (x 1), and then dried over MgSO 4 . After filtration and concentration in vacuo, the residue was suspended in methylene chloride and was crystallized by slowly adding diethyl ether. The resulting solid was filtered and washed with diethyl ether.
To a solution of 4-cyclohexyl-2-methyl-lH-imidazole (1.0 equiv) in DMF was added trityl chloride (1.3 equiv) and triethyl amine (2.2 equiv) and stirred at room temperature for 6 h. After the reaction mixture was concentration in vacuo, it was treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (x 3). The combined organic layers were washed with brine (x 1), and then dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , n- Hexanes:EtOAc 7:l → 1:1).
4-Cy clohexy 1-2-methy 1- 1 -trityl- lH-imidazole
1 H NMR (400 MHz, CD 3 OD) δ 7.35 (m, 9H), 7.12 (m, 6H), 6.39 (s, IH), 2.41 (m, IH), 1.92 (m, 2H), 1.77-1.65 (m, 3H), 1.56 (s, 3H), 1.40-1.18 (m, 5H); LRMS (electrospray) m/z calculated for C 29 H 30 N 2 (M+H) + 407.56, found 407.32.
To a solution of diethylamine (2.6 equiv) in THF (0.6 M) at -78 0 C was added slowly n-BuLi (2.4 equiv) and stirred for 10 min at 0 0 C then cooled back to -78 0 C. A solution of oxazole (or thiazole, 1.0 equiv) in THF (0.6 M) was added to the reaction mixture using cannula at -78 °C and further stirred for 30 min. The reaction mixture was warmed to 25 °C and further stirred for 3 h. The reaction was quenched by the addition of saturated aqueous NH 4 Cl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO 2 , n- Hexanes:EtOAc 9:1).
To a solution of 4-cyclohexyl-2-methyl-l-trityl-l //-imidazole (1.0 equiv) in distilled THF at -78 0 C was added rc-BuLi (1.6 M in hexanes, 2.0 equiv) and stirred at -78 0 C for 30 min then further stirred at room temperature for 30 min. The reaction mixture was cooled back to -78 0 C and added ethyl propionate (3.0 equiv) and stirred at room temperature for 12 h. The reaction was quenched with methanol and concentration in vacuo, the residue was purified via flash column chromatography (SiO 2 , rø-Hexanes:EtOAc 3:1).
l-(4-Cyclohexyl-l-trityl-li/-imidazol-2-yl)butan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.32 (m, 9H), 7.13 (m, 6H), 6.41 (s, IH), 3.19 (s, 2H), 2.45 (m, IH), 2.01-1.88 (m, 4H), 1.76-1.65 (m, 3H), 1.35-1.24 (s, 5H), 0.74 (t, J = 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C 32 H 34 N 2 O (M+H) + 463.63, found 463.37.
To a mixture of benzaldehyde (1.0 equiv), urea (1.5 equiv), and β-keto oxazole (thiazole, or imidazole) (1.0 equiv) was added acetic acid (0.2 M) and stirred at 110 0 C for 16 h. The reaction was slowly quenched with saturated aqueous K 2 CO 3 (caution: gas evolution) and extracted with EtOAc (3 x). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was redissolved with CH 2 Cl 2 and crystallized by the slow addition of hexanes. The resulting precipitate was filtered and washed with cold CH 2 Cl 2 :«-Hexanes (1 :1) solution. Alternatively, the concentrated residue was directly subjected to flash column chromatography (SiO 2 , CH 2 Cl 2 :Me0H = 19:1) to give Biginelli adducts.
General procedure for reduction of nitro groups
X = O 1 S
Y = O , S 1 NH
To a solution of nitro compound (1.0 equiv) in AcOH:HCl (cone.) (9:1, 0.1 M) was added zinc dust (6.0 equiv) and stirred at 80 "C for 1 h. After cooling to 25 0 C, the reaction mixture was quenched with water and extracted with EtOAc (3 x). The combined organic layers were washed with saturated aqueous K 2 CO 3 solution and then dried over MgSO 4 . After filtration and concentration in vacuo, the residue was redissolved in CH 2 Cl 2 /Me0H and crystallized by slowly adding n-Hexanes. The resulting solid was filtered and washed with cold CH 2 Cl 2 :hexanes (1:1) solution.
General procedure for reductive aminations
To a solution of aniline compound (1.0 equiv) in THF (0.1 M) was added molecular sieve, benzaldehyde (2.0 equiv), and AcOH (2.0 equiv) and was stirred at room temperature for 2 h. Then the reaction mixture was treated with sodium triacetoxyborohydride (2.0 equiv) and further stirred overnight at 25 °C. The reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO 2 , CH 2 Cl 2 IMeOH 9:1) to give reductive animation products.
General procedure for amide coupling
To a mixture of Biginelli compound (1.0 equiv), amine (or acid) (1.2 equiv), DMAP (0.2 equiv), and EDC (1.3 equiv) was added DMF (or CH 2 Cl 2 ) (0.3 M) and DIPEA (1.5 equiv) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with CH 2 Cl 2 (3 x). The combined organic layers were dried over MgSO 4 , filtered and concentrated in
vacuo. The resulting residue was purified via flash column chromatography (SiO 2 , CH 2 Cl 2 :Me0H = 19:l).
2-Methyl-5-phenyloxazoIe
1 H NMR (400 MHz, CDCl 3 ) δ 7.35-7.33 (m, 2H), 7.14-7.10 (m, 2H), 7.05-7.01 (m, IH), 6.97 (s, IH), 2.23 (s, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.52.
l-(5-Phenyloxazol-2-yl)butan-2-one
1 U NMR (400 MHz, CD 3 OD) δ 7.66-7.63 (m, 2H), 7.42-7.40 (m, 3H), 7.38-7.31 (m, IH), 4.04 (s, 2H), 2.64-2.59 (m, 2H), 1.05 (t, J= 7.2 Hz, 3H); 13 C NMR (400 MHz, CD 3 OD) δ
204.7, 158.7, 152.4, 128.8, 127.7, 124.0, 123.6, 121.5, 41.1, 35.3, 6.7; TLC R f (n- Hexanes:EtOAc 5:1) = 0.17.
5-(4-Bromophenyl)-2-methyIoxazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.53-7.51 (m, 2H), 7.47-7.45 (m, 2H), 7.20 (s, IH), 2.52 (s, 3H); TLC i?/(n-Hexanes: EtOAc 3:1) = 0.48.
l-(5-(4-BromophenyI)oxazol-2-yl)butan-2-one
1 H NMR (400 MHz, CD 3 OD) δ 7.51-7.49 (m, 4H), 7.41 (s, IH), 4.03 (s, 2H), 2.63-2.58 (m, 2H), 1.03 (t, J= 7.2 Hz, 3H); 13 C NMR (400 MHz, CD 3 OD) δ 204.9, 159.1, 151.4, 132.0,
126.8, 125.6, 125.2, 121.5, 41.3, 35.3, 6.6; TLC £/(rc-Hexanes:EtOAc 5:1) = 0.32.
263
4-(3-ChIoro-4-hydroxyphenyl)-6-ethyl-5-(5-phenyloxazol-2- yI)-3,4-dihydropyrimidin- 2(117)-one (263)
1 H NMR (400 MHz, DMSO-^) δ 9.07 (s, IH), 7.63 (s, IH), 7.58-7.56 (m, 3H), 7.42-7.38 (m, 2H), 7.29-7.24 (m, 2H), 7.08-7.05 (m, IH), 6.86 (d, J= 8.4 Hz, IH), 5.32 (d, J= 3.2 Hz, IH), 2.80-2.72 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H); 13 C NMR (400 MHz, DMSO-^) δ 160.2, 153.1,
153.0, 149.3, 146.1, 137.1, 129.7, 128.6, 128.3, 126.7, 124.1, 124.0, 119.9, 117.3, 96.7, 54.3, 24.6, 13.3.
S-CyclohexyW-methyloxazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.17 (d, J= 1.2 Hz, IH), 2.38 (s, 3H), 1.96-1.94 (m, 2H), 1.77- 1.70 (m, 4H), 1.35-1.27 (m, 5H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.48.
l-(5-Cyclohexyloxazol-2-yI)butan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, J= 1.2 Hz, IH), 3.82 (s, 2H), 2.51-2.45 (m, 3H), 2.01- 1.96 (m, 3H), 1.77-1.66 (m, 5H), 1.36-1.30 (m, 2H), 1.19-1.16 (m, 3H); TLC R f (n- Hexanes:EtOAc 5:1) = 0.43.
264
4-(3-Chloro-4-hydroxyphenyl)-5-(5-cyclohexyloxazol-2-yl)-6-e thyl-3,4- dihydropyrimidin-2(l J fiT)-one (264)
1 H NMR (400 MHz, CD 3 OD) δ 7.38 (d, J= 1.2 Hz, IH), 7.23 (d, J= 2.0 Hz, IH), 7.07-7.04 (m, IH), 6.78 (d, J= 8.4 Hz, IH), 5.42 (s, IH), 2.76-2.63 (m, 2H), 1.94-1.67 (m, 6H), 1.42- 1.18 (m, 8H); 13 C NMR (400 MHz, CD 3 OD) 6 159.8, 154.7, 152.6, 146.6, 143.5, 136.3, 131.7, 128.2, 125.9, 120.2, 116.3, 98.1, 54.8, 35.8, 32.1, 26.0, 25.9, 25.8, 23.9, 11.8; TLC R/ (CH 2 Cl 2 : MeOH 10:1) = 0.52.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 205% z-PrOH in n-Hexanes, 8.0 mL/min): 264a t R = 18.2 min, 264b t R = 25.3 min.
4-Cyclohexyl-2-methyloxazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (s, IH), 2.42 (m, IH), 2.38 (s, 3H), 1.92 (m, 2H), 1.77- 1.61 (m, 4H), 1.38-1.21 (m, 4H); TLC i?/(n-Hexanes:EtOAc 9:1) = 0.25.
l-(4-CycIohexyloxazol-2-yl)propan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, IH), 3.83 (s, 2H), 2.48 (m, IH), 2.20 (s, 3H), 2.00 (m, 2H), 1.78-1.62 (m, 3H), 1.39-1.17 (m, 5H); TLC i?/(n-Hexanes:EtOAc 4:1) = 0.27.
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazoϊ-2-yl) -6-methyl-3,4- dihydropyrimidin-2(lH)-one (265)
1 H NMR (400 MHz, CD 3 OD) δ 7.39 (s, IH), 7.23 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.4, 2.0 Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.44 (m, IH), 2.28 (s, 3H), 1.96 (m, 2H), 1.73 (m, 3H), 1.39-1.22 (m, 5H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 265a t R = 20.1 min, 265b t R = 23.9 min.
l-(4-Cyclohexyloxazol-2-yl)butan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (s, IH), 3.83 (s, 2H), 2.50 (q, J= 7.2 Hz, 2H), 2.48 (m, IH), 1.99 (m, 2H), 1.76 (m, 2H), 1.69 (m, IH), 1.37-1.22 (m, 5H), 1.05 (t, J= 7.2 Hz, 3H); TLC i?/(rc-Hexanes:EtOAc 4:1) = 0.30.
266
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazol-2-yl)- 6-ethyl-3,4- dihydropyrimidin-2(lH)-one (266)
1 H NMR (400 MHz, CD 3 OD) δ 7.34 (s, IH), 7.25 (d, J= 2.4 Hz, IH), 7.07 (dd, J= 8.4, 2.0 Hz, IH), 6.80 (d, J= 8.0 Hz, IH), 5.44 (s, IH), 2.70 (m, 2H), 2.40 (m, IH), 1.92 (m, 2H), 1.72 (m, 2H), 1.65 (m, IH), 1.35-1.24 (m, 5H), 1.94 (t, J= 7.4 Hz, 3H); 13 C NMR (100 MHz,
CD 3 OD) δ 159.6, 152.4, 146.4, 143.3, 136.1, 131.5, 128.0, 125.8, 120.1, 116.2, 98.0, 54.6, 35.6, 31.9, 31.4, 25.8, 25.7, 23.8, 20.2, 11.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in n-Hexanes, 6.5 mL/min): 266a t β = 20.5 min, 266b tj? = 25.3 min.
l-(4-Cyclohexyloxazol-2-yI)pentan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (s, IH), 3.84 (s, 2H), 2.50 (m, IH), 2.47 (t, J= 7.2 Hz 5 2H), 2.00 (m, 2H), 1.78 (m, 2H), 1.67 (m, IH), 1.61 (m, 2H), 1.39-1.25 (m, 5H), 0.90 (t, J= 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.40.
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazoI-2-yl)- 6-propyl-3,4- dihydropyrimidin-2(lH)-one (267)
1 H NMR (400 MHz, CD 3 OD) δ 7.38 (s, IH), 7.24 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.4, 2.0
Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.67 (m, 2H), 2.43 (m, IH), 1.94 (bs, 2H),
1.76-1.59 (m, 5H), 1.42-1.23 (m, 5H), 0.97 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) =
0.62.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20%
/-PrOH in «-Hexanes, 6.5 mL/min): 267a t R = 18.8 min, 267b t R = 24.5 min.
2-(4-CycIohexyIoxazol-2-yl)-l-cyclopropylethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, IH), 3.97 (s, 2H), 2.49 (m, IH), 2.02-1.94 (m, 3H), 1.76 (m, 2H), 1.69 (m, IH), 1.37-1.19 (m, 5H), 1.09 (m, 2H), 0.91 (m, 2H); TLC R f (n- Hexanes:EtOAc 4: 1) = 0.31.
268
4-(3-ChIoro-4-hydroxyphenyl)-5-(4-cyclohexyloxazol-2-yI)- 6-cyclopropyl-3,4- dihydropyrimidin-2(lH)-one (268)
1 U NMR (400 MHz, CD 3 OD) δ 7.40 (s, IH), 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.0 Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.41 (s, IH), 2.57 (m, 2H), 2.44 (m, IH), 1.96 (bs, 2H), 1.77-1.67 (m, 3H), 1.42-1.20 (m, 5H), 0.87 (d, J= 6.8 Hz, 4H).
Enantiomerically pure forms were obtained by crural HPLC (OD-H preparative column, 20% i-PrOH in «-Hexanes, 6.5 mL/min): 268a t R = 33.4 min, 268b t R = 45.9 min.
l-(4-Cyclohexyloxazol-2-yl)-3-methylbutan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (s, IH), 3.89 (s, 2H), 2.70 (m, IH), 2.47 (m, IH), 1.97 (m, 2H), 1.78-1.62 (m, 3H), 1.36-1.19 (m, 5H), 1.11 (d, J= 5.2 Hz, 6H); TLC R f {n- Hexanes:EtOAc 4:1) = 0.38.
269
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyIoxazol-2-yI)- 6-isopropyl-3,4- dihydropyrimidin-2(l//)-one (269)
1 H NMR (400 MHz, CD 3 OD) δ 7.38 (s, IH), 7.20 (d, J= 2.0 Hz 5 IH), 7.03 (dd, J= 8.4, 2.0
Hz 5 IH), 6.78 (d, J= 8.4 Hz, IH), 5.39 (s, IH), 2.43 (m, IH), 2.20 (m, IH), 1.94 (m, 2H) 5
1.77-1.66 (m, 3H), 1.40-1.11 (m, 5H), 0.89 (d, J= 6.4 Hz, 6H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) =
0.57.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 269a t R = 19.3 min, 269b t R = 21.8 min.
4-Cyclohexyl-2-methyIthiazole
1 H NMR (400 MHz, CDCl 3 ) δ 6.64 (s, IH), 2.69 (m, IH), 2.66 (s, 3H), 2.02 (bs, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.43-1.21 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.0, 162.5, 110.3, 40.6, 32.9, 26.3, 26.1, 19.1; TLC i?/(«-Hexanes:EtOAc 4:1) = 0.56.
l-(4-Cyclohexylthiazol-2-yl)butan-2-one
1 H NMR (400 MHz, CDCl 3 ) δ 6.79 (s, IH), 4.08 (s, 2H), 2.72 (m, IH), 2.56 (q, J= 7.2 Hz, 2H), 2.03 (m, 2H), 1.79 (m, 2H), 1.69 (m, IH), 1.43-1.16 (m, 5H), 1.06 (t, J- 7.4 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.45.
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexylthiazol-2-yl) -6-ethyl-3,4- dihydropyrimidin-2(lJϊ)-one (270)
1 H NMR (400 MHz, CD 3 OD) δ 7.22 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.2, 2.2 Hz, IH), 6.86 (s, IH), 6.79 (d, J= 8.4 Hz, IH), 5.39 (s, IH), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (d, J= 12.4 Hz, IH), 1.46-1.25 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC ^/(CH 2 Cl 2 :MeOH 19:1) = 0.42.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in «-Hexanes, 6.5 mL/min): 270a t R = 18.1 min, 270b t R = 27.5 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-phenyl-3,4-dihydro pyrimidin-2(lH)-one (271)
1 K NMR (400 MHz, CD 3 OD) δ 7.31-7.19 (m, 5H), 6.85 (s, IH), 5.47 (s, IH), 2.64 (m, 3H), 1.97 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.45-1.26 (m, 5H) 5 1.22 (t, J= 7.6 Hz, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 19:1) = 0.33.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in rc-Hexanes, 6.5 mL/min): 271a t R = 20.0 min, 271b t R = 33.3 min.
272 4-Benzyl-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyr imidin-2(lH)-one (272)
1 H NMR (400 MHz, CD 3 OD) δ 7.19 (m, 3H), 7.12 (m, 2H), 6.95 (s, IH), 4.78 (t, J= 5.0 Hz, IH), 2.84 (d, J= 5.2 Hz, 2H), 2.74 (m, IH), 2.50 (m, 2H), 2.06 (m, 2H), 1.83 (m, 2H), 1.74 (m, IH), 1.53-1.28 (m, 5H), 1.07 (t, J= 7.4 Hz, 3H); TLC ^(CH 2 Cl 2 MeOH 19:1) = 0.24.
273
4-(l-Bromonaphthalen-2-yl)-5-(4-cyclohexylthiazol-2-yl)-6 -ethyl-3,4-dihydropyrimidin- 2(lH)-one (273)
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (d, J= 8.31 Hz, IH), 7.85 (dd, J= 8.0, 4.8 Hz, 2H), 7.57 (m, 3H), 6.81 (s, IH), 6.34 (s, IH), 5.49(s, IH), 2.64 (q, J= 7.6 Hz, 2H), 2.62 (m, IH), 1.91 (m, IH), 1.85 (m, IH), 1.67 (m, 3H), 1.40-1.23 (m, 8H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.27. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 273a t R = 12.5 min, 273b t R = 16.0 min.
274 5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-hydroxyphenyI)-3,4 -dihydropyrimidin-2(l J H r )- one (274)
1 H NMR (400 MHz, DMSO-<4) δ 9.29 (s, IH), 8.78 (s, IH), 7.43 (s, IH), 7.05 (d, J= 8.4 Hz,
2H), 6.92 (s, IH), 6.63 (d, J= 8.4 Hz, 2H), 5.12 (d, J= 3.2 Hz, IH), 2.66 (m, 2H), 2.54 (m,
IH), 1.88 (m, 2H), 1.71 (m, 2H), 1.62 (m, IH), 1.31 (m, 5H), 1.14 (t, J= 7.4 Hz, 3H); TLC R f
(CH 2 Cl 2 :Me0H 19:1) = 0.17.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 1.0 niL/min): 274a t R = 5.8 min, 274b t R = 8.7 min.
275 5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-hydroxyphenyl)-3,4 -dihydropyrimidin-2(lJϊ)- one (275)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.30 (bs, IH), 8.82 (s, IH), 7.50 (s, IH), 7.03 (t, J= 7.8 Hz,
IH), 6.94 (s, IH), 6.69 (d, J= 7.2 Hz, 2H), 6.57 (d, J= 8.0 Hz, IH), 5.19 (d, J= 3.2 Hz, IH),
2.66 (m, 2H), 2.57 (m, IH), 1.90 (m, 2H), 1.69 (m, 2H), 1.63 (m, IH), 1.36-1.28 (m, 5H),
1.15 (t, J= 7.4 Hz, 3H); TLC ^/(CH 2 Cl 2 : MeOH 19:1) = 0.11.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 1.0 mL/min): 275a t R = 7.9 min, 275b t R = 15.9 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-fluoro-4-hydrox yphenyl)-3,4- dihydropyrimidin-2(lH)-one (276)
1 H NMR (400 MHz, CD 3 OD) δ 7.00 (dd, J= 12.0, 2.0 Hz, IH), 6.95 (dd, J= 8.4, 2.0 Hz, IH), 6.90 (s, IH), 6.82 (t, J= 8.6 Hz, IH), 5.42 (s, IH), 2.66 (m, 3H), 2.00 (m, 2H), 1.83 (m, 2H), 1.75 (d, J= 12.4 Hz, IH), 1.49-1.41 (m, 4H), 1.31 (m, IH), 1.25 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.14.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in π-Hexanes, 6.5 mL/min): 276a t R = 15.6 min, 276b t R = 36.1 min.
4-(2-ChIoro-4-hydroxyphenyI)-5-(4-cyclohexylthiazol-2-yl) -6-ethyl-3,4- dihydropyrimidin-2(liϊ)-one (277)
1 H NMR (400 MHz, CD 3 OD) δ 7.20 (s, IH), 6.89 (s, IH), 6.77 (d, J= 2.4 Hz, IH), 6.67 (dd,
J= 8.4, 2.4 Hz, IH), 5.84 (s, IH), 2.67 (m, IH), 2.63 (q, J= 7.6 Hz, 2H), 1.98 (m, IH), 1.85-
1.71 (m, 3H), 1.57-1.27 (m, 5H), 1.25 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) =
0.12.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25%
/-PrOH in n-Hexanes, 6.5 mL/min): 277a t R = 10.9 min, 277b t R = 12.9 min.
278
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-fluoro-3-hydrox yphenyI)-3,4- dihydropyrimidin-2(lH)-one (278)
1 H NMR (400 MHz, CD 3 OD) δ 6.91 (m, 2H), 6.83 (s, IH), 6.72 (m, IH), 5.38 (s, IH), 2.62 (m, 3H), 1.98 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.26 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.29.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in «-Hexanes, 6.5 mL/min): 278a t R = 15.1 min, 278b t R = 24.28 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(2-methoxyphenyl)- 3,4-dihydropyrimidin-2(liϊ)- one (279)
1 K NMR (400 MHz, CD 3 OD) δ 7.21 (m, IH), 7.17 (dd, J- 7.6, 2.0 Hz, IH), 6.95 (d, J= 8.4 Hz, IH), 6.82 (m, 2H), 5.77 (s, IH), 3.83 (s, 3H), 2.68 (q, J= 7.2 Hz, 2H), 2.64 (m, IH), 1.95 (m, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.44-1.33 (m, 5H), 1.24 (t, J= 7.6 Hz, 3H); TLC R f (CH 2 Cl 2 :Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in «-Hexanes, 6.5 mL/min): 279a t R = 15.1 min, 279b t R = 20.6 min.
5-(4-CycIohexylthiazol-2-yI)-6-ethyl-4-(3-methoxyphenyl)- 3,4-dihydropyrimidin-2(lfi)- one (280)
1 H NMR (400 MHz, CD 3 OD) δ 7.16 (t, J= 8.0 Hz, IH), 6.88-6.83 (m, 3H), 6.76 (dd, J= 8.4, 2.4 Hz, IH), 5.45 (s, IH), 3.71 (s, 3H), 2.64 (m, 3H), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.34 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC # / (CH 2 Cl 2 :Me0H 19:1) = 0.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in n-Hexanes, 6.5 mL/min): 280a t R = 15.2 min, 280b t R = 23.4 min.
5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-4-(4-methoxyphenyl)- 3,4-dihydropyrimidin-2(liϊ)- one (281)
1 H NMR (400 MHz, CD 3 OD) δ 7.21 (d, J= 8.8 Hz, 2H), 6.84 (s, IH), 6.80 (d, J= 8.8 Hz, 2H), 5.39 (s, IH), 3.72 (s, 3H), 2.63 (m, 3H), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45- 1.34 (m, 4H), 1.26 (m, IH), 1.21 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.31. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% Z-PrOH in «-Hexanes, 6.5 mL/min): 281a t R = 13.8 min, 281b t R = 22.1 min.
4-(Benzyloxy)benzaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 9.87 (s, IH), 7.82 (d, J= 8.8 Hz, 2H), 7.43-7.34 (m, 5H), 7.06 (d, J= 8.8 Hz, 2H), 5.14 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 190.9, 163.9, 136.2, 132.2, 130.4, 128.9, 128.5, 127.7, 115.4, 70.5; TLC i?/(«-Hexanes:EtOAc 7:3) = 0.58.
4-(4-(Benzyloxy)phenyl)-5-(4-cyclohexylthiazol-2-yl)-6-et hyI-3,4-dihydropyrimidin- 2(lH)-one (282)
1 H NMR (400 MHz, CD 3 OD) δ 7.37 (d, J= 6.8 Hz, 2H), 7.32 (t, J= 7.0 Hz, 2H), 7.26 (d, J= 6.8 Hz, IH), 7.21 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.84 (s, IH), 5.39 (s, IH), 5.01 (s, 2H), 2.63 (m, 3H), 1.97 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.27 (m, 5H), 1.21 (t, J = 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in «-Hexanes, 6.5 mL/min): 282a t R = 23.5 min, 282b t R = 31.7 min.
283
4-(4-(Benzyloxy)-3-chlorophenyl)-5-(4-cyclohexylthiazol-2 -yl)-6-ethyI-3,4- dihydropyrimidin-2(l#)-one (283)
1 H NMR (400 MHz, CD 3 OD) δ 7.40 (d, J= 7.2 Hz, 2H), 7.32 (t, J= 7.4 Hz, 3H), 7.27 (d, J= 7.6 Hz, IH), 7.16 (dd, J= 8.4, 2.0 Hz, IH), 7.00 (d, J= 8.8 Hz, IH), 6.86 (s, IH), 5.45 (s, IH), 5.10 (s, 2H), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.46-1.27 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.27.
5-(4-CycIohexyIthiazol-2-yI)-6-ethyI-4-(4-phenoxyphenyl)- 3,4-dihydropyrimidin-2(lH)- one (284)
1 H NMR (400 MHz, CD 3 OD) δ 7.29 (m, 4H), 7.06 (t, J= 7.2 Hz, IH), 6.91 (d, J= 7.6 Hz, 2H), 6.87 (s, IH), 6.86 (d, J= 8.4 Hz, 2H), 5.47 (s, IH), 2.64 (m, 3H), 1.96 (m, 2H), 1.79 (t, J = 4.0 Hz, 2H), 1.71 (d, J= 11.6 Hz, IH), 1.45-1.26 (m, 5H), 1.22 (t, J= 7.4 Hz, 3H); TLC R f (CH 2 Cl 2 :Me0H 19:1) = 0.41.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 284a t R = 17.5 min, 284b t R = 34.1 min.
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4- yl)benzonitrile (285)
1 H NMR (400 MHz, CD 3 OD) δ 7.63 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 6.88 (s, IH), 5.66 (s, IH), 2.64 (m, 3H), 1.95 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.43-1.26 (m, 5H), 1.23 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.34.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 1.0 mL/min): 285a t R = 14.5 min, 285b t R = 20.9 min.
4-(5-(4-CyclohexyIthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4-yl)-2- fluorobenzonitrile (286)
1 H NMR (400 MHz, CD 3 OD) δ 7.67 (dd, J= 7.8, 7.0 Hz, IH), 7.31 (m, 2H), 6.92 (s, IH), 5.73 (s, IH), 2.65 (m, 3H), 1.96 (m, 2H), 1.81 (m, 2H), 1.73 (m, IH), 1.45-1.28 (m, 5H), 1.25 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.32.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in π-Hexanes, 6.5 mL/min): 286a t R = 16.4 min, 286b t R = 20.8 min.
3-(5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4- yl)benzonitrile (287)
1 H NMR (400 MHz, CD 3 OD) δ 7.64 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 7.6 Hz, IH), 7.45 (t, J= 7.8 Hz, IH), 6.89 (s, IH), 5.66 (s, IH), 2.65 (m, 3H), 1.93 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.25 (m, 5H), 1.23 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in w-Hexanes, 6.5 mL/min): 287a t R = 19.2 min, 287b t R = 21.3 min.
288
5-(5-(4-Cyclohexylthiazol-2-yI)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4-yl)-2- fluorobenzonitrile (288)
1 H NMR (400 MHz, CD 3 OD) δ 7.70 (m, 2H), 7.29 (t, J= 9.4 Hz, IH), 6.92 (s, IH), 5.68 (s, IH), 2.66 (m, 3H), 1.97 (m, 2H), 1.82 (m, 2H), 1.73 (m, IH), 1.48-1.28 (m, 5H), 1.25 (t, J= 7.6 Hz, 3H); TLC ^ 7 (CH 2 Cl 2 : MeOH 19:1) = 0.21.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 288a t R = 16.5 min, 288b t R = 22.1 min.
289 5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-4-(4-fluorophenyl)-3,4- dihydropyrimidin-2(lH)-one
(289)
1 H NMR (400 MHz, CD 3 OD) δ 7.31 (dd, J= 8.6 Hz, 5.4 Hz, 2H), 6.98 (t, J= 8.8 Hz, 2H), 6.86 (s, IH), 5.50 (s, IH), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.26 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.35 Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 1.0 mL/min): 289a t R = 8.8 min, 289b t R = 14.0 min.
290
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-fluorophenyl)-3 ,4-dihydropyrimidin-2(ljH)-one (290)
1 H NMR (400 MHz, CD 3 OD) δ 7.28 (q, J= 8.0 Hz, IH), 7.14 (d, J= 8.0 Hz, IH), 7.03 (d, J = 10.4 Hz, IH), 6.94 (dt, J= 8.2, 2.4 Hz, IH), 6.89 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 1.98 (m, 2H), 1.81 (m, 2H), 1.73 (d, J= 12.4 Hz, IH), 1.47-1.29 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.56.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% i-PrOH in n-Hexanes, 6.5 mL/min): 290a t R = 13.3 min, 290b t R = 18.3 min.
291
4-(4-Chlorophenyl)-5-(4-cyclohexyIthiazol-2-yl)-6-ethyI-3 ,4-dihydropyrimidin-2(ljiϊ)-one (291)
1 H NMR (400 MHz, CD 3 OD) δ 7.26 (m, 4H), 6.87 (s, IH), 5.51 (s, IH), 2.62 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in ra-Hexanes, 6.5 mL/min): 291a ^ = 13.9 min, 291b t R = 21.8 min.
292
4-(3-Chlorophenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyI-3 ,4-dihydropyrimidin-2(lH)-one
(292)
1 H NMR (400 MHz, CD 3 OD) δ 7.33 (s, IH), 7.26-7.21 (m, 3H), 6.89 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 1.96 (m, 2H), 1.81 (m, 2H), 1.73 (d, J= 12.4 Hz, IH), 1.48-1.28 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.50.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rc-Hexanes, 6.5 mL/min): 292a t R = 14.2 min, 292b t R = 18.6 min.
4-(2-Chlorophenyl)-5-(4-cycIohexylthiazol-2-yl)-6-ethyl-3 ,4-dihydropyrimidin-2(lH)-one
(293)
1 H NMR (400 MHz, CD 3 OD) δ 7.39 (m, IH), 7.33 (m, IH), 7.23-7.20 (m, 2H), 6.84 (s, IH), 5.98 (s, IH), 2.65 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.93 (m, 2H), 1.77 (m, 2H), 1.69 (m, IH), 1.40-1.32 (m, 5H), 1.26 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.38. Enantiomerically pure forms were obtained by cbiral HPLC (OD-H preparative column, 20% i-PrOH in n-Hexanes, 6.5 mL/min): 293a t R = 12 A min, 293b t R = 16.5 min.
4-(4-BromophenyI)-5-(4-cyclohexyIthiazol-2-yl)-6-ethyl-3, 4-dihydropyrimidin-2(lH)-one (294)
1 H NMR (400 MHz, CD 3 OD) δ 7.40 (d, J= 8.8 Hz, 2H), 7.22 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.50 (s, IH), 2.62 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.34 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC ^/(CH 2 Cl 2 :MeOH 19:1) = 0.25. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 294a t R = 14.9 min, 294b t R = 26.3 min.
295
4-(3-Bromophenyl)-5-(4-cyclohexyIthiazol-2-yI)-6-ethyl-3,4-d ihydropyrimidin-2(l J H r )-one
(295)
1 H NMR (400 MHz, CD 3 OD) δ 7.49 (t, J= 1.6 Hz, IH), 7.37 (d, J= 8.0 Hz, IH), 7.30 (d, J= 7.6 Hz, IH), 7.19 (t, J= 7.8 Hz, IH), 6.90 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 2.00 (m, 2H), 1.82 (m, 2H), 1.72 (m, IH), 1.49-1.29 (m, 5H), 1.24 (t, J= 7.6 Hz, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 19:1) = 0.33.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in «-Hexanes, 6.5 mL/min): 295a t R = 24.3 min, 295b t R = 35.1 min.
296
5-(4-Cyclohexylthiazol-2-yl)-4-(3,5-difluorophenyl)-6-ethyl- 3,4-dihydropyrimidin-2(l J fiT)- one (296)
1 H NMR (400 MHz, CD 3 OD) δ 6.93 (s, IH), 6.91 (dd, J= 8.4, 2.0 Hz, 2H), 6.79 (tt, J= 9.0, 2.4 Hz, IH), 5.62 (s, IH), 2.66 (m, 2H), 1.97 (m, 2H), 1.81 (m, 2H), 1.73 (m, IH), 1.48-1.36 (m, H), 1.29 (m, IH), 1.25 (t, J= 7.6 Hz, 3H); TLC £/(CH 2 Cl 2 :Me0H 19:1) = 0.23. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in rc-Hexanes, 6.5 mL/min): 296a t R = 14.4 min, 296b t R = 20.1 min.
297
5-(4-CycIohexylthiazol-2-yl)-4-(3,5-dibromophenyl)-6-ethy l-3,4-dihydropyriinidin- 2(l#)-one (297)
1 H NMR (400 MHz, CD 3 OD) δ 7.57 (d, J= 1.6 Hz, IH), 7.48 (d, J= 1.6 Hz, 2H), 6.93 (s, IH), 5.62 (s, IH), 2.66 (m, 3H), 2.01 (m, 2H), 1.82 (m, 2H), 1.74 (m, IH), 1.44 (m, 4H), 1.32 (m, IH), 1.26 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.23.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% i-PrOH in n-Hexanes, 6.5 mL/min): 297a t R = 14.8 min, 297b t R = 17.7 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyI-4-(4-(trifluoromethy l)phenyl)-3,4- dihydropyrimidin-2(liϊ)-one (298)
1 H NMR (400 MHz, CD 3 OD) δ 7.54 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 6.86 (s, IH), 5.63 (s, IH), 2.64 (m, 3H), 1.94 (m, 2H), 1.78 (m, 2H), 1.69 (m, IH), 1.40-1.32 (m, 4H), 1.23 (m, IH), 1.21 (t, J = 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.31. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 298a t R = 14.6 min, 298b t R = 18.7 min.
299
4-(3,5-Bis(trifluoromethyl)phenyl)-5-(4-cyclohexylthiazol -2-yl)-6-ethyl-3,4- dihydropyrimidin-2(liϊ)-one (299)
1 H NMR (400 MHz, CD 3 OD) δ 7.92 (s, 2H), 7.82 (s, IH), 6.92 (s, IH), 5.87 (s, IH), 2.67 (m, 3H), 1.94 (m, 2H), 1.80 (m, 2H), 1.73 (m, IH), 1.45-1.34 (m, 5H), 1.27 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.30.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 299a t R = 12.2 min, 299b t R = 13.7 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-nitrophenyl)-3, 4-dihydropyrimidin-2(lH)-one
(300)
1 R NMR (400 MHz, DMSO-J 6 ) δ 9.01 (s, IH), 8.15 (d, J= 8.4 Hz, 2H), 7.75 (s, IH), 7.52 (d, J= 8.8 Hz, 2H), 6.99 (s, IH), 5.54 (d, J= 3.6 Hz, IH), 2.66 (m, IH), 2.59 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H), 1.62 (m, IH), 1.30 (m, 5H), 1.16 (t, J= 7.4 Hz, 3H); TLC R f (CH 2 Cl 2 :Me0H 19:1) = 0.35
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 1.0 mL/min): 300a t R = 8.0 min, 300b t R = 10.6 min.
4-(4-Aminophenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3, 4-dihydropyrimidin-2(lH)-one
(301)
1 H NMR (400 MHz, CD 3 OD) δ 7.04 (d, J= 8.4 Hz, 2H), 6.83 (s, IH), 6.61 (d, J= 8.8 Hz, 2H), 5.28 (s, IH), 2.65 (m, IH), 2.62 (q, J= 7.6 Hz, 2H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.24 (m, 5H), 1.21 (t, J= 7.4 Hz, 3H); TLC .K 7 (CH 2 Cl 2 : MeOH 19:1) = 0.15. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 1.0 mL/min): 301a t R = 19.7 min, 301b t R = 34.4 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-nitrophenyl)-3, 4-dihydropyrimidin-2(lH)-one (302)
1 H NMR (400 MHz, CD 3 OD) δ 8.21 (t, J= 2.0 Hz, IH), 8.08 (td, J= 8.4, 4.0 Hz, IH), 7.74 (d, J= 7.6 Hz, IH), 7.52 (t, J= 7.8 Hz, IH), 6.88 (s, IH), 5.76 (s, IH), 2.66 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.95 (m, 2H), 1.78 (m, 2H), 1.71 (d, J= 13.2 Hz, IH), 1.44-1.26 (m, 5H), 1.25 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.27.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 302a t R = 19.3 min, 302b t R = 23.8 min.
4-(3-AminophenyI)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3, 4-dihydropyrimidin-2(lH)-one
(303)
1 H NMR (400 MHz, CD 3 OD) δ 6.98 (t, J= 7.6 Hz, IH), 6.85 (s, IH), 6.69 (s, IH), 6.62 (d, J = 7.6 Hz, IH), 6.57 (dd, J= 8.0 Hz, 1.2 Hz, IH), 5.31 (s, IH), 2.63 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.41 (m, 4H), 1.25 (m, IH), 1.21 (t, J= 7.6 Hz, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 19:1) = 0.15.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 50% z-PrOH in rc-Hexanes, 6.5 mL/min): 303a t R = 14.5 min, 303b t R = 18.4 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(2-nitrophenyl)-3, 4-dihydropyrimidin-2(lH)-one
(304)
1 H NMR (400 MHz, CD 3 OD) δ 7.85 (d, J= 8.0 Hz, IH), 7.60 (m, 2H), 7.42 (m, IH), 6.79 (s, IH), 6.21 (s, IH), 2.72 (m, 2H), 2.51 (m, IH), 1.80-1.66 (m, 3H), 1.36-1.21 (m, 8H); TLC R 1 (CH 2 Cl 2 MeOH 19:1) = 0.36.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in rc-Hexanes, 6.5 niL/min): 304a t R = 17.3 min, 304b t R = 23.1 min.
(S)-4-(4-(BenzyIamino)phenyl)-5-(4-cyclohexylthiazol-2-yI )-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (305a)
1 H NMR (400 MHz, CD 3 OD) δ 7.55 (d, J= 8.4 Hz, 2H), 7.50-7.42 (m, 5H), 7.33 (d, J- 8.4 Hz, 2H), 7.08 (s, IH), 5.72 (s, IH), 4.62 (s, 2H), 2.75 (m, 3H), 2.07 (m, 2H), 1.91 (m, 2H), 1.84 (m, IH), 1.56-1.34 (m, 5H), 1.29 (t, J= 7.2 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.31.
λ r -(4-(5-(4-CycIohexylthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetr ahydropyrimidin-4- yl)phenyl)acetamide (306)
1 H NMR (400 MHz, CD 3 OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.46 (s, IH), 2.68 (m, IH), 2.65 (q, J= 7.2 Hz, 2H), 1.98 (m, 2H), 1.81 (m, 2H), 1.72 (m, IH), 1.47-1.29 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.38. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% → 40% /-PrOH in n-Hexanes, 6.5 mL/min): 306a t R = 17.5 min, 306b t R = 60.0 min.
1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J= 7.6 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.54 (t, J= 7.2 Hz, IH), 7.47 (t, J= 7.4 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 6.86 (s, IH), 5.49 (s, IH), 2.66 (m, IH), 2.65 (q, J= 7.6 Hz, 2H), 1.97 (m, 2H), 1.80 (m, 2H), 1.71 (m, IH), 1.46-1.35 (m, 4H), 1.27 (m, IH), 1.23 (t, J= 7.4 Hz, 3H); TLC 7J 7 (CH 2 Cl 2 : MeOH 9:1) = 0.56. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% /-PrOH in H-Hexanes, 6.5 mL/min): 307a t R = 11.8 min, 307b /^ = 16.1 min.
5-(4-CyclohexylthiazoI-2-yI)-6-ethyl-4-(pyridin-3-yl)-3,4 -dihydropyrimidin-2(lJϊ)-one
(308)
1 H NMR (400 MHz, CD 3 OD) δ 8.50 (d, J= 2.4 Hz, IH), 8.39 (dd, J= 4.8, 1.2 Hz, IH), 7.82 (d, J= 8.0 Hz, IH), 7.37 (dd, J= 7.8, 5.0 Hz, IH), 6.90 (s, IH), 5.71 (s, IH), 2.68 (m, 3H),
1.97 (m, 2H), 1.80 (m, 2H), 1.73 (d, J= 12.0 Hz, IH), 1.45-1.28 (m, 5H), 1.26 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.04.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in ra-Hexanes, 6.5 mL/min): 308a t R = 17.6 min, 308b t R = 23.0 min.
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(pyridin-2-yl)-3,4 -dihydropyrimidiii-2(ljH)-one (309)
1 H NMR (400 MHz, CD 3 OD) δ 8.44 (d, J= 4.4 Hz, IH), 7.71 (dt, J= 8.6, 1.6 Hz, IH), 7.36 (d, J= 7.6 Hz, IH), 7.24 (t, J= 6.2 Hz, IH), 6.85 (s, IH), 5.59 (s, IH), 2.60 (m, 3H), 1.89 (m, 2H), 1.77 (m, 2H), 1.69 (m, IH), 1.39-1.31 (m, 4H), 1.26-1.18 (m, 4H); TLC R 1 (CH 2 Cl 2 :Me0H 19:1) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 309a t R = 15.7 min, 309b t R = 19.6 min.
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4-yl)benzoic acid (310)
1 U NMR (400 MHz, CD 3 OD) δ 7.90 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.61 (s, IH), 2.65 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.71 (d, J= 12.4 Hz 5 IH), 1.45- 1.34 (m, 4H), 1.27 (m, IH), 1.23 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.29.
Methyl 4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrah ydropyrimidin-4- yl)benzoate (311)
1 H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H) 5 6.86 (s, IH), 5.61 (s, IH), 3.85 (s, 3H), 2.63 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44- 1.33 (m, 4H), 1.29 (m, IH), 1.23 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.48. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rø-Hexanes, 6.5 mL/min): 311a ϊ R = 12.1 min, 311b t R = 17.4 min.
312
Benzyl 4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyI-2-oxo-l,2,3 5 4-tetrahydropyrimidin-4- yl)benzoate (312)
1 H NMR (400 MHz, CD 3 OD) δ 7.95 (d, J= 8.4 Hz, 2H), 7.44-7.24 (m, 7H), 6.88 (s, IH), 5.63 (s, IH), 5.32 (s, 2H), 2.64 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.72 (m, IH), 1.45-1.35 (m, 4H), 1.28 (m, IH), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.47. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 312a t R = 14.6 min, 312b t R = 18.5 min.
1 H NMR (400 MHz, CD 3 OD) δ 7.75 (d, J = 8.4 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.28 (m, 4H), 7.21 (m, IH), 6.87 (s, IH), 5.60 (s, IH), 4.52 (s, 2H), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.44-1.33 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC R f (CH 2 Cl 2 :Me0H 9:1) = 0.44.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% → 40% /-PrOH in n-Hexanes, 6.5 mL/min): 313a ^ = 51.1 min, 313b t R = 52.9 min.
314
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3 5 4-tetrahydropyrimidin-4-yl)-iV-(4- methoxybenzyl)benzamide (314)
1 H NMR (400 MHz, CD 3 OD) δ 7.73 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.22 (d, J= 8.8 Hz, 2H), 6.86 (s, IH), 6.84 (d, J= 8.8 Hz, 2H), 5.60 (s, IH), 4.45 (s, 2H), 3.74 (s, 3H), 2.63 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.61.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% /-PrOH in «-Hexanes, 6.5 mL/min): 314a fø = 25.2 min, 314b t R = 35.6 min.
Methyl 4-((4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-te trahydropyrimidin-4- yl)benzamido)methy l)benzoate (315)
1 H NMR (400 MHz, CD 3 OD) δ 7.95 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 4H), 6.87 (s, IH), 5.61 (s, IH), 4.59 (s, 2H), 3.86 (s, 3H), 2.63 (m, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.44-1.34 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC R f (CH 2 Cl 2 MeOH 9:1) = 0.50.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% z-PrOH in n-Hexanes, 6.5 niL/min): 315a fø = 27.6 min, 315b ϊ R = 49.4 min.
1 H NMR (400 MHz, CD 3 OD) δ 7.69 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.0 Hz, 2H), 6.87 (s, IH), 5.60 (s, IH), 3.16 (d, J= 7.2 Hz, 2H), 2.62 (m, 3H), 1.97 (m, 2H), 1.80-1.55 (m, 9H), 1.44-1.34(m, 4H), 1.26-1.16 (m, 7H), 1.94 (m, 2H); TLC ^/(CH 2 Cl 2 :MeOH 9:1) = 0.54. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in n-Hexanes, 6.5 mL/min): 316a fø = 16.2 min, 316b fø = 23.6 min.
3-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tet rahydropyrimidin-4-yl)benzoic acid (317)
1 U NMR (400 MHz, CD 3 OD) δ 8.00 (s, IH), 7.86 (d, J= 7.6 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.35 (t, J= 7.6 Hz, IH), 6.84 (s, IH), 5.61 (s, IH), 2.64 (q, J= 7.6 Hz, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.44-1.29 (m, 5H), 1.23 (t, J= 7.4 Hz, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 9:1) = 0.22.
Methyl 3-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3 ? 4-tetrahydropyrimidin-4- yl)benzoate (318)
1 R NMR (400 MHz, CD 3 OD) δ 7.99 (s, IH), 7.86 (d, J= 7.6 Hz, IH), 7.56 (d, J= 7.6 Hz, IH), 7.38 (t, J= 7.8 Hz, IH), 6.85 (s, IH), 5.63 (s, IH), 3.85 (s, 3H), 2.65 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.34.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% Z-PrOH in «-Hexanes, 6.5 mL/min): 318a t R = 15.3 min, 318b t R = 17.8 min.
iV-Benzyl-3-(5-(4-cycIohexylthiazoI-2-yl)-6-ethyl-2-oxo-l ,2,3,4-tetrahydropyrimidiii-4- yl)benzamide (319)
1 H NMR ^OO MHZ, CD 3 OD) δ 7.81 (t, J= 1.8 Hz, IH), 7.68 (td, J= 8.0, 1.4 Hz, IH), 7.48 (td, J= 7.6, 1.6 Hz, IH), 7.36 (t, J= 7.8 Hz, IH), 7.32-7.27 (m, 4H), 7.23 (m, IH), 6.85 (s, IH), 5.59 (s, IH), 4.53 (s, 2H), 2.64 (m, 3H), 1.93 (m, 2H), 1.76 (m, 2H), 1.69 (m, IH), 1.43- 1.27 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.50. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 319a t R = 34.8 min, 319b t R = 39.9 min.
320
5-(4-CycIohexylthiazol-2-yl)-6-ethyl-4-(4-hydroxyphenyl)- 3,4-dihydropyrimidine-2(lH)- thione (320)
1 B. NMR (400 MHz, CD 3 OD) δ 7.12 (d, J= 8.8 Hz, 2H), 6.88 (s, IH), 6.67 (d, J= 8.4 Hz, 2H), 5.36 (s, IH), 2.69 (m, 3H), 1.97 (m, 2H), 1.80 (m, 2H), 1.71 (m, IH), 1.48-1.30 (m, 4H), 1.24 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.54. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 320a t R = 22.4 min, 320b t R = 25.7 min.
5-(4-Cyclohexyl-lJjr-imidazol-2-yl)-6-ethyl-4-(4-methoxyp henyl)-3,4-dib.ydropyrimidin- 2(lH)-one (321)
1 H NMR (400 MHz, CD 3 OD) δ 7.08 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 6.59 (s, IH), 5.34 (s, IH), 3.72 (s, 3H), 2.45 (m, IH), 2.38 (m, IH), 2.13 (m, IH), 1.92 (m, 2H), 1.79-
1.76 (m, 3H), 1.36-1.26 (m, 5H), 1.07 (t, J= 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C 22 H 28 N 4 O 2 (M+H) + 381.48, found 381.27.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rc-Hexanes, 6.5 mL/min): 321a t R = 19.0 min, 321b t R = 24.0 min.
322
5-(4-Cyclohexyl-ljfir-imidazol-2-yl)-6-ethyl-4-(3-fluoro-4-h ydroxyphenyl)-3,4- dihydropyrimidin-2(l J fiT)-one (322)
1 H NMR (400 MHz, CD 3 OD) δ 6.83 (dd, J= 12.8, 2.0 Hz, IH), 6.79-6.75 (m, 2H), 6.62 (s, IH), 5.30 (s, IH), 2.50 (m, IH), 2.36 (m, IH), 2.11 (m, IH), 1.95 (m, 2H), 1.80-1.69 (m, 3H), 1.40-1.26 (m, 5H), 1.07 (t, J= 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C 21 H 25 FN 4 O 2 (M+H) + 385.45, found 385.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 5% i- PrOH and MeOH in «-Hexanes, 0.85 mL/min): 322a t R = 35.0 min, 322b t R = 42.0 min.
6-(6-(2-(Benzo[rf][l,3]dioxol-5-yl)ethyl)-5-(4-cyclohexyl thiazoI-2-yl)-2-oxo-l,2,3,4- tetrahydropyrimidin-4-yl)-2H-benzo[λ][l,4]oxazin-3(4H)-one (323)
1 H NMR (400 MHz, CDCl 3 ) δ 9.07 (brs, IH), 8.0 (brs, IH), 6.83-6.64 (m, 7H), 6.35 (brs, IH), 5.87 (s, 2H), 5.41 (s, IH), 4.48 (d, J= 4.4 Hz, 2H), 3.03-2.87 (m, 4H), 2.68 (m, IH), 2.02 (m, 2H), 1.79-1.70 (m, 3H), 1.37-1.20 (m, 5H) ; LRMS (electrospray) m/z calculated for C 30 H 30 N 4 O 5 S (M+H) + 559.65, found 559.34.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 25% r-PrOH in H-Hexanes, 0.85 mL/min): 323a t R = 39.0 min, 323b t R = 59.0 min.
Triazine scaffold analogs
General procedure for the synthesis of triazine subunit 1 analogs
To a solution of aryl ketone (5.87 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added phenyltriniethylammonium tribromide (11.75 mmol, 2.0 equiv) in small portions over 10 min. A white precipitate forms and the solution becomes yellow over one hour. The suspension was filtered and rinsed with THF. The filtrate was concentrated in vacuo and then subjected to flash column chromatography to give desired dibromide A.
To a solution of the dibromide (1.0 equiv) in anhydrous THF (0.6 M ) under Ar was added neat morpholine (4.2 equiv) all at once at 25 0 C. The resulting solution was slowly heated to 65 0 C over 1 h and aged at this temperature for 24-96 h, at which a 97% conversion was typically obtained as determined by 1 H NMR spectroscopy. After cooling to 25 0 C, the suspension was filtered through a fritted funnel and the wet cake was washed with CHCl 3 . The combined filtrate was then concentrated to give the crude aminal intermediate B, which was used without further purification.
To a solution of crude aminal B in MeOH (0.6 M) under Argon was added all at once solid aminoguanidine bicarbonate (AGB, 1.0 equiv with respect to dibromide), followed by slow addition of neat AcOH (3.0 equiv) over 10-15 min at 25 0 C. The resulting suspension was stirred at 25 °C for 2 h, at which time CO 2 evolution ceased, and then slowly heated to reflux and aged for 24-48 h. After cooling to 25 0 C, the resulting suspension was concentrated in vacuo. The residue was treated with H 2 O and small amount Of CH 2 Cl 2 to precipitate aminotriazine, cooled to 0 0 C, aged for 1 h, filtered through a fritted funnel and washed with cold MeOH:H 2 O (4:1). The collected solid was freeze dried in vacuo to give solely the 5- substituted-3 -aminotriazine.
General procedure for the preparation of substituted aryl methyl ketones
To a 0 0 C solution of phenol derivatives (40.9 mmol, 1.0 equiv) and triflic anhydride (81.8 mmol, 2.0 equiv) in CH 2 Cl 2 (40 mL) was added slowly pyridine (81.8 mmol, 2.0 equiv) and
stirred at room temperature for 40 min. The reaction mixture was sequentially washed with brine (20 mL) and water (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give trifluoromethanesulfonates.
To a solution of above trifluoromethanesulfonate (7.95 mmol, 1.0 equiv) and triethylamine (15.9 mmol, 2.0 equiv) in DMF (22 mL) was added butyl vinyl ether (38.9 mmol, 5.0 equiv), l,3-bis(diphenylphosphinopropane) (0.22 mmol, 0.028 equiv), and palladium ( II ) acetate (0.20 mmol, 0.025 equiv) at room temperature. The reaction mixture was heated to 80 ° C for 30 min and then cooled to 25 °C. The resulting mixture was treated with aqueous IN HCl (10 mL) and stirred for 30 min. The solution was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl methyl ketones.
To a 0 °C solution of substituted aryl compound (24.97 mmol, 1.0 equiv) and TMEDA (34.96 mmol, 1.4 equiv) in THF (50 mL) was added slowly rø-BuLi (1.6 M in hexanes, 29.96 mmol, 1.2 equiv). The reaction mixture was warmed to 25 "C and stirred for 3 h. After cooled to 0 °C, the reaction was treated with DMF (49.94 mmol, 2.0 equiv) and stirred at room temperature for 30 min. The reaction was quenched by the addition of aqueous IN HCl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give formylated products.
To a 0 0 C solution of above formylated compounds (8.77 mmol, 1.0 equiv) in Et 2 O (29 mL) was added MeMgCl (2.97 M in THF, 13.15 mmol, 1.5 equiv). The reaction mixture was
warmed to room temperature and further stirred for 4 h. The reaction was quenched by the addition of saturated aqueous NH 4 Cl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give alcohol products.
To a solution of above alcohols (8.89 mmol, 1.0 equiv) in CH 2 Cl 2 (10 mL) was added PCC (22.23 mmol, 2.5 equiv) and SiO 2 (4.79 g) in CH 2 Cl 2 (13 mL). The resulting suspension was stirred at 25 °C for 6 h. The reaction mixture was filtered through a pad of silica gel and then concentrated in vacuo. The residue was purified via flash column chromatography to give ketone compounds.
General procedure for the synthesis of nitrile substituted methyl ketones
To a 0 °C solution of hydroxy acetophenone derivatives (33.2 mmol, 1.0 equiv) in CH 2 Cl 2 (110 mL) was added Et 3 N (43.3 mmol, 1.3 equiv) and stirred for 15 min. The reaction mixture was treated with Tf 2 O (43.3 mmol, 1.3 equiv) at 0 °C. The resulting solution was stirred at 25 0 C for overnight. The reaction was quenched with H 2 O (20 mL). The reaction mixture was extracted with CH 2 Cl 2 (3 x) and the combined organic layers were washed with brine and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl triflates.
To a 0 0 C solution of triflate compound (24.8 mmol, 1.0 equiv) and Zn(CN) 2 (49.6 mmol, 2.0 equiv) in DMF (31 mL) was added Pd(PPh 3 ) 4 (0.744 mmol, 0.03 equiv). The suspension was stirred at 120 °C for 2 h. After cooling to 25 °C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (20 mL) and extracted with CH 2 Cl 2 (3 x 30 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl nitriles.
General procedure for the conversion of methoxy to nitrile group
To a solution of starting material (0.74 mmol, 1.0 equiv) in dry CH 2 Cl 2 (30 mL) was added dropwise BBr 3 (7.4 mmol, 10 equiv) at 0 °C. The resulting solution was stirred at 25 °C for 15 h. The reaction was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) solution and extracted with CH 2 Cl 2 (3 x 30 mL). The combined organic layers were dried over Na 2 SO 4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of hydroxy compound (0.41 mmol, 1.0 equiv) in pyridine (0.5 mL) was added slowly Tf 2 O (0.57 mmol, 1.4 equiv) at 0 0 C. The resulting solution was stirred at 25 °C for 4 h, and then quenched with H 2 O (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of triflate compound (0.69 mmol, 1.0 equiv) and anhydrous Zn(CN) 2 (2.75 mmol, 4.0 equiv) in DMF (7 mL) was added Pd(PPh 3 ) 4 (0.10 mmol, 0.15 equiv) at 25 °C. The suspension was stirred at 120 0 C for 4 h under Ar. After cooled to 25 0 C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (20 mL) and extracted with CH 2 Cl 2 (3 x 30 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of biaryl subunit 1 analogs
To a solution of boronic acid (2.73 mmol, 1.2 equiv) and bromoaniline (2.27 mmol, 1.0 equiv) in toluene-H 2 O (5:2, v/v, 23 mL) was added Pd(PPh 3 ) 4 (0.060 mmol, 0.03 equiv), followed by sat. K 2 CO 3 (16 mL) at 25 0 C under Ar. The reaction mixture was heated to reflux (oil bath temp 120 0 C) for overnight then cooled to ambient temperature. The solid was removed by filtration through a pad of celite, and the filtrate was poured into a separatory funnel. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined layers were dried over Na 2 SO 4 , filtered, concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give cross-coupled products.
To a solution of boronic acid (1.05 equiv), dichloropyrimidine (1.0 equiv), Pd 2 (dba) 3 (0.02 equiv) and K 3 PO 4 (3.0 equiv) in dioxane was added P(Z-Bu) 3 (10wt% in hexanes, 0.04 equiv) at 25 ° C under Ar. The reaction mixture was stirred at 70 0 C for overnight. After cooled to room temperature, the reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO 2 , n- Hexanes-.EtOAc 9:1) to give Suzuki coupling products.
General procedure for the conversion of chloride to amino groups
A, , C = CH, N, or N=O Method A
1. PMB-NH 21 NMP, 150 0 C, 12 h 2. TFA Method B NH 4 OH, EtOH, 80 c C, 12 h
Method A p-Methoxy benzylamine (4.12 mmol, 10.0 equiv) and K 2 CO 3 (2.47 mmol, 6.0 equiv) were added to a solution of biaryl chloride (0.41 mmol, 1.0 equiv) in NMP. The mixture was heated to 150 0 C for overnight. After cooling to room temperature, the crude reaction mixture was
extracted with EtOAc (3 x). The combined organic layers were washed with water (4 x), followed by brine (2 x) and then dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give PMB adducts.
A solution of above PMB compounds (1.141 mmol, 1.0 equiv) in TFA (8.5 mL, 0.1 equiv) was heated to 120 ° C for overnight. After cooled to room temperature, the crude reaction mixture was extracted with EtOAc (3 x). The combined organic layers were washed with saturated aqueous NaHCO 3 (2 x) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give amino products.
Method B
A mixture of pyrimidine (2.510 mmol, 1.0 equiv), ethanol (8 mL) and NH 4 OH (28% in water, 25.1 mmol, 10 equiv) in a sealed tube was kept in an oil bath for 24 h at 80 0 C. After cooled to 25 °C, the reaction mixture was concentrated under reduced pressure and then partitioned between CH 2 Cl 2 (3 x) and water. The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give amino products.
General procedure for the conversion of chloride to propargylated amino groups
A = CH, N, or N=O
B = Me, CF 3 , Cl 1 Br, CN
To a sealed tube was added pyrimidine (1.0 equiv), propargyl amine (3.0 equiv), and DMF (0.1 M). The reaction mixture was stirred for 3 h at 140 °C. After cooled to room temperature, the reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO 2 , «-Hexanes: EtOAc 7:3).
To a solution of alkyne (1.0 equiv) and azide (1.2 equiv) in t-BuOH/H 2 O (1:1, 0.25 M) was added sodium ascorbate (0.1 equiv) and copper sulfate pentahydrate (0.01 equiv) and stirred
for 2 h at 25 "C. The reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO 2 , n- Hexanes:EtOAc 3:7).
324 5-Phenyl-l ,2,4-triazin-3-amine (324)
1 H NMR (400 MHz, DMSOcfe) δ 9.22 (s, IH), 8.18-8.16 (m, 2H), 7.61-7.54 (m 3H), 7.24 (bs, 2H); 13 C NMR (100 MHz, DMSO-^) δ 163.7, 155.5, 137.8, 134.7, 132.5, 129.7, 127.9; TLC ^ 7 (CH 2 Cl 2 IMeOH 10:1) = 0.60.
1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (d, J= 8.4 Hz, IH), 8.07 (d, J= 8.0 Hz, IH), 7.95-7.90 (m, 2H), 7.68-7.64 (m, IH), 7.60-7.57 (m, IH), 7.54-7.50 (m, IH), 6.83 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 188.6, 134.1, 133.9, 130.9, 130.4, 128.6, 127.5, 127.0, 125.4, 124.1, 42.3; TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.49.
326 5-(6-Methoxynaphthalen-2-yl)-l,2,4-triazin-3-amine (326)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.30 (s, IH), 8.72 (s, IH), 8.19 (dd, J = 8.4, 1.6 Hz, IH), 7.96-7.93 (m, 2H), 7.39 (d, J= 2.0 Hz, IH), 7.23 (dd, J= 8.8, 2.4 Hz, IH), 7.18 (bs, 2H), 3.88 (s, 3H).
2,2-Dibromo-l-(4-tert-butylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J= 8.4 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 6.67 (s, IH), 1.34 (s, 9H); 13 C NMR (IOO MHz, CDCl 3 ) δ 185.8, 158.8, 141.2, 129.9, 128.3, 126.2, 66.0, 40.1, 35.4, 32.1; TLC i?/(Hexanes:EtOAc 2:1) = 0.87.
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.15 (s, IH), 8.07 (dd, J= 8.8, 4.0 Hz, 2H), 7.52 (dd, J= 5.4, 3.4 Hz, 2H), 7.16 (bs, 2H), 1.24 (s, 9H); 13 C NMR (100 MHz, DMSO-^) δ 163.7, 155.5, 155.4, 137.7, 131.9, 127.8, 126.6, 35.4, 31.5; TLC R f (CH 2 Cl 2 :MeOH 10:1) = 0.40.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.74 (s, IH), 7.47 (d, J= 7.2 Hz, IH), 7.40-7.37 (m, IH), 7.32-7.28 (m, 2H), 7.20 (bs, 2H), 2.38 (s, 3H); 13 C NMR (100 MHz, DMSO-J 15 ) δ 163.5, 159.3, 140.8, 137.0, 135.3, 131.8, 130.8, 130.1, 126.9, 20.7; TLC £/ (CH 2 Cl 2 : MeOH 10:1) = 0.40.
1 U NMR (400 MHz, DMSO-J 6 ) δ 9.35 (s, IH), 8.80 (s, IH), 8.23 (dd, J= 8.6, 1.4 Hz, IH), 8.06 (d, J= 13.8, 6.2 Hz, 2H) 7.99-7.97 (m, IH), 7.63-7.57 (m, 2H) 5 7.25 (bs, 2H); TLC R 1 (CH 2 Cl 2 :Me0H 10:1) = 0.73.
2,2-Dibromo-l-(4-chIorophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 6.60 (s, IH); 13 C NMR (IOO MHz, CDCl 3 ) δ 185.1, 141.3, 131.4, 129.5, 129.3, 39.5; TLC R f (n- Hexanes:EtOAc 2:1) = 0.87.
5-(4-Chlorophenyl)-l,2,4-triazin-3-amine (330)
1 H NMR (400 MHz, DMS(W 6 ) δ 9.19 (s, IH), 8.14 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.25 (bs, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.7, 154.4, 137.6, 137.4, 133.5, 129.8, 129.7; TLC R f (CH 2 Cl 2 MeOH 10:1) = 0.40.
2,2-Dibromo-l-(2,4-dimethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J= 8.4 Hz, IH), 7.14 (bs, IH), 7.09 (d, J= 8.0 Hz, IH), 6.69 (s, IH), 2.50 (s, 3H), 2.38 (s, 3H); TLC i?/(Hexanes:Et 2 O 5:1) = 0.61.
S-(2,4-DimethylphenyI)-l,2,4-triazin-3-amine (331)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.72 (s, IH), 7.39 (d, J= 8.0 Hz, IH), 7.15-7.10 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.4, 159.2, 140.7, 140.5, 137.0, 132.6, 132.4, 130.2, 127.5, 21.5, 20.8; TLC R f (CH 2 Cl 2 : MeOH 20:1) = 0.36.
2,2-Dibromo-l-(4-ethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 6.70 (s, IH), 2.74 (q, J= 7.6 Hz, 2H), 1.28 (t, J= 7.6 Hz, 3H); TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.66.
5-(4-EthyIphenyl)-l,2,4-triazin-3-amine (332)
1 H NMR (400 MHz, DMSO-^ 6 ) δ 9.16 (s, IH), 8.06 (d, J= 8.0 Hz, 2H), 7.36 (d, J= 8.0 Hz, 2H), 7.15 (bs, 2H), 2.64 (q, J= 7.6 Hz, 2H), 1.17 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 163.7, 155.5, 148.8, 137.7, 132.1, 129.2, 128.0, 28.8, 15.9; TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.23.
2,2-Dibromo-l-(4-bromophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.99-7.96 (m, 2H), 7.67-7.65 (m, 2H), 6.59 (s, IH); TLC R f (n- Hexanes:Et 2 O 2:1) = 0.69.
1 H NMR (400 MHz, DMSO-^ 5 ) δ 9.20 (s, IH), 8.09 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.25 (bs, 2H); TLC R 1 (CH 2 Cl 2 : MeOH 20:1) = 0.27.
2,2-Dibromo-l-(2-(trifluoromethyl)phenyI)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.79-7.75 (m, IH), 7.72-7.68 (m, IH), 7.68-7.64 (m, 2H) 5 6.45 (s, IH); TLC i?/(Hexanes:Et 2 O 2:1) = 0.45.
1 U NMR (400 MHz, DMSO-J 6 ) δ 8.66 (s, IH), 7.89 (d, J= 7.6 Hz, IH), 7.81-7.78 (m, IH), 7.75-7.71 (m, IH), 7.60 (d, J= 7.2 Hz, IH), 7.35 (bs, 2H); TLC ^(CH 2 Cl 2 =MeOH 20:1) = 0.31.
5-/j-Tolyl-l,2,4-triazin-3-amine (335)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.15 (s, IH), 8.04 (d, J= 7.2 Hz, 2H), 7.33 (d, J= 7.6 Hz,
2H), 7.15 (bs, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.7, 155.4, 142.7, 137.6,
131.8, 130.4, 127.9, 21.7.
1 H NMR (400 MHz, CDCl 3 ) δ 7.75-7.45 (m, IH), 7.44-7.33 (m, 6H), 7.02-6.98 (m, 2H), 5.14 (s, 2H), 2.59 (s, 3H); TLC #/(rc-Hexanes:EtOAc 3:1) = 0.37.
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.83 (m, IH), 7.54-7.39 (m, 6H), 7.10-7.04 (m, 3H), 5.21 (s, 2H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.42.
5-(2-(Benzyloxy)phenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.02 (s, IH), 7.83 (s, IH), 7.50-7.28 (m, 6H), 7.11 (s, 4H), 5.22 (s, 2H).
2,2-Dibromo-l-(2-chlorophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (dd, J= 7.2, 1.2 Hz, IH), 7.46-7.42 (m, 2H), 7.38-7.34 (m, IH), 6.74 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 189.0, 134.2, 133.2, 131.3, 131.1, 130.7, 127.4, 42.3; TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.43.
5-(2-ChIorophenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.81 (s, IH), 7.59-7.58 (m, 2H), 7.54-7.47 (m, 2H), 7.35 (bs, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.7, 157.0, 140.8, 134.7, 132.5, 132.0, 131.8, 130.8, 128.4.
5-(3-MethoxyphenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.19 (s, IH), 7.71 (d, J= 8.0 Hz, IH), 7.66 (s, IH), 7.43 (t, J= 8.0 Hz, IH), 7.20 (bs, 2H), 7.12 (dd, J= 8.0, 2.4 Hz, IH), 3.80 (s, 3H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 163.7, 160.4, 155.3, 137.9, 136.1, 130.9, 120.3, 118.4, 112.8, 56.0.
2,2-Dibromo-l-(2,5-dimethoxyphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (d, J= 3.2 Hz, IH), 7.01 (s, IH), 7.07 (dd, J= 3.2, 0.8 Hz, IH), 6.91 (d, J= 9.2 Hz, IH), 3.88 (s, 3H), 3.78 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.7, 154.1, 153.0, 122.5, 115.7, 113.5, 56.7, 56.1, 44.8; TLC /?/(rc-Hexanes:EtOAc 5:1) = 0.49.
5-(2,5-Dimethoxyphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-^ 5 ) δ 9.01 (s, IH), 7.39 (d, J= 2.8 Hz, IH), 7.13 (bs, 2H), 7.09- 7.08 (m, 2H), 3.80 (s, 3H), 3.72 (s, 3H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 164.0, 155.3, 154.0, 152.8, 141.3, 124.3, 118.9, 115.6, 114.4, 56.9, 56.2.
2,2-Dibromo-l-(2,5-dimethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (s, IH), 7.26 (dd, J= 5.4, 2.2 Hz, IH), 7.20 (d, J= 8.0 Hz, IH), 6.69 (s, IH), 2.47 (s, 3H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 188.9, 137.2, 135.6, 133.7, 132.4, 132.3, 128.6, 42.6, 21.1, 20.7; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.70.
5-(2,5-DimethylphenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, OMSO-Cl 6 ) δ 8.72 (s, IH), 7.28 (s, IH), 7.20-7.18 (m, 4H), 2.32 (s, 3H), 2.28 (s, 3H); 13 C NMR (IOO MHz, DMSO-J 6 ) δ 163.5, 159.3, 140.8, 135.9, 135.1, 133.8, 131.8, 131.4, 130.5, 21.0, 20.2.
1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (dd, J= 8.0, 1.6 Hz, IH), 7.40 (dt, J= 7.2, 1.2 Hz, IH), 7.29-7.23 (m, 2H), 2.87 (q, J= 7.6 Hz, 2H), 2.58 (s, 3H), 1.22 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.3, 144.2, 137.9, 131.4, 130.4, 128.9, 125.6, 29.9, 27.0, 15.9; TLC R 1 («-Hexanes:Et 2 O 5:1) = 0.51.
2,2-Dibromo-l-(2-ethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (dd, J= 7.6 Hz, IH), 7.49 (dt, J= 7.6, 1.2 Hz, IH), 7.37 (d, J= 7.2 Hz, IH), 7.30-7.28 (m, IH), 6.66 (s, IH), 2.82 (q, J= 7.2 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.0, 146.0, 132.7, 132.3, 130.7, 127.8, 125.7, 42.3, 27.0, 15.8; TLC i?/(«-Hexanes:Et 2 O 5:1) = 0.54.
5-(2-EthylphenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (s, IH), 7.42-7.29 (m, 4H), 7.20 (bs, 2H), 2.71 (q, J= 7.6 Hz, 2H), 1.00 (t, J= 7.2 Hz, 3H); TLC R 1 (CH 2 Cl 2 :MeOH 20:1) = 0.31.
1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (bd, J= 7.6 Hz, IH), 7.42-7.41 (m, 2H), 7.25-7.21 (m, IH), 3.51-3.41 (m, IH), 2.57 (s, 3H), 1.24 (d, J= 6.8 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ D203.7, 147.7, 138.9, 131.0, 127.6, 126.5, 125.4, 30.7, 29.2, 24.1; TLC λ/(»-Hexanes:Et 2 O 5:1) = 0.53.
1 H NMR (400 MHz, CDCl 3 ) δ 7.53-7.44 (m, 3H), 7.28-7.23 (m, IH), 6.59 (s, IH), 3.20 (h, J = 6.8 Hz, IH), 1.28 (d, J= 6.4 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.9, 149.6, 133.0, 132.3, 127.0, 126.7, 125.5, 42.9, 30.2, 24.2; TLC i?/(n-Hexanes:Et 2 O 5:1) = 0.69.
5-(2-Isopropylphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.59 (s, IH), 7.43 (bs, 2H), 7.26 (bs, 2H), 7.19 (bs, 2H), 4.02 (bs, IH), 1.10 (d, J= 6.8 Hz, 6H); TLC R 1 (CH 2 Cl 2 :MeOH 20:1) = 0.43.
2,2-Dibromo-l-(4-methoxyphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.06-8.04 (m, 2H), 6.96-6.94 (m, 2H), 6.64 (s, IH), 3.87 (s, 3H); TLC i?/(π-Hexanes:EtOAc 5:1) = 0.48.
5-(4-Methoxyphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-^) δ 9.13 (s, IH), 8.12 (d, J- 7.6 Hz, 2H), 7.07 (s, 4H), 3.80 (s, 3H).
2,2-Dibromo-l-(2-methoxyphenyl)ethanone
1 H NMR ^OO MHZ, CDCl 3 ) 6 7.85 (dd, J= 7.6, 1.6 Hz, IH), 7.57-7.53 (m, IH), 7.10 (s, IH), 7.09-7.05 (m, IH), 7.00 (d, J= 8.4 Hz, IH), 3.97 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 6 187.8, 158.2, 135.2, 132.6, 122.2, 121.4, 111.7, 56.0, 44.7; TLC 7?/(rc-Hexanes:Et 2 O 5:1) = 0.39.
5-(2-Methoxyphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.00 (s, IH), 7.80 (dd, J = 7.6, 1.6 Hz, IH), 7.53-7.48 (m, IH), 7.17 (d, J = 8.4 Hz, IH), 7.11 (bs, 2H), 7.10-7.06 (m, IH), 3.86 (s, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 164.0, 158.5, 155.7, 141.4, 133.5, 131.2, 121.6, 112.9, 56.5; TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.22.
1 H NMR (400 MHz, CDCl 3 ) δ 7.94-7.92 (m, 2H), 7.44-7.33 (m, 5H), 7.02-6.99 (m, 2H), 5.12 (s, 2H), 2.54 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 8.05-8.03 (m, 2H), 7.39-7.34 (m, 5H), 7.03-7.00 (m, 2H), 6.63 (s, IH), 5.13 (s, 2H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.53.
5-(4-(Benzyloxy)phenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.13 (s, IH), 8.12 (d, J= 8.8 Hz, IH), 7.83 (d, J= 8.0 Hz, 2H), 7.39-7.29 (m, 6H), 7.18-7.07 (m, 2H), 5.21 (s, 2H).
2,2-Dibromo-l-/M-toIylethanone
1 U NMR (400 MHz, CDCl 3 ) δ 7.87-7.86 (m, 2H), 7.46-7.36 (m, 3H), 6.72 (s, IH), 2.44 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.4, 139.2, 135.5, 131.1, 130.3, 129.0, 127.0, 40.0, 21.6; TLC i?/(π-Hexanes:Et 2 O 10:1) = 0.54.
5-m-Tolyl-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-^ 6 ) δ 9.20 (s, IH), 8.00 (s, IH), 7.95 (d, J= 7.6 Hz, IH), 7.44- 7.37 (m, 2H), 7.23 (s, 2H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 136.1, 154.9, 138.4, 137.2, 133.9, 132.4, 128.9, 127.7, 124.4, 21.0; TLC ^ 7 (CH 2 Cl 2 :MeOH 20:1) = 0.28.
2,2-Dibromo-l-(2-fluorophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (t, J= 7.6 Hz, IH), 7.64-7.59 (m, IH), 7.31 (t, J= 7.8 Hz, IH), 7.23-7.15 (m, IH), 6.85 (d, J= 2.4 Hz, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 184.5, 159.9, 136.3, 134.1, 125.4, 117.1, 116.9, 43.3; TLC i?/(«-Hexanes:Et 2 O 10:1) = 0.54.
5-(2-FIuorophenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.20 (s, IH), 8.00-7.97 (m, IH), 7.64-7.57 (m, IH), 7.46- 7.27 (m, 4H); 13 C NMR (IOO MHz, DMSO-J 6 ) δ 163.9, 159.9, 153.1, 140.3, 134.3, 131.2, 125.9, 123.0, 117.4; TLC ^y(CH 2 Cl 2 =MeOH 20:1) - 0.28.
1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J= 7.6 Hz, IH), 7.79 (dt, J= 8.8, 2.0 Hz IH), 7.50 (m, IH), 7.35 (td, J= 8.2, 2.8 Hz, IH), 6.63 (d, J= 1.2 Hz, IH); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.90.
5-(3-Fluorophenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, IH), 7.84 (s, 2H), 7.51 (m, IH), 7.26 (s, IH), 5.38 (bs, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.39.
2,2-Dibromo-l-(3-chlorophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, IH), 7.98 (d, J= 7.6 Hz, IH), 7.61 (d, J= 8.4 Hz, IH), 7.46 (t, J= 8.0 Hz, IH), 6.61 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 185.0, 135.5, 134.6, 132.6, 130.4, 130.0, 128.0, 39.2; TLC i?y(n-Hexanes:Et 2 O 5:1) = 0.63.
5-(3-Chlorophenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.27 (s, IH), 8.21 (s, IH), 8.13 (d, J= 7.6 Hz, IH), 7.66- 7.63 (m, IH), 7.58 (t, J= 7.8 Hz, IH), 7.32 (s, 2H); 13 C NMR (100 MHz, OMSO-d 6 ) δ 163.0, 153.4, 137.2, 136.2, 134.0, 131.5, 131.0, 126.9, 125.9; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.29.
2,2-Dibromo-l-(3-(trifluoromethyl)phenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, IH), 8.32 (d, J= 7.6 Hz, IH), 7.90 (d, J= 7.6 Hz, IH), 7.67 (t, J= 8.0 Hz, IH), 6.62 (s, IH); 13 C NMR (IOO MHz, CDCl 3 ) δ 185.0, 133.1, 131.7, 130.98, 130.95, 129.8, 126.96, 126.93, 39.1; TLC i?/(«-Hexanes:Et 2 O 10:1) = 0.48.
5-(3-(Trifluoromethyl)phenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.36 (s, IH), 8.23 (d, J= 8.0 Hz, IH), 8.18 (s, IH), 7.97 (d, J= 8.0 Hz, IH), 7.77 (t, J= 8.0 Hz, IH), 7.38 (s, 2H); TLC ^(CH 2 Cl 2 MeOH 20:1) = 0.26.
1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (m, 2H), 7.39 (m, 6H), 7.18 (m, IH), 5.11 (s, 2H), 2.59 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.9, 158.9, 138.5, 136.5, 129.6, 128.6, 128.1, 127.5, 121.3, 120.3, 113.5, 70.2, 26.7; TLC i?/(«-Hexanes:EtOAc 4:1) = 0.53.
1 U NMR (400 MHz, CDCl 3 ) δ 7.66 (m, 2H), 7.42 (m, 6H), 7.25 (m, IH), 6.67 (s, IH), 5.12 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.0, 159.3, 136.4, 132.3, 130.2, 128.9, 128.5, 122.4, 122.0, 115.4, 70.6, 39.8; TLC i?/(n-Hexanes:EtOAc 19:1) = 0.47.
5-(3-(BenzyIoxy)phenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz 3 CDCl 3 ) δ 9.08 (s, IH), 7.73 (s, IH), 7.65 (d, J= 7.0 Hz, IH), 7.42 (m, 6H), 7.17 (dd, J= 8.4, 1.6 Hz, IH), 5.40 (bs, 2H), 5.16 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 162.6, 159.4, 156.2, 138.8, 136.5, 135.3, 130.3, 128.7, 128.2, 127.5, 120.0, 118.9, 113.5, 70.3; TLC ^/(CH 2 Cl 2 MeOH 9:1) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 7.08-6.91 (m, 3H), 5.39-5.34 (m, IH), 2.43 (s, 6H), 1.52 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 140.5, 135.6, 129.4, 126.8, 67.6, 21.4, 20.6; TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.49.
1 H NMR (400 MHz, CDCl 3 ) δ 7.15 (t, J= 7.6 Hz, IH), 7.10 (d, J= 7.6 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 208.4, 142.6, 132.2, 128.5, 127.7, 32.1, 19.1; TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.59.
1 U NMR (400 MHz, CDCl 3 ) δ 7.26 (t, J= 1.6 Hz, IH), 7.08 (d, J= 7.6 Hz, 2H), 6.31 (s, IH), 2.35 (s, 6H); 13 C NMR (IOO MHz, CDCl 3 ) δ 192.8, 135.8, 135.0, 130.4, 128.2, 44.0, 20.2; TLC i?/(«-Hexanes:Et 2 O 5:1) = 0.61.
5-(2,6-Dimethylphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, CD 3 OD) δ 8.46 (s, IH), 7.23 (t, J= 7.6 Hz, IH), 7.11 (d, J= 7.6 Hz, 2H), 2.09 (s, 6H); 13 C NMR (IOO MHz, MeOH-^) δ 163.5, 161.8, 141.1, 135.4, 135.0, 129.2, 127.8, 18.8; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.32.
2,2-Dibromo-l-(3-ethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J= 8.8 Hz, 2H), 7.48 (d, J= 7.6 Hz, IH), 7.42 (t, J= 7.4 Hz, IH), 6.73 (s, IH), 2.73 (q, J= 7.6 Hz, 2H), 1.28 (t, J= 7.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 145.2, 134.2, 130.9, 129.1, 128.8, 127.0, 39.8, 28.7, 15.3; TLC R f (n- Hexanes:EtOAc 19:1) = 0.54.
5-(3-Ethylphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-^ 6 ) δ 9.18 (s, IH), 7.99 (s, IH), 7.94 (d, J= 7.2 Hz, IH), 7.41 (m, 2H), 7.18 (bs, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-dβ) δ 163.1, 155.0, 144.7, 137.2, 134.0, 131.3, 129.0, 126.5, 124.7, 28.1, 15.5; TLC R f (CH 2 Cl 2 :Me0H 19:1) = 0.39.
5-(2,3-Dimethoxyphenyl)-l,2,4-triazin-3-amme
1 H NMR (400 MHz, DMSO-^) δ 8.89 (s, IH), 7.30 (dd, J= 7.4, 1.4 Hz, IH), 7.23-7.17 (m, 5H), 3.84 (s, 3H), 3.73 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.33.
1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J= 7.6 Hz, IH), 7.12 (t, J= 7.6 Hz, IH ), 7.06 (d, J = 6.8 Hz, IH), 5.19-5.16 (m, IH), 2.27 (s, 3H), 2.22 (s, 3H), 1.68 (d, J= 3.2 Hz, IH), 1.45 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 143.9, 137.1, 133.1, 129.1, 126.0, 122.4, 67.4, 24.2, 20.8, 14.7; TLC i?/(«-Hexanes: EtOAc 5:1) = 0.43.
1 K NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J= 7.6 Hz, IH), 7.25 (d, J= 6.4 Hz, IH ), 7.14 (t, J= 7.6 Hz, IH), 2.56 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.0, 140.1, 138.5, 135.5, 132.7, 125.9, 125.4, 30.6, 20.6, 16.7; TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.58.
2,2-Dibromo-l-(2,3-dimethylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J= 7.6 Hz, IH), 7.33 (d, J= 7.6 Hz, IH ), 7.17 (t, J= 7.8 Hz, IH), 6.61 (s, IH), 2.34 (s, 3H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 190.2, 139.0, 137.3, 134.4, 133.9, 125.5, 125.0, 43.2, 20.7, 16.8; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.79.
5-(2,3-DimethylphenyI)-l,2,4-triazin-3-amine
1
H NMR (400 MHz,
1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J= 7.8, 1.8 Hz, IH), 7.45-7.35 (m, 3H), 7.19-7.13 (m, 2H), 7.02 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 8.0 Hz, IH), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.2, 156.7, 156.6, 133.8, 130.73, 130.71, 130.2, 124.1, 123.7, 119.5, 119.1, 31.8; TLC _K/(/»-Hexanes:Et 2 O 10:1) = 0.34.
2,2-Dibromo-l-(2-phenoxyphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (dd, J= 8.0, 2.0 Hz, IH), 7.18-7.41 (m, 3H), 7.27-7.23 (m, 2H), 7.18 (s, IH), 7.16-7.11 (m, 2H), 6.83 (d, J= 7.6 Hz, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 187.4, 156.9, 155.0, 135.1, 132.9, 130.5, 125.4, 123.8, 123.6, 120.5, 117.6, 44.8; TLC R f (n- Hexanes:Et 2 O 10:1) = 0.39.
5-(2-PhenoxyphenyI)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.99 (s, IH), 7.94 (dd, J= 8.0, 1.6 Hz, IH), 7.57-7.53 (m, IH), 7.40-7.32 (m, 3H), 7.27 (br, 2H), 7.14 (t, J= 7.4 Hz, IH), 7.02 (m, 3H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 163.4, 156.2, 154.7, 154.4, 140.1, 132.9, 131.1, 130.2, 126.3, 124.3, 119.5, 118.4; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.34.
2,2-Dibromo-l-(4-fluorophenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.17-8.14 (m, 2H), 7.19 (t, J= 8.4 Hz, 2H), 6.62 (t, J - 2.0 Hz, IH); 13 C NMR (I OO MHZ, CDCl 3 ) δ 184.5, 167.6, 165.0, 132.7 (d, J= 38.4 Hz), 127.1, 116.2 (d, J= 89.2 Hz), 39.3; TLC i?/(«-Hexanes:Et 2 O 5:1) = 0.61.
5-(4-Fluorophenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-^) δ 9.20 (s, IH), 8.24-8.20 (m, 2H), 7.28 (t, J- 8.8 Hz, 2H), 7.22 (bs, 2H); 13 C NMR (IOO MHz, DMS(Mj) δ 166.3, 163.6, 154.5, 137.6, 131.2 (d, J= 12.0 Hz), 130.5 (d, J= 36.0 Hz), 116.8 (d, J= 86.0 Hz); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.44.
1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (dt, J= 8.8, 2.0 Hz, 2H), 7.74-7.71 (m, 2H), 7.65-7.62 (m, 2H), 7.51-7.46 (m, 2H), 7.45-7.40 (m, IH), 6.72 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 185.6, 147.2, 139.3, 130.3, 129.4, 129.1, 128.6, 127.5, 127.3, 39.7; TLC i?/(«-Hexanes:Et 2 O 5:1) = 0.61.
5-(Biphenyl-4-yl)-l,2,4-triazin-3-amine
1 B. NMR (400 MHz, DMSO-fife) δ 9.24 (s, IH), 8.24 (m, 2H), 7.84 (m, 2H), 7.73 (m, 2H), 7.47 (m, 2H), 7.40 (m, IH), 7.21 (bs, 2H); TLC R f (CH 2 Cl 2 :MeOH 20:1) = 0.33.
l-(Biphenyl-3-yI)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (t, J= 1.8 Hz, IH), 7.94 (d, J= 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, IH), 7.64-7.62 (m, 2H), 7.55 (t, J= 7.6 Hz, IH), 7.48 (t, J= 7.4 Hz, 2H), 7.41-7.37 (m, IH), 2.66 (s, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 198.3, 141.9, 140.4, 137.8, 132.0, 129.2, 129.1, 128.0, 127.40, 127.39, 127.2, 27.0; TLC λ / («-Hexanes:Et 2 O 10:1) = 0.32.
1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (t, J= 1.8 Hz, IH), 8.06 (d, J= 8.0 Hz, IH), 7.86 (d, J= 7.6 Hz, IH), 7.63-7.57 (m, 3H), 7.49 (t, J= 7.6 Hz, 2H), 7.44-7.40 (m, IH), 6.74 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 142.4, 139.8, 133.3, 131.6, 129.6, 129.3, 128.7, 128.6, 128.3, 127.4, 39.9; TLC i?/(ra-Hexanes:Et 2 O 10:1) = 0.36.
5-(Biphenyl-3-yl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.32 (s, IH), 8.40 (s, IH), 8.14 (d, J= 8.0 Hz, IH), 7.86 (d, J= 7.6 Hz, IH), 7.73 (d, J= 7.6 Hz, IH), 7.63 (t, J= 8.0 Hz, IH), 7.48 (t, J= 7.2 Hz, 2H), 7.39 (t, J= 7.2 Hz, IH), 7.24 (bs, 2H); 13 C NMR (IOO MHz, OMSO-d 6 ) δ 163.8, 155.4, 141.7, 140.1, 138.0, 135.4, 130.8, 130.4, 129.7, 128.6, 127.6, 127.0, 126.2; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.37.
2,2-Dibromo-l-(2-bromophenyl)ethanone
1 K NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J= 8.0 Hz, IH), 7.56 (d, J= 7.6 Hz, IH), 7.44-7.37 (m, 2H), 6.72 (s, IH); 13 C NMR (IOO MHz, CDCl 3 ) δ 189.6, 136.7, 133.7, 133.0, 131.0, 127.8, 119.3, 41.9; TLC i?/(«-Hexanes:Et 2 O 10:1) = 0.51.
5-(2-Bromophenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSOd 6 ) δ 9.04 (s, IH), 7.79 (d, J= 8.0 Hz, IH), 7.59-7.53 (m, 2H), 7.49.7.45 (m ; m), 7.38 (s, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.0, 157.7, 140.1, 136.1, 133.2, 131.8, 131.2, 128.1, 120.5; TLC /J 7 (CH 2 Cl 2 =MeOH 20:1) = 0.25.
1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J= 8.0 Hz, IH), 7.42-7.37 (m, 2H), 7.24-7.20 (m, IH), 3.06-3.01 (m, IH), 2.57 (s, 3H), 1.84-1.74 (m, 5H), 1.47-1.35 (m, 4H), 1.30-1.22 (m, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 203.8, 146.6, 139.1, 130.9, 127.6, 127.1, 125.3, 40.0, 34.5, 30.8, 26.9, 26.2; TLC /?/(rc-Hexanes:Et 2 O 1:1) = 0.56.
2,2-Dibromo-l-(2-cyclohexylphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.51-7.44 (m, 3H), 7.27-7.23 (m, IH), 6.56 (s, IH), 2.79-2.73 (m, IH), 1.89-1.74 (m, 5H), 1.51-1.35 (m, 4H), 1.32-1.24 (m, IH); 13 C NMR (IOO MHz, CDCl 3 ) δ 190.1, 148.3, 133.3, 132.2, 127.7, 126.8, 125.5, 43.0, 40.9, 34.6, 26.7, 26.1; TLC R f (rc-Hexanes:Et 2 O 5:1) = 0.65.
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.61 (s, IH), 7.43-7.42 (m, 2H), 7.32-7.26 (m, 2H), 7.21 (bs, 2H), 2.72 (X, J= 11.2 Hz, IH), 1.71-1.61 (m, 5H), 1.42-1.36 (m, 2H), 1.19-1.17 (m, 3H); 13 C NMR (100 MHz, DMSO- J 6 ) δ 163.4, 159.9, 146.3, 140.9, 134.9, 130.7, 129.9, 127.3, 126.5, 39.6, 34.5, 31.4, 27.0, 26.2; TLC R 1 (CH 2 Cl 2 MeOH 20:1) = 0.44.
5-(Biphenyl-2-yl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 7.87 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.65-7.55 (m, 3H), 7.50 (d, J= 7.6 Hz, IH), 7.40-7.75 (m, 2H), 7.23 (s, 2H), 7.20-7.17 (m, IH); TLC R f (n- Hexanes:Et 2 O 1 :1 + 0.5% MeOH) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 7.73-7.71 (m, IH), 7.44-7.39 (m, IH), 6.97-6.90 (m, 2H), 4.14- 4.09 (m, 2H), 1.46 (t, J= 7.2 Hz, 3H); TLC i?/(n-Hexanes:Et 2 O 10:1) = 0.18.
2,2-Dibromo-l-(2-ethoxyphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (t, J= 5.6 Hz, IH), 7.50-7.49 (m, IH), 7.11 (d, J= 4.4 Hz, IH), 6.96-6.93 (m, IH), 4.19-4.14 (m, 2H), 1.54-1.50 (m, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.42.
5-(2-Ethoxyphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.05 (s, IH), 7.81 (d, J= 7.6 Hz, IH), 7.47 (t, J= 7.6 Hz, IH), 7.15-7.04 (m, 4H), 4.15-4.10 (m, 2H), 1.34 (d, J= 6.8 Hz, 3H).
1 H NMR (400 MHz, CDCl 3 ) δ 7.71-7.68 (m, IH), 7.42-7.37(m, IH), 6.95-6.91 (m, 2H), 4.70- 4.64 (m, IH), 2.60 (s, 3H), 1.38 (t, J= 2.4 Hz, 6H); TLC ^/(rc-Hexanes: Et 2 O 10:1) = 0.16.
2,2-Dibromo-l-(2-isopropoxyphenyl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (dd, J= 7.8, 1.8 Hz, IH), 7.50 (m, IH), 7.12 (s, IH), 7.02 (dt, J= 7.6, 1.2 Hz, IH), 6.96 (d, J= 8.8 Hz, IH), 4.74 (m, IH), 1.45 (d, J= 6.4 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 188.6, 156.6, 134.9, 132.8, 123.2, 121.0, 113.4, 71.4, 44.4, 21.9; TLC i?/(n-Hexanes:EtOAc 9:1) = 0.50.
5-(2-Isopropoxyphenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-c/ 6 ) δ 9.03 (s, IH), 7.80 (dd, J= 7.8, 1.8 Hz, IH), 7.46 (m, IH), 7.16 (d, J= 8.4 Hz, IH), 7.10 (bs, 2H), 7.04 (t, J= 7.4 Hz, IH), 4.73 (m, IH), 1.28 (d, J= 6.4 Hz, 6H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.39.
1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (dd, J= 7.6, 1.6 Hz, IH), 7.65-7.61 (m, IH), 7.43 (t, J= 7.6 Hz, IH), 7.36 (d, J= 8.4 Hz, IH), 6.72 (s, IH); 13 C NMR (100 MHz, CDCl 3 ) δ 186.9, 162.3, 134.5, 132.2, 127.5, 127.3, 120.84, 120.83, 42.2; TLC λ/(«-Hexanes:Et 2 O 10:1) = 0.48.
5-(2-(Trifluoromethoxy)phenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.85 (s, IH), 7.86 (dd, J= 7.6, 1.6 Hz, IH), 7.73-7.69 (m, IH), 7.62-7.55 (m, 2H), 7.39 (br, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 163.9, 154.7, 146.5, 140.3, 133.4, 132.2, 129.5, 129.0, 122.7, 119.3; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.30.
1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (dd, J= 7.2, 1.6 Hz, IH), 7.30-7.22 (m, 2H), 7.08 (d, J= 7.6 Hz, IH), 6.55 (t, J= 74.0 Hz, IH), 5.24 (q, J= 6.4 Hz, IH), 1.95 (s, IH), 1.50 (d, J= 6.4 Hz, 3H); TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.25.
1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (dd, J= 7.6, 1.2 Hz, IH), 7.54-7.50 (m, IH), 7.30 (t, J= 7.6 Hz, IH), 7.18 (d, J= 8.4 Hz, IH), 6.60 (t, J= 73.6 Hz, IH), 2.63 (s, 3H); TLC R f (n- Hexanes:Et 2 O 2:1) = 0.42.
1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J= 7.6, 1.6 Hz, IH), 7.62-7.58 (m, IH), 7.37-7.33 (m, IH), 7.22 (d, J= 8.0 Hz, IH), 6.87 (s, IH), 6.62 (t, J= 72.8 Hz, IH); TLC R f (n- Hexanes:Et 2 O 2:1) = 0.44.
5-(2-(Difluoromethoxy)phenyl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-d*) δ 8.86 (s, IH), 7.81 (d, J= 6.8 Hz, IH), 7.60 (t, J= 6.8 Hz, IH), 7.40 (t, J= 7.2 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 7.26 (bs, 2H), 7.26 (t, J= 73.6 Hz, IH); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.36.
2,3-Dihydrobenzofuran-7-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 10.19 (s, IH), 7.58 (d, J= 8.0 Hz, IH), 7.40 (d, J= 7.2 Hz, IH), 6.93 (t, J= 7.6 Hz, IH), 4.73 (t, J= 8.8 Hz, 2H), 3.24 (t, J= 8.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.3, 162.4, 131.1, 129.7, 127.6, 120.8, 119.9, 72.9, 28.9; TLC R f (n- Hexanes:EtOAc 5:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 7.13-7.10 (m, 2H), 6.84 (t, J= 7.4 Hz, IH), 4.60 (t, J= 8.6 Hz, 2H), 3.21 (t, J= 8.8 Hz, 2H), 1.52 (d, J= 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 156.9, 127.6, 127.3, 124.7, 124.0, 120.8, 71.6, 67.2, 29.8, 23.3; TLC i?/(n-Hexanes:EtOAc 3:1) - 0.21.
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J= 8.4 Hz, IH), 7.34 (d, J= 6.8 Hz, IH), 6.88 (t, J= 7.6 Hz, IH), 4.69 (t, J= 8.8 Hz, 2H), 3.24 (t, J= 8.6 Hz, 2H), 2.61 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.3, 160.6, 129.7, 129.4, 128.3, 121.0, 120.5, 72.1, 31.1, 29.2; TLC R f (n- Hexanes:Et 2 O 10:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J= 8.4 Hz, IH), 7.42 (d, J= 7.2 Hz, IH), 7.21 (s, IH), 6.95 (t, J= 7.6 Hz, IH), 4.76 (t, J= 8.8 Hz, 2H), 3.28 (t, J= 8.8 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.0, 159.8, 131.3, 130.1, 129.4, 121.6, 114.8, 72.9, 44.1, 29.1, 29.0; TLC R f (n-Hexanes:Et 2 O 10:1) = 0.46.
5-(2,3-Dihydrobenzofuran-7-yl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.20 (s, IH), 7.91 (d, J= 8.0 Hz, IH), 7.40 (d, J= 7.2 Hz, IH), 7.15 (s, 2H), 6.97 (t, J= 7.6 Hz, IH), 4.69 (t, J= 8.8 Hz, 2H), 3.23 (t, J= 8.6 Hz, 2H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 163.7, 159.7, 153.8, 134.0, 130.1, 129.3, 127.4, 121.6, 116.5, 72.8, 29.1; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.38.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.98 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.20 (d, J= 7.2 Hz, IH), 7.08 (bs, 2H), 6.93 (t, J= 7.4 Hz, IH), 4.23 (t, J= 4.8 Hz, 2H), 2.78 (t, J= 6.2 Hz, 2H), 1.93 (t, J= 5.0 Hz, 2H); TLC tf/(«-Hexanes:EtOAc 2:1) = 0.10.
Benzo[<f][l,3]dioxole-4-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 10.09 (s, IH), 7.24 (d, J= 4.0 Hz, IH), 6.99 (d, J= 7.6 Hz, IH), 6.90 (t, J= 7.8 Hz, IH), 6.10 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 188.2, 149.4, 149.1, 122.0, 121.3, 119.6, 113.6, 102.7; TLC i?/(rc-Hexanes: EtOAc 5:1) = 0.43.
1 U NMR (400 MHz, CDCl 3 ) δ 6.82 (d, J= 7.6 Hz, IH), 6.73 (d, J= 7.6 Hz, IH), 6.66 (dd, J = 7.8, 1.0 Hz, IH), 5.82 (dd, J= 8.8, 1.2 Hz, 2H), 4.90-4.89 (m IH), 3.32 (bs, IH), 1.42 (d, J = 6.4 Hz, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 147.3, 144.0, 127.7, 121.8, 118.9, 107.7, 101.0, 65.7, 23.5; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.21.
1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (d, J= 8.4 Hz, IH), 6.95 (d, J= 7.6 Hz, IH), 6.86 (t, J= 7.8 Hz, IH), 6.07 (s, 2H), 2.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 195.7, 148.8, 148.2, 121.6, 121.5, 120.5, 112.7, 101.8, 30.5; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.27.
1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J= 8.2, 1.4 Hz, IH), 7.01 (d, J= 7.8, 1.4 Hz, IH), 6.93-6.89 (m, 2H), 6.10 (s, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 183.5, 148.7, 147.7, 122.8, 122.6, 114.2, 114.1, 102.2, 62.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.45.
5-(Benzo [d\ [1 ,3] dioxol-4-yl)-l ,2,4-triazin-3-amine
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.08 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.24 (bs, 2H), 7.09 (d, J= 7.6 Hz, IH), 6.98 (d, J= 8.0 Hz, IH), 6.17 (s, 2H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 163.8, 152.6, 148.8, 147.5, 139.4, 122.9, 120.7, 116.7, 112.0, 102.5; TLC i?/ (CH 2 Cl 2 : MeOH 10:1) = 0.53.
2,3-Dihydrobenzo [b] [1 ,4] dioxine-5-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 10.17 (s, IH), 7.18 (d, J= 7.6 Hz, IH), 6.90 (d, J= 8.0 Hz, IH), 6.70 (t, J= 7.8 Hz, IH), 4.19 (d, J= 2.4 Hz, 2H), 4.12 (d, J= 2.8 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 188.9, 146.6, 144.2, 125.1, 123.2, 120.9, 120.6, 64.7, 64.0; TLC R f (n- Hexanes:EtOAc 5:1) = 0.39.
1 H NMR (400 MHz, CDCl 3 ) δ 6.90 (d, J= 7.2, 1.6 Hz, IH), 6.83-6.75 (m, 2H), 5.05-5.03 (m, IH), 4.28-4.26 (m 2H), 4.24-4.22 (m, 2H), 2.47 (bs, IH), 1.40 (d, J= 3.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) d 143.6, 140.8, 134.2, 121.3, 118.3, 116.6, 66.2, 64.5, 64.3, 23.2; TLC R f («-Hexanes:EtOAc 5:1) = 0.14.
l-(2,3-Dihydrobenzo[6][l,4]dioxm-5-yl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (dd, J= 7.6, 1.2 Hz, IH), 6.99 (d, J= 8.0, 1.2 Hz, IH), 6.84 (t, J= 7.8 Hz, IH), 4.35-4.33 (m, 2H), 4.29-4.27 (m, 2H), 2.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.1, 144.2, 143.8, 128.7, 122.5, 121.5, 121.0, 64.6, 64.0, 31.9; TLC R f (n- Hexanes:EtOAc 5:1) = 0.24.
2,2-Dibromo-l-(2,3-dihydrobenzo[6][l,4]dioxin-5-yl)ethano ne
1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J= 7.6 Hz, IH), 7.07-7.05 (m, 2H), 6.93-6.89 (m, IH), 4.38 (t, J= 2.0 Hz, 2H), 4.31 (t, J= 2.8 Hz, 2H); TLC λ/C/j-HexanesiEtOAc 5:1) = 0.57.
5-(2,3-Dihydrobenzo [b] [1 ,4] dioxin-5-yl)-l ,2,4-triazin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 9.22 (s, IH), 7.49 (dd, J= 7.0, 2.0 Hz, IH), 7.01 (dd, J= 8.0, 2.0 Hz, IH), 6.94 (t, J= 8.0 Hz, IH), 5.42 (bs, 2H), 4.35-4.29 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.0, 155.8, 144.2, 143.1, 142.7, 123.7, 123.0, 121.8, 120.7, 64.7, 64.1; TLC R 1 (CH 2 Cl 2 :Me0H 10:1) = 0.40.
2,3-Dihydro-lH-mden-4-ol
1 U NMR (400 MHz, CDCl 3 ) δ 7.05 (t, J= 7.8 Hz, IH), 6.85 (d, J= 7.6 Hz, IH), 6.63 (d, J= 7.6 Hz, IH), 4.92 (bs, IH), 2.94 (t, J= 7.6 Hz, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.11 (m, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 151.8, 146.7, 129.3, 127.7, 117.0, 112.5, 33.2, 28.7, 25.0; TLC R 1 (n-Hexanes:EtOAc 4:1) = 0.50.
2,3-Dihydro-lH r -inden-4-yl trifluoromethanesulfonate
1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (m, 2H), 7.02 (d, J= 7.2 Hz, IH), 3.00 (m, 4H), 2.12 (m, 2H); TLC i?/(R-Hexanes:EtOAc 4:1) = 0.76.
1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J= 7.6 Hz, IH), 7.33 (d, J= 7.2 Hz, IH), 7.16 (m, IH), 3.18 (t, J= 7.4 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 2.51 (s, 3H), 2.00 (m, 2H); TLC R f (n- Hexanes:EtOAc 7:3) = 0.67.
2,2-Dibromo-l-(2,3-dihydro-lH-inden-4-yl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J= 7.6 Hz, IH), 7.43 (d, J= 7.6 Hz, IH), 7.22 (t, J= 7.4 Hz, IH), 6.72 (s, IH), 3.22 (t, J= 7.2 Hz, 2H), 2.91 (t, J= 7.4 Hz, 2H), 2.07 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.2, 148.2, 147.3, 130.2, 127.8, 127.3, 126.5, 41.3, 34.2, 32.7, 25.0; TLC i?/(rc-Hexanes:EtOAc 9:1) = 0.58.
5-(2,3-Dihydro-lH-inden-4-yl)-l,2,4-triazin-3-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.87 (s, IH), 7.59 (d, J= 7.6 Hz, IH), 7.38 (d, J= 7.2 Hz, IH), 7.26 (t, J= 7.6 Hz, IH), 7.08 (bs, 2H), 3.13 (t, J= 7.4 Hz, 2H), 2.86 (t, J= 7.4 Hz, 2H), 1.97 (m, 2H); 13 C NMR (IOO MHz, DMSO-^ 6 ) δ 163.2, 157.9, 146.1, 144.0, 139.4, 131.3, 127.4, 127.2, 126.7, 33.3, 32.6, 25.4; TLC ^ 7 (CH 2 Cl 2 MeOH 19:1) = 0.39.
5,6,7,8-Tetrahydronaphthalen-l-yl trifluoromethanesulfonate
1 H NMR (400 MHz, CDCl 3 ) 8 7.06 (m, 3H), 2.76 (q, J= 6.4 Hz, 4H), 1.78 (m, 4H); TLC R f OHexanesiEtOAc 19:1) = 0.55.
1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (dd, J= 7.2, 1.6 Hz, IH), 7.13 (m, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 2.51 (s, 3H), 1.73 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.9, 138.6, 136.7, 132.5, 126.2, 125.0, 30.2, 30.1, 27.7, 23.1, 22.4; TLC i?/(rc-Hexanes: EtOAc 9:1) = 0.41.
2,2-Dibromo-l-(5,6,7,8-tetrahydronaphthaIen-l-yl)ethanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J= 7.6 Hz, IH), 7.24 (m, IH), 7.15 (t, J= 7.6 Hz, IH), 6.62 (s, IH), 2.89 (bs, 2H), 2.81 (bs, 2H), 1.79 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.1, 139.3, 138.4, 133.8, 133.1, 132.1, 125.0, 42.8, 30.0, 27.3, 22.8, 22.3; TLC R f (n- Hexanes:EtOAc 9:1) = 0.56.
5-(5,6,7,8-Tetrahydronaphthalen-l-yl)-l,2,4-triazin-3-ami ne
1 U NMR (400 MHz, DMSO-J 6 ) δ 8.66 (s, 1.0H), 7.19 (s, 3H), 7.17 (bs, 2H), 3.29 (s, 2H), 2.75 (m, 3H), 1.67 (m, 3H); 13 C NMR (100 MHz, DMSO-^ 6 ) δ 163.1, 159.5, 140.7, 138.1, 135.5, 131.4, 127.2, 126.0, 29.7, 27.3, 23.0, 22.6; TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.39.
4-Acetyl-3-methylphenyl trifluoromethanesulfonate
1 H NMR (400 MHz, CDCl 3 ) 8 7.74 (d, J= 8.4 Hz, IH), 7.18-7.13 (m, IH), 2.56 (s, 3H), 2.54 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.89.
4-Acetyl-3-methylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J= 8.0 Hz, IH), 7.55-7.52 (m, 2H), 2.57 (s, 3H), 2.50 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.80.
4-(2,2-Dibromoacetyl)-3-methylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J= 12.8 Hz, IH), 7.59-7.56 (m, 2H), 6.50 (s, IH), 2.48 (s, 3H); TLC i?/(«-Hexanes:Et 2 O 10:1) = 0.51.
4-(3-Amino-l,2,4-triazin-5-yl)-3-methylbenzonitrile
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.78 (d, J= 2.0 Hz, IH), 7.83 (s, H), 7.78 (d, J= 8.0 Hz, IH), 7.64 (d, J= 8.0 Hz, IH), 7.31 (s, IH), 2.39 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.53.
1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J= 8.4 Hz, IH), 7.22 (d, J= 2.8 Hz, IH), 7.07-7.04
(m, IH), 3.88 (s, 3H), 2.56 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.25.
2,2-Dibromo-l-(4-methoxy-2-(trifluoromethyl)phenyl)ethano ne
1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J= 8.4 Hz, IH), 7.26-7.25 (m, IH), 7.10-7.07 (m, IH), 6.48 (s, IH), 3.90 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 10:1) = 0.49.
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.65 (s, IH), 7.60 (d, J= 9.6 Hz, IH), 7.38-7.36 (m, IH), 7.31 (s, 2H), 3.90 (s, 3H).
1 H NMR (400 MHz, CD 3 OD) δ 8.60 (s, IH), 7.47 (d, J= 8.8 Hz, IH), 7.20 (d, J= 2.4 Hz, IH), 7.12-7.09 (m, IH); TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.11.
4-(3-Amino-l,2,4-triaziπ-5-yl)-3-(trifluoromethyl)phenyl trifluoromethane sulfonate
1 H NMR (400 MHz, CD 3 OD) δ 8.69 (s, IH), 7.91 (s, IH), 7.84-7.82 (m, 2H); TLC R f (n- Hexanes:EtOAc 1 :1) = 0.38.
1 H NMR (400 MHz, CD 3 OD) δ 8.68 (s, IH), 8.29 (s, IH), 8.14 (d, J= 8.0 Hz, IH), 7.81-7.79 (m, IH); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.25.
1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J= 8.4 Hz, IH), 7.38 (d, J= 2.4 Hz, IH), 7.27 (dd, J= 8.6, 2.6 Hz, IH), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.6, 150.4, 139.1, 133.0, 131.1, 123.7, 120.2, 117.0, 30.7; TLC /?/(«-Hexanes:EtO Ac 5:1) = 0.52.
1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J= 1.2 Hz, IH), 7.60 (dd, J= 8.0, 1.2 Hz, IH), 7.57 (d, J= 8.0 Hz, IH), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.0, 143.1, 133.8, 131.9, 130.5, 129.6, 116.6, 115.6, 30.6; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.37.
1 U NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J= 1.2 Hz, IH), 7.73 (d, J= 7.6 Hz, IH), 7.68 (dd, J= 8.0, 1.2 Hz, IH), 6.64 (s, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 187.3, 138.3, 133.6, 131.9, 131.2, 130.6, 116.6, 116.3, 41.0; TLC i?/(n-Hexanes: EtO Ac 5:1) = 0.38.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.84 (s, IH) 5 8.23 (d, J= 1.6 Hz, IH), 7.97 (dd, J= 7.8, 1.4 Hz, IH), 7.79 (d, J= 8.0 Hz, IH), 7.45 (bs, 2H); 13 C NMR (100 MHz, DMSO-J 15 ) δ 163.5, 155.5, 140.1, 139.0, 134.1, 132.6, 132.6, 131.9, 117.5, 114.7; TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.23.
Biphenyl-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.56-7.51 (m, 2H), 7.49-7.29 (m, 2H), 7.28-7.19 (m, 2H), 6.98 (dd, J= 7.6, 0.8 Hz, IH), 6.89 (t, J= 1.8 Hz, IH), 6.66 (dd, J= 7.4, 1.8 Hz, IH), 3.65 (bs, 2H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 146.9, 142.7, 141.6, 129.9, 128.8, 127.4, 127.3, 117.9, 114.3, 114.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.27.
2'-Chlorobiphenyl-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.46 (m, IH), 7.36-7.21 (m, 4H), 6.86-6.84 (m, IH), 6.76- 6.75 (m, IH), 6.72-6.69 (m, IH), 3.69 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 146.4, 141.0, 140.8, 132.7, 131.5, 130.1, 129.2, 128.7, 127.0, 120.1, 116.5, 114.7; TLC R f (n- Hexanes:EtOAc 5:1) = 0.31.
2'-(TrifluoromethyI)biphenyl-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J= 7.6 Hz, IH ), 7.52 (t, J= 7.4 Hz, IH), 7.43 (t, J= 7.6 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.17 (t, J= 7.8 Hz, IH), 6.72-6.69 (m, 2H), 6.64 (s, IH), 3.71 (bs, 2H); 13 C NMR (IOO MHz, CDCl 3 ) δ 145.9, 141.8, 141.2, 132.1, 131.4, 128.8, 128.4, 127.4, 126.3, 126.2, 126.1, 125.8, 123.0, 119.8, 16.1, 114.6; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.23.
2 ' -Methylbipheny 1-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.26-7.18 (m, 5H), 6.73 (d, J= 7.6 Hz, IH ), 6.70-6.64 (m, 2H), 3.55 (bs, 2H), 2.29 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 146.3, 143.4, 142.4, 135.6, 130.4, 129.8, 129.2, 127.4, 125.9, 120.0, 116.2, 113.8, 20.7; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.39.
2'-MethoxybiphenyI-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.29 (m, 2H), 7.24-7.18 (m, IH), 7.03-6.91 (m, 3H), 6.86 (d, J= 2.4 Hz, IH ), 6.67-6.65 (m, IH), 3.80 (s, 3H), 3.67 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 156.7, 146.3, 139.9, 131.1, 131.0, 129.1, 128.7, 120.9, 120.3, 116.7, 114.1, 111.5, 55.8; TLC i?/(n-Hexanes: EtOAc 5:1) = 0.10.
Biphenyl-3-ol
1 H NMR (400 MHz, CDCl 3 ) δ 7.57 (d, J= 7.2 Hz, 2H), 7.43 (t, J= 7.6 Hz, 2H), 7.36-7.29 (m, 2H), 7.17 (d, J= 7.6 Hz, IH), 7.07-7.06 (m, IH), 6.82 (dd, J= 8.0, 2.4 Hz, IH), 4.85 (s, IH); TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.34.
2'-Methylbiphenyl-3-ol
1 H NMR (400 MHz, CDCl 3 ) δ 7.29-7.21 (m, 5H), 6.89 (d, J= 7.6 Hz, IH), 6.83-6.77 (m, 2H), 4.82 (s, IH); TLC tf/(rc-Hexanes:Et 2 O 2:1) = 0.42.
2'-Chlorobiphenyl-3-ol
1 H NMR (400 MHz, CDCl 3 ) δ 7.45-7.42 (m, IH), 7.30-7.22 (m, 4H), 7.00-6.98 (m, IH), 6.92- 6.91 (m, IH), 6.85 (ddd, J= 8.0, 2.4, 0.8 Hz, IH), 5.43 (bs, IH); 13 C NMR (100 MHz, CDCl 3 )
δ 155.0, 140.9, 140.0, 132.3, 131.2, 129.9, 129.3, 128.6, 126.8, 122.1, 116.5, 114.6; TLC R f 0-Hexanes:Et 2 O 2:1) = 0.37.
2'-(TrifluoromethyI)biphenyI-3-ol
1 U NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J= 7.6 Hz, IH), 7.48 (t, J= 6.8 Hz, IH), 7.41 (t, J= 7.6 Hz, IH), 7.27-7.20 (m, 2H), 6.89-6.82 (m, 3H), 6.01 (bs, IH); TLC i?/(rc-Hexanes:Et 2 O 2:1) = 0.36.
2'-MethoxybiphenyI-3-ol
1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.28 (m, 3H), 7.10-7.08 (m, IH), 7.04-6.97 (m, 3H), 6.80 (ddd, J= 8.0, 2.4, 0.4 Hz, IH), 4.80 (s, IH), 3.81 (s, 3H); TLC i?/(«-Hexanes:Et 2 O 2:1) = 0.26.
5-PhenyIpyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (d, J= 1.6 Hz, IH), 8.08 (d, J= 2.4 Hz, IH), 7.70-7.64 (m, IH), 7.56-7.52 (m, IH), 7.48-7.43 (m, 2H), 7.40-7.36 (m, IH), 7.16 (t, J= 2.2 Hz, IH), 3.77 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.20.
5-ø-TolyIpyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J= 2.4 Hz, IH), 7.67 (d, J= 7.2 Hz, IH), 7.46 (d, J= 2.8 Hz, IH), 7.27-7.17 (m, 2H), 6.92 (t, J= 2.0 Hz, IH), 3.73 (bs, 2H), 2.25 (s, 3H); TLC R f («-Hexanes: EtOAc 1 :1 with 0.5% MeOH) = 0.21.
5-(2-Chlorophenyl)pyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J= 2.0 Hz, IH), 8.07 (s, IH), 7.69-7.64 (m, IH), 7.56- 7.52 (m, IH), 7.48-7.43 (m, IH), 7.32-7.29 (m, IH), 7.07 (s, IH), 3.77 (s, 2H); TLC R f (n- Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.18.
5-(2-(Trifluoromethyl)phenyl)pyridin-3-amiiie
1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J= 2.4 Hz, IH), 7.98 (s, IH), 7.76 (d, J= 7.6 Hz, IH), 7.69-7.64 (m, IH), 7.60-7.44 (m, IH), 7.32 (d, J= 7.6 Hz, IH), 6.95 (s, IH), 3.75 (s, 2H); TLC i?/(«-Hexanes: EtOAc 1 :1 with 0.5% MeOH) = 0.14.
5-(2-Methoxyphenyl)pyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J= 2.0 Hz, IH), 8.04 (d, J= 2.8 Hz, IH), 7.36-7.32 (m, IH), 7.29 (dd, J= 7.6, 1.6 Hz, IH), 7.16 (t, J= 2.2 Hz, IH), 7.05-7.01 (m, IH), 6.98 (d, J = 8.4 Hz, IH), 3.81 (s, 3H), 3.72 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.16.
5-(2,6-Dimethylphenyl)pyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J= 2.8 Hz, IH), 7.84 (d, J= 1.6 Hz, IH), 7.67-7.65 (m, IH), 7.17 -7.07 (m, 2H), 6.78 -6.77 (m, IH), 2.03 (s, IH); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.11.
1 U NMR (400 MHz, CDCl 3 ) δ 8.12 (s, IH), 8.11 (s, IH), 7.50 (s, IH), 7.46 (d, J= 8.0 Hz, IH), 7.22 (d, J = 7.6 Hz, IH), 6.91 (s, IH), 4.50 (bs, 2H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 143.5, 143.4, 138.5, 137.3, 136.7, 136.0, 133.9, 130.5, 129.6, 121.2, 119.0, 111.4, 20.3; TLC i?/(«-Hexanes: EtOAc 1:2) = 0.34.
5-(2-Chloro-4-fluorophenyl)pyridin-3-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J= 2.4 Hz, IH), 8.01 (d, J= 1.2 Hz, IH), 7.67-7.62 (m, IH), 7.46 -7.42 (m, IH), 7.29-7.19 (m, 2H), 7.05 -7.00 (m, 2H), 3.75 (s, 2H); TLC R f (n- Hexanes:EtOAc 3:1) = 0.10.
6-Phenylpyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.93-7.89 (m, 2H), 7.51-7.33 (m, 4H), 7.09-7.05 (m, IH), 6.45- 6.41 (m, IH), 4.50 (bs, 2H); TLC i?/(n-Hexanes: EtOAc 5:1) = 0.16.
6-ø-Tolylpyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (t, J= 7.8 Hz, IH), 7.29 (d, J= 6.8 Hz, IH), 7.19-7.17 (m, 3H), 6.64 (d, J= 7.6 Hz, IH), 6.34 (d, J= 8.0 Hz, IH), 4.53 (bs, 2H), 2.29 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 158.7, 158.1, 141.0, 138.0, 135.8, 130.7, 129.5, 128.1, 125.9, 114.3, 106.7, 20.4; TLC i?/(n-Hexanes:EtOAc 2:1) - 0.29.
6-(2-ChIorophenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.93-7.89 (m, 2H), 7.51-7.41 (m, 3H), 7.32-7.24 (m, 2H), 6.90 (d, J= 7.2 Hz, IH), 6.45 (d, J= 8.0 Hz, IH), 4.61 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 158.4, 155.6, 139.8, 137.9, 132.4, 131.4, 130.2, 129.4, 127.0, 115.1, 107.6; TLC R f (n- Hexanes:EtOAc 2:1) = 0.32.
6-(2-(Trifluoromethyl)phenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J= 8.0 Hz, IH), 7.54 (t, J= 7.4 Hz, IH), 7.46-7.41 (m, 3H), 6.72 (d, J= 7.2 Hz, IH), 6.45 (d, J= 8.4 Hz, IH), 4.56 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 158.0, 156.4, 140.5, 137.9, 131.7, 131.5, 128.5, 128.2, 126.5, 126.4, 125.7, 123.0, 114.3, 114.2, 107.7; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.37.
6-(2-Methoxyphenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J= 7.2 Hz, IH), 7.42 (t, J= 7.6 Hz, IH), 7.31 (t, J= 7.2 Hz, IH), 7.12 (d, J= 7.2 Hz, IH), 7.03 (t, J= 7.2 Hz, IH), 6.95 (d, J= 8.0 Hz, IH), 6.38 (d, J= 8.4 Hz, IH), 4.57 (bs, 2H), 3.76 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 158.5, 157.2, 154.7, 137.7, 131.1, 129.8, 129.7, 121.1, 115.5, 111.7, 107.0, 55.8; TLC R f (n- Hexanes:EtOAc 2:1) = 0.19.
4-ø-Tolylpyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J= 5.6 Hz, IH), 7.27-7.13 (m, 4H), 6.57-6.56 (m, IH), 6.39 (s, IH), 4.77 (bs, 2H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 158.5, 151.4, 147.4,
139.6, 134.7, 130.2, 128.7, 127.8, 125.6, 114.8, 108.6, 20.0; TLC i?/(«-Hexanes:EtOAc 1:1) = 0.13.
4-(2-Chlorophenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J= 5.2 Hz, IH), 7.43 (m, IH), 7.26 (m, 3H), 6.68 (dd, J= 5.4, 1.4 Hz, IH), 6.52 (s, IH), 4.52 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 3:2) = 0.16.
4-(2-(Trifluoromethyl)phenyI)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J= 5.2 Hz, IH), 7.73 (d, J= 8.0 Hz, IH), 7.56 (t, J= 7.4 Hz, IH), 7.48 (t, J= 7.6 Hz, IH), 7.28 (d, J= 7.6 Hz, IH), 6.61 (d, J= 5.2 Hz, IH), 6.45 (s, IH), 4.76 (bs, 2H); TLC #/(rc-Hexanes:EtOAc 1:1) = 0.20.
4-(2-Methoxyphenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J= 5.2 Hz, IH), 7.40 (dd, J= 7.67, 11.8 Hz, IH), 7.47-7.43 (m, IH), 7.37-7.33 (m, IH), 7.31-7.29 (m, IH), 6.82 (dd, J= 5.0, 1.0 Hz, IH), 6.67 (s, IH), 4.47 (bs, 2H), 3.81 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.12.
4-(2-Aminopyridin-4-yl)benzonitriIe
1 H NMR (400 MHz, CD 3 OD) δ 7.96 (d, J= 5.2 Hz, IH), 7.79 (m, 4H), 6.85 (dd, J= 5.4, 1.4 Hz, IH), 6.82 (s, IH); TLC i?/(rc-Hexanes:EtOAc 3:7) = 0.21.
4-(2-Aminopyridin-4-yl)-3-methylbenzonitrile
1 H NMR (400 MHz, CD 3 OD) δ 7.96 (d, J= 5.2 Hz, IH), 7.66 (s, IH), 7.61 (dd, J= 8.0, 1.2 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 6.55 (dd, J= 5.4, 1.4 Hz, IH), 6.51 (s, IH), 2.31 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.13.
4-(2-Chloro-4-fluorophenyl)pyridin-2-amine
1 H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J= 5.2 Hz, IH), 7.61 (m, IH), 7.34 (dd, J= 8.4, 6.0 Hz, IH), 7.29 (dd, J= 8.8, 2.8 Hz, IH), 7.12 (dt, J= 8.4, 2.8 Hz, IH), 6.59 (s, IH); TLC R f (n- Hexanes:EtOAc 3:7) = 0.37.
2-Chloro-4-cyanophenyl trifluoromethanesulfonate
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J= 2.0 Hz, IH), 7.67-7.65 (m, IH), 7.49 (d, J= 8.8 Hz, IH); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.92.
3-Chloro-4-(2-chloropyridin-4-yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J= 5.2 Hz, IH), 7.79 (d, J= 2.0 Hz, IH), 7.65-7.63 (m, IH), 7.41 (d, J= 8.0 Hz, IH), 7.37 (s, IH), 7.27-7.25 (m, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.68.
3-ChIoro-4-(2-(4-methoxybenzylamino)pyridin-4-yl)benzonit rile
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J= 4.8 Hz, IH), 7.73 (s, IH), 7.59-7.56 (m, IH), 7.38- 7.36 (m, IH), 7.27 (d, J= 7.6 Hz, 2H), 6.86 (d, J= 7.2 Hz, 2H), 6.59 (d, J= 5.2 Hz, IH), 6.35 (s, IH), 4.45 (d, J= 5.6 Hz, 2H), 3.78 (s, 3H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.08.
4-(2-Aminopyridin-4-yl)-3-chlorobenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.17-8.15 (m, IH), 7.77 (d, J= 1.6 Hz, IH), 7.62-7.60 (m, IH), 7.42 (d, J= 8.0 Hz, IH), 6.68-6.66 (s, IH), 6.51 (t, J= 1.6 Hz, IH), 4.57 (s, 2H); TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.37.
4-(2-Chloropyridin-4-yl)-3-(trifluoromethyl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, J= 4.8 Hz, IH), 8.06 (s, IH), 7.91-7.88 (m, IH), 7.43 (d, J= 8.0 Hz, IH), 7.27 (s, IH), 7.16 (d, J= 4.8 Hz, IH); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.48.
4-(2-(4-Methoxybenzylamino)pyridin-4-yl)-3-(trifluorometh yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J= 4.8 Hz, IH), 7.96 (s, IH), 7.78 (d, J= 8.0 Hz, IH), 7.38 (d, J= 7.6 Hz, IH), 7.22 (d, J= 8.4 Hz, 2H), 6.81 (d, J= 8.4 Hz, 2H), 6.47 (d, J= 4.8 Hz, IH), 6.25 (s, IH), 5.26 (t, J= 5.2 Hz, IH), 4.39 (d, J= 5.2 Hz, 2H), 3.73 (s, 3H); TLC R f («-Hexanes:EtOAc 5:1) = 0.15.
4-(2-Aminopyridin-4-yl)-3-(trifluoromethyl)benzonitrile
1 H NMR ^OO MHZ, CDCl 3 ) 6 8.11-8.10 (m, IH), 8.01 (s, IH), 7.85-7.82 (m, IH), 7.42 (d, J= 8.0 Hz, IH), 6.38 (s, IH), 4.51 (s, 2H); TLC R 1 (CH 2 Cl 2 :MeOH 20:1) = 0.08.
4-(2,6-Dimethylphenyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) 6 8.12 (d, J= 5.2 Hz, IH), 7.18-7.14 (m, IH), 7.09 (d, J= 7.2 Hz, 2H), 6.47 (d, J= 5.2 Hz, IH), 6.31 (s, IH), 4.56 (s, 2H), 2.06 (s, 6H); TLC R f (n- Hexanes:EtOAc 2:1) = 0.30.
4-(2-Chloropyridin-4-yl)-3,5-dimethylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J= 5.2 Hz, IH), 7.39 (s, 2H), 7.13 (s, IH), 7.03 (dd, J = 5.2, 1.2 Hz, IH), 2.05 (s, 6H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.51.
4-(2-(4-MethoxybenzyIamino)pyridin-4-yl)-3,5-dimethylbenz onitrile
1 H NMR (400 MHz, CDCl 3 ) 6 8.15 (d, J= 4.8 Hz, IH), 7.33 (s, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.85 (d, J= 8.0 Hz 3 2H), 6.32 (d, J= 4.8 Hz, IH), 6.08 (s, IH), 5.11 (bs, IH), 4.42 (d, J= 5.6 Hz, 2H), 3.78 (s, 3H), 2.02 (s, 6H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
4-(2-Aminopyridin-4-yl)-3,5-dimethylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) 6 8.11 (d, J= 5.2 Hz, IH), 7.34 (s, 2H), 6.35 (dd, J= 5.0, 1.4 Hz, IH), 6.24 (s, IH), 4.79 (bs, 2H), 2.02 (s, 6H); TLC i?/(rc-Hexanes:EtOAc 1:2) = 0.26.
6-ø-Tolylpyrazin-2-amine
1 R NMR (400 MHz, CDCl 3 ) δ 8.00 (s, IH), 7.91 (s, IH), 7.35 (d, J= 6.8 Hz, IH ), 7.30-7.24 (m, 3H), 4.68 (bs, 2H), 2.36 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 153.8, 153.0, 137.4, 136.3, 134.4, 131.1, 130.3, 129.7, 129.0, 126.2, 20.5; TLC ^(rc-Hexanes: EtOAc 2:1) = 0.19.
6-(2-Chlorophenyl)pyrazin-2-amine
1 U NMR (400 MHz, CDCl 3 ) δ 8.20 (s, IH), 7.94 (s, IH), 7.51-7.49 (m, IH), 7.47-7.44 (m, IH), 7.34-7.31 (m, 2H), 4.74 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.0, 150.0, 136.6, 134.9, 132.6, 131.5, 131.0, 130.4, 130.2, 127.2; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.13.
6-(2-(Trifluoromethyl)phenyl)pyrazin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, IH), 7.97 (s, IH), 7.75 (d, J= 7.6 Hz, IH), 7.60 (t, J= 7.2 Hz, IH), 7.52 (t, J= 7.2 Hz, IH), 7.45 (d, J= 6.8 Hz, IH), 4.71 (bs, 2H); TLC R f (n- Hexanes:EtOAc 2:1) = 0.15.
6-(2-Methoxyphenyl)pyrazin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (s, IH), 7.84 (s, IH), 7.69 (dd, J= 7.6, 1.6 Hz, IH), 7.34- 7.31 (m, IH), 7.04-7.01 (m, IH), 6.95 (d, J= 8.4 Hz, IH ), 4.64 (bs, 2H), 3.82 (s, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 157.4, 154.1, 149.0, 135.8, 131.1, 130.6, 130.6, 130.0, 126.4, 121.2, 111.6, 55.8; TLC i?/(π-Hexanes:EtOAc 2:1) = 0.13.
6-(2,6-DimethyIphenyl)pyrazin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, IH), 7.83 (s, IH), 7.18 (t, J= 7.6 Hz, IH), 7.09-7.07 (m, 2H), 4.71 (bs, 2H), 2.07 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.3, 152.7, 137.2, 136.4, 134.6, 132.3, 132.2, 130.4, 128.7, 127.9, 20.4; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.37.
4-(6-Aminopyrazin-2-yl)-3-methylbenzonitriIe
1 H NMR (400 MHz, DMSO-J 6 ) δ 7.87 (s, IH), 7.81 (s, IH), 7.76 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.52 (d, J= 7.6 Hz, IH), 6.54 (bs, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 155.8, 150.6, 142.9, 138.2, 134.7, 132.1, 131.6, 131.0, 130.3, 119.4, 111.6, 20.4; TLC R f (n- Hexanes:EtOAc 1:2) = 0.53.
4-ø-Tolylpyrimidin-2-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.25 (d, J= 4.8 Hz, IH), 7.35-7.24 (m, 4H), 6.65-6.61 (m, 3H), 2.39 (s, 3H); 13 C NMR (IOO MHz, DMSO-J 6 ) δ 167.8, 164.1, 158.9, 139.2, 131.3, 129.6, 129.4, 126.4, 110.5, 20.7; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
2-Chloro-4-(2-chlorophenyl)pyrimidine
1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (d, J= 5.2 Hz, IH), 7.71-7.69 (m, 2H), 7.49-7.47 (m, IH), 7.41-7.37 (m, 2H); TLC 7?/(«-Hexanes:EtOAc 5:1) = 0.72.
4-(2-Chlorophenyl)pyrimidin-2-amine
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.31 (d, J= 4.8 Hz, IH), 7.56-7.53 (m, 2H), 7.48-7.42 (m, 2H), 6.79-6.76 (m, 3H), 5.75 (s, 2H); TLC #/(«-Hexanes:EtOAc 2:1) = 0.20.
2-Chloro-4-(2-(trifluoromethyl)phenyl)pyrimidine
1 U NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.2 Hz, IH), 7.67-7.57 (m, 2H), 7.51 (d, J= 7.2 Hz, IH), 7.40 (d, J= 5.2 Hz, IH); TLC i?/(«-Hexanes:EtOAc 5:1) 0.75.
4-(2-(Trifluoromethyl)phenyl)pyrimidin-2-amine
1 K NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J= 5.2 Hz, IH), 7.74 (d, J= 7.6 Hz, IH), 7.61 (t, J= 7.4 Hz, IH), 7.53 (t, J= 7.6 Hz, IH), 7.45 (d, J= 8.0 Hz, IH), 6.74 (d, J= 5.2 Hz, IH), 5.11 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.36.
4-(2-Methoxyphenyl)pyrimidin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J= 5.6 Hz, IH), 7.81 (dd, J= 7.6, 1.6 Hz, IH), 7.25- 7.12 (m, 2H), 7.05 (d, J= 7.6 Hz, IH), 6.95 (d, J= 6.0 Hz, IH), 5.08 (bs, 2H), 3.85 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.30.
4-(2,6-DimethyIphenyl)pyrimidin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (d, J= 5.2 Hz, IH), 6.79 (t, J= 7.6 Hz, IH), 7.06 (d, J= 7.2 Hz, 2H), 6.54 (d, J= 5.2 Hz, IH), 5.33 bs, 2H), 2.09 (s, 6H); ); 13 C NMR (100 MHz, CDCl 3 ) δ 169.4, 163.3, 158.5, 138.5, 135.2, 128.6, 127.9, 112.3, 20.1; TLC R f (n- Hexanes:EtOAc 1 :1) = 0.25.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.34 (d, J= 4.8 Hz, IH), 7.81 (s, IH), 7.75 (d, J= 8.0 Hz, IH), 7.57-7.54 (m, IH), 6.77 (s, 2H), 6.72 (d, J= 4.8 Hz, IH), 2.38 (s, 3H); TLC R f (n- Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.26.
4-(2-Chlorophenyl)-iV-(prop-2-ynyl)pyrimidiii-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J= 4.8 Hz, IH), 7.59 (t, J= 4.6 Hz, IH), 7.44 (m, IH), 7.33 (m, 2H), 6.96 (d, J= 4.8 Hz, IH), 5.72 (bs, IH), 4.22 (dd, J= 5.6, 2.4 Hz, 2H), 2.20 (t, J = 2.6 Hz, IH); TLC i?/(n-Hexanes:EtOAc 4:1) = 0.29.
N-(Prop-2-ynyl)-4-(2-(trifluoromethyI)phenyl)pyrimidin-2- amme
1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, J= 5.2 Hz, IH), 7.77 (d, J= 7.6 Hz, IH), 7.62 (t, J= 7.4 Hz, IH), 7.55 (t, J= 7.6 Hz, IH), 7.49 (d, J= 7.6 Hz, IH), 6.75 (d, J= 5.2 Hz, IH), 5.35 (bs, IH), 4.27 (dd, J= 5.6, 2.4 Hz, 2H), 2.23 (t, J= 2.2 Hz, IH); TLC λ//ι-Hexanes:EtOAc 4:1) = 0.24.
4-(2-Chloropyrimidin-4-yl)-3-methylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (d, J= 5.2 Hz, IH), 7.62 (d, J= 4.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, IH), 7.39 (d, J= 4.8 Hz, IH), 2.48 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.4, 161.6, 160.3, 140.6, 138.1, 134.9, 130.6, 130.1, 119.7, 118.4, 114.0, 20.5; TLC R f (n- Hexanes:EtOAc 5:1) = 0.18.
1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (d, J= 4.8 Hz, IH), 7.57 (m, 2H), 7.50 (d, J= 8.0 Hz, IH), 6.71 (d, J= 5.2 Hz, IH), 5.59 (bs, IH), 4.24 (m, 2H), 2.46 (s, 3H), 2.24 (s, IH); TLC R f (n- Hexanes:EtOAc 2:1) = 0.31.
5-Methyl-4-phenylpyrimidin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, IH), 7.51-7.550 (m, 2H), 7.45-7.39 (m, 3H), 5.13 (bs, 2H), 2.15 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.4, 161.9, 160.1, 138.7, 132.3, 129.2, 128.7, 128.6, 128.5, 117.7, 16.2; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.46.
5-Methyl-4-ø-toIyIpyrimidin-2-amine
1 H NMR (400 MHz, CD 3 OD) δ 8.18 (s, IH), 7.28 (m, 3H), 7.11 (d, J= 7.6 Hz, IH), 2.11 (s, 3H), 1.87 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.25.
4-(2-Chlorophenyl)-5-methylpyrimidin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, IH), 7.43 (dd, J= 5.8, 3.4 Hz, IH), 7.34-7.31 (m, 2H), 7.23 (dd, J= 6.0, 3.6 Hz, IH), 5.21 (bs, 2H), 1.94 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.4, 161.7, 159.5, 137.7, 132.2, 130.1, 129.9, 129.7, 127.2, 119.1, 14.8; TLC R f (n- Hexanes:EtOAc 1 :2) = 0.39.
5-Methyl-4-(2-(trifluoromethyl)phenyl)pyrimidin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.59 (t, J= 7.6 Hz, IH), 7.52 (t, J= 8.0 Hz, IH), 7.24 (d, J= 7.6 Hz, IH), 5.09 (bs, 2H), 1.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.4, 161.7, 159.5, 137.7, 132.2, 130.1, 129.9, 129.7, 127.2, 119.1, 14.8; TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.48.
4-(2-Methoxyphenyl)-5-methylpyrimidin-2-amine
1 H NMR (400 MHz, CD 3 OD) δ 8.09 (s, IH), 7.42 (m, IH), 7.17 (dd, J= 7.6, 1.6 Hz, IH), 7.08 (d, J= 8.4 Hz, IH), 6.79 (t, J= 7.6 Hz, IH), 3.78 (s, 3H), 1.90 (s, 3H); TLC R f (n- Hexanes:EtOAc 1:1) = 0.29.
1 H NMR (400 MHz, CD 3 OD) δ 8.20 (s, IH), 7.84 (d, J= 8.4 Hz, 2H), 7.73(d, J= 8.4 Hz, 2H), 2.14 (s, 3H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 164.5, 160.2, 143.1, 132.0, 129.5, 128.8, 118.2, 116.9, 112.7, 14.5; TLC i?/(n-Hexanes: EtOAc 1:2) = 0.33.
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, IH), 7.56-7.53 (m, 2H), 7.23(d, J= 8.4 Hz, IH), 5.08 (bs, 2H), 2.16 (s, 3H), 1.88 (s, 3H); 13 C NMR (IOO MHz, CDCl 3 ) δ 166.0, 161.6, 160.1, 142.8, 137.0, 134.2, 129.9, 128.9, 118.8, 112.7, 19.3, 14.8; TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.32.
1 U NMR (400 MHz, CDCl 3 ) δ 8.16 (s, IH), 7.23-7.17 (m, 2H), 7.07-7.02 (m, IH), 5.73 (bs, 2H), 1.92 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.3, 161.3, 159.6, 133.9, 133.2, 131.1, 131.0, 118.7, 117.3, 114.5, 14.3; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
1 H NMR (400 MHz, CD 3 OD) δ 8.20 (s, IH), 7.97 (s, IH), 7.88 (d, J= 8.0 Hz, IH), 7.82 (dd, J= 8.0, 1.2 Hz, IH), 7.66 (t, J= 7.6 Hz, IH), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.1, 162.2, 160.2, 139.9, 133.1, 132.5, 132.2, 129.3, 118.1, 116.9, 112.5, 14.5; TLC R f (n- Hexanes:EtOAc 1:2) = 0.24.
3-(2-Amino-5-methylpyrimidin-4-yl)-2-fluorobenzonitrile
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.21 (s, IH), 8.03-7.99 (m, IH), 7.79-7.75 (m, IH), 7.51- 7.47 (m, IH), 6.56 (s, IH), 1.89 (s, 3H); TLC J?/(«-Hexanes:EtOAc 3:1) = 0.17.
1 H NMR (400 MHz, CD 3 OD) δ 8.21 (s, IH), 8.09-7.83 (m, 2H), 7.55-7.40 (m, IH), 1.99 (s, 3H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.22.
1 U NMR (400 MHz, CDCl 3 ) δ 8.22 (s, IH), 7.63-7.55 (m, 3H), 5.21 (s, 2H), 1.93 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.12.
2-(2-Amino-5-methylpyrimidin-4-yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (s, IH), 7.84 (d, J= 7.6 Hz, IH), 7.75 (d, J= 8.0 Hz, IH), 7.50 (t, J= 8.2 Hz, IH), 7.37 (t, J= 7.4 Hz, IH), 5.58 (bs, 2H), 2.04 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.8, 162.2, 160.9, 142.5, 134.2, 133.8, 132.3, 129.1, 118.0, 112.3, 15.4; TLC J?/(n-Hexanes:EtOAc 1 :2) = 0.20.
2-Chloro-4-(4-cyano-2-methylphenyl)pyrimidine-5-carbonitr ile
1 R NMR (400 MHz, CDCl 3 ) δ 9.00 (s, IH), 7.66-7.63 (m, 2H), 7.51 (d, J= 8.0 Hz, IH), 2.37 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.55.
1 H NMR (400 MHz, CD 3 OD) δ 8.64 (s, IH), 7.72 (s, IH), 7.67 (d, J= 8.0 Hz, IH), 7.50 (d, J = 8.0 Hz, IH), 2.33 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.42.
4-(2-Chloro-5-(trifluoromethyl)pyrimidiii-4-yl)-3-methylb enzoiiitrile
1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, IH), 7.63 (s, IH), 7.60 (d, J= 8.4 Hz, IH), 7.28 (d, J= 8.0 Hz, IH), 2.18 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 9:1) = 0.30.
4-(2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylben zonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, IH), 7.81 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.65 (s, 2H), 7.39 (d, J= 7.6 Hz, IH), 2.10 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.42.
4-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylbe nzonitriIe
1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, IH), 7.60-7.56 (m, 2H), 7.26 (d, J= 8.4 Hz, IH), 2.20 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.70.
4-(2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylben zonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (s, IH), 7.56-7.54 (m, 2H), 7.25 (d, J= 8.4 Hz, IH), 5.49 (bs, 2H), 2.17 (s, 3H); TLC R f (n-Uexams: EtOAc 1 :2) = 0.48.
4-(2,5-Dichloropyrimidin-4-yl)-3-methylbenzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, IH), 7.59-7.57 (m, 2H), 7.35 (d, J= 8.0 Hz, IH), 2.23 (s, 3H); TLC fl/(rc-Hexanes:EtOAc 2:1) = 0.43.
4-(2-Amino-5-chloropyrimidin-4-yl)-3-methylbenzonitrile
1 H NMR (400 MHz 3 CDCl 3 ) 5 8.71 (s, IH), 7.61-7.55 (m, 2H), 7.31 (d, J= 8.0 Hz, IH), 5.14 (bs, 2H), 2.24 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.68.
General procedure for the synthesis of pyrazole subunit 2 analogs
To a suspension of 1,3-diketones (12.33 mmol, 1.0 equiv) in EtOH 95% (12 mL) was added dropwise hydrazine monohydrate (15.41 mmol, 1.2 equiv). The reaction mixture was heated to reflux for 30 min, and then cooled to room temperature. The solution was concentrated under reduced pressure and then partitioned between EtOAc (3 x) and water. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give pyrazole compounds.
To a 0 °C solution of pyrazoles (1.90 mmol, 1.0 equiv) in anhydrous acetonitrile (10 mL) were added triethylamine (6.45 mmol, 3.4 equiv), DMAP (0.38 mmol, 0.2 equiv), and BoC 2 O (2.84 mmol, 1.5 equiv) successively. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was partitioned between EtOAc (3 x) and brine. The combined
organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give Boc-protected pyrazole.
A mixture of Boc-protected pyrazole (0.77 mmol, 1.0 equiv), NBS (0.93 mmol, 1.2 equiv) and AIBN (0.154 mmol, 0.2 equiv) in ClCH 2 CH 2 Cl (6 mL) was heated at 90 °C for 2 h. After cooled to 25 0 C, the reaction mixture was concentrated under reduced pressure. The resulting residue was directly purified by flash column chromatography on silica gel to give brominated products.
General procedure for the preparation of aryl methyl ketones
A solution of halide (or triflate) (1.0 equiv), Zn(CN) 2 (3.0 equiv) , and Pd(PPh 3 ) 4 (0.04 equiv) in anhydrous DMF (0.8 M) was heated at 120 ° C for 2 h. After cooling, the reaction was quenched with saturated aqueous NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x ) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give nitrile compounds.
To a solution of aryl nitriles (36.0 mmol, 1.0 equiv) in THF/diethyl ether (20 mL/30 mL) at -78 0 C was added MeMgI (3.0 M in diethyl ether) (108 mmol, 1.36 equiv) and stirred for 45 min at -78 0 C. After removal of bath, extra THF (20 mL) was added and was stirred for 1 hr at 25 °C. The reaction mixture was treated with 2N HCl (aq) (50 mL) and was further stirred for 1-2 h at 25 °C. The reaction was quenched with saturated aqueous NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x ) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give corresponding aryl methyl ketone compounds.
General procedure for the preparation of Boc-protected pyrazoles
A, B, C = CH, N, or N= O
To a solution of aryl methyl ketones (6.9 mmol, 2.0 equiv) in dry toluene (10 ml) at 0 0 C was added LiHMDS (1.0 M in THF, 2.0 equiv) (fast adding), 1 min later acetyl chloride (1.0 equiv) (fast adding) and was stirred at 25 °C for 1 min. The reaction mixture was then treated with AcOH (4 mL) and was stirred for 2 min at 25 0 C. To the mixture was added THF (10 mL), EtOH (20 mL), and hydrazine monohydrate (6.7 mL, 41 equiv) successively. The resulting reaction mixture was heated at 90 ° C for 1 h. The reaction was quenched with IN NaOH solution and extracted with EtOAc (3 x ) and dried over MgSO 4. After filtration and concentration in vacuo, the residue was subjected to the following step without further purification.
To the crude product above (1.0 equiv) was added CH 3 CN (0.3 M), Et 3 N (2.0 equiv), DMAP (0.2 equiv), and BoC 2 O (1.2 equiv) and was stirred at 25 °C for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x ) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of PMB-protected pyrazole subunit 2.
To a solution of pyrazoles (2.30 mmol, 1.0 equiv) in DMF (15 mL) was added slowly NaH (60% in mineral oil, 2.54 mmol, 1.1 equiv), followed by l-(bromomethyl)-4-methoxybenzene (2.54 mmol, 1.1 equiv) at 25 °C. The suspension was stirred at room temperature for 15 h, and then quenched with a mixture of saturated aqueous NH 4 Cl (10 mL) and H 2 O (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and
concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give PMB-protected pyrazoles.
To a solution of PMB-protected pyrazoles (0.59 mmol, 1.0 equiv) in Et 2 O (3 mL) was added slowly LiAlH 4 (0.77 mmol, 1.3 equiv) at 25 0 C. The suspension was stirred at 25 0 C for Ih, and then quenched by the addition of H 2 O (30 μL), 15% NaOH (30 μL), H 2 O (90 μL) successively. After stirred at 25 °C for 30 min, the suspension was filtered and rinsed thoroughly with 5% MeOHZCH 2 Cl 2. The filtrate was concentrated in vacuo to give desired alcohols.
To a solution of above alcohols (0.62 mmol, 1.0 equiv) in CH 2 Cl 2 (15 mL) was added PPh 3 (1.23 mmol, 2.0 equiv) and CBr 4 (1.23 mmol, 2.0 equiv) successively at 0 °C. The suspension was stirred at 25 °C for 30 min, and then quenched with a mixture of saturated aqueous NaHCO 3 (10 mL) and H 2 O (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give bromide compounds
General procedure for the synthesis of triazole subunit 2.
A solution of sodium methoxide (16.53 mmol, 1.5 equiv) in anhydrous ethanol (12 mL) was added to a solution of acetamide hydrochloride (16.53 mmol, 1.5 equiv) in anhydrous EtOH (25 mL) at room temperature. The milky slurry was stirred at room temperature for 30 min and filtered. To the ethanol filtrate was added to benzohydrazide (11.02 mmol, 1.0 equiv) and the reaction mixture was stirred at room temperature for overnight. The resulting slurry was cooled to 0 °C, stirred for 2 h and the precipitated was collected by filtration, rinsed with cold anhydrous EtOH and dried in vacuo to afford acyl amidrazone. A slurry of acyl amidrazone (1.85 mmol, 1.0 equiv) in a mixture of xylene (3 mL) and 1-octanol (0.15 mL) was refluxed in an apparatus fitted with a Dean-Stark trap. After 45 min, a rapid evolution of water ensued
and the starting material dissolved. The solution was allowed to cool to room temperature and was cooled to -5 °C and stirred for 30 min. The precipitated product was collected by filtration, washed with cold xylenes (4 x 15 mL) and dried in vacuo to give triazole products.
General procedure for the synthesis of triazole subunit 2 via click chemistry
To a solution of anilines (5.48 mmol, 1.0 equiv) in CH 3 CN (11 mL, 0.5 M) at 0 °C was added tert-butyl nitrite (8.24 mmol, 1.5 equiv). After dropwise addition of azidotrimethylsilane (6.62 mmol, 1.2 equiv), the mixture was stirred for 3 h at room temperature. The solution was concentrated under reduced pressure and then the resulting residue was directly purified via flash column chromatography (SiO 2 , «-Hexanes: EtOAc 19:1) to give aryl azides.
To a solution of aryl azides (1.68 mmol, 1.0 equiv) and propargyl alcohol (1.68 mmol, 1.0 equiv) in t-BuOH/H 2 O (1 :1, 7 mL, 0.25 M) was added sodium ascorbate (0.17 mmol, 0.1 equiv) and copper sulfate pentahydrate (0.02 mmol, 0.01 equiv) and stirred for 16 h at 25 0 C. The reaction was quenched by the addition of water and extracted with CH 2 Cl 2 (4 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO 2 , ra-Hexanes: EtOAc 3:7) to give a click adducts.
To a solution of above alcohols (0.25 mmol, 1.0 equiv) in CHCl 3 (2.5 mL, 0.1 M) was added MnO 2 (2.3 mmol, 8.0 equiv) and the reaction mixture was refluxed for 2.5 h at 90 0 C. The reaction was cooled to room temperature and then filtered through a pad of celite. After concentrated in vacuo, the residue was purified via flash column chromatography (SiO 2 , n- Hexanes: EtOAc 9:1) to give aldehydes.
General procedure for the synthesis of THP-protected subunit 2
To a solution of aryl ketones (8.25 mmol, 1.0 equiv) in toluene (17 mL) was added DMFDMA (10.73 mmol, 1.3 equiv). The reaction mixture was heated to 100 °C until complete by TLC (usually > 20 h) and concentrated in vacuo. The resulting residue was redissolved in EtOH (17 mL) and treated with hydrazine hydrate (9.91 mmol, 1.2 equiv) at room temperature. The reaction mixture was heated to 120 °C for 16 h and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to pyrazoles.
To a solution of pyrazoles (3.44 mmol, 1.0 equiv) and DHP (27.56 mmol, 8.0 equiv) in toluene/CH 3 CN (1/1 = 5.74 mL/5.74 mL) was added TFA (517 μmol, 15 mol%). The reaction mixture was heated to 80 0 C until complete by TLC (usually > 24 h). The reaction was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc (3 x). The combined organic layers were washed with brine and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography to give THP -protected pyrazoles.
To a -78 °C solution of THP-protected pyrazoles (1.06 mmol, 1.0 equiv) in THF (3.6 mL) was added H-BuLi (1.6 M in rø-hexanes, 1.27 mmol, 1.2 equiv). The reaction mixture was warmed to 0 "C and stirred for 10 min. The reaction mixture was treated with DMF (994 μmol, 1.2 equiv) at 0 °C. After 30 min at 0 0 C, the reaction was stirred further 1.5 h at 25 °C. The reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography to give formylated pyrazoles.
General scheme for the synthesis of subunit 2 furan derivatives.
To a -78 °C solution of 5-(furan-2-yl)-3-methyl-lH-pyrazole (1.82 g, 12.3 mmol, 1.0 equiv) and TMEDA (4.05 niL, 27.1 mmol, 2.2 equiv) in TηF (18 mL) was H-BuLi (1.6 M in hexane, 16.9 mmol, 27.1 mmol, 2.2 equiv). The reaction mixture was slowly warmed to 0 °C for 30 min while stirring. After cooling to -78 "C, CO 2 gas was bubbled and slowly warmed to room temperature. To the reaction mixture was added 4N HCl in dioxane (8 mL). The solution was evaporated to obtain a crude solid. The crude material was washed with Et 2 O and CH 2 Cl 2 to give carboxylated compound which is used in the following step without further purification.
To a solution of carboxylated compound in MeOH (0.2 M, 60 mL) was added SOCl 2 (3.6 mL, 49.2 mmol, 4.0 equiv) at room temperature. The reaction mixture was heated at 75 °C overnight. After removed the solvent under reduced pressure, the resulting residue was treated with saturated aqueous NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x ). The combined organic layers were dried over MgSO 4 . After filteration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of subunit 2 indazole derivatives.
A, B, C = CH, N NBS, AIBN
1 ,2-dichloroethane
(or CCI 4 )
90 0 C
To a solution of 2-fluoroacetophenone derivatives (14.48 mmol, 1.0 equiv) in ethylene glycol (10 mL) was added hydrazine monohydrate (15.06 mmol, 1.04 equiv) at 25 "C. After 2 h at 25
0 C, the reaction was heated to 165 °C and stirred until complete by TLC. After cooled to 25 °C, the mixture was extracted with CH 2 Cl 2 (3 x). The combined organic layers were washed with saturated aqueous NaHCO 3 and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to indazole analogs.
To a solution of above indazole analogs (6.05 mmol, 1.0 equiv) in anhydrous acetonitrile (30 mL) was added Et 3 N (20.52 mmol, 3.4 equiv) and DMAP (1.21 mmol, 0.2 equiv) successively at 25 °C. The resulting reaction mixture was stirred at 25 "C until complete by TLC (usually < 3 h) and was partitioned between EtOAc (2 x) and brine. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give Boc-protected indazoles.
A solution of above Boc-protected indazoles (2.69 mmol, 1.0 equiv), NBS (3.23 mmol, 1.2 equiv), and AIBN (0.54 mmol, 0.2 equiv) in 1 ,2-dichloroethane (21 mL, 0.13 M) was heated to 90 ° C and stirred until complete by TLC (usually < 3 h).The reaction mixture was concentrated under reduced pressure with silica gel and then directly purified via flash column chromatography on silica gel to give brominated products.
3-methyl-5-phenyI-l/7-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 10.39 (bs, IH), 7.72-7.70 (m, 2H), 7.41-7.40 (m, 2H), 7.33- 7.26 (m, IH), 6.36 (s, IH), 2.33 (s, 3H); TLC i?/(n-Hexanes: EtOAc 2:1) = 0.14.
1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.85 (m, 2H), 7.42-7.33 (m, 3H), 6.46 (s, IH), 2.56 (s, 3H), 1.67 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 153.6, 149.1, 144.8, 132.3, 129.0, 128.7, 126.5, 107.6, 85.1, 28.2, 15.0; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.68.
1 U NMR (400 MHz, CDCl 3 ) δ 7.86-7.83 (m, 2H), 7.41-7.35 (m, 3H), 6.77 (s, IH), 4.77 (s, 2H), 1.69 (s, 9H); TLC i?/(n-Hexanes:Et 2 O 5:1) = 0.32.
1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (s, 2H), 6.91 (d, J= 8.0 Hz, 2H), 6.28 (s, IH), 3.78 (s, 3H), 2.27 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 3:1) = 0.12.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80-7.78 (m, 2H), 6.93-6.91 (m, 2H), 6.40 (s, IH), 3.83 (s, 3H), 2.54 (s, 3H), 1.66 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.62.
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J= 8.8 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 6.71 (s, IH), 4.76 (s, 2H), 3.82 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.52.
1 1 HH NNMMRR ((440000 MMHHzz,, CCDDCCll 33 )) δδ 77..4477--77..4444 (m, 2H), 7.38-7.34 (m, IH), 7.09-7.06 (m, IH), 6.11
(s, IH), 3.87 (s, 3H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 10:1) = 0.53.
3-(3-Methoxyphenyl)-5-methyl-liϊ-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (d, J= 5.2 Hz, 3H), 6.88-6.83 (m, IH), 6.35 (s, IH), 3.82 (s, 3H), 2.30 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.12.
1 H NMR (400 MHz, CDCl 3 ) δ 7.44-7.39 (m, 2H), 7.32-7.28 (m, IH), 6.91-6.88 (m, IH), 6.44 (s, IH), 3.86 (s, 3H), 2.55 (s, 3H), 1.67 (s, 9H); TLC i?/(ra-Hexanes: EtOAc 1:1) = 0.78.
1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.38 (m, 2H), 7.32-7.28 (m, IH), 6.92-6.89 (m, IH), 6.76 (s, IH), 4.76 (s, 2H), 3.84 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.52.
3-(Iodomethyl)-5-phenyIisoxazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.75-7.73 (m, 2H), 7.46-7.41 (m, 3H), 6.54 (s, IH), 4.32 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) d 170.9, 162.7, 130.6, 129.2, 127.3, 126.0, 100.0, -10.2; TLC i?/(n-Hexanes:EtOAc 2:1) = 0.94.
1 H NMR (400 MHz, CDCl 3 ) δ 7.85-7.83 (m, IH), 7.46-7.39 (m, IH), 7.03-6.93 (m, 2H), 6.40 (s, IH), 3.89 (s, 3H), 2.16 (s, 2H); TLC i?/(n-Hexanes:EtOAc 10:1) = 0.42.
3-(2-Methoxyphenyl)-5-methyl-l//-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.64-7.61 (m, IH), 7.29-7.25 (m, IH), 7.03-6.98 (m, 2H), 6.41 (s, IH), 3.96 (s, 3H), 2.32 (s, 3H); TLC i?/(π-Hexanes:EtOAc 1:1) = 0.24.
1 H NMR (400 MHz 5 CDCl 3 ) δ 8.01-7.99 (m, IH), 7.32-7.28 (m, IH), 7.01-6.92 (m, 2H), 6.65 (s, IH), 3.86 (s, 3H), 2.53 (s, 3H), 1.64 (s, 9H); TLC iJyC/i-HexanesiEtOAc 3:1) = 0.51.
1 H NMR (400 MHz, CDCl 3 ) δ 8.05-8.03 (m, 2H), 7.38-7.30 (m, IH), 7.02-6.93 (m, 3H), 4.78 (s 5 2H), 3.88 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.62.
3-F 2 ClCCO 2 Na (5.15 g, 33.8 mmol, 2.3 equiv) was added to a solution Of Cs 2 CO 3 (6.70 g, 20.6 mmol, 1.4 equiv), alcohol (2.0 g, 14.7 mmol, 1.0 equiv), DMF (0.25 m, 60 mL), and water (4.0 M, 3.6 mL). The solution was heated to 100 ° C for 2 h, cooled to room temperature, and poured into a solution OfNH 4 Cl (aq). The solution was extracted with EtOAc, and the organic layer was washed with brine and dried (MgSO 4 ). The crude product was purified by silica chromatography eluting with a EtOAc/hexane (20%) which afforded 1.33 g (49%) of 1-
(4-(difluoromethoxy)phenyl)ethanone: 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J= 8.8 Hz, 2H), 7.18 (d, J= 8.8 Hz, 2H), 6.60 (t, J= 73.0 Hz, IH), 2.60 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J= 8.8 Hz, 2H), 7.14 (d, J= 8.4 Hz, 2H), 6.54 (t, J= 73.8 Hz, IH), 6.43 (s, IH), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J= 8.8 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 6.76 (s, IH), 6.55 (t, J= 73.6 Hz, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
4-(3-Oxobutanoyl)benzonitrile
1 1 HH NNMMRR ((440000 MMHHzz,, CCDDCCll 33 )) δδ 77..'95-7.92 (m, 2H), 7.73-7.71 (m, 2H), 6.17 (s, IH), 2.22 (s,
3H); TLC tf/(n-Hexanes:EtOAc 10:1) = 0.39.
4-(5-MethyI-l/7-pyrazol-3-yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J= 7.6 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H) 5 6.50 (s, IH), 2.31 (s, 3H); TLC i?/(«-Hexanes: EtOAc 3:1) = 0.10.
1 H NMR (400 MHz, CDCl 3 ) δ 7.95-7.93 (m, 2H), 7.68-7.66 (m, 2H), 6.47 (s, IH), 2.56 (s, 3H), 1.66 (s, 9H); TLC tf/(rc-Hexanes:EtOAc 3:1) = 0.62.
1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.0 Hz, 2H), 6.81 (s, IH), 4.77 (s, 2H), 1.69 (s, 9H); TLC i?/(rc-Hexanes:EtOAc 3:1) = 0.62.
3-(3-Methyl-i//-pyrazol-5-yl)benzonitrile
LRMS (electrospray) m/z calculated for C n H 9 N 3 (M+H) + 184.08, found 184.19.
LRMS (electrospray) m/z calculated for Cj 6 H 17 N 3 O 2 (M+H) + 284.13, found 284.34.
LRMS (electrospray) m/z calculated for C 16 H 17 BrN 3 O 2 (M+H) + 364.05, found 364.26.
3-(4-Bromophenyl)-5-methyl-ll/-pyrazole
1 H NMR (400 MHz, CD 3 OD) δ 7.61 (d, J= 6.4 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 6.39 (s, IH), 2.29 (s, 3H); TLC i?/(«-Hexanes:EtOAc 10:1) = 0.13.
1 H NMR (400 MHz, CDCl 3 ) δ 7.72-7.70 (m, 2H), 7.50 (d, J= 8.4 Hz, 2H), 6.41 (s, IH), 2.53 (s, 3H), 1.65 (s, 9H); TLC /?/(«-Hexanes:EtOAc 3:1) = 0.68.
1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J= 7.2 Hz, 2H), 7.52 (d, J= 6.8 Hz, 2H), 6.74 (s, IH), 4.76 (s, 2H), 1.69 (s, 9H); TLC i?/(rc-Hexanes: EtOAc 5:1) = 0.65.
1 R NMR (400 MHz, CDCl 3 ) δ 7.86 (m, IH), 7.42 (m, IH), 7.30 (m, 2H), 6.65 (s, IH), 2.58 (s, 3H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.56.
1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (m, IH), 7.43 (m, IH), 7.31 (m, 2H), 7.00 (s, IH), 4.81 (s, 2H), 1.71 (s, 9H); TLC #/(rc-Hexanes:EtOAc 5:1) = 0.56.
1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (s, IH), 7.73 (m, IH), 7.32 (m, 2H), 6.44 (s, IH), 2.56 (s, 3H), 1.68 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.61.
1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (s, IH), 7.73 (m, IH), 7.35 (m, 2H), 6.78 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.61.
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J= 8.8 Hz, 2H), 7.35 (d, J= 8.4 Hz, 2H), 6.41 (s, IH), 2.54 (s, 3H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 6.77 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.66.
5-(4-Fluorophenyl)-3-methyl-ljH r -pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 12.42 (br, IH), 7.80 (dd, J= 5.2, 1.2 Hz, 2H), 7.08 (dd, J= 5.7, 1.2 Hz, 2H), 6.37 (s, IH), 2.54 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (dd, J= 5.2, 1.3 Hz, 2H), 7.08 (dd, J= 5.7, 1.2 Hz, 2H), 6.38 (s, IH), 2.56 (s, 3H), 1.65 (s, 9H)
1 1 HH NNMMRR ((440000 MMHHzz,, CCDDCCll 33 )) δδ 77..8833 ((ddcd, J= 5.2, 1.3 Hz, 2H), 7.07 (dd, J= 5.7, 1.2 Hz, 2H), 6.72 (s, IH), 4.77 (s, 2H), 1.67 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.63-7.60 (m, 2H), 7.34-7.31 (m, IH), 7.04-7.00 (m, IH), 6.38 (s, IH), 2.51 (s, 3H), 1.66 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (m, 2H), 7.38 (q, J= 6.0 Hz, IH), 7.07 (td, J= 8.4, 2.4 Hz, IH), 6.78 (s, IH), 4.79 (s, 2H), 1.71 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.66.
1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (m, IH), 7.34 (m, IH), 7.19 (m, IH), 7.11 (m, IH), 6.61 (m, IH), 2.57 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.59.
1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (dt, J- 7.8, 1.6 Hz, IH), 7.28 (m, IH), 7.15 (dt, J= 7.4, 0.8 Hz, IH), 7.07 (ddd, J = 11.2, 8.4, 1.2 Hz, IH), 6.88 (d, J= 3.6 Hz, IH), 4.74 (s, 2H), 1.66 (s, 9H); TLC tf/(n-Hexanes:EtOAc 5:1) = 0.59.
5-(2-Chloro-4-fluorophenyl)-3-methyl-liϊ-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J= 15.2, 2.4 Hz, IH), 7.15 (dd, J= 11.2, 6.0 Hz, IH), 7.02. (dd, J= 19.2, 5.2 Hz, IH), 6.57 (s, IH), 2.50 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J= 15.2, 2.4 Hz, IH), 7.14 (dd, J= 11.2 7.01 (dd, J= 19.2, 5.2 Hz, IH), 6.59 (s, IH), 2.55 (s, 3H), 1.51 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J= 15.2, 2.4 Hz, IH), 7.16 (dd, J= 11.2, 6.0 Hz, IH), 7.02 (dd, J= 19.2, 5.2 Hz, IH), 6.94 (s, IH), 4.77 (s, 2H), 1.68 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.01-7.99 (m, IH), 7.32-7.28 (m, IH), 7.01-6.92 (m, 2H), 6.65 (s, IH), 3.86 (s, 3H), 2.53 (s, 3H), 1.64 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (dd, J= 6.6, 1.8 Hz, IH), 7.77 (m, IH), 7.16 (t, J= 8.4 Hz, IH), 6.74 (s, IH), 4.77 (s, 2H), 1.71 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J= 2.8 Hz, IH), 7.37 (d, J= 8.4 Hz, IH), 7.27 (dd, J- 8.2, 3.0 Hz, IH), 6.68 (s, IH), 2.60 (s, 3H), 1.70 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.72.
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J= 2.4 Hz, IH), 7.37 (d, J= 8.8 Hz, IH), 7.28 (dd, J- 8.4, 2.8 Hz, IH), 7.01 (s, IH), 4.80 (s, 2H), 1.72 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.72.
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J= 8.4 Hz, IH), 7.42 (d, J= 2.4 Hz, IH), 7.28-7.24 (m, IH), 6.62 (s, IH), 2.55 (s, 3H), 1.64 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J= 8.4 Hz, IH), 7.39 (d, J= 2.4 Hz, IH), 7.25 (dd, J= 8.4, 2.0 Hz, IH), 6.96 (s, IH), 4.76 (s, 2H), 1.67 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (dd, J= 9.0, 6.2 Hz, IH), 7.35 (dd, J= 8.4, 2.4 Hz, IH), 7.08-7.0 (m, IH), 6.57 (s, IH), 2.55 (s, 3H), 1.64 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.76-7.73 (m, IH), 7.35 (d, J= 8.0 Hz, IH), 7.06 (t, J= 7.8 Hz, IH), 6.94 (s, IH), 4.79 (s, 2H), 1.69 (s, 9H)
1 1 HH NNMMRR ((440000 MMHHzz,, CCDDCCll 33 )) δδ 7.62 (d, J= 8.8 Hz, IH), 6.86 (s, IH), 6.77 (dd, J= 8.8, 2.4 Hz, IH), 3.78 (s, 3H), 2.57 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J= 8.4 Hz, IH), 6.93 (s, IH), 6.83 (d, J= 8.8 Hz, IH), 6.60 (s, IH), 3.81 (s, 3H), 1.64 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J= 8.4 Hz, IH), 6.94-6.93 (m, 2H), 6.84 (d, J= 8.8, 2.4 Hz, IH), 4.77 (s, 2H), 3.80 (s, 3H), 1.68 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (t, J= 8.8 Hz, IH), 6.73 (dd, J= 8.8, 2.8 Hz, IH), 6.63 (dd, J= 13.0, 2.6 Hz, IH), 6.52 (d, J= 4.0 Hz, IH), 3.81 (s, 3H), 2.53 (s, 3H), 1.65 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (t, J= 8.8 Hz, IH), 6.85 (d, J= 3.6 Hz, IH), 6.75-6.62 (m, 2H), 4.76 (s, 2H), 3.82 (s, 3H), 1.69 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (dd, J= 7.2, 2.0 Hz, IH), 7.71-7.67 (m, IH), 7.14 (t, J- 8.6 Hz, IH), 6.38 (s, IH), 2.54 (s, 3H), 1.65 (s, 9H)
3-Methyl-5-(4-nitrophenyl)-l/7-pyrazole
1 H NMR (400 MHz, CD 3 OD) δ 8.26 (d, J= 8.8 Hz, 2H), 7.97 (d, J= 8.0 Hz, 2H), 6.58 (s, IH), 2.35 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.18.
1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (dd, J= 6.8, 1.6 Hz, IH), 1.72-7.69 (m, IH), 7.16 (t, J- 8.4 Hz, IH), 6.72 (s, IH), 4.75 (s, 2H), 1.69 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J= 8.4 Hz, IH), 7.27-7.25 (m, IH), 7.09-7.04 (m, IH), 6.40 (s, IH), 3.93 (s, 3H), 2.53 (s, 3H), 1.65 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (dd, J= 8.2, 1.8 Hz, IH), 7.29-7.25 (m,- IH), 7.08-7.03 (m, IH), 6.73 (s, IH), 4.74 (s, 2H), 3.90 (s, 3H), 1.68 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J= 8.8 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H), 6.54 (s, IH), 2.59 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J= 9.2 Hz, 2H), 8.02 (d, J= 8.8 Hz, 2H), 6.86 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.43.
3-Methyl-5-(3-nitrophenyl)-lJBT-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (s, IH), 8.46 (s, IH), 8.14-8.08 (m, 2H), 7.64 (t, J= 8.0 Hz, IH), 6.44 (s, IH), 2.38 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, IH), 8.22-8.16 (m, 2H), 7.56 (t, J= 8.0 Hz, IH), 6.52 (s, IH), 2.57 (s, 3H), 1.66 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (s, IH), 8.22-8.19 (m, 2H), 7.58 (t, J= 8.0 Hz, IH), 6.88 (s, IH), 4.89 (s, 2H), 1.65 (s, 9H)
B
1 U NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 7.6 Hz, IH), 7.47 (d, J= 7.8 Hz 5 IH), 6.20 (s, IH), 2.53 (s, 3H), 1.64 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J= 8.2, 1.0 Hz, IH), 7.78 (dd, J= 7.8, 1.4 Hz, IH), 7.64-7.59 (m, IH), 6.54 (s, IH), 4.75 (s, 2H), 1.68 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d,. J= 2.0 Hz, IH), 8.02 (dd, J= 8.4, 2.4 Hz, IH), 7.57 (d, J= 8.4 Hz, IH), 6.49 (s, IH), 2.58 (s, 3H). 1.68 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.43.
1 B. NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J= 2.0 Hz, IH), 8.03 (dd, J= 8.6, 1.8 Hz, IH), 7.60 (d, J= 8.4 Hz, IH), 6.83 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J= 2.0 Hz, IH), 8.08 (d, J= 8.8 Hz, IH), 7.70-7.67 (m, IH), 6.76 (s, IH), 2.55 (s, 3H), 1.63 (s, 9H); TLC #/(rc-Hexanes:EtOAc 1 :1) = 0.89.
1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (t, J= 1.2 Hz, IH), 8.11 (d, J= 8.4 Hz, IH), 7.74-7.71 (m, IH), 7.11 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(CH 2 Cl 100%) = 0.72.
1 U NMR (400 MHz, CDCl 3 ) δ 8.41 (d, J= 6.0 Hz, IH), 7.67 (d, J= 2.4 Hz, IH), 6.81-6.78 (m, IH), 3.98 (s, 3H), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.90.
1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (d, J= 6.0 Hz, IH), 7.69 (d, J= 2.4 Hz, IH), 7.17 (s, IH), 6.84-6.82 (m, IH), 4.78 (s, 2H), 3.91 (s, 3H), 1.72 (s, 9H); TLC i?/(CH 2 Cl 100%) = 0.41.
1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (dd, J= 11.4, 4.2 Hz, IH), 7.26 (d, J= 6.8 Hz, IH), 6.93 (d, J= 8.4 Hz, IH), 3.94 (s, 3H)
1 1 HH NNMMRR ((440000 MMHHzz,, CCDDCCll 33 )) δδ 7.69-7.65 (m, IH), 7.62-7.60 (m, IH), 6.91 (dd, J= 8.2, 1.0 Hz, IH), 3.98 (s, 3H), 2.67 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J= 7.6 Hz, IH), 7.58 (t, J= 8.0 Hz, IH), 6.78 (s, IH), 6.68 (d, J= 8.0 Hz, IH), 3.94 (s, 3H), 2.55 (s, 3H), 1.66 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J= 7.2 Hz, IH), 7.61 (t, J= 7.6 Hz, IH), 7.10 (s, IH), 6.71 (d, J= 8.4 Hz, IH), 4.78 (s, 2H), 3.98 (s, 3H), 1.70 (s, 9H)
1 R NMR (400 MHz, CDCl 3 ) δ 8.55 (d, J= 5.2 Hz, IH), 8.00 (d, J= 2.0 Hz, IH), 7.44 (dd, J= 5.2, 2.0 Hz, IH), 2.69 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.1. 155.0. 150.2. 145.7. 127.3. 122.4. 26.0; TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.69.
1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J= 5.6 Hz, IH), 8.17 (d, J= 1.6 Hz, IH 6.78 (s, IH), 2.55 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.44.
1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J= 5.2 Hz, IH), 8.20 (d, J= 2.4 Hz, IH), 7.28 (dd, J = 5.4, 1.8 Hz, IH), 7.14 (s, IH), 4.79 (s, 2H), 1.73 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.44.
1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J= 7.6 Hz, IH), 7.80 (t, J- 7.8 Hz, IH), 7.51 (d, J- 8.0 Hz, IH), 2.70 (s, 3H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.66.
1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J= 7.6 Hz, IH), 7.63 (t, J= 7.6 Hz, IH), 7.21 (d, J= 7.6 Hz, IH), 6.79 (s, IH), 2.50 (s, 3H), 1.62 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.53.
1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J= 7.6 Hz, IH), 7.66 (t, J= 7.8 Hz, IH), 7.26 (d, J= 7.6 Hz, IH), 7.13 (s, IH), 4.72 (s, 2H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.53.
5-Methoxypicolinonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J= 2.8 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.26 (dd, J- 8.6, 3.0 Hz, IH), 3.95 (s, 3H); TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.23.
1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J= 2.8 Hz, IH), 8.06 (d, J= 8.8 Hz, IH), 7.27 (dd, J= 8.8, 3.2 Hz, IH), 3.94 (s, 3H), 2.69 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.35.
1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (d, J= 2.8 Hz, IH), 8.09 (d, J= 9.2 Hz, IH), 8.24 (d, J= 2.8 Hz, IH), 6.75 (s, IH), 3.88 (s, 3H), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.41.
1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (d, J= 2.8 Hz, IH), 8.08 (d, J= 8.8 Hz, IH), 7.24 (dd, J- 7.8, 3.8 Hz, IH), 7.06 (s, IH), 4.76 (s, 2H), 3.87 (s, 3H), 1.69 (s, 9H); TLC R f (n- Hexanes:EtOAc 2:1) = 0.42.
1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, J= 2.8 Hz, IH), 8.15 (dd, J= 8.8, 4.8 Hz, IH), 7.45- 7.40 (m, IH), 6.74 (s, IH), 2.55 (s, 3H), 1.66 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (d, J= 2.8 Hz, IH), 8.16 (dd, J= 9.0, 4.6 Hz, IH), 7.47- 7.42 (m, IH), 7.08 (s, IH), 4.76 (s, 2H), 1.70 (s, 9H)
3-Methyl-5-(4-(trifluoromethoxy)phenyl)-l£T-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 11.17 (bs, IH), 7.69 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.4 Hz, 2H), 6.27 (s, IH), 2.20 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.28.
1 H NMR (400 MHz, CDCl 3 ) δ 7.82-7.80 (m, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.34 (s, IH), 2.47 (s, 3H), 1.59 (s, 9H); TLC #/(rc-Hexanes:Et 2 O 2:1) = 0.57.
1 H NMR (400 MHz, CDCl 3 ) δ 7.90-7.88 (m, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.77 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC _fy(«-Hexanes:Et 2 O 2:1) = 0.57.
4-Acetyl-λyV-dimethylbenzenesulfonamide
1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J= 1.3 Hz, 2H), 7.86 (d, J= 1.6 Hz, 2H), 2.72 (s, 6H), 2.64 (s, 3H)
1 H NMR (400 MHz, DMSO-^) δ 12.82 (br, IH), 7.99 (d, J= 2.1 Hz, 2H), 7.74 (d, J= 2.1 Hz, 2H), 6.58 (s, IH), 2.61 (s, 6H), 2.27 (s, 3H)
ter^-Butyl 3-(4-(λ r ,λ'-dimethylsulfamoyl)phenyl)-5-methyl-lJϊ-pyrazole-l-carb oxylate
1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J= 8.43 Hz, 2H), 7.78 (d, J= 8.0 Hz, 2H), 6.49 (s, IH), 2.69 (s, 6H), 2.56 (s, 3H), 1.66 (s, 9H)
/e/-/-Butyl 5-(bromomethyl)-3-(4-(7V,N-(limethylsuIfamoyl)phenyl)-lJ c /-pyrazole-l- carboxylate
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J= 8.43 Hz, 2H), 7.80 (d, J= 8.0 Hz, 2H), 6.83 (s, IH), 4.78 (s, 2H), 2.69 (s, 6H), 1.70 (s, 9H)
Methyl l-(4-methoxybenzyl)-3-/?-tolyl-l/3T-pyrazole-5-carboxylate
1 H NMR (400 MHz, CDCl 3 ) δ 7.70-7.68 (m, 2H), 7.27-7.18 (m, 4H), 7.08 (s, IH), 6.87-6.79 (m, 3H), 5.70 (s, 2H) 5 3.84 (s, 3H), 3.74 (s, 3H), 2.35 (s, 3H),; TLC i?/(Hexanes: EtOAc 5:1) = 0.68.
1 H NMR (400 MHz, CD 3 OD) δ 7.63-7.61 (m, 2H), 7.24-7.10 (m, 4H), 6.86 (t, J= 8.8 Hz, 2H), 6.56 (s, IH), 5.34 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 2.32 (s, 3H); TLC R f (Hexanes:EtOAc 1 :1) = 0.45.
1 H NMR (400 MHz, CD 3 OD) δ 7.64-7.62 (m, IH), 7.24-7.14 (m, 4H), 6.88-6.86 (m, 3H), 6.68 (s, IH), 5.37 (s, 2H), 4.51 (s, 2H), 3.74 (s, 3H), 2.32 (s, 3H),; TLC i?/(Hexanes:EtOAc 1 :1) = 0.89.
Methyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate
1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J= 8.8 Hz, 2H), 7.04 (s, IH) 6.98 (d, J= 9.2 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 190.4, 167.6, 164.4, 162.9, 130.3, 127.7, 114.2, 97.9, 55.6, 53.1; TLC i?/(n-Hexanes:EtOAc 2:1) = 0.24.
Methyl 3-(4-methoxyphenyl)-liϊ-pyrazole-5-carboxylate
1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J= 8.8 Hz, 2H), 7.03 (s, IH), 6.96 (d, J= 8.8 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.24.
5-(4-methoxyphenyl)-l//-pyrazole-3-carboxylic acid
1 H NMR (400 MHz, OMSO-d 6 ) δ 7.72 (d, J= 8.8 Hz, 2H), 7.05 (s, IH), 6.96 (d, J= 9.2 Hz, 2H), 3.76 (s, 3H).
1 H NMR (400 MHz, CD 3 OD) δ 7.57 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.45 (s, IH), 4.56 (s, 2H), 3.75 (s, 3H); TLC /Jy(CH 2 Cl 2 =MeOH 20:1) = 0.07.
3-(4-Methoxyphenyl)-lfi r -pyrazole-5-carbaldehyde
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.86 (s, IH), 7.74 (d, J- 8.8 Hz 5 2H), 7.00 (d, J= 8.8 Hz, 2H), 3.76 (s, 3H); TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.28.
(3-(4-(Dimethylamino)phenyl)-liZ-pyrazol-5-yl)methaiiol
1 H NMR (400 MHz, CD 3 OD) δ 7.52 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 6.46 (s, IH), 4.62 (s, 2H), 2.94 (s, 6H); TLC R f (CH 2 Cl 2 MeOH 10:1) = 0.26.
3-(4-(Dimethylamino)phenyl)-lH-pyrazole-5-carbaldehyde
1 U NMR (400 MHz, CD 3 OD) δ 9.86 (s, IH), 7.54-7.50 (m, 2H), 6.89 (bs, IH), 6.79-6.75 (m, 2H), 2.95 (s, 6H); TLC R 1 (CH 2 Cl 2 MeOH 10:1) = 0.41.
1 -(Furan-2-y l)butane-l ,3-dione
1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (t, J= 0.6 Hz, IH), 7.09 (d, J= 3.6 Hz 5 IH) 5 6.47 (dd, J- 3.6, 1.2 Hz 5 IH) 5 6.01 (s, IH), 2.05 (s, 3H); TLC #/(ra-Hexanes:EtOAc 2:1) = 0.70.
5-(Furan-2-yl)-3-methyl-lH-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 10.08 (bs, IH), 7.41 (t, J= 1.0 Hz, IH), 6.58 (d, J= 3.2 Hz, IH) 5 6.43 (dd, J= 3.2, 2.0 Hz, IH), 6.26 (s, IH) 5 2.32 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.37.
1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J= 1.6 Hz, IH), 6.80 (d, J= 3.2 Hz, IH), 6.44 (dd, J= 3.4, 1.8 Hz, IH), 6.36 (s, IH), 2.53 (s, 3H), 1.63 (s, 9H); TLC λ/w-HexanesrEtOAc 2:1) = 0.65.
1 H NMR (400 MHz, CDCl 3 ) δ 6.79 (d, J= 3.6 Hz, IH), 6.67 (s, IH), 6.38 (d, J= 4.0 Hz, IH), 4.72 (s, 2H), 1.65 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.33.
5-(3-Methyl-liϊ-pyrazol-5-yl)furan-2-carboxylic acid
1 H NMR (400 MHz, CD 3 OD) δ 7.24 (d, J= 3.6 Hz, IH), 6.79 (d, J= 3.6 Hz, IH), 6.46 (s, IH), 2.33 (s, 3H).
Methyl 5-(3-methyl-lIZ-pyrazoI-5-yl)furan-2-carboxylate
1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (bs, IH), 7.24 (d, J= 3.6 Hz, IH), 6.90 (m, IH), 6.49 (s, IH), 3.90 (s, 3H), 2.41 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.33.
1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J= 3.6 Hz, IH), 6.96 (d, J= 3.6 Hz, IH), 6.55 (s, IH), 3.89 (s, 3H), 2.54 (s, 3H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.54.
1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J= 3.6 Hz, IH), 6.99 (d, J= 3.6 Hz, IH), 6.89 (s, IH), 4.74 (s, 2H), 3.89 (s, 3H), 1.69 (s, 9H); TLC /J/w-HexanesiEtOAc 2:1) = 0.54.
3-Methyl-5-(thiophen-2-yl)-l//-pyrazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.26-7.21 (m, 3H), 7.02 (t, J= 4 Hz, IH), 6.25 (s, IH), 2.31 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.29-7.25 (m, 2H), 7.16 (t, J= 4 Hz, IH), 6.22 (s, IH), 2.38 (s, 3H), 1.52 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J= 4.0 Hz, IH), 7.04 (d, J= 4.0 Hz, IH), 4.79 (s, 2H), 1.67 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 3.75 (bs, 4H), 3.59 (bs, 2H), 3.37 (bs, 2H), 2.59 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.4, 169.5, 139.9, 138.2, 128.8, 127.5, 67.0, 43.0, 26.9; TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.43.
Methyl 4-(4-(morpholine-4-carbonyl)phenyl)-2,4-dioxobutanoate
1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J= 7.6 Hz, 2H), 7.49 (d, J= 7.6 Hz, 2H), 7.03 (s, IH), 3.90 (s, 3H), 3.71 (bs, 4H), 3.59 (bs, 2H), 3.37 (bs, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.2, 170.2, 169.9, 162.3, 140.2, 135.8, 128.1, 127.5, 98.0, 66.7, 53.2, 29.6; TLC #/(CH 2 Cl 2 :Me0H 19:1) = 0.46.
Methyl 5-(4-(morpholine-4-carbonyI)phenyl)-lH-pyrazole-3-carboxylat e
1 H NMR (400 MHz, CD 3 OD) δ 7.85 (bs, 2H), 7.48 (d, J= 8.0 Hz, 2H), 7.19 (s, IH), 3.89 (s, 3H), 3.72 (bs, 6H), 3.47 (bs, 2H); TLC ^(CH 2 Cl 2 MeOH 19:1) = 0.35.
Methyl l-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-l/jT -pyrazole-5- carboxylate
1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.35 (s, IH), 6.91 (d, J= 8.8 Hz, 2H), 5.81 (s, 2H), 3.96 (s, 3H), 3.90-3.51 (m, 1 IH); TLC i?/(rc-Hexanes:EtOAc 1 : 1) = 0.31.
(4-(5-(Hydroxymethyl)-l-(4-methoxybenzyl)-l//-pyrazol-3- yl)phenyl)(morpholino)methanone
1 H NMR (400 MHz, DMSO-J 6 ) δ 7.78 (d. J= 8.4 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.14 (d. J = 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.66 (s, IH), 5.40 (bs, IH), 5.26 (s, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.52 (bs, 6H), 3.29 (bs, 2H); 13 C NMR (100 MHz, DMSO-J 6 ) δ 169.6, 159.3, 148.8, 145.1, 135.3, 134.8, 129.9, 129.4, 128.3, 125.4, 114.5, 103.5, 66.8, 55.7, 54.7, 53.8, 52.7; TLC i?/(«-Hexanes:EtOAc 3:7) = 0.39.
(4-(5-(Bromomethyl)-l-(4-methoxybenzyl)-lH r -pyrazol-3- yl)phenyl)(morpholino)methanone
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J= 7.6 Hz, 2H), 7.53 (d, J= 7.6 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.61 (s, IH), 5.40 (s, 2H), 4.31 (s, 2H), 3.76 (s, 3H), 3.74-3.42 (bs, 8H); TLC i?/(«-Hexanes:EtOAc 2:3) = 0.37.
1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J= 2.8 Hz, IH), 6.16 (d, J= 2.8 Hz, IH), 2.31 (s, 3H), 1.64 (s, 9H);TLC i?/(«-Hexanes: EtOAc 2:1) = 0.57.
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J= 2.8 Hz, IH), 6.44 (d, J= 2.8 Hz, IH), 4.47 (s, 2H), 1.64 (s, 9H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.64.
5-Methyl-3-phenyl-l//-l,2,4-triazole
as white solid: 1 H NMR (400 MHz, CD 3 OD) δ 7.96-7.94 (m, 2H), 7.46-7.38 (m, 3H), 2.45 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.3, 161.3, 159.6, 133.9, 131.1, 131.0, 118.7, 117.3, 114.5, 14.3; TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.46.
1 H NMR (400 MHz, CDCl 3 ) δ 8.14-8.12 (m, 2H), 7.42-7.40 (m, 3H), 2.76 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes: EtOAc 1 :2) = 0.83.
1 H NMR (400 MHz, CDCl 3 ) δ 8.15-8.13 (m, 2H), 7.42-7.41 (m, 3H), 4.81 (s, 2H), 1.70 (s, 9H); TLC R f (n-Hexanes: EtOAc 2:1) = 0.58.
Azidobenzene
1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (t, J= 8.0 Hz, 2H), 7.12 (t, J= 7.2 Hz, IH), 7.02 (d, J- 7.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 140.2, 130.0, 125.1, 119.2; TLC R f (n- Hexanes:EtOAc 7:3) = 0.88.
(l-Phenyl-lH-l,2,3-triazoI-4-yl)methanol
1 H NMR (400 MHz, CD 3 OD) δ 8.41 (s, IH), 7.82 (d, J= 8.0 Hz, 2H), 7.56 (t, J= 7.8 Hz, 2H), 7.47 (t, J= 7.0 Hz, IH), 4.74 (s, 2H); TLC i?/(rc-Hexanes:EtOAc 3:7) = 0.20.
1 -Phenyl- IiY-1, 2,3-triazole-4-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 10.19 (s, IH), 8.52 (s, IH), 7.74 (d, J= 8.0 Hz, 2H), 7.49 (m, 3H); TLC i?/(«-Hexanes:EtOAc 3:7) = 0.84.
1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, IH), 7.27 (s, 3H), 2.32 (s, 3H), 1.60 (s, 9H); TLC (R f 0?-Hexanes:EtOAc 3:1) = 0.68.
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, IH), 7.39-7.30 (m, 4H), 2.41 (s, 3H), 1.63 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.42.
1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, IH), 7.53-7.51 (m, 2H), 7.50-7.41 (m, 2H), 7.40-7.35 (m, IH), 4.46 (s, 2H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.52.
5-Pheny 1- lH-py razole
1 H NMR (400 MHz, CDCl 3 ) δ 7.77-7.74 (m, 2H), 7.62 (d, J= 2.4 Hz, IH), 7.44-7.31 (m, 3H), 6.62 (d, J= 2.0 Hz, IH); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.22.
3-Pheny 1- 1 -(tetrahy dro-2/f-py ran-2-yl)- 1 H-py razole
1 H NMR (400 MHz, CDCl 3 ) δ 7.84-7.81 (m, 2H), 7.64 (d, J= 2.4 Hz, IH), 7.40-7.36 (m, 2H), 7.31-7.27 (m, IH), 6.61 (d, J= 2.4 Hz, IH), 5.44 (dd, J= 9.4, 3.0 Hz, IH), 4.12-4.08 (m, IH), 3.76-3.70 (m, IH), 2.43-2.04 (m, 3H), 1.78-1.52 (m, 3H); TLC ^(n-Hexanes^tOAc 2:1) = 0.57.
1 H NMR (400 MHz, CDCl 3 ) δ 9.99 (s, IH), 7.85 (d, J= 7.6 Hz, 2H), 7.42 (t, J= 7.8 Hz, 2H), 7.36-7.33 (m, IH), 7.22 (s, IH), 6.15 (dd, J= 9.6, 2.8 Hz, IH), 4.09-4.04 (m, IH), 3.80-3.74 (m, IH), 2.57-2.48 (m, IH), 2.18-2.04 (m, 2H), 1.81-1.52 (m, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.59.
5-(4-Methoxy phenyl)- lH-py razole
1 H NMR (400 MHz, CD 3 OD) δ 7.64 (s, 3H), 6.96-6.93 (m, 2H), 6.53 (s, IH), 3.79 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.47.
3-(4-Methoxyphenyl)-l-(tetrahydro-2//-pyran-2-yl)-li/-pyr azole
1 H NMR (400 MHz, CDCl 3 ) δ 7.74-7.71 (m, 2H), 7.58 (d, J= 2.4 Hz, IH), 6.91-6.88 (m, 2H), 6.51 (d, J= 2.4 Hz, IH), 5.41-5.37 (m, IH), 4.11-4.05 (m, IH), 3.84 (s, 3H), 3.80-3.67 (m, IH), 2.16-2.02 (m, 2H), 1.71-1.51 (m, 3H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.82.
3-(4-Methoxyphenyl)-l-(tetrahydro-2/T-pyraπ-2-yl)-lH-pyr azole-5-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (s, IH), 7.76-7.73 (m, 2H), 7.12 (s, IH), 6.93-6.09 (m, 2H), 4.12-4.03 (m, IH), 3.84 (s, 3H), 2.50-2.00 (m, 2H), 1.75-1.50(m, 3H); TLC R f (n- Hexanes:EtOAc 1:1) = 0.88.
4-(lH-Pyrazol-5-yl)pyridine
1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J= 4.8 Hz, 2H), 7.71 (d, J= 5.2 Hz, 2H), 7.68 (d, J = 2.4 Hz, IH), 6.75 (d, J= 2.4 Hz 3 IH); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.23.
4-(l-(Tetrahydro-2H-pyran-2-yl)-ljH r -pyrazol-3-yl)pyridine
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (m, 2H), 7.70 (d, J= 5.2 Hz, 2H), 7.68 (d, J= 2.4 Hz, IH), 6.70 (d, J= 2.4 Hz, IH), 5.45 (dd, J= 9.2, 2.8 Hz, IH), 4.11-4.08 (m, IH), 3.77-3.70 (m, IH), 2.21-2.04 (m, 3H), 1.75-1.61 (m, 3H); TLC ^ 7 (CH 2 Cl 2 MeOH 20:1) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (s, IH), 8.66 (d, J= 6.0 Hz, 2H), 7.72 (d, J= 6.0 Hz, 2H), 7.31 (s, IH), 6.15 (dd, J= 9.4, 2.6 Hz, IH), 4.08-4.04 (m, IH), 3.80-3.74 (m, IH), 2.54- 2.45 (m, IH), 2.17-2.14 (m, IH), 2.09-2.04 (m, IH), 1.82-1.62 (m, 3H); TLC R f (CH 2 Cl 2 :Et0Ac 2:1) = 0.17.
3-(l/7-PyrazoI-5-yl)pyridine
1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (s, IH), 8.58 (dd, J= 4.8, 1.6 Hz, IH), 8.10 (d, J= 6.8 Hz, IH), 7.67 (d, J= 2.4 Hz, IH), 7.35 (dd, J= 8.0, 4.8 Hz, IH), 6.70 (d, J= 2.4 Hz, IH); TLC ^(CH 2 Cl 2 =MeOH 20:1) = 0.22.
3-(l-(Tetrahydro-2//-pyran-2-yl)-l/7-pyrazoI-3-yl)pyridii ie
1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, IH), 8.53 (d, J= 3.6 Hz, IH), 8.13 (d, J= 8.0 Hz, IH), 7.67 (d, J= 2.8 Hz, IH), 7.32-7.29 (m, IH), 6.65 (d, J= 2.4 Hz, IH), 5.44 (dd, J= 9.6, 2.8 Hz, IH), 4.12-4.09 (m, IH), 3.77-3.71 (m, IH), 2.24-2.04 (m, 3H), 1.79-1.57 (m, 3H); TLC R 1 (CH 2 Cl 2 :Et0Ac 2:1) = 0.23.
1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (s, IH), 9.07 (s, IH), 8.59 (d, J= 4.8 Hz, IH), 8.16 (d, J = 8.0 Hz, IH), 7.35 (dd, J= 8.0, 4.8 Hz, IH), 7.28 (s, IH), 6.16 (dd, J= 9.8, 2.6 Hz, IH), 4.08 (d, J= 10.0 Hz, IH), 3.81-3.75 (m, IH), 2.56-2.46 (m, IH), 2.15-2.05 (m, 2H), 1.82-1.60 (m, 3H); TLC i?/(CH 2 Cl 2 :Et0Ac 20:1) = 0.45.
(£)-3-(Dimethylamino)-l-(pyridin-2-yl)prop-2-en-l-one
1 HNMR (400 MHz, CDCl 3 ) δ 8.60-8.58 (m, IH), 8.11 (d, J= 6.8 Hz, IH), 7.87 (d, J= 12.4 Hz, IH), 7.89-7.74 (m, IH), 7.34-7.30 (m, IH), 6.42 (d, J= 12.4 Hz, IH), 3.13 (d, J= 12.4 Hz, 3H), 2.97 (d, J= 12.0 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.01.
2-(l//-Pyrazol-5-yl)pyridine
1 H NMR (400 MHz, CD 3 OD) δ 8.54 (d, J= 3.2 Hz, IH), 7.96 (s, IH), 7.86-7.82 (m, IH), 7.70 (s, IH), 7.33-7.30 (m, IH), 6.89 (s, IH); TLC ^ 7 (CH 2 Cl 2 MeOH 10:1) - 0.69.
1 H NMR (400 MHz, CDCl 3 ) δ 8.60-8.58 (m, IH), 7.97 (d, J= 4.0 Hz, IH), 7.69-7.64 (m, 2H), 7.17-7.14 (m, IH), 6.92 (d, J= 2.4 Hz, IH), 5.45-5.42 (m, IH), 4.10-4.05 (m, IH), 3.73-3.66 (m, IH), 2.16-2.01 (m, 3H), 1.77-1.57 (m, 4H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.48.
3-(Pyridin-2-yl)-l-(tetrahydro-2JET-pyran-2-yl)-lJϊ-pyra zole-5-carbaldehyde
1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (s, IH), 8.60 (d, J= 4.8 Hz, IH), 8.05 (d, J= 8.0 Hz, IH), 7.73-7.69 (m, 2H), 7.57 (s, IH), 7.24-7.20 (m, IH), 6.18-6.15 (m, IH), 4.07-4.04 (m, IH), 3.78-3.72 (m, IH), 2.54-2.44 (m, IH), 2.14-2.00 (m, 2H), 1.78-1.58 (m, 3H); TLC R f (n- Hexanes:EtOAc 1:1) = 0.57.
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (t, J- 4.0 Hz, IH), 7.43 (t, J= 4.0 Hz, IH), 7.36 (t, J= 7.4 Hz, IH), 7.13 (t, J= 4.0 Hz, IH), 6.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) d 143.5, 141.3, 126.9, 122.9, 120.4, 120.3, 109.9, 12.2; TLC λ/(/i-Hexanes:EtOAc 2:1) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (dd, J= 8.0, 2.0 Hz, IH), 7.38 (dt, J= 7.6, 2.0 Hz, IH), 7.27 (dt, J= 8.0, 1.2 Hz, IH), 7.18 (dd, J= 8.0, 1.2 Hz, IH), 2.19 (s, 3H), 1.51 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.3, 151.6, 148.5, 132.3, 129.8, 129.4, 126.0, 123.1, 83.3, 27.6, 17.8; TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.28.
1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J= 8.8 Hz, IH), 7.83 (d, J= 6.8 Hz, IH), 7.53 (t, J= 7.8 Hz, IH ), 7.35 (t, J- 7.6 Hz, IH), 4.77 (s, 2H), 1.71 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) d 149.2, 148.2, 140.1, 128.6, 125.8, 123.1, 120.1, 114.5, 84.0, 28.1, 12.1; TLC R f (n- Hexanes:EtOAc 5:1) = 0.46.
1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J= 8.8 Hz, IH), 6.79-6.77 (m, 2H), 3.84 (s, 3H), 2.53 (s, 3H); 13 C NMR (IOO MHZ, CDCl 3 ) δ 160.0, 142.6, 121.2, 117.8, 112.3, 99.6, 91.0, 55.7, 12.1; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.14.
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J= 8.8 Hz, IH), 7.60 (s, IH), 6.96 (d, J= 8.8 Hz, IH), 4.71 (s, 2H), 3.89 (s, 3H), 1.70 (s, 9H); 13 C NMR (100 MHz, CDCl 5 ) δ 160.0, 142.6, 121.2, 117.8, 112.3, 99.6, 91.0, 55.7, 12.0; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.75.
1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (dd, J= 6.0, 3.0 Hz, IH), 8.40 (dd, J= 10.0, 3.0 Hz, IH), 7.45 (dd, J= 10.0, 8.0 Hz, IH), 2.75 (s, 3H)
3-Methyl-5-nitro-l//-indazoIe
1 U NMR (400 MHz, CDCl 3 ) δ 10.04 (s, IH), 8.67 (s, IH), 8.27 (d, J= 6.8 Hz, IH), 7.47 (d, J = 7.2 Hz, IH), 2.64 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, IH), 8.37 (d, J= 6.8 Hz, IH), 8.22 (d, J= 7.2 Hz, IH), 2.65 (s, 3H), 1.67 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, IH), 8.42 (d, J= 6.8 Hz, IH), 8.27 (d, J= 7.2 Hz, IH), 4.78 (s, 2H), 1.72 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (dd, J= 4.8, 1.6 Hz, IH), 8.18 (dd, J= 8.0, 1.6 Hz, IH), 7.29 (dd, J= 8.0, 4.8 Hz, IH), 4.72 (s, 2H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 9.53 (s, IH), 8.57 (d, J= 5.2 Hz, IH), 7.77 (dd, J= 5.2, 1.2 Hz, IH), 4.79 (s, 2H), 1.75 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.64.
1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (dd, J= 8.0, 8.0 Hz, IH), 6.97 (dd, J= 8.0, 1.0 Hz, IH), 4.72 (s, 2H), 1.71 (s, 9H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.56.
2-(BromomethyI)benzo[rf]thiazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J= 8.0 Hz, IH), 7.84 (d, J= 7.8 Hz, IH), 7.46 (t, J= 4.4 Hz ,1H), 7.36 (t, J= 4.5 Hz, IH), 4.78 (s, 2H)
1 H NMR (400 MHz, CDCl 3 ) δ 7.91-7.89 (m, IH), 7.66-7.63 (m, IH), 7.30-7.28 (m, 2H), 2.82 (s, 3H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.79.
1 H NMR (400 MHz, CDCl 3 ) δ 7.97-7.94 (m, IH), 7.72-7.70 (m, IH), 7.39-7.31 (m, 2H), 4.93 (s, 2H), 1.73 (s, 9H); TLC £/(rc-Hexanes:EtOAc 3:1) = 0.89.
1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J= 4.0 Hz, IH), 7.50 (d, J= 7.2 Hz, IH), 7.03-7.00 (m, IH), 6.78 (s, IH), 2.28 (s, 3H), 1.51 (s, 9H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J= 5.2 Hz, IH), 7.52 (d, J= 7.6 Hz, IH), 7.05-7.00 (m, IH), 6.72 (s, IH), 2.68-2.62 (m, 2H), , 1.51 (s, 9H), 1.35-1.23 (m, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.38-8.35 (m, IH), 7.94-7.92 (m, IH), 7.17 (s, IH), 7.13-7.08 (m, IH), 2.36 (s, 3H) ); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.87.
1 H NMR (400 MHz, CDCl 3 ) δ 8.49-8.46 (m, IH), 7.86-7.83 (m, IH), 7.36 (d, J= 0.8 Hz, IH), 7.17-7.14 (m, IH), 7.23 (s, 3H), 1.65 (s, 9H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.65.
1 H NMR (400 MHz, CDCl 3 ) δ 10.91 (s, IH), 8.87 (d, J= 1.2 Hz, IH), 8.48 (d, J= 1.6 Hz, IH), 7.49 (s, IH), 6.69 (d, J= 2.4 Hz, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.36.
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J= 8.4 Hz, IH), 7.99 (d, J= 7.6 Hz, IH), 7.32 (t, J= 8.0 Hz, IH), 2.72 (s, 3H); TLC #/(rc-Hexanes:EtOAc 1 :1) = 0.35.
1 H NMR (400 MHz, CDCl 3 ) δ 8.30-8.28 (m, IH), 8.14-8.12 (m, IH), 7.41 (t, J= 8.4 Hz, IH), 2.93 (s, 3H), 1.73 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.89.
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J= 8.0 Hz, IH), 7.94 (d, J= 8.4 Hz, IH), 7.29 (t, J= 8.2 Hz, IH), 4.73 (s, 2H), 1.56 (s, 9H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.63.
2-Methyl-3/jT-imidazo [4,5-6] pyridine
1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, J= 4.0 Hz, IH), 8.01 (d, J= 7.2 Hz, IH), 7.26-7.21 (m, IH), 2.74 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.72.
1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (t, J= 2.2 Hz, IH), 7.91-7.88 (m, IH), 7.26-7.21 (m, IH), 2.74 (s, 3H), 1.69 (s, 9H); TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.89.
1 H NMR (400 MHz, CDCl 3 ) δ 8.54-8.53 (m, IH), 8.01-7.99 (m, IH), 7.33-7.29 (m, IH), 4.89 (s, 2H), 1.74 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.92.
2-(Bromomethyl)benzo[rf]oxazole
1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J= 8.4 Hz, IH), 7.53 (d, J= 7.6 Hz, IH), 7.59-7.32 (m, 2H), 4.57 (s, 2H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J= 8.0 Hz, IH), 7,80 (d, J= 8.0 Hz, IH), 7.43 (t, J= 8.4 Hz, IH), 2.76 (s, 3H)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (dd, J= 8.4, 0.8 Hz, IH), 7.86 (dd, J= 8.2, 0.6 Hz, IH), 7.51 (t, J= 8.2 Hz, IH), 4.64 (s, 2H)
2-Methyloxazolo [4,5-6] pyridine
1 U NMR (400 MHz, CDCl 3 ) δ 8.53 (dd, J= 5.0, 1.4 Hz, IH), 7.77 (d, J= 8.2, 1.4 Hz, IH), 7.28-7.24 (m, IH), 2.72 (s, 3H)
2-(Bromomethyl)oxazolo [4,5-6] pyridine
1 U NMR (400 MHz, CDCl 3 ) δ 8.60-8.56 (m, IH), 7.84 (t, J= 7.2 Hz, IH), 7.34-7.28 (m, IH), 4.78 (s, 2H)
General procedure for coupling subunit 1 and 2.
To a 0 °C solution of subunit 1 (0.41 mmol, 1.0 equiv) in THF (1 niL) was added dropwise n- BuLi (1.6 M in THF, 0.38 mmol, 1.1 equiv). The reaction mixture was stirred at 0 "C for 1 h. After stirring at 25 0 C for 10 min, the reaction mixture was cooled to 0 °C, and then a solution of subunit 2 (0.41 mmol, 1.2 equiv) in THF (1 mL) was added via cannula. After 1 h at 0 "C, the reaction was quenched by the addition of saturated aqueous NH 4 Cl (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel to give coupled adducts.
A, B, C = CH, N, or N=O
To a solution of Boc-protected compound (0.19 mmol, 1.0 equiv) in 4N HCl in dioxane (3.93 mmol, 2.0 equiv) was stirred at 25 °C for 2 h, and then quenched with aqueous saturated K 2 CO 3 (10 mL) and H 2 O (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 10 mL) and
dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
To a solution of PMB-protected compound (0.045 mmol, 1.0 equiv) in TFA (4 mL) was stirred at 120 °C for 30 min, and then quenched with aqueous IN NaOH (5 ml) and H 2 O (5 mL). The mixture was extracted with CH 2 Cl 2 (3 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for C-N bond formation via reductive animation
Subunit 1 subunit 2 A, B, C = CH, N, or N=O
A solution of subunit 1 (0.295 mmol, 1.0 equiv) and subunit 2 aldehyde (0.324 mmol, 1.1 equiv) in MeOH (6 mL) was stirred for 1 h at 25 °C and then treated with AcOH (4.130 mmol, 14 equiv). The reaction was stirred for 15 min at 25 °C, after which NaCNBH 3 (0.590 mmol, 2 equiv) was added in several small portions. After stirred at 25 0 C under Ar overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo with silica gel. The residue was purified via flash column chromatography to give desired reductive animation products.
Subunit 1
for 5 h at 25 °C, the reaction mixture was treated with NaBH(OAc) 3 (586 μmol, 2.0 equiv) at 25 °C. After stirred at 25 °C for 16 h, the reaction was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via preparative TLC to THP -protected reductive animation products.
A solution of above THP-protected compounds (71 μmol, 1.0 equiv) in 1 mL of HCl/MeOH (stock solutions were prepared by adding 10 mL AcCl to 100 mL MeOH over 5 min with ice- cooling) was stirred at 25 ° C for 3 h. The reaction mixture was quenched with saturated aqueous K 2 CO 3 solution and extracted with EtOAc (2 x 15 mL). The organic layers were washed with brine (30 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via preparative HPLC to give corresponding deprotected products.
General procedure for coupling via C-Q bond formation
To a solution of subunit 1 (0.33 mmol, 1.1 equiv) and Cs 2 CO 3 (0.36 mmol, 1.2 equiv) in DMF (450 μL, 0.7 M) was added Boc-protected bromopyrazole subunit 2 (0.30 mmol, 1.0 equiv). The reaction mixture was heated at 90 0 C for 1 h. After cooled to 25 °C, the reaction mixture was concentrated to remove DMF and then partitioned with EtOAc/H 2 O. The organic layer was washed with brine and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the resulting residue was purified via flash column chromatography on silica gel to give coupled products.
To a 0 0 C solution of THP-protected pyrazole subunit 2 (0.193 rnrnol, 2.0 equiv) in DMF (1.4 mL) was added slowly NaH (0.115 mmol, 1.2 equiv). The reaction mixture was heated at 60 °C for 30 min and then treated with subunit 1 (0.095 mmol, 1.0 equiv) at 25 0 C. The resulting solution was stirred at 100 °C for 12 h. After cooled to 25 °C, the reaction was quenched with saturated aqueous NaHCO 3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give coupled products.
To a solution of THP-protected coupled compound (0.067 mmol, 1.0 equiv) in 130 μL of HCl/MeOH (stock solutions were prepared by adding 10 mL AcCl to 100 mL MeOH over 5 min with ice-cooling) was stirred at 25 0 C for 5 h. The reaction mixture was quenched with a mixture of saturated aqueous NaHCO 3 (10 mL) and H 2 O (10 mL). The mixture was extracted with CH 2 Cl 2 (3 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give deprotected products.
General procedure for amide coupling between subunit 1 and subunit 2
To a solution of carboxylic acid (0.27 mmol, 1.0 equiv) in DMF (1 mL) was added 1,1'- carbonyldiimidazole (0.29 mmol, 1.1 equiv) at 25 °C. The reaction mixture was heated for 3 h at 60 °C and then treated with a solution of biarylamine (0.29 mmol, 1.1 equiv) in DMF (1 mL). The reaction was kept at 60 0 C for overnight. After cooled to 25 °C, the mixture was concentrated under reduced pressure and directly purified via flash column chromatography on silica gel to give amide products.
General procedure for the conversion of fluoride to amino group
To an oven-dried sealed tube charged with fluoro compounds (0.259 mmol, 1.0 equiv) and PMBNH 2 (3.88 mmol, 15.0 equiv) was added NMP (2.0 mL) under Ar. The reaction mixture was heated to 95 °C for 12 h. After cooled to 25 °C, the reaction mixture was quenched by the addition H 2 O (10 mL) and extracted with EtOAc (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of above compounds (1.67 mmol, 1.0 equiv) in TFA (3.0 mL) was heated in a sealed tube at 120 ° C for 2 h. After cooled to 25 °C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (20 mL) and H 2 O (5 mL). The mixture was extracted with EtOAc (3 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give amine products.
General procedure for the conversion of fluoride to alkoxy & ketone group
To a solution of starting material (0.05 mmol, 1.0 equiv) in MeOH (0.3 mL) was added sodium methoxide (0.05 mL, 0.22 mmol, 4.0 eq, 25% in methanol) at 25 °C, and the mixture was stirred at 90 °C. After 3 h at 90 °C, the reaction mixture was treated with additional sodium methoxide (0.05 mL, 0.22 mmol, 4.0 eq, 25% in methanol). The reaction mixture was stirred at 63 °C for 15 h, and then quenched with H 2 O (10 mL)and extracted with CH 2 Cl (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of starting material (0.02 mmol, 1.0 equiv) in dry CH 2 Cl (2 niL) was added dropwise BBr 3 (0.2 mmol, 10 equiv) at 0 °C. The resulting solution was stirred at 25 "C for 15 h, and then quenched with saturated aqueous NaHCO 3 (10 mL) solution and extracted with CH 2 Cl (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the demethylation & Mitsunobu reaction
To a 0 °C solution of starting material (1.09 mmol, 1.0 equiv) in CH 2 Cl 2 (50 mL) was added slowly BBr 3 (10.87 mmol, 10.0 equiv) under Ar. The resulting solution was stirred at 0 0 C until complete by TLC (usually < 4 h). The reaction was quenched by the addition of saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (3 x 20 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give demethylated products.
To a 0 0 C solution of the above demethylated compounds (0.08 mmol, 1.0 equiv) and alcohol (0.24 mmol, 3.0 equiv) in CH 2 Cl 2 (2.0 mL) was added PPh 3 (0.624 mmol, 8.0 equiv) and DIAD (0.32 mmol, 4.0 equiv) successively. The resulting suspension was stirred at 25 "C for 12 h, and then quenched by the addition of H 2 O (10 mL) and extracted with CH 2 Cl 2 (3 x 10 mL) and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give ether products.
General procedure for the conversion of bromide to nitrile and hvdrodehalogenation
To a suspension of bromo compounds (0.112 mmol, 1.0 equiv) and sodium acetate (0.224 mmol, 2.0 equiv) in MeOH (5 niL) was added 10% Pd/C (6 mg) at 25 "C. The resulting reaction mixture was stirred under 1 tam of hydrogen at 25 "C for overnight. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give hydrodehalogenated products.
To a suspension of bromo compounds (0.118 mmol, 1.0 equiv) and zinc cyanide (preactived, 0.591 mmol, 5.0 equiv) in anhydrous DMF (400 μL) was added Pd(PPh 3 ) 4 (0.018 mmol, 15 mol%) under Ar at 25 °C. The resulting suspension was heated at 120 °C and stirred until complete by TLC (usually 2 h). After cooled to 25 0 C, the reaction was quenched by the addition of saturated aqueous NaHCO 3 and extracted with EtOAc (3 x ). The combined organic layers were washed with brine and dried over MgSO 4 . After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give nitrile products.
General procedure for the conversion of ester to amide analogs
To a solution of acid (0.075 mmol, 1.0 equiv), BOP (0.11 mmol, 1.5 equiv), and Et 3 N (0.23 mmol, 3 equiv) in DMF (0.5 mL) was added amines (0.15 mmol, 2 equiv) at 25 °C. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with CH 2 Cl 2 (3 x ). The combined organic layers were dried over MgSO 4; filtered and concentrated in vacuo. The resulting residue was purified via flash column chromatography on silica gel.
General procedure for the coupling between subunitl & 2 via click chemistry
A, B, C = CH, N, or N=O
Azide (0.100 mmol, 1.2 equiv) and alkyne (0.082 mmol, 1.0 equiv) were suspended in a 1:1 mixture of water and tert-butyl alcohol (300 μL, 0.25 M). Sodium ascorbate (8.1 μmol, 81 μL of freshly prepared 0.1 M solution in water, 0.1 equiv) was added, followed by copper sulfate pentahydrate (0.2 mg, 0.81 μmol, in 50 μL of water). The heterogeneous mixture was stirred at 25 °C for 2 h and TLC analysis indicated complete consumption of the reactants. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give click adducts.
336 5-Phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin -3-amine (336)
1 U NMR (400 MHz, OMSO-d 6 ) δ 9.27 (d, J= 12 Hz, IH), 8.12 (d, J= 6.8 Hz, 2H), 7.73-7.67 (m, 2H), 7.56 (d, J= 7.2 Hz, 3H), 7.36-7.25 (m, 3H), 6.59 (s, IH), 4.66 (d, J= 21.6 Hz, 2H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.42.
5-(Naphthalen-l-yl)-iV-((5-phenyl-lJH r -pyrazoI-3-yl)inethyl)-l,2,4-triaziii-3-amine (337)
1 H NMR (400 MHz, DMSO-^ 5 ) δ 8.96 (s, IH), 8.24 (s, IH), 8.10 (d, J= 8.0 Hz, IH), 8.01 (d, J= 7.6 Hz, IH), 7.80-7.61 (m, 5H), 7.54-7.27 (m, 4H), 6.61 (s, IH), 4.68 (s, 2H); TLC R f (n- Hexanes:EtOAc 1:1) = 0.40; LRMS (electrospray) m/z calculated for C 23 H 19 N 6 (M+H) + 379.17, found 379.14.
(338)
1 H NMR (400 MHz, DMSO-^ 6 ) δ 13.02 (bs, 0.5H), 12.7 (bs, 0.5H), 8.81 (s, IH), 8.16 (bs, IH), 7.69 (d, J= 13.6 Hz, 2H), 7.44 (d, J= 7.6 Hz, IH), 7.36 (s, 2H), 7.25 (s, IH), 7.13 (s, IH), 6.55 (s, IH), 4.61 (s, 2H), 2.35 (s, 3H), 2.30 (s, 3H); TLC i?/(n-Hexanes:EtOAc 3:7) = 0.53.
1 H NMR (400 MHz, DMSO-^) δ 13.03 (s, 0.5H), 12.76 (s, 0.5H), 8.83 (d, J= 10.4 Hz, IH), 8.24 (bs, IH), 7.69 (d, J= 16.8 Hz, 2H), 7.51 (d, J= 6.8 Hz, IH), 7.48-7.25 (m, 6H), 6.54 (d, J= 16.8 Hz, IH), 4.62 (s, 2H), 2.42 (s, 3H); TLC ^/(CH 2 Cl 2 : MeOH 9:1) = 0.45.
5-(6-Methoxynaphthalen-2-yl)-λ'-((5-phenyl-liϊ-pyrazol- 3-yl)methyl)-l,2,4-triazin-3- amine (340)
1 H NMR (400 MHz, CDCl 3 ) δ 11.12 (bs, IH) 9.62 (s, IH), 8.71 (s, IH), 8.28 (dd, J= 8.6, 1.8 Hz, IH), 7.96 (dd, J= 8.6, 5.8 Hz, 2H), 7.84 (bs, 2H), 7.46 (t, J= 7.4 Hz, 2H), 7.38-7.26 (m, 4H), 6.73 (s, IH), 5.36 (d, J= 5.6 Hz, 2H), 4.04 (s, 3H); TLC ^/(CH 2 Cl 2 : MeOH 9:1) = 0.56.
(m, 4H), 6.73 (s, IH), 5.36 (d, J= 5.6 Hz, 2H), 4.04 (s, 3H); TLC R/ (CH 2 Cl 2 :MeOH 9:1) = 0.56.
5-(4-ChlorophenyI)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)- l,2,4-triazin-3-ainine (341)
1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, IH), 8.01 (d, J= 8.0 Hz, 2H), 7.63 (d, J= 7.6 Hz, 2H) , 7.55 (d, J= 7.2 Hz, 2H), 7.45 (t, J= 7.8 Hz, 2H), 7.37 ( t, J= 7.4 Hz, IH), 6.54 (s, IH), 4.83 (d, J= 4.8 Hz, 2H); TLC .fy(Hexanes:EtOAc 1 :2) = 0.22; LRMS (electrospray) m/z calculated for C 19 H 16 ClN 6 (M+H) + 363.11, found 363.09.
5-(4-Bromophenyl)-λ / -((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (342)
1 U NMR (400 MHz, DMSOd 6 ) δ 12.96 (bs, IH), 9.30 (s, IH), 8.28 (bs, IH), 8.17 (d, J= 8.0 Hz, 2H), 7.77 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 7.6 Hz, 2H), 7.37 (t, J= 7.0Hz, 2H), 7.27 (m, IH), 6.60 (s, IH), 4.66 (s, 2H); TLC ^(w-HexanesiEtOAc 3:7) = 0.37.
5-(4-ter^-ButylphenyI)-iV-((5-phenyl-lH-pyrazol-3-yl)meth yl)-l,2,4-triazin[-3-amine (343)
1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (s, IH), 7.99 (d, J= 7.6 Hz, 2H), 7.66 (d, J= 7.6 Hz, 2H), 7.49 (d, J= 7.6 Hz, 2H), 7.34 (t, J= 7.2 Hz, 2H), 7.27 (d, J= 7.6 Hz, IH), 6.54 (s, IH), 4.84 (d, J= 5.2 Hz, 2H), 1.33 (s,9H); TLC i?/(Hexanes:EtOAc 1:2) = 0.27; LRMS (electrospray) m/z calculated for C 23 H 25 N 6 (MH-H) + 385.21, found 385.19.
1 H NMR (400 MHz, CDCl 3 ) δ 11.12 (bs, IH) 9.57 (s, IH), 8.69 (s,lH), 8.23 (dd, J= 8.4, 1.6 Hz, IH), 7.99 (dd, J= 11.4, 8.2 Hz, 2H), 7.90 (d, J= 7.6 Hz, IH), 7.75 (bs, IH), 7.60 (m, 2H), 7.37 (t, J= 7.8 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 6.64 (s, IH), 5.29 (d, J= 3.6 Hz, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.52.
5-(4-Ethylphenyl)-λ r -((5-phenyl-l J H r -pyrazol-3-yl)methyI)-l,2,4-triazin-3-amine (345)
1 H NMR(400MHz, DMSO-J 6 ) δ 13.00 (bs, 0.5H), 12.81 (bs, 0.5H), 9.23 (s, IH), 8.12 (d, J = 8.0 Hz, 3H), 7.69 (d, J= 6.8 Hz, 2H), 7.36 (dd, J= 12.8, 8.0 Hz, 4H), 7.25 (d, J- 6.4Hz, IH), 6.57 (s, IH), 4.64 (s, 2H), 2.65 (q, J= 8.0 Hz, 2H), 1.18 (t, J= 7.8 Hz, 3H); TLC R f (n- Hexanes:EtOAc 3:7) = 0.36.
1 H NMR (400 MHz, DMSO-<4) δ 9.22 (d, J= 13.6 Hz, IH), 8.09 (d, J= 8.0 Hz, 2H), 7.71- 7.63 (m, 2H), 7.36-6.56 (m, 5H), 6.56 (s, IH), 4.65 (d, J= 21.2 Hz, 2H), 2.35 (s, 3H); LRMS (electrospray) m/z calculated for C 20 H 19 N 6 (M+H) + 343.17, found 343.16.
1 H NMR (400 MHz, DMSO-c/ δ ) δ 8.75 (s, IH), 7.90 (d, J= 7.6 Hz, IH), 7.82-7.63 (m, 5H), 7.36-7.25 (m, 3H), 6.53 (s, IH), 4.60 (s, 3H); LRMS (electrospray) m/z calculated for C 20 Hi 6 F 3 N 6 (M+H) + 397.14, found 397.16.
5-(2-FluorophenyI)- J /V-((5-phenyl-lH r -pyrazol-3-yl)inethyl)-l,2,4-triazin-3-ainine (348)
1 U NMR (400 MHz, DMSO-J 6 ) δ 13.05 (s, 0.5H), 12.82 (s, 0.5H), 9.03 (s, IH), 8.07 (s, IH), 7.73-7.62 (m, 3H), 7.44-7.28 (m, 5H), 6.62 (s, IH), 4.67 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.21.
349
5-(2-(Benzyloxy)phenyl)-iV-((5-phenyI-lH-pyrazoI-3-yl)met hyl)-l,2,4-triaziii-3-amine (349)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.09 (s, IH), 7.87 (s, IH), 7.68 (d, J= 6.8 Hz, 2H), 7.52- 7.26 (m, 9H), 7.09 (t, J= 7.6Hz, IH), 6.56 (s, IH), 5.23 (s, 2H), 4.60 (s, 2H).
5-(Naphthalen-l-yl)-λ'-((5-/7-tolyl-lH-pyrazol-3-yl)meth yI)-l,2,4-triazin-3-amine (350)
1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, IH), 8.21 (d, J =7.6 Hz, IH), 7.98-7.89 (m, 2H), 7.68- 7.45 (m, 6H), 7.10 (d, J=7.2 Hz, 3H), 4.82 (s, 2H), 2.31 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.23.
5-(2-EthylphenyI)-iV-((5-pheiiyI-liϊ-pyrazoI-3-yI)methyl )-l,2,4-triaziii-3-amiiie (351)
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.77 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.45-7.30 (m, 7H), 6.55 (s, IH), 4.83 (d, J= 5.2 Hz, 2H), 2.81-2.78 (m, 2H), 1.20-1.17 (m, 3H).
7V-((5-(4-Methoxyphenyl)-liϊ-pyrazol-3-yl)methyI)-5-(iia phthalen-l-yl)-l,2,4-triazin-3- amine (352)
1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, IH), 8.20 (d, J= 8.4 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.90-7.88 (m, IH), 7.66 (d, J= 7.2 Hz, IH), 7.53-7.43 (m, 5H), 6.78 (d, J= 8.8 Hz, 2H), 6.42 (s, IH), 4.80 (s, 2H), 3.75 (s, 3H).
5-(3-(Benzyloxy)phenyl)-λ r -((5-phenyl-lJϊ-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amine
(353)
1 H NMR (400 MHz, DMSOd 6 ) δ 13.04 (bs, 0.5H), 12.82 (bs, 0.5H), 9.28 (s, IH), 8.25 (bs, IH), 7.83-7.69 (m, 4H), 7.49-7.22 (m, 10H), 6.66 (s, IH), 5.18 (s, 2H), 4.66 (bs, 2H); TLC R 1 (CH 2 Cl 2 :Me0H 9:1) = 0.64.
5-(Naphthalen-l-yl)-iV-((5-o-tolyl-lH r -pyrazoI-3-yI)methyl)-l,2,4-triazin-3-amine (354)
1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, IH), 8.25 (d, J= 7.2 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.92 (d, J= 8.0 Hz, IH), 7.70 (d, J= 6.8 Hz, IH), 7.57-7.49 (m, 3H), 7.36 (d, J= 7.2 Hz, IH), 7.26-7.18 (m, 3H), 6.42 (s, IH), 4.89 (bs, 2H), 2.04 (s, 3H); TLC #/(«-Hexanes:EtOAc 2:1) = 0.50; LRMS (electrospray) m/z calculated for C 24 H 21 N 6 (M+H) + 393.18, found 393.35.
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.90 (s, IH), 7.70-7.60 (m, 4H), 7.56-7.49 (m, 2H), 7.47- 7.34 (m, 2H), 121-126 (m, IH), 6.57 (s, IH), 4.62 (bs, 2H); LRMS (electrospray) m/z calculated for C 19 Hi 6 ClN 6 (M+H) + 363.11, found 363.16.
1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, IH), 8.22 (d, J= 8.4 Hz, IH), 8.00 (d, J= 8.0 Hz, IH), 7.92 (d, J= 7.6 Hz, IH), 7.75-7.70 (m, 2H), 7.59-7.50 (m, 4H), 7.44-7.24 (m, 3H), 6.58 (s, IH), 4.93 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.64; LRMS (electrospray) m/z calculated for C 23 Hi 8 N 5 O (M+H) + 380.15, found 380.16
5-(2,5-Dimethoxyphenyl)-N-((5-phenyl-liϊ-pyrazol-3-yl)me thyl)-l,2,4-triazin-3-ainine
(357)
1 H NMR (400 MHz, CD 3 OD) δ 9.16 (s, IH), 7.71-7.56 (m, 3H), 7.37-7.29 (m, 3H), 7.10-7.05 (m, 2H), 6.61 (s, IH), 4.73 (bs, 2H), 3.88 (s, 3H), 3.72 (s, 3H); LRMS (electrospray) m/z calculated for C 21 H 21 N 6 O 2 (M+H) + 389.17, found 389.20.
5-(2-Methoxyphenyl)-N-((5-phenyl-l J H r -pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (358)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.08 (s, IH), 7.88-7.86 (m, IH), 7.69-7.68 (m, 2H), 7.51 (t, J= 7.8 Hz, IH), 7.37-7.33 (m, 2H), 7.27-7.25 (m, IH), 7.18 (d, J= 8.4 Hz, IH), 7.08 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.61 (bs, 2H), 3.87 (s, 3H); LRMS (electrospray) m/z calculated for C 20 H 19 N 6 O (M+H) + 359.16, found 359.28.
5-(2,5-Dimethylphenyl)-7V-((5-phenyl-liϊ-pyrazol-3-yl)me thyI)-l,2,4-triazin-3-amiiie
(359)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.81 (s, IH), 7.70-7.69 (m, 2H), 7.38-7.32 (m, 3H), 7.27- 7.24 (m, IH), 7.20-7.15 (m, 2H), 6.56 (s, IH), 4.59 (bs, 2H), 2.28 (s, 3H), 2. 24 (s, 3H); LRMS (electrospray) m/z calculated for C 21 H 21 N 6 (M+H) + 357.18, found 357.10.
N-((5-Phenyl-lJϊ-pyrazol-3-yl)methyl)-5-(3-(trifluoromet hyl)phenyl)-l,2,4-triaziii-3- amine (360)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.06 (s, 0.5H), 12.81 (s, 0.5H), 9.43 (s, IH), 8.59 (s, 2H), 7.98 (d, J= 7.6 Hz, IH), 7.82 (t, J= 7.8 Hz, IH), 7.71 (m, 2H), 7.38 (m, 2H), 7.28 (m, IH), 6.62 (s, IH), 4.69 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.23.
5-(2-Isopropylphenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methyl )-l,2,4-triazin-3-amine (361)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.05 (s, 0.5H), 12.78 (s, 0.5H), 8.76 (s, IH), 7.72 (s, 2H), 7.49 (d, J= 4.0 Hz, 2H), 7.39-7.29 (m, 5H), 6.56 (s, IH), 4.62 (s, IH), 3.25-3.19 (m, IH), 1.10 (m, 6H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) == 0.23.
5-(3-Methoxyphenyl)-iV-((5-phenyl-lf- r -pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine (362)
1 U NMR (400 MHz, OMSO-d 6 ) δ 9.27 (s, IH), 7.77 (d, J= 8.0 Hz, lH),7.70-7.68 (m, 3H), 7.45 (t, J= 7.8 Hz, IH), 7.37-7.33 (m, 2H), 7.26-7.25 (m, IH), 7.14 (d, J= 8.0 Hz, IH ), 6.58 (s, IH), 4.63 (bs, 2H). 3.80 (s, 3H); LRMS (electrospray) m/z calculated for C 20 H 19 N 6 O (M+H) + 359.16, found 359.21.
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.05 (s, 0.5H), 12.82 (s, 0.5H), 9.27 (s, IH), 8.04 (s, IH), 8.01 (d, J= 7.2 Hz, IH), 7.72 (m, 2H), 7.47-7.38 (m, 5H), 7.28 (m, IH), 6.62 (s, IH), 4.68 (s, 2H), 2.35 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.22.
5-(3-Chlorophenyl)-λ r -((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (364)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.06 (s, 0.5H), 12.83 (s, 0.5H), 9.34 (s, IH), 8.26 (s, IH), 8.19 (d, J= 7.6 Hz, IH), 7.72-7.58 (m, 4H), 7.38-7.28 (m, 3H), 6.62 (s, IH), 4.68 (s, 2H); TLC 22/-(CH 2 Cl 2 MeOH 20:1) = 0.25.
5-(2-Chlorophenyl)-7V-((5-(4-methoxyphenyl)-lH-pyrazol-3- yl)methyl)-l,2,4-triazin-3- amine (365)
1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, IH), 7.62 (d, J= 7.6 Hz, IH), 7.55 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.0 Hz, IH), 7.45-7.37 (m, 2H), 6.92 (d, J= 7.2 Hz, 2H), 6.47 (s, IH), 4.80 (bs, 2H), 3.81 (s, 3H); LRMS (electrospray) m/z calculated for C 20 H 18 ClN 6 O (M+H) + 393.12, found 393.14.
5-(2-BromophenyI)-7V-((5-phenyl-ljEr-pyrazol-3-yl)methyl) -l,2,4-triazin-3-amine (366)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.01 (s, 0.5H), 12.81 (s, 0.5H), 8.82 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.67-7.65 (m, 2H), 7.56-7.54 (m, IH), 7.50 (t, J= 7.4 Hz, IH), 7.45-7.40 (m, IH), 7.37-7.33 (m, 2H), 7.24 (t, J= 7.2 Hz, IH), 6.55 (s, IH), 4.60 (s, 2H); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.38.
5-(2,6-DimethyIphenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methy l)-l,2,4-triazin-3-amine
(367)
1 H NMR (400 MHz, DMSO-J 6 ) δ 12.92 (s, IH), 8.60 (s, IH), 7.69 (d, J= 7.2 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.30-7.23 (m, 2H), 7.13 (d, J= 7.6 Hz, 2H), 6.54 (s, IH), 4.60 (s, 2H), 2.01 (s, 6H) ; TLC ^(CH 2 Cl 2 MeOH 20:1) = 0.24.
5-(2-Methoxyphenyl)-iV-((5-(4-methoxyphenyl)-ljy r -pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (368)
1 H NMR (400 MHz, DMSO-J 6 ) δ 12.88 (s, 0.5H), 12.71 (s, 0.5H), 9.68 (s, IH), 8.02 (dd, J = 7.8, 1.8 Hz), IH), 7.61 (m, 3H), 7.27 (d, J = 8.4 Hz, IH), 7.16 (t, J = 7.4 Hz, IH), 6.95 (bs, 2H), 6.44 (s, IH), 5.15 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H); TLC /J 7 (CH 2 Cl 2 :MeOH 9:1) = 0.43.
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.48 (s, 0.5H), 12.84 (s, 0.5H), 8.76 (s, IH), 7.92 (d, J = 7.6 Hz, IH), 7.84-7.75 (m, 2H), 7.66-7.60 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 6.44 (s, IH), 4.60 (s, 2H), 3.75 (s, 3H) ; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.28.
1 H NMR (400 MHz, DMSO-^ 6 ) δ 12.99 (bs, 0.5H), 12.81 (bs, 0.5H), 9.25 (s, IH), 8.22 (bs, IH), 8.03 (s, IH), 8.00 (d, J= 7.2 Hz, IH), 7.69 (d, J= 6.8 Hz, 2H), 7.43 (m, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.25 (t, J= 6.8 Hz 5 IH), 6.58 (s, IH), 4.64 (s, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.26.
4-(3-((5-(Naphthalen-l-yI)-l,2,4-triazin-3-ylamino)methyl )-lH-pyrazol-5-yl)benzamide
(371)
1 H NMR (400 MHz, CD 3 OD) δ 8.92 (s, IH), 8.32 (s, IH), 8.08 (d, J= 7.2 Hz, IH), 7.95-7.76 (m, 6H), 7.58 (s, IH), 7.47-7.27 (m, 2H), 6.78 (s, IH); TLC i?/(«-Hexanes: EtOAc 1:1) = 0.09; LC/MS (EI) m/z calcd for C 24 H 20 N 7 O (M+H) + 422.45, found 422.11
4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl )-liϊ-pyrazol-5-yl)benzoic acid
(372)
1 H NMR (400 MHz, CD 3 OD) δ 8.84 (s, IH), 8.19 (s, IH), 8.01 (d, J= 6.8 Hz, 3H), 8.91 (d, J
= 6.4 Hz, IH), 7.79-7.74 (m, 3H), 7.56-7.48 (m, 3H), 6.71 (s, IH), 4.55 (s, 2H); TLC R f
(CH 2 Cl 2 MeOH 10:1) = 0.21; LC/MS (EI) m/z calcd for C 24 H 19 N 6 O 2 (M+H) + 423.44, found
423.13
N-((5-(4-Bromophenyl)-lH-pyrazol-3-yI)methyl)-5-(naphthaI en-l-yl)-l,2,4-triazin-3- amine (373)
1 H NMR (400 MHz DMSO-fifc) δ 8.93 (s, IH), 8.20 (s, 2H), 8.08 (d, J= 8.0 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.78-7.54 (m, 6H), 6.62 (s, IH), 4.62 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1:1) = 0.03.
5-(Biphenyl-2-yl)-7V-((5-phenyl-ljH r -pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (374) 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.00 (s, 0.5H), 12.75 (s, 0.5H), 7.99 (s, IH), 7.71-7.69 (m, 3H), 7.60 (t, J= 7.6 Hz, IH), 7.53 (t, J= 7.4 Hz, IH), 7.46 (d, J= 7.6 Hz, IH), 7.38-7.26 (m, 6H), 6.52 (s, IH), 4.48 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.34.
5-(2,3-Dimethylphenyl)-λ r -((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine
(375)
1 R NMR (400 MHz, OMSO-d 6 ) δ 8.73 (s, IH), 7.69 (d, J= 6.4 Hz, 2H), 7.38-7.17 (m, 6H),
6.56 (s, IH), 4.59 (bs, 2H), 2.33 (s, 3H), 2.18 (s, 3H); TLC .Sy(CH 2 Cl 2 =MeOH 10:1) = 0.49.
4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl )-lλT-pyrazol-5-yl)benzonitrile
(376)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.94 (s, IH), 8.09 (s, IH), 8.07-8.00 (m, IH), 7.98-7.92 (m, 4H), 7.81-7.76 (m, 3H), 7.63-7.59 (m, IH), 7.52 (s, IH), 6.76 (s, IH), 4.65 (s, 2H); TLC R f {n- Hexanes:EtOAc 1:1) = 0.05; LC/MS (EI) m/z calcd for C 24 H 18 N 7 (M+H) + 404.44, found 404.09.
377 5-(2-Phenoxyphenyl)-iV-((5-phenyl-lH;-pyrazol-3-yl)methyl)-l ,2,4-triaziii-3-amine (377)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.06 (s, 0.5H), 12.79 (s, 0.5H), 9.06 (s, IH), 8.00 (d, J = 6.0 Hz, IH), 7.72 (s, 2H), 7.57 (t, J= 7.0 Hz, IH), 7.40-7.33 (m, 6H), 7.29 (br, 2H), 7.14 (t, J = 7.4 Hz, IH), 7.06-7.00 (m, 3H), 6.58 (s, IH), 4.62 (s, 2H) ; TLC 22/(CH 2 Cl 2 MeOH 20:1) = 0.33.
5-(2,3-Dimethoxyphenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)met hyl)-l,2,4-triaziii-3-amine
(378)
1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, IH), 7.69 (d, J= 7.6 Hz, 2H), 7.38-7.34 (m, 3H), 7.27- 7.17 (m, 3H), 6.57 (s, IH), 4.61 (bs, 2H), 3.80 (s, 3H), 3.70 (s, 3H); TLC 2?/(CH 2 Cl 2 :Me0H 10:1) = 0.53.
379 iV-((5-(3-Methoxyphenyl)-lH-pyrazol-3-yI)methyl)-5-(naphthal en-l-yl)-l,2,4-triazin-3- amine (379)
1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, IH), 8.19 (d, J= 8.4 Hz, IH), 7.95 (d, J= 8.4 Hz, IH), 7.89 ( t, J= 7.6 Hz, IH), 7.65 (d, J= 6.8 Hz, IH), 7.52-7.43 (m, 3H), 7.24-7.18 (m, 3H), 6.82- 6.79 (m, IH), 6.49 (s, IH), 4.79 (s, 2H), 3.76 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.12.
5-(Biphenyl-4-yl)-iV-((5-phenyl-l J fir-pyrazoI-3-yl)methyl)-l,2,4-triazin-3-amine (380)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.06 (s, 0.5H), 12.84 (s, 0.5H), 9.35 (s, IH), 8.33 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.78-7.72 (m, 4H), 7.51 (t, J= 7.6 Hz, 2H), 7.44-7.37 (m, 3H), 7.29-7.27 (m, IH), 6.63 (s, IH), 4.70 (s, 2H); TLC ^/(CH 2 Cl 2 :MeOH 20:1) = 0.31.
5-(4-FIuorophenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methyl)-l ,2,4-triazin-3-amine (381)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.26 (s, IH), 8.29-8.25 (m, 2H), 7.78-7.68 (m, 2H), 7.40- 7.35 (m, 4H), 7.30-7.34 (m, IH), 6.57 (s, IH), 4.64 (bs, 2H).
1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, IH), 8.26 (d, J= 7.6 Hz, IH), 7.97 (d, J= 8.4 Hz, IH), 7.90 ( t, J= 7.2 Hz, IH), 7.70 (d, J= 6.8 Hz, IH), 7.61-7.48 (m, 4H), 7.29-7.24 (m, IH), 7.01- 6.96 (m, 2H), 6.64 (s, IH), 4.86 (s, 2H), 3.93 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.13.
5-(Biphenyl-3-yl)-λ'-((5-phenyl-lH-pyrazol-3-yI)methyl)- l,2,4-triaziii-3-amme (383)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.03 (s, 0.5H), 12.84 (s, 0.5H), 9.42 (s, IH), 8.46 (s, IH), 8.21 (d, J= 7.6 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 7.77-7.64 (m, 5H), 7.49 (t, J= 7.4 Hz, 2H),
7.43-7.36 (m, 3H), 7.27 (m, IH), 6.63 (s, IH), 4.69 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) : 0.34.
5-(2-Cyclohexylphenyl)-iV-((5-phenyl-ljH r -pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine
(384)
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.70 (s, IH), 7.61 (d, J= 6.8 Hz, 2H), 7.44 (s, IH), 7.35- 7.25 (m, 5H), 6.53 (s, IH), 4.84 (s, 2H), 2.84 (s, IH), 2.03-1.68 (m, 5H), 1.47 (d, J= 10.0 Hz, 2H), 1.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.49.
5-o-tolyl-N-((3-p-tolyI-lH-pyrazol-5-yl)methyl)-l,2,4-tri azin-3-amine (385)
1 H NMR (400 MHz, CDCl 3 ) δ 8.73 (s, IH), 7.51-7.45 (m,3H), 7.37-7.24 (m, 3H), 7.13 (d, J =7.6 Hz, 2H), 4.80 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H); TLC i?/(Hexanes: EtOAc 1:1) = 0.19.
7V-((5-PhenyI-lH-pyrazol-3-yI)methyI)-5-(3-(trifluorometh oxy)phenyI)-l,2,4-triaziii-3- amine (386)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.32 (s, IH), 8.23 (d, J= 7.6 Hz, IH), 7.14 (s, IH), 7.70- 7.60 (m, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.34 (s, 2H), 7.24 (s, IH), 6.57 (s, IH), 4.64 (s, 2H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.25.
387
5-(3-FIuorophenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)- l,2,4-triazin-3-amine (387)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.04 (bs, 0.5H), 12.79 (bs, 0.5H), 9.30 (s, IH), 8.30 (bs, IH), 8.06 (d, J= 7.6 Hz, IH), 8.01 (d, J= 10.0 Hz, IH), 7.69 (bs, 2H), 7.59 (q, J= 8.0 Hz, IH), 7.42 (dt, J= 8.4, 2.0 Hz, IH), 7.35 (bs, 2H), 7.25 (bs, IH), 6.58 (s, IH), 4.65 (bs, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.18.
5-(4-(Benzyloxy)phenyl)-7V-((5-phenyl-lH-pyrazol-3-yI)met hyl)-l,2,4-triazin-3-amine
(388)
1 H NMR (400 MHz, DMSO-^) δ 9.21 (s, IH), 8.19 (d, J= 8.8 Hz, 3H), 7.68 (s, 2H), 7.45- 7.31 (m, 8H), 7.16 (d, J= 8.8 Hz, IH), 6.57 (s, IH), 5.19 (s, 2H), 4.63 (s, 2H).
5-(4-Methoxyphenyl)-7V-((5-phenyl-li7-pyrazol-3-yl)methyl )-l,2,4-triazin-3-ainine (389)
1 H NMR (400 MHz, OMSO-d 6 ) δ 9.20 (s, IH), 8.18 (d, J= 9.2 Hz, 2H), 7.68 (s, 2H), 7.34 (s, 2H), 7.24 (s, IH), 7.07 (d, J= 8.8 Hz, 2H), 6.57 (s, IH), 4.62 (s, 2H), 3.81 (s, 3H).
7V-((5-Phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3-amine (390)
1 H NMR (400 MHz, CD 3 OD) δ 7.67 (d, J= 7.2 Hz, 2H ), 7.53-7.50 (m, 2H), 7.38-7.33 (m, 4H), 7.29-7.23 (m, 2H), 7.16 (t, J= 7.8 Hz, IH), 6.93-6.92 (m, IH), 6.87-6.85 (m, IH), 6.69- 6.66 (m, IH), 6.59 (s, IH), 4.39 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.21.
2'-Methyl-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3 -ainine (391)
1 H NMR (400 MHz, CD 3 OD) δ 7.66 (d, J= 7.6 Hz, 2H), 7.36 (t, J= 7.4 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 7.16-7.11 (m, 5H), 6.67 (d, J= 8.0 Hz, IH), 6.59-6.53 (m, 3H), 4.36 (s, 2H), 2.14 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.34; LRMS (electrospray) m/z calculated for C 23 H 22 N 3 (M+H) + 340.18, found 340.17.
J /V-((5-PhenyI-l/- r -pyrazoI-3-yl)methyl)-2'-(trifluoromethyl)biphenyl-3-amine (392)
1 H NMR (400 MHz, CD 3 OD) δ 7.70-7.66 (m, 3H), 7.55 (t, J= 7.4 Hz, IH), 7.46 (t, J= 7.4 Hz, IH), 7.39-7.35 (m, 2H), 7.31-7.29 (m, 2H), 7.13 (t, J= 7.8 Hz, IH), 6.72 (d, J= 8.0 Hz, IH), 6.62 (s, IH), 6.57-6.55 (m, 2H), 4.35 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.36; LRMS (electrospray) m/z calculated for C 23 Hi 9 F 3 N 3 (M+H) + 394.15, found 394.09.
2'-Methoxy-λ r -((5-phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3-amine (393)
1 H NMR (400 MHz, CD 3 OD) δ 7.64 (d, J= 8.0 Hz, 2H), 7.33 (t, J= 7.6 Hz, 2H), 7.26-7.18 (m, 3H), 7.10 (t, J= 7.8 Hz, IH), 6.94-6.88 (m, 2H), 6.81 (s, IH), 6.73 (d, J= 7.2 Hz, IH), 6.64-6.61 (m, IH), 6.54 (s, IH), 4.32 (s, 2H), 3.63 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.29; LRMS (electrospray) m/z calculated for C 23 H 22 N 3 O (M+H) + 356.18, found 356.15.
2'-Chloro-7V-((5-phenyl-ljfir-pyrazoI-3-yI)inethyl)biphen yl-3-amiiie (394)
1 H NMR (400 MHz, CD 3 OD) δ 7.63 (d, J= 8.4 Hz, 2H), 7.37-7.31 (m, 3H), 7.26-7.18 (m, 4H), 7.12 (d, J= 7.0 Hz, IH), 6.68-6.65 (m, 2H), 6.60 (dd, J= 6.0, 1.2 Hz, IH), 6.54 (s, IH), 4.32 (s, 2H); TLC i?/(n-Hexanes: EtOAc 2:1) = 0.32; LRMS (electrospray) m/z calculated for C 22 H 19 ClN 3 (M+H) + 360.13, found 360.03.
395 4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl)-l Z- r -pyrazol-5-yl)phenol (395)
1 U NMR (400 MHz, CD 3 OD) δ 8.86 (s, IH), 8.22 (bs, IH), 8.04 (d, J= 8.0 Hz 5 IH), 7.94 (d, J= 8.4 Hz, IH), 7.76 (d, J= 7.2 Hz, IH), 7.59 (t, J= 7.2 Hz, IH), 7.51 (m, 3H), 7.45 (bs, IH), 6.80 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 5.06 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.47.
3-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamiiio)methy l)-lZr-pyrazol-5-yl)phenoI (396)
1 H NMR (400 MHz, CD 3 OD) δ 8.86 (s, IH), 8.20 (bs, IH), 8.03 (d, J= 8.0 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 7.76 (d, J= 6.8 Hz, IH), 7.58 (t, J= 7.8 Hz, IH), 7.50 (t, J= 7.2 Hz, IH), 7.43 (bs, IH), 7.18 (m, 3H), 6.74 (dd, J= 9.0, 2.2 Hz, IH), 6.57 (s, IH), 4.90 (s, 2H); TLC R 1 (CH 2 Cl 2 MeOH 9:1) = 0.46.
1 U NMR (400 MHz, CD 3 OD) δ 8.87 (s, IH), 8.18 (bs, IH), 8.03 (d, J= 8.4 Hz, IH), 7.93 (d, J= 8.0 Hz, IH), 7.76 (d, J= 6.4 Hz, IH), 7.58 (t, J= 7.8 Hz, 2H), 7.49 (m, IH), 7.42 (bs, 2H), 7.14 (m, IH), 6.87 (m, 2H), 6.71 (s, IH), 5.18 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.67.
2-(3-((5-Phenyl-lH-pyrazol-3-yl)methylamino)-l,2,4-triazi n-5-yI)phenol (398)
1 H NMR (400 MHz, CD 3 OD) δ 9.27 (s, IH), 8.03 (dd, J= 8.0, 1.6 Hz, IH), 7.68 (d, J= 7.6 Hz, 2H), 7.40 (m, 3H), 7.29 (t, J= 7.4 Hz, IH), 6.97 (t, J= 8.8 Hz, 2H), 6.64 (s, IH), 5.18 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.63.
5-(4-Fluorophenyl)-λ r -((5-phenyl-lJϊ-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (399)
1 H NMR (400 MHz, DMSO-cfe) δ 9.26 (s, IH), 8.29-8.25 (m, 2H), 7.78-7.68 (m, 2H), 7.40- 7.35 (m, 4H), 7.30-7.34 (m, IH), 6.57 (s, IH), 4.64 (bs, 2H).
5-(Biphenyl-4-yl)-7V-((5-phenyl-lH r -pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine (400)
1 U NMR (400 MHz, DMSO-J 6 ) δ 13.06 (s, 0.5H), 12.84 (s, 0.5H), 9.35 (s, IH), 8.33 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.78-7.72 (m, 4H), 7.51 (t, J= 7.6 Hz, 2H), 7.44-7.37 (m, 3H), 7.29-7.27 (m, IH), 6.63 (s, IH), 4.70 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.31.
5-(BiphenyI-3-yl)-7V-((5-phenyl-ljH r -pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (401)
1 H NMR (400 MHz, DMSO-^ 6 ) δ 13.03 (s, 0.5H), 12.84 (s, 0.5H), 9.42 (s, IH), 8.46 (s, IH), 8.21 (d, J= 7.6 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 7.77-7.64 (m, 5H), 7.49 (t, J= 7.4 Hz, 2H), 7.43-7.36 (m, 3H), 7.27 (m, IH), 6.63 (s, IH), 4.69 (s, 2H); TLC ^/(CH 2 Cl 2 :MeOH 20:1) = 0.34.
N-((lH r -pyrazol-3-yl)methyl)-5-(naphthaIen-l-yI)-l,2,4-triazin-3-am ine (402)
1 H NMR (400 MHz, CD 3 OD) δ 8.86 (s, IH), 8.24-8.23 (m, IH), 8.05 (d, J= 8.0 Hz, IH), 7.96 (d, J= 7.6 Hz, IH), 7.77 (d, J= 7.2 Hz, IH), 7.66-7.50 (m, 4H), 6.32 (bs, IH), 4.74 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.55.
403
7V-((lH r -pyrazol-3-yl)methyI)-5-(2-chIorophenyl)-l,2,4-triazin-3-ami ne (403)
1 H NMR (400 MHz, CD 3 OD) δ 8.90 (s, IH), 7.68 (d, J= 6.0 Hz, IH), 7.58-7.47 (m, 4H), 6.31 (bs, IH), 4.74 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1:2) = 0.10.
(4-(3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl )-ll/-pyrazoϊ-5- yl)phenyl)(morpholino)methanone (404)
1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, IH), 7.64 (d, J= 8.4 Hz, 2H), 7.53 (dd, J= 7.6, 1.6 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 7.40 (td, J- 7.6, 1.6 Hz, IH), 7.34 (m, 3H), 6.50 (bs, IH), 5.05 (bs, 2H), 3.69 (bs, 6H), 3.46 (bs, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.17.
405
5-(2-Ethoxyphenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)- l,2,4-triazin-3-amiiie (405)
1 H NMR (400 MHz, CD 3 OD) δ 9.71 (s, IH), 8.09 (dd, J= 8.0, 1.6 Hz, IH), 7.62 (bs, 2H), 7.50 (m, IH), 7.35 (t, J= 7.6 Hz, IH), 7.26 (t, J= 7.2 Hz, IH), 7.12 (d, J= 8.4 Hz, IH), 7.06 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 5.23 (s, 2H), 4.19 (q, J= 6.8 Hz, 2H), 1.45 (t, J= 7.0 Hz, 3H); TLC £/(CH 2 Cl 2 :Me0H 19:1) = 0.22.
406
5-(2-Isopropoxyphenyl)-N-((5-phenyl-lH-pyrazol-3-yl)methy l)-l,2,4-triazin-3-amine (406)
1 H NMR (400 MHz, CD 3 OD) δ 9.72 (s, IH), 8.08 (dd, J= 7.8, 1.8 Hz, IH), 7.62 (bs, 2H), 7.53 (m, IH), 7.36 (t, J= 6.8 Hz, 2H), 7.29 (m, IH), 7.18 (d, J= 8.4 Hz, IH), 7.07 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.77 (m, IH), 1.38 (d, J= 6.0 Hz, 6H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.29.
7V-((lH-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl )-l,2,4-triazin-3-amine (407)
1 H NMR (400 MHz, CD 3 OD) δ 8.41 (s, IH), 7.61 (d, J= 6.8 Hz, IH), 7.53-7.45 (m, 2H), 7.34 (d, J= 7.2 Hz, IH), 7.28-7.27 (m, IH), 6.01 (bs, IH), 4.44 (s, 2H); TLC T^(CH 2 Cl 2 : MeOH 5:1) = 0.53.
N-((5-Phenyl-lJy-pyrazol-3-yl)methyl)-5-(2-(trifluorometh oxy)phenyl)-l,2,4-triazin-3- amine (408)
1 H NMR (400 MHz, DMSO-^ 6 ) δ 13.07 (s, 0.5H), 12.82 (s, 0.5H), 8.93 (s, IH), 7.92 (s, J= 7.2 Hz, IH), 7.74-7.67 (m, 3H), 7.62-7.53 (m, 2H), 7.39 (m, 2H), 7.29 (m, IH), 6.60 (s, IH), 4.66 (s, 2H) ; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.31.
409
5-(2-(Difluoromethoxy)phenyl)-iV-((5-phenyl-lJir-pyrazol- 3-yl)methyl)-l,2,4-triazin-3- amine (409)
1 H NMR (400 MHz, DMSO-^) δ 8.94 (s, IH), 7.87 (d, J= 7.6 Hz, IH ), 7.70-7.60 (m, 3H), 7.46-7.25 (m, 6H), 6.57 (s, IH), 4.62 (bs, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.51.
5-(2,3-Dihydrobenzofuran-7-yl)-iV-((5-phenyl-lH-pyrazol-3 -yl)methyl)-l,2,4-triaziii-3- amine (410)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.01 (s, 0.5H), 12.87 (s, 0.5H), 9.23 (s, IH), 7.95 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.2 Hz, 2H), 7.41 (d, J= 7.2 Hz, IH), 7.36 (t, J= 7.6 Hz, 2H), 7.28- 7.25 (m, IH), 6.98 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.68 (t, J= 8.8 Hz, 2H), 4.63 (s, 2H), 3.21 (t, J= 8.8 Hz, 2H) ; TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.30.
411
5-(Chroman-8-yl)-iV-((5-phenyI-lH r -pyrazol-3-yI)methyI)-l,2,4-triazin-3-amine (411)
1 H NMR (400 MHz, DMSO-^ 6 ) δ 9.05 (s, IH), 7.67-7.66 (m, 3H), 7.34-7.32 (m, 2H), 7.25- 7.20 (m, 2H), 6.92 (t, J= 7.6 Hz, IH), 6.54 (s, IH) 5 4.59 (bs, 2H), 4.23 (t, J= 5.2 Hz, 2H) 5 2.78 (t, J= 6.2 Hz, 2H), 1.95-1.90 (m, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.39; LRMS (electrospray) m/z calculated for C 22 H 2 !N 6 0(M+H) + 385.18, found 385.12.
5-(2,3-Dihydro-lH r -inden-4-yl)-λ^-((5-phenyl-lJ5 r -pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (412)
1 H NMR (400 MHz, CD 3 OD) δ 8.87 (s, IH), 7.64 (m, 3H), 7.35 (m, 3H), 7.25 (m, 2H), 6.58 (s, IH) 5 4.73 (s, 2H), 3.13 (m, 2H), 2.89 (t, J= 7.4 Hz, 2H) 5 1.99 (t, J= 7.4 Hz, 2H), 1.26 (m, 2H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.19.
1 H NMR (400 MHz, CD 3 OD) δ 8.63 (s, IH), 7.66 (d, J= 7.6 Hz, 2H) 5 7.36 (t, J= 7.4 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 7.19 (m, 3H), 6.57 (s, IH), 4.69 (s, 2H), 2.78 (t, J= 6.4 Hz, 2H), 2.68 (bs, IH), 1.72 (m, 2H), 1.61 (bs, 2H), 1.28 (m, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.20.
414
5-(Benzo[<^[l,3]dioxol-4-yl)-N-((5-phenyl-lJSr-pyrazol -3-yl)methyI)-l,2,4-triazin-3-amme (414)
1 H NMR (400 MHz, DMSO-^) δ 9.13 (s, IH), 7.80-7.60 (m, 3H), 7.35-7.30 (m, 2H), 7.29- 7.24 (m, IH), 7.10 (d, J= 7.2 Hz, IH), 6.99 (t, J= 7.8 Hz, IH), 6.57 (s, IH), 6.19 (s, 2H), 4.62 (bs, 2H); TLC £/ (CH 2 Cl 2 : MeOH 10:1) = 0.42.
5-(2,3-Dihydrobenzo[A][l,4]dioxin-5-yl)-iV-((5-phenyl-l J H r -pyrazol-3-yI)methyl)-l,2,4- triazin-3-amine (415)
1 H NMR (400 MHz, DMSO-^) δ 9.07 (s, IH), 7.68-7.66 (m, 2H), 7.41-7.25 (m, 4H), 7.02 (dd, J= 8.0, 1.6 Hz, IH), 6.94 (t, J= 7.8 Hz, IH), 6.56 (s, IH), 4.60 (bs, 2H), 4.34 (t, J= 2.2 Hz, 2H), 4.29 (t, J= 2.4 Hz, 2H); TLC ^/(CH 2 Cl 2 : MeOH 10:1) = 0.56.
416
7V-((5-(4-Methoxyphenyl)-lλT-pyrazol-3-yl)methyl)-iV-met hyl-5-(2- (trifluoromethyl)phenyl)-l,2,4-triazin-3-amine (416)
1 K NMR (400 MHz, CDCl 3 ) δ 8.74 (s, IH), 7.78 (d, J= 7.6 Hz, IH), 7.65-7.57 (m, 4H), 7.44 (d, J= 7.6 Hz, IH), 6.85 (d, J= 8.8 Hz, 2H), 6.42 (s, IH), 4.74 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H); TLC ^(CH 2 Cl 2 MeOH 20:1) = 0.30.
3-Methyl-4-(3-((5-phenyl-liϊ-pyrazol-3-yl)methylainino)- l,2,4-triaziii-5-yI)benzonitrile
(417)
1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (s, IH), 7.61 (d, J= 7.2 Hz, 2H), 7.57-7.52 (m, 3H), 7.38- 7.28 (m, 3H), 6.52 (s, IH), 4.81 (s, 2H), 2.45 (s, 3H); TLC R f (CH 2 Cl 2 :MeOH 10:1) = 0.33; LRMS (electrospray) m/z calculated for C 2I H n N 7 (M+H + ) 367.41, found 367.94.
3-((Biphenyl-3-yloxy)methyl)-5-phenyl-l J fiT-pyrazole (418)
1 K NMR (400 MHz, CDCl 5 ) δ 7.65 (d, J= 8.0 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H ), 7.43-7.18 (m, 9H), 6.94 (t, J= 4.6 Hz, IH ), 6.63 (s, IH), 5.13 (s, 2H); TLC i?/(o-Hexanes:EtOAc 2:1) = 0.40; LRMS (electrospray) m/z calculated for C 22 H 19 N 2 O (M+H) + 327.15, found 327.12.
3-((2'-Methylbiphenyl-3-yloxy)methyl)-5-phenyl-lH-pyrazol e (419)
1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J= 7.6 Hz, 2H), 7.38-7.21 (m, 8H), 6.95-6.93 (m, 3H), 6.62 (s, IH), 5.11 (s, 2H), 2.24 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.37; LRMS (electrospray) m/z calculated for C 23 H 21 N 2 O (M+H) + 341.17, found 341.06.
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J= 7.6 Hz, 2H), 7.58 (t, J= 4.4 Hz, IH), 7.48-7.37 (m, 7H), 7.17-7.14 (m, 2H), 7.07 (dd, J= 8.2, 2.2 Hz, IH ), 6.74 (s, IH), 5.19 (s, 2H); TLC R 1 (rc-Hexanes:EtOAc 2:1) = 0.43; LRMS (electrospray) m/z calculated for C 22 H 18 ClN 2 O (M+H) + 361.11, found 361.05.
5-Phenyl-3-((2'-(trifluoromethyl)biphenyl-3-yloxy)methyl) -lH-pyrazole (421)
1 R NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J= 8.8 Hz, IH), 7.62 (d, J= 7.2 Hz, 2H), 7.52-7.22 (m, 7H), 7.01 (d, J= 7.2 Hz, IH), 6.95-6.91 (m, 2H), 6.61 (s, IH), 5.14 (s, 2H); TLC R f (n- Hexanes: EtOAc 2:1) = 0.47; LRMS (electrospray) m/z calculated for C 23 H 18 F 3 N 2 O (M+H) + 395.14, found 395.11.
3-((2'-Methoxybiphenyl-3-yloxy)methyl)-5-phenyl-l//-pyraz ole (422)
1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (dd, J= 5.2, 3.2 Hz, 2H), 7.40 (t, J= 7.2 Hz, 2H), 7.35- 7.28 (m, 4H) 5 7.20-7.19 (m, IH), 7.14-7.12 (m, IH), 7.03-6.95 (m, 3H), 6.64 (s, IH), 5.18 (s, 2H), 3.79 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.47; LRMS (electrospray) m/z calculated for C 23 H 21 N 2 O 2 (M+H) + 357.16, found 357.10.
423
4-(2-Chlorophenyl)-2-((5-phenyl-l//-pyrazol-3-yl)methoxy) pyrimidine (423)
1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J= 5.2 Hz, IH), 7.71-7.69 (m, IH), 7.66-7.64 (m, IH), 7.49.7.46 (m, IH), 7.39-7.29 (m, 7H), 6.68 (s, IH), 5.56 (s, 2H); TLC ^(CH 2 Cl 2 MeOH 10:1) = 0.48.
424 2-((5-Phenyl-lH r -pyrazol-3-yl)methoxy)-4-(2-(trifluoromethyl)phenyI)pyrimidi ne (424)
1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.2 Hz, IH), 7.70-7.68 (m, 2H), 7.62-7.57 (m, 2H), 7.49 (d, J= 7.2 Hz, IH), 7.38-7.34 (m, 2H), 7.30-7.28 (m, IH), 7.12 (d, J= 4.8 Hz, IH), 6.67 (s, IH), 5.55 (s, 2H); TLC R f (CH 2 Cl 2 :MeOH 10:1) = 0.50.
425 iV-(2'-Methylbiphenyl-3-yl)-5-phenyl-lH-pyrazoIe-3-carboxami de (425)
1 H NMR (400 MHz, CD 3 OD) δ 7.71-7.68 (m, 4H), 7.47-7.35 (m, 4H), 7.26-7.15 (m, 4H), 7.07 (d, J= 8.0 Hz, IH), 2.22 (s, 3H); TLC tf/(rc-Hexanes:EtOAc 2:1) = 0.53.
426 iV-(2'-Chlorobiphenyl-3-yl)-5-phenyl-l J BT-pyrazole-3-carboxamide (426)
1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (bs, IH), 7.78-7.73 (m, 2H), 7.60-7.58 (m, 2H), 7.50-7.31 (m, 5H), 7.30-7.11 (m, IH ), 6.98 (s, IH); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.40.
427 iV-(5-(2-Chloropb.enyl)pyridin-3-yI)-5-phenyl-lH-pyrazole-3- carboxamide (427)
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.06 (d, J= 1.6 Hz, IH), 8.37 (s, 2H), 7.85 (d, J= 7.2 Hz, 2H), 7.65-7.63 (m, IH), 7.54-7.47 (m, 5H), 7.39 (t, J= 7.4 Hz, IH), 7.30 (s, IH); TLC R f (n- Hexanes:EtOAc 1 :1) = 0.34.
428 5-Phenyl-iV-(5-(2-(trifluoromethyl)phenyl)pyridin-3-yl)-ljHr -pyrazole-3-carboxamide
(428)
1 H NMR (400 MHz, CD 3 OD) δ 9.01 (d, J= 2.4 Hz, IH), 8.33 (s, IH), 8.25 (s, IH), 7.86 (d, J = 7.6 Hz, IH), 7.74 (t, J= 7.2 Hz, 3H), 7.65 (t, J=7.6 Hz, IH), 7.47 (t, J= 7.2 Hz, 3H), 7.39 (t, J= 7.2 Hz, IH), 7.18 (s, IH); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.67.
5-(2-Chlorophenyl)-iV-((4-phenyl-lJ ι y-pyrazol-3-yI)methyI)-l,2,4-triaziii-3-amine (429)
1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, IH), 7.65 (s, IH), 7.56-7 '.47 (m, IH), 7.44-7.25 (m, 8H), 4.92 (d, J= 5.2 Hz, 2H); TLC i?/(n-Hexanes: EtOAc 1:1) = 0.11; LRMS (electrospray) m/z calculated for C 19 H 15 ClN 6 (M+H + ) 362.82, found 363.09.
430
4-(2-Chlorophenyl)-iV-((l-phenyl-lJϊ-l,2,3-triazol-4-yl) methyl)pyridiii-2-amine (430)
1 H NMR (400 MHz, CD 3 OD) δ 8.37 (s, IH), 8.02 (dd, J= 5.0, 1.4 Hz, IH), 7.78 (d, J= 7.6 Hz, 2H), 7.53 (t, J= 7.8 Hz, 2H), 7.45 (m, 2H), 7.33 (m, 3H), 6.63 (dd, J= 5.2, 1.2 Hz, 2H), 4.69 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.20.
4-(2-Chlorophenyl)-N-((l-phenyl-lH-l,2,3-triazol-4-yI)met hyI)pyrimidin-2-amine (431)
1 U NMR (400 MHz, CD 3 OD) δ 8.33 (d, J= 4.8 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H), 7.50 (t, J= 7.8 Hz, 3H), 7.44 (m, 2H), 7.36 (m, 2H), 6.88 (d, J= 5.2 Hz, IH), 4.75 (s, 2H); TLC R f (n- Hexanes:EtOAc 3:7) = 0.45.
1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J- 4.8 Hz, IH), 8.31 (bs, IH), 7.78 (t, J= 8.6 Hz, 3H), 7.69 (t, J= 7.0 Hz, IH), 7.62 (t, J= 7.6 Hz, IH), 7.57-7.45 (m, 5H), 6.74 (d, J= 4.8 Hz, IH), 4.90 (s, 2H); TLC i?/(π-Hexanes:EtOAc 3:7) = 0.43.
5-(2-ChlorophenyI)-7V-((5-phenyl-lH-l,2,4-triazol-3-yl)me thyI)-l,2,4-triazin-3-amine
(433)
1 H NMR (400 MHz, CD 3 OD) δ 8.95 (s, IH), 7.98-7.96 (m, 2H), 7.63-7.45 (m, 7H), 4.88 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.23; LRMS (electrospray) m/z calculated for C 18 H 15 C1N 7 (M+H) + 364.11, found 363.90.
5-PhenyI-λ'-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3- amine (434)
1 H NMR (400 MHz, CD 3 OD) δ 8.02 (d, J= 1.6 Hz, IH), 7.98 (d, J= 2.8 Hz, IH), 7.69 (d, J= 7.2 Hz, 2H), 7.57-7.54 (m, 2H), 7.45-7.35 (m, 5H), 7.34-7.28 (m, 2H), 6.63 (s, IH), 4.46 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.13.
5-Phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3-a mine hydrochloride (435)
1 H NMR (400 MHz, CD 3 OD) δ 8.35 (s, IH), 8.15 (d, J= 2.4 Hz, IH), 8.04 (t, J= 2.2 Hz, IH), 7.77 (dd, J= 7.8, 1.8 Hz, 2H), 7.73 (dd, J= 7.8, 1.4 Hz, 2H), 7.60-7.46 (m, 6H), 6.99 (s, IH), 4.75 (s, 2H).
436 7V-((5-Phenyl-l//-pyrazol-3-yI)methyl)-5-o-tolylpyridm-3-ami ne (436)
1 U NMR (400 MHz, CD 3 OD) δ 7.99 (d, J= 2.4 Hz, IH), 7.70 (m, 3H), 7.40 (t, J= 7.2 Hz, 2H), 7.33-7.31 (m, IH), 7.25-7.19 (m, 3H), 7.15 (d, J= 7.2 Hz, IH), 7.00 (s, IH), 6.61 (s, IH), 4.43 (s, 2H), 2.15 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.28.
N-((5-Phenyl-liy-pyrazoI-3-yl)methyl)-5-ø-tolyIpyridin-3-ai nine hydrochloride (437) 1 U NMR (400 MHz, CD 3 OD) δ 8.17 (d, J= 2.4 Hz, IH), 8.05 (s, IH), 7.77-7.73 (m, 3H), 7.52-7.44 (m, 3H), 7.41-7.27 (m, 4H), 6.91 (s, IH), 4.68 (s, 2H), 2.24 (s, 3H).
5-(2-Chlorophenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)p yridin-3-amine (438)
1 H NMR (400 MHz, CD 3 OD) δ 8.02, (s, IH), 7.80 (s, IH), 7.68 (d, J= 6.8 Hz, 2H), 7.48 (t, J = 3.8 Hz, IH), 7.41-7.29 (m, 6H), 7.13 (s, IH), 6.61 (s, IH), 4.43 (s, 2H); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.31.
5-(2-Chlorophenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)p yridin-3-amine hydrochloride (439)
1 H NMR (400 MHz, CD 3 OD) δ 8.23 (d, J= 2.8 Hz, IH), 8.18 (s, IH), 7.87 (t, J= 2.0 Hz, IH), 7.78-7.76 (m, 2H), 7.60-7.58 (m, IH), 7.54-7.47 (m, 6H), 6.97 (s, IH), 4.72 (s, 2H).
1 H NMR (400 MHz, CD 3 OD) δ 8.04 (d, J= 2.0 Hz, IH), 7.78 (d, J= 7.6 Hz, IH), 7.71-7.63 (m, 4H), 7.57 (t, J= 7.6 Hz, IH), 7.41-7.30 (m, 4H), 7.03 (s, IH), 6.60 (s, IH), 4.41 (s, 2H); TLC J^(CH 2 Cl 2 =MeOH 20:1) = 0.26.
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (d, J= 2.4 Hz, IH), 8.11 (s, IH), 7.88 (d, J= 7.6 Hz, IH), 7.79-7.76 (m, 4H), 7.72 (t, J= 7.4 Hz, IH), 7.56-7.49 (m, 4H), 7.01 (s, IH), 4.75 (s, 2H).
5-(2-Methoxyphenyl)-iV-((5-phenyl-liϊ-pyrazol-3-yI)methy l)pyridiii-3-amine (442)
1 H NMR (400 MHz, CD 3 OD) δ 7.93 (d, J= 2.4 Hz, IH), 7.89 (s, IH), 7.69 (bs, 2H), 7.41- 7.31 (m, 4H), 7.27-7.22 (m, 2H), 7.04 (d, J= 8.4 Hz, IH), 7.00 (t, J= 7.4 Hz, IH), 6.62 (s, IH), 4.42 (s, 2H), 3.73 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.26.
5-(2-Methoxyphenyl)-λ'-((5-phenyl-lH-pyrazoI-3-yl)methyl )pyridin-3-amine hydrochloride (443)
1 H NMR (400 MHz, CD 3 OD) δ 8.17 (s, IH), 8.09 (d, J= 2.8 Hz, IH), 7.95 (t, J= 2.0 Hz, IH), 7.80-7.77 (m, 2H), 1.55-1 Al (m, 4H), 7.43 (dd, J= 7.6, 1.6 Hz, IH), 7.17 (d, J= 8.4 Hz, IH), 7.11 (t, J= 7.6 Hz, IH), 7.00 (s, IH), 4.72 (s, 2H), 3.82 (s, 3H).
3-Methyl-4-(5-((3-phenyl-l-(tetrahydro-2iy-pyran-2-yl)-l/ /-pyrazol-5- yl)methylamino)pyridin-3-yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (s,lH), 7.91 (s, IH), 7.75 (d, J= 7.2 Hz, 2H), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.35 (t, J= 7.6 Hz, 2H), 7.29-7.25 (m, 2H), 6.82 (s, IH), 6.54 (s, IH), 5.43 (dd, J= 9.2, 2.8 Hz, IH), 4.51 (dd, J= 14.8, 6.0 Hz, IH), 4.42 (dd, J= 14.6, 4.6 Hz, IH), 3.99-3.97 (m, IH), 3.66-3.60 (m, IH), 2.55-2.47 (m, IH), 2.24 (s, 3H), 2.17-2.14 (m, IH), 2.09-2.02 (m, IH), 1.73-1.60 (m, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.43.
3-Methyl-4-(5-((5-phenyl-lH-pyrazol-3-yl)methylamino)pyri din-3-yl)benzoiiitrile (444)
1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (s, IH), 7.84 (s, IH), 7.58 (d, J= 7.2 Hz, 2H), 7.48 (s, IH), 7.45 (d, J= 8.0 Hz, IH), 7.37-7.28 (m, 3H), 7.20 (d, J= 8.0 Hz, IH), 6.82 (s, IH), 6.48 (s, IH), 4.39 (s, 2H), 2.17 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.20.
3-(4-Cyano-2-methylphenyl)-5-((5-phenyl-liy-pyrazol-3-yl) methylamino)pyridine 1- oxide (445)
1 H NMR (400 MHz, CD 3 OD) δ 9.26 (t, J= 1.6 Hz, IH), 7.70-7.68 (m, 3H), 7.64-7.61 (m, 2H), 7.43-7.38 (m, 3H), 7.35-7.31 (m, IH), 6.88 (s, IH), 6.63 (s, IH), 4.43 (s, 2H), 2.25 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.43.
1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, IH), 7.78 (s, IH), 7.59 (d, J= 4.4 Hz, 2H), 7.36-7.30 (m, 3H), 7.14-7.12 (m, IH), 7.07 (s, 2H), 6.75 (s, IH), 6.48 (s, 2H), 4.38 (s, 2H), 1.98 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.53.
5-(2-ChIoro-4-fluorophenyl)-N-((5-phenyl-ljBr-pyrazol-3-y l)methyl)pyridin-3-amine
(447)
1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J= 2.4 Hz, IH), 7.95 (s, IH), 7.58 (d, J= 7.6 Hz, 2H), 7.38 -7.28 (m, 3H), 7.22-7.15 (m, 2H), 7.00-6.95 (m, 2H), 6.49 (s, IH), 4.39 (s, 2H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.21.
6-Phenyl-λ r -((5-phenyl-ljH r -pyrazol-3-yl)methyl)pyridin-2-amine (448)
1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J= 7.6 Hz, 2H), 7.63 (d, J= 8.0 Hz, 2H), 7.45-7.24 (m, 7H), 7.06 (d, J= 7.2 Hz, IH), 6.47 (s, IH), 6.33 (d, J= 8.0 Hz, IH), 4.60 (bs, 2H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.27.
1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J= 8.0 Hz, 2H), 7.49-7.42 (m, 2H), 7.37-7.34 (m, 2H), 7.29-7.24 (m, 4H), 6.74 (d, J= 7.2 Hz, IH ), 6.45 (s, IH), 6.40 (d, J= 8.4, IH ), 4.56 (d, J= 5.2, 2H), 2.40 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.22.
450 6-(2-ChlorophenyI)-N-((5-phenyl-lH-pyrazol-3-yl)methyl)pyrid in-2-amine (450)
1 H NMR (400 MHz, CDCl 3 ) δ 7.68-7.65 (m, 2H), 7.55 (dd, J= 7.2, 2.0 Hz, IH), 7.50-7.44 (m, 2H), 7.35-7.27 (m, 5H), 6.92 (d, J= 7.6 Hz, IH), 6.45-6.43 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.10.
J /V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-6-(2-(trifluoromethyl) phenyl)pyridin-2-amine (451)
1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (t, J= 8.0 Hz, IH), 7.62-7.60 (m, IH), 7.54 (t, J= 7.4, IH), 7.48-7.42 (m, 5H), 7.33 (t, J= 7.4 Hz, IH ), 7.28-7.24 (m, IH), 6.71 (d, J= 7.2 Hz, IH), 6.49-6.40 (m, 2H), 4.50 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.14.
6-(2-Methoxyphenyl)-N-((5-phenyM/7-pyrazoI-3-yl)methyl)py ridin-2-amine (452)
1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 7.6, IH), 7.45 (t, J= 7.8 Hz, lH),7.37-7.34 (m, 3H), 7.29-7.25 (m, IH), 7.04-7.01 (m, 2H), 6.95 (d, J= 7.2, IH), 6.46 (s, IH), 6.38 (d, J= 8.4 Hz, IH), 4.55 (s, 2H), 3.96 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.14.
7V-((5-Phenyl-liϊ-pyrazol-3-yl)methyl)-4-o-toIylpyridin- 2-amine (453)
Yellow oil: 1 H NMR (400 MHz, CD 3 OD) δ 7.99 (d, J= 4.0 Hz, IH), 7.70-7.67 (m, 2H), 7.37- 7.35 (m, 2H), 7.30-7.29 (m, 1H),7.23-7.13 (m, 4H), 6.58 (s, IH), 6.54 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.55 (s, 2H), 2.20 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.21.
454 4-(2-Chlorophenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyri din-2-amine (454)
1 H NMR (400 MHz, DMSO-J 6 ) δ 12.92 (bs, 0.5H), 12.73 (bs, 0.5H), 8.06 (d, J= 6.0 Hz, IH), 7.89 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 7.2 Hz, 2H), 7.33 (t, J= 6.4 Hz, 2H), 7.22 (m, IH), 6.99 (bs, IH), 6.81 (s, 2H), 6.53 (s, IH), 4.47 (s, 2H); TLC R 1 (CH 2 Cl 2 MeOH 19:1) = 0.14.
455
4-(2-Chlorophenyl)-iV-((5-(4-(dimethylamino)phenyl)-lJϊ- pyrazol-3-yl)methyl)pyridin-2- amine (455)
1 H NMR (400 MHz, CD 3 OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.50 (d, J= 8.8 Hz, 2H), 6.79 (t, J= 3.4 Hz, IH), 7.33 (dd, J= 8.6, 4.6 Hz, 3H), 6.75 (d, J= 8.8 Hz, 2H), 6.62 (d, J= 6.8 Hz, 2H), 6.42 (s, IH), 4.52 (s, 2H), 2.93 (s, 6H); TLC ^(CH 2 Cl 2 MeOH 19:1) = 0.24.
7V-((5-Phenyl-l/- r -pyrazol-3-yI)methyl)-4-(2-(trifluoromethyl)pheiiyl)pyridin- 2-amine (456)
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J= 5.6 Hz, IH), 7.75-7.71 (m, 3H), 7.56 (t, J= 7.2 Hz, IH), 7.49 (t, J= 7.6 Hz 5 IH), 7.40 (t, J= 7.6 Hz, 2H), 7.33-7.27 (m, 2H), 6.63 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 6.43 (s, IH) 5 4.61 (d, J= 5.6 Hz 5 2H); TLC #/(CH 2 Cl 2 :Me0H 20:1) = 0.39.
457
4-(2-Methoxyphenyl)-7V-((5-phenyl-lH-pyrazol-3-yI)methyI)pyr idin-2-amine (457) White solid: 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J= 5.2 Hz, IH), 7.71 (d, J= 8.0 Hz, 2H), 7.39-7.26 (m, 5H), 7.00 (t, J= 7.4 Hz, IH), 6.95 (d, J= 8.4 Hz, IH) 5 6.63 (s, IH), 6.48 (s, IH), 4.59 (s, 2H), 3.77 (s, 3H); TLC 7?/(«-Hexanes:EtOAc 1 :1) = 0.08.
4-(2-ChIoro-4-fluorophenyl)-λ r -((5-phenyl-lH f -pyrazol-3-yl)inethyl)pyridiii-2-amine
(458)
1 H NMR (400 MHz 5 CD 3 OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.66 (d, J= 6.8 Hz, 2H) 5 7.36 (m, 3H), 7.29 (dd, J= 8.6, 2.6 Hz, 2H), 7.12 (dt, J= 8.2, 2.0 Hz, IH), 6.59 (m, 3H), 4.55 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.25.
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J= 5.2 Hz, IH), 7.72 (d, J= 8.0 Hz, 2H), 7.40 (t, J= 7.4 Hz, 2H), 7.34-7.31 (m, IH), 7.18-7.07 (m, 3H), 6.50 (s, IH), 6.48 (d, J= 5.2 Hz, IH), 6.28 (s, IH), 4.61 (d, J= 4.4 Hz, 2H), 2.05 (s, 6H); TLC ^ 7 (CH 2 Cl 2 -MeOH 20:1) = 0.34.
460 3-Methyl-4-(2-((5-phenyl-lH r -pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile (460)
1 H NMR (400 MHz 5 CDCl 3 ) δ 8.21 (d, J= 5.2 Hz, IH), 7.70 (d, J= 1.6 Hz, 2H), 7.54 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.40 (t, J= 7.4 Hz, 2H), 7.33 (d, J= 7.2 Hz, IH) 5 7.25 (d, J= 9.2 Hz, IH), 6.55 (dd, J= 6.4, 2.4 Hz, IH), 6.51 (s, IH) 5 6.35 (s, IH), 4.62 (d, J= 4.8 Hz, 2H), 2.26 (s, 3H); TLC ^ 7 (CH 2 Cl 2 :MeOH 20:1) = 0.28.
4-(4-Cyano-2-methyIphenyI)-2-((5-phenyl-l J H r -pyrazol-3-yl)methylamino)pyridine 1- oxide (461)
1 H NMR (400 MHz, CD 3 OD) δ 8.19 (d, J= 6.8 Hz, IH), 7.67-7.65 (m, 3H) 5 7.59 (t, J= 8.8 Hz, 1), 7.47-7.31 (m, 4H) 5 6.90 (d, J= 2.4 Hz 5 IH), 6.71 (dd, J= 6.8, 2.0 Hz, IH), 6.62 (s, IH), 4.64 (s 5 2H) 5 2.20 (s, 3); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.30.
3,5-Dimethyl-4-(2-((5-phenyl-lH-pyrazol-3-yI)methylamino) pyridiii-4-yl)benzonitrile (462)
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J= 5.2 Hz, IH), 7.67 (d, J= 7.6 Hz, 2H), 7.39-7.34 (m, 5H), 6.47 (s, IH), 6.37 (d, J= 5.2 Hz, IH), 5.54 (s, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.14 (s, 6H).
3-Chloro-4-(2-((5-phenyHjBT-pyrazol-3-yI)methylamino)pyri din-4-yl)benzonitrile (463)
1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J= 5.2 Hz, IH), 7.31 (s, IH), 7.67 (d, J= 7.6 Hz, 2H), 7.56 (d, J= 8.0 Hz, IH), 7.39-7.36 (m, 3H), 7.35-7.24 (m, IH), 6.64 (d, J= 5.2 Hz, IH), 6.48 (s, IH), 6.44 (s, IH), 5.32 (s, IH), 4.61 (d, J= 5.6 Hz, IH); TLC R f (CH 2 Cl 2 : MeOH 20:1) = 0.57; LRMS (electrospray) m/z calculated for C 22 H 16 ClN 5 (M+H + ) 385.85, found 385.93.
4-(2-((5-Phenyl-ljH r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (464)
1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J= 5.2 Hz, IH), 7.99 (d, J= 1.2 Hz, IH), 7.81-7.78 (m, IH), 7.65 (d, J= 7.2 Hz, 2H), 7.38-7.30 (m, 3H), 7.29-7.27 (m, IH), 6.54 (d, J= 5.2 Hz, IH), 6.47 (s, IH), 6.34 (s, IH), 5.45 (s, IH), 4.58 (d, J= 5.6 Hz, IH); TLC /Jy(CH 2 Cl 2 JMeOH 10:1) = 0.68.
4-(2-Chlorophenyl)-λ r -((3-(pyridin-4-yl)-l-(tetrahydro-2JH r -pyran-2-yl)-lH-pyrazol-5- yl)methyI)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (s, 2H), 8.17 (d, J= 5.2 Hz, IH), 7.66 (d, J= 4.8 Hz, 2H), 7.45-7.42 (m, IH), 7.31-7.25 (m, 3H), 6.70 (dd, J= 5.2, 1.2 Hz, IH), 6.66 (s, IH), 6.49 (s, IH), 5.50 (dd, J= 9.6, 2.8 Hz, IH), 4.80 (dd, J= 15.6, 6.0 Hz, IH), 4.65 (dd, J= 15.4, 5.0 Hz, IH), 4.02-3.99 (m, IH), 3.64-3.58 (m, IH), 2.57-2.48 (m, IH), 2.15-2.02 (m, 2H), 1.73-1.57 (m, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.70.
465 4-(2-Chlorophenyl)-iV-((5-(pyridin-4-yl)-lH-pyrazol-3-yl)met hyl)pyridiii-2-amine (465)
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J= 6.4 Hz, 2H), 8.23 (d, J= 5.2 Hz, IH), 7.66 (d, J= 6.0 Hz, 2H), 7.49-7.44 (m, IH), 7.34-7.27 (m, 3H), 6.77 (d, J= 5.6 Hz, IH), 6.58 (s, IH), 6.53 (s, IH), 4.64 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.16.
4-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl )-liϊ-pyrazol-5-yl)pyridine 1-oxide (466)
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (d, J= 6.8 Hz, 2H), 8.08 (d, J= 5.6 Hz, IH), 7.90 (d, J= 6.4 Hz, 2H), 7.66 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.35 (d, J= 7.6, IH), 6.78 (s, IH), 6.58 (d, J= 5.2 Hz, IH), 6.51 (s, IH), 4.64 (s, 2H), 2.28 (s, 3H); TLC ^(CH 2 Cl 2 MeOH 10:1) = 0.21.
3-Methyl-4-(2-((5-(pyridm-3-yl)-lH-pyrazoI-3-yl)methylami no)pyridin-4-yl)benzonitrile
(467)
1 H NMR (400 MHz, CD 3 OD) δ 8.92 (s, IH), 8.47 (d, J= 3.6 Hz, IH), 8.17 (s, IH), 8.08 (d, J = 5.2 Hz, IH), 7.66 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.48 (t, J= 6.2 Hz, IH), 7.36 (d, J= 8.0 Hz, IH), 6.72 (s, IH), 6.57 (d, J= 5.2 Hz, IH), 6.52 (s, IH), 4.63 (s, 2H), 2.28 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.15.
4-(2-ChlorophenyI)-iV-((3-(pyridm-3-yl)-l-(tetrahydro-2H- pyran-2-yI)-lH-pyrazol-5- yl)methyl)pyridin-2-amine
1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, IH), 8.52 (d, J= 4.0 Hz, IH), 8.13-8.08 (m, 2H), 7.47- 7.43 (m, IH), 7.33-7.22 (m, 4H), 6.72 (dd, J= 5.2, 1.2 Hz, IH), 6.63 (s, IH), 6.54 (s, IH), 5.50 (dd, J= 9.6, 2.8 Hz, IH), 4.76 (d, J= 15.6 Hz, IH), 4.65 (d, J= 15.6 Hz, IH), 4.03-3.99 (m, IH), 3.67-3.61 (m, IH), 2.58-2.48 (m, IH), 2.15-2.03 (m, 2H), 1.77-1.59 (m, 3H); TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.30.
468 4-(2-Chlorophenyl)-iV-((5-(pyridiii-3-yl)-lH-pyrazol-3-yl)me thyl)pyridin-2-ainine (468)
1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (s, IH), 8.55 (d, J= 4.4 Hz, IH), 8.18 (d, J= 5.2 Hz, IH), 8.07 (d, J= 7.6 Hz, IH), 7.48-7.46 (m, IH), 7.34-7.26 (m, 4H), 6.78 (d, J= 5.6 Hz, IH), 6.01 (s, IH), 6.56 (s, IH), 4.66 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.16.
4-(2-Chlorophenyl)-λ r -((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methyl)pyridin-2-amine (469)
1 H NMR (400 MHz, CD 3 OD) δ 8.51 (d, J= 3.6 Hz, IH), 8.02 (d, J= 5.6 Hz, IH), 7.91 (d, J= 5.2 Hz, IH), 7.82 (t, J= 7.0 Hz, IH), 7.47 (m, IH), 7.37-7.28 (m, 4H), 6.81 (s, IH), 6.63 (m, 2H), 4.60 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.37.
3-Methyl-4-(2-((3-(pyridin-4-yl)-l-(tetrahydro-2H r -pyran-2-yl)-lJH r -pyrazol-5- yl)methylamino)pyridin-4-yl)benzonitrile
1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J= 5.6 Hz, 2H), 8.18 (d, J= 5.2 Hz, IH), 7.65 (d, J = 6 Hz, 2H), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.25-7.23 (m, IH), 6.66 (s, IH), 6.55 (d, J = 5.6 Hz, IH), 6.31 (s, IH), 5.52 (dd, J= 9.2, 2.8 Hz, IH), 4.83 (dd, J= 15.2, 6.4 Hz, IH), 4.65
(dd, J= 15.4, 5.0 Hz, IH), 4.00-3.97 (m, IH), 3.65-3.59 (m, IH), 2.56-2.48 (m, IH), 2.25 (s, 3H), 2.16-2.04 (m, 2H), 1.71-1.61 (m, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.32.
3-Methyl-4-(2-((5-(pyridin-4-yl)-lH-pyrazoI-3-yl)methylam ino)pyridin-4-yl)benzonitrile
(470)
1
H NMR (400 MHz, CD 3
OD) δ 8.53 (s, 2H), 8.08 (d, J= 5.3 Hz, IH), 7.78 (s, 2H), 7.66 (s, IH), 7.35 (d, J= 8.0 Hz, IH), 6.80 (s, IH), 6.57 (d, J= 5.2 Hz, IH), 6.52 (s, IH), 4.64 (s, 2H), 2.28 (s, 3H); TLC
3-MethyI-4-(2-((5-(pyridin-4-yl)-lH-pyrazoI-3-yl)methyIam ino)pyridin-4-yl)benzonitrile hydrochloride (471)
1 H NMR (400 MHz, CD 3 OD) δ 8.79 (d, J= 6.8 Hz, 2H), 8.43 (d, J= 6.8 Hz, 2H), 8.01 (d, J= 6.4 Hz, IH), 7.73 (s, IH), 7.68 (d, J= 8.4 Hz, IH), 7.46 (d, J= 7.6 Hz, IH), 7.26 (s, IH), 7.10 (s, IH), 7.00 (d, J= 6.4 Hz, IH), 4.84 (s, 2H), 2.32 (s, 3H).
3-Methyl-4-(2-((5-(pyridin-3-yl)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yl)benzonitrile hydrochloride (472)
1 H NMR (400 MHz, CD 3 OD) δ 9.26 (s, IH), 8.95 (d, J= 8.4 Hz, IH), 8.78 (d, J= 5.2 Hz, IH), 8.11 (dd, J= 8.2, 5.8 Hz, IH), 8.02 (d, J= 6.4 Hz, IH), 7.76 (s, IH), 7.71 (d, J= 8.0 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 7.11 (s, IH), 7.08 (s, IH), 7.03 (dd, J= 6.8, 1.6 Hz, IH), 4.83 (s, 2H), 2.35 (s, 3H).
3-Methyl-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yI)benzonitrile
(473)
1 H NMR (400 MHz, CDCl 3 with 20% CD 3 OD) δ 8.49 (d, J= 4.8 Hz, 2H), 8.04 (d, J= 5.6 Hz, 2H), 7.73-7.70 (m, IH), 7.49-7.31 (m, 2H), 7.22-7.19 (m, 2H), 6.72 (s, IH), 6.47 (d, J= 5.6 Hz, IH), 4.53 (s, 2H), 2.20 (s, 3H); TLC R 1 (CH 2 Cl 2 : MeOH 20:1) = 0.56.
3-Methyl-4-(2-((5-(pyridin-2-yl)-ljH r -pyrazol-3-yl)methyIamino)pyridin-4-yl)benzonitrile hydrochloride (474)
1 H NMR (400 MHz, CDCl 3 with 20% CD 3 OD) δ 8.69 (d, J= 5.6 Hz, IH), 8.56-8.52 (m, IH), 8.37 (d, J= 8.0 Hz, IH), 8.03 (d, J= 6.4 Hz, IH), 7.88 (d, J= 7.2 Hz, IH), 7.75 (m, IH), 7.69 (d, J= 8.0 Hz, IH), 7.46 (d, J= 8.0 Hz, IH), 7.22 (s, IH), 7.10 (m, 2H), 7.04-7.02 (s, IH), 2.33 (s, 3H).
3-Chloro-4-(2-((5-(pyridin-4-yl)-l.fir-pyrazol-3-yl)methy lamino)pyridin-4-yl)benzonitrile
(475)
1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (dd, J= 4.6, 1.8 Hz, 2H), 8.10 (d, J= 5.6 Hz, IH), 7.74
(d, J= 1.6 Hz, IH), 7.67 (m, 2H), 7.59 (dd, J= 8.0, 1.6 Hz, IH), 7.37 (d, J= 8.0 Hz, IH),
6.66 (dd, J= 5.8, 1.4 Hz, IH), 6.65 (s, IH), 6.57 (s, IH); TLC ^ 7 (CH 2 Cl 2 MeOH 10:1) =
0.30.
3-Chloro-4-(2-((5-(pyridin-3-yl)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yl)benzonitrile
(476)
1 U NMR (400 MHz, CDCl 3 ) δ 8.96 (s, IH), 8.53 (s, IH), 8.14 (d, J= 5.6 Hz, IH), 8.08 (d, J= 8.0 Hz, IH), 7.75 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.39 (d, J= 7.6 Hz, IH), 7.35 (m, IH), 6.71 (d, J= 5.6 Hz, IH), 6.67 (s, IH), 6.57 (s, IH), 4.70 (s, IH); TLC ^/(CH 2 Cl 2 :MeOH 10:1) = 0.30.
3-Chloro-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yl)benzonitrile
(477)
1 U NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J= 4.0 Hz, IH), 8.16 (d, J= 5.6 Hz, IH), 7.75 (s, IH), 7.73 (d, J= 7.6 Hz, IH), 7.67 (d, J= 7.6 Hz, IH), 7.60 (d, J= 8.0 Hz, IH), 7.40 (d, J= 8.0 Hz, IH), 7.23 (m, IH), 6.75 (s, IH), 6.67 (d, J= 5.6 Hz, IH), 6.63 (s, IH) 5 4.65 (s, IH); TLC i?/(CH 2 Cl 2 :Me0H 10:1) == 0.30.
4-(2-((5-(Pyridin-4-yl)-lJϊ-pyrazoI-3-yl)methylamino)pyr idin-4-yl)-3- (trifluoromethyl)benzonitrile (478)
1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J= 4.8 Hz, 2H), 8.21 (d, J= 5.2 Hz, IH), 8.04 (s, IH), 7.87 (d, J= 7.6 Hz, IH), 7.73 (d, J= 5.2 Hz, 2H), 7.43 ( d, J= 8.0 Hz, IH), 6.63 (d, J= 5.6 Hz, IH), 6.61 (s, IH), 6.48 (s, IH), 4.67 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.30.
4-(2-((5-(Pyridin-3-yl)-l/7-pyrazoI-3-yl)methylamino)pyri din-4-yl)-3- (trifluoromethyl)benzonitrile (479)
1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, IH), 8.54 (d, J= 4.4 Hz, IH), 8.15 (d, J= 5.6 Hz, IH), 8.10 (d, J= 7.6 Hz, IH), 8.04 (s, IH), 7.87 (d, J= 8.0 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.37 (dd, J= 7.4, 5.0 Hz, IH), 6.62 (d, J= 5.2 Hz, IH), 6.57 (s, IH), 6.55 (s, IH); 4.68 (s, IH); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.30.
4-(2-((5-(Pyridin-2-yl)-ljH r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (480)
1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J= 4.0 Hz, IH), 8.08 (d, J= 5.2 Hz, IH), 8.02 (s, IH), 7.85 (d, J= 6.4 Hz, IH), 7.74 (m, IH), 7.65 (d, J= 7.6 Hz, IH), 7.42 (d, J= 7.6 Hz, IH), 7.23 (m, IH), 6.75 (s, IH), 6.58 (m, 2H), 4.64 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.34.
481 iV-((5-PhenyI-lJϊ-pyrazol-3-yl)methyl)-6-o-tolylpyrazin-2-a mine (481)
1 H NMR (400 MHz, CD 3 OD) δ 7.93 (s, IH), 7.73 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.40-7.27 (m, 7H), 6.59 (s, IH), 4.53 (s, 2H), 2.30 (s, 3H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.24.
482 6-(2-Chlorophenyl)-λ'-((5-phenyl-lH-pyrazol-3-yl)methyl)pyr azin-2-amine (482)
1 H NMR (400 MHz, CD 3 OD) δ 7.93 (s, IH), 7.92 (s, IH), 7.68-7.66 (m, 2H), 7.54-7.52 (m, IH), 7.50-7.47 (m, IH), 7.38-7.36 (m, 5H), 6.59 (s, IH), 4.62 (s, 2H); TLC R f (n- Hexanes:EtOAc 2:1) = 0.18; LRMS (electrospray) m/z calculated for C 2O H 17 C1N 5 (M+H) + 362.12, found 361.79.
(483)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.01 (s, IH), 7.82 (d, J= 8.0 Hz, IH ), 7.76 (s, IH), 7.73- 7.61 (m, 4H), 7.54 (d, J= 7.6 Hz, IH ), 7.36 (t, J= 7.2 Hz, 2H ), 121-125 (m, IH), 6.54 (s, IH), 4.44 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.24.
484 6-(2-Methoxyphenyl)-N-((5-phenyl-lH-pyrazol-3-yI)methyl)pyra zin-2-amine (484)
1 H NMR (400 MHz, CD 3 OD) δ 8.22 (s, IH), 7.79-7.65 (m, 2H), 7.64 (d, J= 7.2 Hz, 2H), 7.34-7.22 (m, 4H), 7.02-6.95 (m, 2H), 6.55 (s, IH), 4.61 (s, 2H), 3.80 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.47; LRMS (electrospray) m/z calculated for C 21 H 19 N 5 O(M+H) + 358.17, found 358.06.
6-(2,6-Dimethylphenyl)-iV-((5-phenyl-ljlϊ-pyrazoI-3-yl)m ethyl)pyrazin-2-amine (485)
1 H NMR (400 MHz, CD 3 OD) δ 7.90 (s, IH), 7.64-7.61 (m, 2H), 7.55 (s, IH), 7.37-7.29 (m, 3H), 7.17-7.13 (m, IH), 7.07-7.04 (m, 2H), 6.53 (s, IH), 4.56 (s, 2H), 2.06 (s, 6H); LRMS (electrospray) m/z calculated for C 22 H 22 N 5 (M+H) + 356.19, found 356.02.
1 H NMR (400 MHz, CD 3 OD) δ 7.95 (s, IH), 7.80 (s, IH), 7.66-7.65 (m, 2H), 7.61-7.58 (m, 2H), 7.53-7.51 (m, IH), 7.37 (t, J= 7.6 Hz, 2H), 7.31-7.29 (m, IH), 6.55 (s, IH), 4.61 (s, 2H), 2.31 (s, 3H); TLC ^ 7 (CH 2 Cl 2 MeOH 10:1) = 0.38.
7V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-4-o-tolylpyrimidin- 2-amine (487)
1 B. NMR (400 MHz, CDCl 3 ) δ 8.73 (d, J= 5.2 Hz, IH), 7.80 (d, J= 6.8 Hz, 2H), 7.42-7.22 (m, 7H), 7.16 (d, J= 5.2 Hz, IH), 6.63 (s, IH), 5.51 (s, 2H), 2.34 (s, 3H), 1.66 (s, 9H), 1.47 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.19.
488 4-(2-Chlorophenyl)-λ r -((5-phenyl-ljH r -pyrazol-3-yl)methyl)pyrimidin-2-amine (488)
1 H NMR (400 MHz, CD 3 OD) δ 8.12 (d, J= 5.2 Hz, IH), 7.45-7.44 (m, 2H), 7.32-7.30 (m, IH), 7.26-7.24 (m, IH), 7.19-7.12 (m, 4H), 7.08-7.05 (m, IH), 6.68 (d, J= 4.8 Hz, IH), 6.34 (s, IH), 4.43 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.28; LRMS (electrospray) m/z calculated for C 2O H 17 C1N 5 (M+H) + 362.12, found 362.00.
J /V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-4-(2-(trifluoromethyl) phenyl)pyrimidin-2-amine (489)
1 H NMR (400 MHz, CD 3 OD) δ 8.33 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.6 Hz, IH), 7.66-7.58 (m, 4H), 7.48 (d, J= 7.2 Hz, IH), 7.35-7.34 (m, 2H), 7.29-7.27 (m, IH), 6.71 (d, J= 5.2 Hz, IH), 6.53 (s, IH), 4.64 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.33.
490 4-(2-MethoxyphenyI)-7V-((5-phenyl-llf-pyrazol-3-yl)methyl)py rimidin-2-aiiiine (490)
1 H NMR (400 MHz, CD 3 OD) δ 8.25 (d, J= 5.2 Hz, IH), 7.82-7.80 (m, IH), 7.70-7.68 (m, 2H), 7.43-7.36 (m, 3H), 7.29-7.27 (m, IH), 7.19 (d, J= 5.2 Hz, IH), 7.09 (d, J= 8.4 Hz, IH), 7.01 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.67 (s, 2H), 3.85 (s, 3H); TLC ^(CH 2 Cl 2 MeOH 10:1) = 0.33.
4-(2,6-Dimethylphenyl)-N-((5-phenyl-lH-pyrazol-3-yl)methy l)pyrimidin-2-amine (491)
1 H NMR (400 MHz 5 CD 3 OD) δ 8.09 (d, J= 4.8 Hz, IH), 7.39 (m, 2H), 7.09 (m, 2H), 7.01 (m, IH), 6.79 (t, J= 7.6 Hz, IH), 6.79 (m, 2H), 6.28 (d, J= 5.2 Hz, IH), 6.26 (s, IH), 4.35 (s, 2H), 1.76 (s, 6H); TLC ^/(CH 2 Cl 2 MeOH 19:1) = 0.29.
3-Methyl-4-(2-((5-phenyI-lJϊ-pyrazol-3-yl)methylainino)p yriinidiii-4-yI)benzonitrile (492)
1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (d, J= 4.8 Hz, IH), 7.63 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 4.8 Hz, 2H) 5 7.50 (d, J= 8.4 Hz, IH) 5 7.39 (t 5 J= 7.8 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 6.71 (d, J= 7.8 Hz, IH), 6.50 (s, IH) 5 4.70 (d 5 J= 6.4 Hz 5 2H), 2.43 (s, 3H); TLC R f (n- Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.10.
5-Methyl-4-phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyI)py rimidm-2-amme (493)
1 H NMR (400 MHz, CD 3 OD) δ 8.22 (s, IH), 7.69-7.67 (m, 2H), 7.57-7.56 (m, 2H), 7.46-7.40 (m, 3H), 7.38-7.28 (m, 3H), 6.57(s, IH), 4.57 (s, 2H), 2.17 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.25; LRMS (electrospray) m/z calculated for C 21 H 20 N 5 (M+H) + 342.17, found 342.08.
494 5-Methyl-λ^-((5-phenyl-lH-pyrazoI-3-yl)methyl)-4-o-tolylpyr imidin-2-amine (494)
1 H NMR (400 MHz, CD 3 OD) δ 8.23 (s, IH), 7.66 (d, J= 6.8 Hz, 2H), 7.39-7.22 (m, 5H), 7.11 (d, J= 8.0 Hz, 2H), 6.53 (s, IH), 4.60 (s, 2H), 2.11 (s, 3H), 1.87 (s, 3H); TLC R f (n- Hexanes:EtOAc 3:7) = 0.33.
4-(2-Chlorophenyl)-5-methyl-λ L ((5-phenyl-lH-pyrazol-3-yl)methyl)pyrimidin-2-amine (495)
1 H NMR (400 MHz, CD 3 OD) δ 8.22 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.49 (t, J= 4.6 Hz, IH), 7.42-7.34 (m, 5H), 7.30-7.25 (m, IH), 6.55 (s, IH), 4.60 (s, 2H), 1.90 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.50.
496
5-Methyl-7V-((5-phenyl-lJE- r -pyrazol-3-yl)methyl)-4-(2- (trifluoromethyl)phenyl)pyrimidin-2-amine (496)
1 H NMR (400 MHz, CD 3 OD) δ 8.24 (s, IH), 7.81(d, J= 8.0 Hz, IH), 7.70-7.61 (m, 4H), 7.39-7.29 (m, 4H), 6.53 (s, IH), 4.60 (s, 2H), 1.87 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.36.
4-(2-Methoxyphenyl)-5-methyl-iV-((5-phenyl-lJϊ-pyrazol-3 -yl)methyl)pyriiiiidiii-2-anime
(497)
1 H NMR (400 MHz, CD 3 OD) δ 8.15 (s, IH), 7.68 (d, J= 6.0 Hz, 2H), 7.44-7.26 (m, 4H), 7.18 (dd, J= 7.6, 1.6 Hz, IH), 7.08 (d, J= 8.8 Hz, IH), 7.03 (t, J= 7.4 Hz, IH), 6.55 (s, IH), 4.60 (s, 2H), 3.78 (s, 3H), 1.92 (s, 3H); TLC i?/(«-Hexanes:EtOAc 3:7) = 0.29.
4-(5-Methyl-2-((5-phenyl-ljH r -pyrazol-3-yl)methyIamino)pyrimidin-4-yl)benzoiiitrile (498)
1 H NMR (400 MHz, CD 3 OD) δ 8.26 (s, IH), 7.82 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.70-7.60 (m, 2H), 7.40-7.22 (m, 3H), 6.55(s, IH), 4.64 (s, 2H), 2.17 (s, 3H); TLC R f (CH 2 Cl 2 MeOH 10:1) = 0.30.
3-Methyl-4-(5-methyl-2-((5-phenyl-lH-pyrazol-3-yl)methyIa mino)pyrimidin-4- yl)benzonitrile (499)
1 H NMR (400 MHz, CD 3 OD) δ 8.28 (s, IH), 7.70-7.60 (m, 4H), 7.38-7.32 (m, 4H), 6.52 (s, IH), 4.60 (s, 2H), 2.12 (s, 3H), 1.88 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.35.
500 2-(5-Methyl-2-((5-phenyl-lH-pyrazol-3-yl)methylamino)pyrimid in-4-yl)benzonitrile
(500)
1 H NMR (400 MHz, CD 3 OD) δ 8.17 (s, IH), 7.72-7.70 (m, 2H), 7.57-7.49 (m, 2H), 7.37-7.30 (m, 5H), 6.56 (s, IH), 4.62 (s, 2H), 2.00 (s, 3H).
3-(5-Methyl-2-((5-phenyl-l J H-pyrazol-3-yl)methylamino)pyrimidin-4-yl)benzoiiitrile (501)
1 H NMR (400 MHz, CD 3 OD) δ 8.25 (s, IH), 7.96 (s, IH), 7.89 (d, J= 8.4 Hz, IH), 7.80 (d, J = 8.0 Hz, IH), 7.66-7.62 (m, 3H), 7.38-7.36 (m, 2H), 7.31-7.29 (m, IH), 6.56 (s, IH), 4.64 (s, 2H), 2.18 (s, 3H);TLC ^/(CH 2 Cl 2 :MeOH 10:1) = 0.68; LRMS (electrospray) m/z calculated for C 22 H 19 N 6 (M+H) + 367.17, found 366.89.
4-(2-Chloro-4-fluorophenyl)-5-methyI-N-((5-phenyl-lH-pyra zol-3-yl)methyl)pyrimidiii- 2-amine (502)
1 H NMR (400 MHz, CD 3 OD) δ 8.25 (s, IH), 7.78-7.62 (m, 2H), 7.49-7.22 (m, 5H), 7.19 (t, J = 8.6 Hz, IH), 6.55 (s, IH), 4.61 (s, 2H), 1.94 (s, 3H); TLC ^(CH 2 Cl 2 MeOH 10:1) = 0.34.
4-Chloro-3-(5-methyl-2-((5-phenyl-liϊ-pyrazol-3-yl)methy Iamino)pyriinidiii-4- yl)benzonitrile (503)
1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, IH), 7.65-7.57 (m, 2H), 7.56 (d, J= 3.2 Hz, 2H), 7.38- 7.27 (m, 2H), 7.24 (s, IH), 6.47 (s, IH), 5.93 (s, IH), 4.63 (d, J= 5.2 Hz, 2H), 1.95 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.28; LRMS (electrospray) m/z calculated for C 22 H 17 ClN 6 (M+H + ) 400.86, found 400.96.
4-Fluoro-3-(5-methyl-2-((5-phenyl-lH-pyrazoI-3-yI)methyla mino)pyrimidin-4- yl)benzonitrile (504)
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, IH), 7.72-7.61 (m, 2H), 7.60 (d, J= 7.2 Hz, 2H), 7.35- 7.31 (m, 2H), 7.28-7.24 (m, 2H), 6.46 (s, IH), 6.32 (s, IH), 4.63 (d, J= 6.0 Hz, 2H), 1.99 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.33; LRMS (electrospray) m/z calculated for C 22 H 17 FN 6 (M+H + ) 384.41, found 384.98.
2-Fluoro-3-(5-methyl-2-((5-phenyl-l J fir-pyrazol-3-yI)methylamino)pyrimidin-4- yl)benzonitrile (505)
1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, IH), 7.35-7.26 (m, 4H), 7.04-6.91 (m, 4H), 6.13 (s, IH), 5.81 (s, IH), 4.31 (d, J= 6.0 Hz, 2H), 1.70 (s, 3H); TLC ^ 7 (CH 2 Cl 2 : MeOH 10:1) = 0.33; LRMS (electrospray) m/z calculated for C 22 H 17 FN 6 (M+H + ) 384.41, found 384.98.
4-(4-Cyano-2-methylphenyl)-2-((5-phenyl-liϊ-pyrazol-3-yl )methylamino)pyrimidine-5- carbonitrile (506)
1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (s, 0.9H), 8.66 (s, IH), 7.71-7.65 (m, 8H), 7.52-7.50 (m, 2H), 7.38-7.30 (m, 6H), 6.58 (s, IH), 6.51 (s, IH), 4.72 (s, 2H), 4.64 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H); LRMS (electrospray) m/z calculated for C 23 H 19 N 7 (M+H) + 392.16, found 392.04.
3-MethyI-4-(2-((5-phenyl-l J fir-pyrazoI-3-yl)methyIamino)-5-(trifluoromethyI)pyrimidin- 4-yl)benzonitrile (507)
1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, IH), 8.57 (s, IH), 7.42-7.29 (m, 16H), 6.50 (s, IH), 6.39 (s, IH), 4.74 (s, 2H), 4.64 (s, 2H), 2.12 (s, 6H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.37; LRMS (electrospray) m/z calculated for C 23 H 19 F 3 N 6 (M+H) + 435.15, found 435.00.
508
N-((lH-indazol-3-yl)methyl)-5-(2-chlorophenyl)-l,2,4-tria zin-3-amine (508)
1 H NMR (400 MHz, DMSO-έfc) δ 8.91 (s, IH), 7.84-7.81 (m, IH), 7.65-7.63 (m, 2H), 7.60- 7.55 (m, IH), 7.53-7.48 (m, 2H), 7.32 (t, J= 7.4 Hz, IH), 7.08-7.05 (m, IH), 4.96 (bs, 2H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.37; LRMS (electrospray) m/z calculated for Ci 7 Hi 4 ClN 6 (M+H) + 337.10, found 336.98.
5-(2-Chlorophenyl)-7V-((6-methoxy-l/r-indazol-3-yl)methyl )-l,2,4-triazin-3-amine (509)
1 H NMR (400 MHz, CD 3 OD) δ 8.88 (s, IH), 7.66-7.62 (m, 2H), 7.56-7.42 (m, 3H), 6.88 (s, IH), 6.71 (d, J= 7.6 Hz, IH), 4.99 (s, 2H), 3.83 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1)= 0.33.
510 iV-((lH-Pyrazolo[3,4-6]pyridin-3-yl)methyl)-5-(2-chloropheny l)-l,2,4-triazin-3-amine
(510)
1 H NMR (400 MHz, CD 3 OD) δ 8.87 (s, IH), 8.45 (dd, J= 4.4, 1.2 Hz, IH), 8.29 (d, J= 7.6 Hz, IH), 7.60 (d, J= 7.2 Hz, IH), 7.54-7.40 (m, 3H), 7.12 (dd, J= 8.0, 4.4 Hz, IH), 5.03 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.27.
4-(3-((l iϊ-Pyrazolo [3,4-6] py ridin-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (511)
1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (s, IH), 8.60 (t, J= 3.2 Hz, IH), 7.59-7.57 (m, 2H), 7.51 (d, J= 8.4 Hz, IH), 5.12 (s, IH), 2.41 (s, 3H); TLC R/ (CH 2 Cl 2 MeOH 10:1) = 0.25; LRMS (electrospray) m/z calculated for C 18 H 14 N 8 (MH-H + ) 342.36, found 342.94.
4-(2-((lH-Pyrazolo[3,4-6]pyridin-3-yl)methylamino)pyridin -4-yl)-3-methylbenzonitrile
(512)
1 H NMR (400 MHz, OMSO-d 6 ) δ 13.36 (s, IH), 8.46 (dd, J= 4.8, 1.6 Hz, IH), 8.25 (dd, J= 8.0, 1.6 Hz, IH), 8.07 (dd, J= 4.8, 1.2 Hz, IH), 7.78 (s, IH), 7.70 (dd, J= 8.0, 1.2 Hz, IH), 7.34 (d, J= 8.0 Hz, IH), 7.22 (m, IH), 7.12 (dd, J= 8.0, 4.4 Hz, IH), 6.49 (d, J= 1.6 Hz, IH), 6.48 (s, IH), 4.80 (s, 2H), 2.20 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.16.
7V-((lH-pyrazolo[3,4-c]pyridin-3-yI)methyl)-5-(2-chloroph enyl)-l,2,4-triazin-3-amine
(513)
1 H NMR (400 MHz, CD 3 OD) δ 8.92 (d, J= 0.8 Hz, IH), 8.88 (s, IH), 8.11 (d, J= 6.0 Hz, IH), 7.84 (d, J= 5.2 Hz, IH), 7.60 (d, J= 7.6 Hz, IH), 7.57-7.49 (m, 2H), 7.43 (m, IH), 5.08 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.12.
4-(2-((lH-Pyrazolo[3,4-b]pyridin-3-yl)methylamino)pyridin -4-yl)-3-chlorobenzoiiitrile
(514)
1 H NMR (400 MHz, CD 3 OD) δ 8.45 (dd, J= 4.6, 1.0 Hz, IH), 8.28 (d, J= 8.0 Hz, IH), 8.08 (d, J= 5.2 Hz, IH), 7.90 (d, J = 1.6 Hz, IH), 7.72 (dd, J= 7.8, 1.0 Hz, IH), 7.50 (d, J= 8.0 Hz, IH), 7.14 (dd, J= 8.0 Hz, 4.8 Hz, IH), 6.62 (s, 2H), 4.88 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 19:l) = 0.16.
4-(2-((lJBT-Pyrazolo[3,4-6]pyridin-3-yl)methylamiiio)pyri din-4-yl)-3- (trifluoromethyl)benzonitrile (515)
1 H NMR (400 MHz, CD 3 OD) δ 8.45 (d, J= 4.4 Hz, IH), 8.25 (d, J= 8.0 Hz, IH), 8.16 (s, IH), 8.05 (d, J= 5.2 Hz, IH), 8.00 (d, J= 8.0 Hz, IH), 7.52 (d, J= 8.0 Hz, IH), 7.13 (dd, J= 8.0, 4.8 Hz, IH), 6.53 (d, J= 5.2 Hz, 2H), 4.88 (s, 2H); TLC ^y(CH 2 Cl 2 =MeOH 19:1) = 0.25.
4-(2-((lH-pyrazolo[3,4-6]pyridin-3-yl)methylamino)-5-meth yIpyrimidin-4-yl)-3- methylbenzonitrile (516)
1 H NMR (400 MHz, CD 3 OD) δ 8.44 (d, J= 4.4 Hz, IH), 8.26 (s, IH), 8.21 (d, J= 7.2 Hz, IH), 7.65 (s, IH), 7.62 (d, J= 8.0 Hz, IH), 7.29 (d, J= 8.0 Hz, IH), 7.06 (dd, J= 7.8, 4.6 Hz, IH), 4.89 (s, 2H), 2.03 (s, 3H), 1.86 (s, 3H); TLC ^ 7 (CH 2 Cl 2 : MeOH 19:1) = 0.13.
4-(2-((lH-Pyrazolo[3,4-A]pyridin-3-yl)methylamino)-5-chlo ropyrimidin-4-yl)-3- methylbenzonitrile (517)
1 H NMR (400 MHz, CD 3 OD) δ 8.42 (d, J= 4.4 Hz, IH), 8.37 (s, IH), 8.21-8.19 (m, 2H), 7.64 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.06 (s, IH), 4.87 (s, 2H), 2.18 (s, 3H); LRMS (electrospray) m/z calculated for C 19 Hi 4 ClFN 7 (M+H) + 376.11, found 375.87.
4-(2-((lJEr-Pyrazolo[3,4-6]pyridin-3-yl)methylamino)-5-(t rifluoromethyl)pyrimidin-4-yl)- 3-methylbenzonitrile (518)
TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.56; LRMS (electrospray) m/z calculated for C 20 H 15 F 3 N 7 (M+H) + 410.13, found 409.87.
5-(2-Chlorophenyl)-N-((6-fluoro-lH-pyrazolo[3,4-6]pyridin -3-yl)methyl)-l,2,4-triazin-3- amine (519)
1 H NMR (400 MHz, CD 3 OD) δ 8.88 (s, IH), 8.36 (bs, IH), 7.61 (d, J= 7.2 Hz, IH), 7.54 (dd, J= 8.0, 1.6 Hz, IH), 7.49 (dt, J= 7.6, 2.0 Hz, IH), 7.44 (dt, J= 7.4, 1.6 Hz, IH), 6.76 (d, J= 8.4 Hz, IH), 5.00 (s, 2H); TLC #/(«-Hexanes:EtOAc 1:1) = 0.27.
3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl)-λ r -(4-methoxybenzyl)-lH- py razolo [3,4-ό] py ridin-6-amine (520)
1 H NMR (400 MHz, DMSO-^) δ 12.45 (s, IH), 8.86 (s, IH), 8.39 (bs, IH), 7.67 (m, IH), 7.60 (m, 2H), 7.55 (dt, J= 10.8, 1.6 Hz, IH), 7.49 (t, J= 10.0 Hz, IH), 7.30 (t, J= 5.6 Hz, IH), 7.20 (t, J= 8.6 Hz, 2H), 6.82 (m, 2H), 6.29 (d, J= 8.0 Hz, IH), 4.73 (bs, 2H), 4.41 (d, J = 5.6 Hz, IH), 3.67 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.14.
3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl)-lH r -pyrazolo[3,4-ό]pyridin-6- amine (521)
1 H NMR (400 MHz, DMSO-J 6 ) δ 12.35 (s, IH), 8.87 (s, IH), 8.30 (bs, IH), 7.68 (bs, IH), 7.60 (m, 2H), 7.53 (dt, J= 7.6, 1.6 Hz, IH), 7.47 (dt, J= 7.4, 1.6 Hz, IH), 6.20 (bs, 3H), 4.73 (bs, 2H); TLC ^/(CH 2 Cl 2 :MeOH 9:1) = 0.59.
4-(3-((6-Fluoro-lH-pyrazolo[3,4-A]pyridin-3-yI)methyIamin o)-l,2,4-triazin-5-yI)-3- methylbenzonitrile (522)
1 H NMR (400 MHz, DMSO-J 6 ) δ 13.47 (s, IH), 8.85 (s, IH), 8.67 (bs, IH), 8.39 (s, IH), 7.82 (s, IH), 7.77 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.6 Hz, IH), 6.88 (d, J= 8.8 Hz, IH), 4.87 (bs, 2H), 2.29 (bs, 3H); TLC #/(CH 2 Cl 2 :Me0H 9:1) = 0.40.
4-(3-((6-AnIiIiO-IH-PyFaZoIo [3,4-6] py ridin-3-yI)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (523)
1 H NMR (400 MHz, DMSO-J 6 ) δ 12.34 (s, IH), 8.83 (s, IH), 8.35 (bs, IH), 7.82 (s, IH), 7.78 (d, J= 8.0 Hz, IH), 7.68 (bs, IH), 7.67 (d, J= 8.0 Hz, IH), 6.19 (s, 3H), 4.70 (bs, 2H), 2.33 (bs, 3H); TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.39.
4-(2-((6-Fluoro-lH r -pyrazolo[3,4-6]pyridin-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (524)
1 H NMR (400 MHz, CDCl 3 with 20% CD 3 OD) δ 8.16 (t, J= 8.0 Hz, IH), 7.98 (d, J= 4.8 Hz, IH), 7.41 (s, IH), 7.38 (d, J= 8.0 Hz, IH), 7.12 (d, J= 7.6 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 6.40-6.39 (m, IH), 6.30 (s, IH), 4.72 (s, 2H), 2.04 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.47; LRMS (electrospray) m/z calculated for C 20 Hi 5 FN 6 (M+H + ) 358.37, found 359.01.
4-(2-((6-Amino-li/-pyrazoIo[3,4-ό]pyridin-3-yI)methylami no)pyridin-4-yl)-3- methylbenzonitrile (525)
1 H NMR (400 MHz, OMSO-d 6 ) δ 8.06 (d, J= 6.0 Hz, IH), 7.77 (s, IH), 7.70 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.0 Hz, IH), 7.05 (t, J= 6.0 Hz, IH), 6.47-6.46 (m, 2H), 6.23 (d, J= 8.8 Hz, IH), 6.19 (s, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.20 (s, 3H); TLC R f (CH 2 Cl 2 MeOH 20:1) = 0.38; LRMS (electrospray) m/z calculated for C 20 H 17 N 7 (M+H + ) 355.40, found 355.88.
3-Chloro-4-(2-((6-fluoro-lH r -pyrazoIo[3,4-6]pyridin-3-yl)methylamino)pyridin-4- yl)benzonitrile (526)
1 H NMR (400 MHz, CDCl 3 ) δ 8.24-8.20 (m, IH), 7.73 (t, J= 1.6 Hz, IH), 7.59-7.56 (m, IH), 7.37 (d, J= 8.0 Hz, IH), 6.77-6.75 (m, IH), 6.64-6.62 (m, IH), 6.49 (s, IH), 5.26 (s, IH), 4.92 (d, J= 5.6 Hz, 2H); TLC R 1 (CH 2 Cl 2 : MeOH 10:1) = 0.47; LRMS (electrospray) m/z calculated for C 19 H 12 ClFN 6 (M+H + ) 378.79, found 378.86.
4-(2-((6-Amino-l//-pyrazolo[3,4-ό]pyridin-3-yl)methylami no)pyridin-4-yl)-3- chlorobenzonitrile (527)
1 U NMR (400 MHz, DMSO-J 6 ) δ 8.13 (d, J= 1.6 Hz, IH), 8.07 (d, J= 5.2 Hz, IH), 7.87- 7.85 (m, IH), 7.69 (d, J= 8.8 Hz, IH), 7.53 (d, J= 7.6 Hz, IH), 7.12 (t, J= 5.2 Hz, IH), 6.53 (s, IH), 6.51-6.49 (m, IH), 6.21 (d, J= 8.8 Hz, 2H), 6.17 (s, 2H), 4.60 (d, J= 6.0 Hz, 2H); TLC Rf (CH 2 Cl 2 :MeOH 5:1) = 0.91; LRMS (electrospray) m/z calculated for C 19 H 14 ClN 7 (M+H + ) 375.81, found 375.87.
4-(2-((6-Fluoro-lJϊ-pyrazolo[3,4-6]pyridin-3-yI)methylai nino)pyridiii-4-yl)-3- (trifluoromethyl)benzonitrile (528)
1 U NMR (400 MHz, CDCl 3 ) δ 8.16 (t, J= 7.2 Hz, IH), 8.01 (s, IH), 7.84 (d, J= 8.4 Hz, IH), 7.42 (d, J= 8.0 Hz, IH), 6.77 (d, J= 8.4 Hz, IH), 6.56 (d, J= 5.6 Hz, IH), 6.40 (s, IH), 5.28 (d, J= 1.6 Hz, IH), 4.92 (d, J= 5.2 Hz, 2H); TLC R f (CH 2 Cl 2 : MeOH 20:1) = 0.47; LRMS (electrospray) m/z calculated for C 20 Hj 2 F 4 N 6 (M+H + ) 412.34, found 412.99.
4-(2-((6-Amino-Hr-pyrazolo[3,4-6]pyridin-3-yl)methylamino )pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (529)
1 H NMR (400 MHz, CD 3 OD) δ 8.11 (s, IH), 8.06-8.04 (m, IH), 8.02-8.00 (m, IH), 7.78 (d, J = 8.8 Hz, IH), 7.54 (d, J= 8.0 Hz, IH), 6.54 (s, IH), 6.53 (s, IH), 4.72 (s, 2H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.52; LRMS (electrospray) m/z calculated for C 20 H 14 F 3 N 7 (MH-H + ) 409.37, found 410.25.
4-(5-ChIoro-2-((6-fluoro-l//-pyrazolo[3,4-ό]pyridin-3-yl )methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (530)
1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, IH) 5 8.13 (bs, IH), 7.58-7.56 (m, 2H), 7.31 (d, J= 8.0 Hz, IH), 6.74-6.73 (bs, IH), 4.94 (s, 2H), 2.21 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.31; LRMS (electrospray) m/z calculated for Ci 9 H 14 ClFN 7 (M+H) + 394.10, found 393.89.
4-(2-((6-Amino-lH-pyrazolo[3,4-o]pyridin-3-yl)methylamino )-5-chloropyriinidiii-4-yl)-3- methylbenzonitrile (531)
1 H NMR (400 MHz, OMSO-d 6 ) δ 12.36 (s, IH), 8.47 (bs, IH), 8.10-8.05 (m, 0.4H), 8.04-8.01 (m, 1.4H), 7.84-7.74 (m, 3.4H), 7.46-7.42 (m, IH), 7.30-7.28 (m, 0.7H), 6.23 (s, 3H), 4.64- 4.62 (m, 2H), 2.14-2.08 (m, 3.4H); LRMS (electrospray) m/z calculated for Ci 9 H 16 ClN 8 (MH-H) + 391.12, found 390.90.
4-(2-((6-Fluoro-l/f-pyrazolo[3,4-6]pyridin-3-yl)methylami no)-5- (trifluoromethyl)pyrimidin-4-yl)-3-methyIbenzonitrile (532)
TLC i?/(CH 2 Cl 2 :Me0H 19:1) = 0.35; LRMS (electrospray) m/z calculated for C 20 H 14 F 4 N 7 (M+H) + 428.12, found 427.82.
4-(2-((6-Amino-lH-pyrazolo[3,4-ό]pyridin-3-yl)methylamin o)-5- (trifluoromethyl)pyrimidin-4-yl)-3-methylbenzonitrile (533)
TLC i?/(CH 2 Cl 2 :Me0H 9:1) = 0.48; LRMS (electrospray) m/z calculated for C 20 H 16 F 3 N 8 (M+H) + 425.15, found 424.96.
4-(2-((5-(4-Methoxyphenyl)-li7-pyrazol-3-yl)methylamino)p yridin-4-yl)-3- methylbenzonitrile (534)
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J= 4.8 Hz, IH), 7.59 (d, J= 8.0 Hz, 2H), 7.52-7.48 (m, H), 7.24 (s, IH), 6.93-6.91 (m, IH), 6.53 (d, J= 5.2 Hz, IH), 6.40 (s, IH), 6.32 (s, IH), 5.06 (s, IH), 4.59 (d, J= 6.0 Hz, IH), 3.82 (s, IH), 2.14 (s, IH); TLC R 1 (CH 2 Cl 2 : MeOH 20:1) = 0.63.
4-(2-((5-(4-Hydroxyphenyl)-lH-pyrazol-3-yl)methylamino)py ridin-4-yl)-3- methylbenzonitrile (535)
1 H NMR (400 MHz, CD 3 OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.55 (s, IH), 7.51-7.49 (m, IH), 7.46 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 7.6 Hz, IH), 6.79-6.77 (m, 2H), 6.48-6.45 (m, 2H), 6.41 (s, IH), 4.51 (s, 2H), 2.19 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.43.
3-Methyl-4-(2-((5-(4-(2-morpholinoethoxy)phenyl)-l/7-pyra zol-3- yl)methyIamino)pyridin-4-yl)benzonitrile (536)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J= 5.2 Hz, IH), 7.57 (d, J= 8.4 Hz, 2H), 7.50 (s, IH), 7.47 (d, J= 8.0 Hz, IH), 7.22 (t, J= 7.6 Hz, IH), 6.90 (d, J= 8.8 Hz, 2H), 6.52-6.50 (m, IH), 6.39 (s, IH), 6.31 (s, IH), 5.36 (s, IH), 4.57 (d, J= 6.0 Hz, 2H), 4.11 (t, J= 6.0 Hz, 2H), 3.71 (t, J= 4.8 Hz, 4H), 2.79 (t, J= 6.0 Hz, 2H), 2.56 (t, J= 4.8 Hz, 4H), 2.22 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.43; LRMS (electrospray) m/z calculated for C 29 H 30 N 6 O 2 (M+H + ) 494.59, found 495.05.
(R)-3-Methyl-4-(2-((5-(4-(morpholin-2-ylmethoxy)phenyl)-l H-pyrazol-3- yl)methylamino)pyridin-4-yl)benzonitrile (537)
1 H NMR (400 MHz, CD 3 OD) δ 8.02 (d, J= 5.2 Hz, IH), 7.55 (d, J= 8.8 Hz, 3H), 7.53-7.51 (m, IH), 7.27 (d, J= 8.0 Hz, IH), 6.92-6.90 (m, 2H), 6.50-6.48 (m, IH), 6.46 (d, J= 2.8 Hz, 2H), 4.83 (s, 3H), 4.53 (s, 2H), 3.96-3.90 (m, 2H), 3.89-3.79 (m, 2H), 3.66-3.60 (m, IH), 3.32 (s, 2H), 2.95-2.92 (m, IH), 2.79-2.68 (m, IH), 2.12 (s, 3H); TLC R f (CH 2 Cl 2 :MeOH 5:1) = 0.11; LRMS (electrospray) m/z calculated for C 28 H 28 N 6 O 2 (M+H + ) 480.56, found 481.12.
4-(2-((5-(5-Bromofuran-2-yl)-lH-pyrazol-3-yl)methylamino) pyridin-4-yl)-3- methylbenzonitrile (538)
1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J= 5.2 Hz, IH), 7.51-7.48 (m, 2H), 7.22 (d, J= 8.4 Hz, IH), 6.56-6.53 (m, 2H), 6.38 (s, IH), 6.34 (d, J= 3.6 Hz, IH), 6.31 (s, IH), 4.57 (d, J= 5.6 Hz, 2H), 2.23 (s, 3H); TLC i?/(rc-Hexanes: EtOAc 1:2) = 0.27.
4-(2-((5-(Furan-2-yl)-l/r-pyrazol-3-yl)methylammo)pyridin -4-yl)-3-methylbenzonitrile
(539)
1 H NMR (400 MHz, CD 3 OD) δ 8.03 (d, J= 3.6 Hz, IH), 7.62 (s, IH), 7.57 (d, J= 8.0 Hz, IH), 7.49 (s, IH), 7.32 (d, J= 8.0 Hz, IH), 6.64 (s, IH), 6.53 (d, J= 4.4 Hz, IH), 6.47-6.44 (m, 3H), 4.55 (sm, 2H), 2.24 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.25; LRMS (electrospray) m/z calculated for C 21 Hi 8 N 5 O (M+H) + 356.15, found 356.01.
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-l i | y-pyrazol-5-yl)furaii-2- carbonitrile (540)
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J= 5.2 Hz, IH), 7.52-7.49 (m, 2H), 7.23 (d, J= 7.2 Hz, IH), 6.56-6.54 (m, 2H), 6.39 (s, IH), 6.34 (d, J= 3.2 Hz, IH), 6.32 (s, 1H),4.57 (d, J= 5.6 Hz, 2H), 2.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.19; LRMS (electrospray) m/z calculated for C 22 H π N 6 O(M+H) + 381.15, found 381.02.
4-(2-((5-(4-CyanophenyI)-2H-pyrazol-3-yl)methylamino)pyri diii-4-yl)-3- methylbenzonitrile (541)
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J= 5.2 Hz, IH), 7.86 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.54-7.51 (m, 2H), 7.24 (d, J= 8.0 Hz, IH), 6.60 (dd, J= 5.4, 1.4 Hz, IH), 6.54 (s, IH), 6.35 (s, IH), 5.12 (br, IH), 4.63(d, J= 6.0 Hz, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C 24 H 18 N 6 (M+H) + 391.16, found 391.41.
4-(2-((5-(3-Cyanophenyl)-i]ϊ-pyrazol-3-yI)methylamino)py ridin-4-yI)-3- methylbenzonitrile (542)
1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (d, J= 5.2 Hz, IH), 8.04-7.99 (m, 2H), 7.58-7.49 (m, 4H), 7.24 (s, IH), 6.60 (dd, J= 5.2, 1.6 Hz, IH), 6.51 (s, IH), 6.35 (s, IH), 5.09 (br, IH), 4.64 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C 24 H 18 N 6 (M+H) + 391.16, found 391.47.
4-(2-((5-(3-Bromo-4-fluorophenyl)-iH-pyrazol-3-yl)methyla mino)pyridin-4-yl)-3- methylbenzonitrile (543)
1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J= 5.2 Hz, IH), 7.93 (dd, J= 6.4, 2.0 Hz, IH), 7.65 (m, IH), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.24 (X, J= 8.2 Hz, IH), 7.11 (X, J= 8.4 Hz, IH), 6.57 (dd, J= 5.2, 0.8 Hz, IH), 6.43 (s, IH), 6.33 (s, IH), 4.60 (d, J= 6.0 Hz, IH), 2.25 (s, IH)
4-(3-((lH-Pyrazolo[3,4-&]pyridin-3-yl)methylamino)-l, 2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (544)
1 H NMR (400 MHz, CD 3 OD) δ 8.72 (s, IH), 8.46-8.45 (m, IH), 8.27 (s, IH), 8.19-8.10 (s, IH), 7.76 (d, J= 8.0 Hz, IH), 7.11 (s, IH), 5.02 (s, 2H); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.11.
4-(3-((6-fluoro-ljH r -pyrazoIo[3,4-b]pyridin-3-yl)methylamino)-l,2,4-triazin-5-yl )-3- (trifluoromethyl)benzonitrile (545)
1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (s, IH), 8.18-8.12 (m, IH), 8.27 (s, IH), 7.98 (d, J= 6.4 Hz, IH), 7.68-7.65 (m, IH), 6.79-6.73 (m, 2H), 5.11 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.32.
4-(3-((6-Amino-lH-pyrazolo[3,4-b]pyridin-3-yl)methylamino )-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (546)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.85 (s, IH), 8.85 (s, IH), 8.33 (d, J= 8.0 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 6.23 (s, 2H), 4.82 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.10
4-(3-((5-(4-Methoxyphenyl)-lH-pyrazol-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (547)
1 H NMR (400 MHz, CD 3 OD) δ 8.77 (s, IH), 7.70 (s, IH), 7.68 (d, J= 0.8 Hz, 2H), 7.60 (s, 2H), 6.95 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.73 (s, 2H), 3.80 (s, 3H), 2.43 (s, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.40.
4-(3-((5-(4-Hydroxyphenyl)-lfl-pyrazoI-3-yl)methylamino)- l,2,4-triaziii-5-yl)-3- methylbenzonitrile (548)
1 H NMR (400 MHz, CD 3 OD) δ 8.76 (s, IH), 7.69 (s, IH), 7.66 (d, J= 0.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 6.81-6.79 (m, 2H), 6.46 (s, IH), 4.70 (s, 2H), 2.43 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.38
549
3-Metb.yl-4-(3-((5-(4-(2-morpholinoethoxy)phenyl)-lJET-py razol-3-yl)methylamino)-l,2,4- triazin-5-yl)benzonitrile (549)
1 H NMR (400 MHz, CD 3 OD) δ 8.76 (s, IH), 7.68 (s, IH), 7.66 (s, 2H), 7.59 (s, 2H), 6.96 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.79 (s, 2H), 4.17-4.14 (m, 2H), 3.79-3.65 (m, 4H), 2.81-2.79 (m, 2H), 2.60-2.57 (m, 4H), 2.42 (s, 3H); TLC ^/(CH 2 Cl 2 :MeOH 15:1) = 0.37.
(S)-3-Methyl-4-(3-((5-(4-(morpholin-2-ylmethoxy)phenyI)-l iϊ-pyrazoI-3- y I)methylamino)-1 ,2,4-triazin-5-yl)benzonitrile (550)
1 H NMR (400 MHz, CD 3 OD) δ 8.77 (s, IH), 7.70-7.58 (m, 4H), 6.96 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.78 (s, 2H), 4.01-3.94 (m, IH), 3.92-3.81 (m, IH), 3.67-3.61 (m, IH), 3.05-2.96 (m, 2H), 2.83-2.43 (m, 4H); TLC i?/(CH 2 Cl 2 :Me0H 5:1) = 0.21.
4-(3-((5-(Pyridin-2-yI)-ljH r -pyrazol-3-yl)methyIamino)-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (551)
1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, IH), 8.59 (d, J= 4.4 Hz, IH), 8.11 (s, 2H), 7.98 (d, J= 8.0 Hz, IH), 7.76-7.67 (m, 3H), 7.62-7.60 (m, 2H), 6.71 (s, IH), 4.82 (s, 2H); TLC R 1 (CH 2 Cl 2 :Me0H 10:1) = 0.47.
4-(2-((l/7-PyrazoIo[3,4-A]pyridin-3-yl)methyIamino)pyrimi diii-4-yl)-3- methylbenzonitrile (552)
1 H NMR (400 MHz, CDCl 3 ) δ 8.57-8.55 (m, IH), 8.46 (d, J- 5.2 Hz, IH), 8.14 (d, J= 7.6 Hz, IH), 7.55-7.54 (m, 2H), 7.49-7.47 (m, IH), 7.10-7.07 (m, IH), 6.68 (d, J= 5.2 Hz, IH), 5.06 (d, J= 5.6 Hz, 2H), 2.39 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.22.
4-(2-((6-Fluoro-lf/-pyrazolo[3,4-ό]pyridin-3-yl)methylam ino)pyrimidiii-4-yl)-3- methylbenzonitrile (553)
1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, J= 5.2 Hz, IH), 8.32-8.28 (m, IH), 7.62-7.59 (m, 2H), 7.50 (d, J= 8.0 Hz, IH), 6.75 (d, J- 5.2 Hz, IH), 4.92 (s, 2H), 2.34 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.52.
4-(2-((6-Amino-l//φyrazolo[3,4-ό]pyridin-3-yl)methylami no)pyrimidin-4-yl)-3- methylbenzonitrile (554)
1 H NMR (400 MHz, DMSO-^) δ 8.41 (d, J- 4.8 Hz, IH), 7.78-7.68 (m, 3H), 7.56 (d, J= 8.0 Hz, IH), 6.76-6.75 ( m, IH), 6.18 (s, IH), 4.66 (d, J= 4.8 Hz, 2H), 2.31 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.26.
3-Methyl-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)pyrimidin-4- yl)benzonitrile (555)
1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, IH), 8.45 (d, J= 5.2 Hz, IH), 7.83-7.70 (m, 2H), 7.68- 7.48 (m, 3H), 7.21-7.19 (m, IH), 6.70 (d, J= 4.8 Hz, IH), 6.66 (d, J= 4.8 Hz, IH), 4.73 (d, J = 5.6 Hz, 2H), 2.46 (s, 3H).
4-(2-((4-Bromo-5-(pyridin-2-yl)-l/- r -pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (556)
1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J= 3.2 Hz, IH), 8.21 (d, J= 5.6 Hz, IH), 7.78 (t, J= 4.0 Hz, 2H), 7.52-7.51 (m, 2H), 7.31-7.26 (m, 2H), 6.53 (d, J= 5.2 Hz, IH), 6.45 (s, 2H), 4.62 (d, J= 5.6 Hz, 2H), 2.29 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.69; LRMS (electrospray) m/z calculated for C 22 H 17 BrN 6 (M+H) + 445.31, found 445.28.
4-(2-((l//-Benzo [d\ imidazol-2-yl)methylamino)pyridin-4-yl)-3-methyIbenzonitrile (557) 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J= 4.8 Hz, IH), 7.81 (s, IH), 7.77 (d, J= 8.0 Hz, IH), 7.55 (s, 2H), 7.24-7.20 (m, 2H), 6.63 (d, J= 5.2 Hz, IH), 6.41 (s, IH), 4.82 (s, 2H), 2.27 (s, 3H); TLC ^ 7 (CH 2 Cl 2 IMeOH 20:1) = 0.46.
4-(2-((lH-Pyrrolo[2,3-^]pyridin-3-yl)methylamino)pyridin- 4-yl)-3-methylbenzonitrile
(558)
1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (d, J= 4.0 Hz, IH), 8.20 (d, J= 5.2 Hz, IH), 8.01-7.99 (m, IH), 7.53 (d, J= 4.4 Hz, IH), 7.50 (s, IH), 7.32 (s, IH), 7.25-7.08 (m, IH), 6.54- 6.52 (m, IH), 6.31 (s, IH), 4.69 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.43
4-(2-((5-(4-FIuorophenyl)-l//-pyrazol-3-yl)methylamino)py ridin-4-yl)-3- methylbenzonitrile (559)
1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J= 5.2 Hz, IH), 7.70-7.67 (m, 2H), 7.54-7.50 (m, 2H), 7.24 (d, J= 8.0 Hz, IH), 7.10-7.06 (m, IH), 6.57-6.56 (m, IH), 6.44 (s, IH), 6.33 (s, IH), 4.61 (d, J= 6.0 Hz, 2H), 2.26 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.19.
560
4-(2-((5-(4-Fluorophenyl)-lH-pyrazol-3-yl)methylamino)pyr idin-4-yI)-3,5- dimethylbenzonitrile (560)
1 U NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J= 5.2 Hz, IH), 7.69-7.65 (m, 2H), 7.35 (d, J= 4.8 Hz, 2H), 7.09-7.04 (m, 2H), 6.42 (s, IH), 6.40-6.38 (m, IH), 6.18 (s, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.04 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.45.
4-(2-((lH-Pyrrolo[2,3-^]pyi*idin-5-yl)methylamino)pyridin -4-yl)-3-methylbenzoiiitrile (561)
1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, IH), 8.19 (d, J= 4.8 Hz, IH), 7.96 (d, J= 1.6 Hz, IH), 7.51 (d, J= 2.0 Hz, IH), 7.49 (s, IH), 7.34 (t, J= 3.0 Hz, IH), 7.24 (s, IH), 6.53-6.52 (m, IH), 6.47-6.46 (m, IH), 6.28 (s, IH), 4.63 (d, J= 6.0 Hz, 2H), 2.28 (s, 3H); TLC R f (n- Hexanes:EtOAc 1:1) = 0.52.
3-Methyl-4-(2-((7-nitro-lH-indol-3-yI)methylamino)pyridii i-4-yl)benzonitrile (562)
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J= 4.4 Hz, IH), 8.03 (d, J= 7.6 Hz, IH), 7.52 (s, IH), 7.50 (d, J= 7.6 Hz, IH), 7.39 (d, J= 2.4 Hz, IH), 7.24-7.19 (m, 2H), 6.54-6.53 (m, IH), 6.31 (s, IH), 4.74 (d, J= 5.2 Hz, 2H), 2.01 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.79.
4-(2-((7-Amino-l/- r -indol-3-yl)methylamino)pyridin-4-yl)-3-methylbenzonitrile (563)
1 H NMR (400 MHz, CD 3 OD) δ 8.02 (d, J= 4.8 Hz, IH), 7.62 (s, IH), 7.58-7.55 (m, IH), 7.32 (d, J= 7.6 Hz, IH), 7.19 (s, IH), 7.08-7.02 (m, 2H), 6.86-6.80 (m, IH), 6.53-6.48 (m, IH), 4.60 (s, 2H), 2.02 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.23.
4-(2-((5-(2-MethoxyphenyI)-l/f-pyrazol-3-yl)methylamino)p yridin-4-yl)-3- methylbenzonitrile (564)
1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J= 5.2 Hz, IH), 7.63-7.61 (m, IH), 7.50-7.47 (m, 2H), 7.31-7.23 (m, 2H), 7.03-6.99 (m, 2H), 6.60 (s, IH), 6.49-6.48 (m, IH), 6.34 (s, IH), 4.59 (d, J = 5.2 Hz, 2H), 3.90 (s, 3H), 2.23 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.55.
4-(2-((5-(3-Methoxyphenyl)-lH-pyrazol-3-yl)methylamino)py ridin-4-yl)-3- methylbenzonitrile (565)
1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J= 5.6 Hz, IH), 7.54 (s, IH), 7.51 (d, J= 5.2 Hz, IH), 7.34-7.21 (m, 4H), 6.89-6.86 (m, IH), 6.56-6.55 (m, IH), 6.49 (s, IH), 6.33 (s, IH), 4.62 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.26 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.31.
4-(2-((5-(2-Hydroxyphenyl)-lH-pyrazol-3-yl)methylamino)py ridin-4-yl)-3- methylbenzonitrile (566)
1 H NMR (400 MHz, CD 3 OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.62 (s, IH), 7.58-7.55 (m, 2H), 7.33 (d, J= 8.0 Hz, IH), 7.15-7.10 (m, 2H), 6.88-6.66 (m, 2H), 6.66 (s, IH), 6.50-6.54 (m, IH), 6.50 (s, IH), 4.61 (s, 2H), 2.50 (s, 3H); TLC ^(CH 2 Cl 2 :MeOH 20:1) = 0.92.
4-(2-((5-(3-Hydroxyphenl)-lH-pyrazol-3-yl)methylamino)pyr idin-4-yl)-3- methylbenzonitrile (567)
1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J= 5.6 Hz, IH), 7.49 (s, IH), 7.47 (s, IH), 7.31-7.20 (m, 2H), 7.17 (d, J = 9.6 Hz, IH), 7.12 (d, J= 7.6 Hz, IH), 6.90-6.88 (m, IH), 6.56 (d, J = 5.2 Hz, IH), 6.42 (s, IH), 6.31 (s, IH), 4.58 (d, J= 5.6 Hz, IH), 2.15 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.46.
4-(2-((5-(6-Butyl-5-chloropyridin-2-yl)-lJϊ-pyrazol-3-yI )methyIamino)pyridin-4-yl)-3- methylbenzonitrile (568)
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J= 5.2 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.51 (s, IH), 7.49 (d, J= 8.0 Hz, IH), 7.40 (d, J= 8.4 Hz, IH), 7.25-7.23 (m, IH), 6.67 (s, IH), 6.52-6.50 (m, IH), 6.33 (s, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.94-2.91 (m, 2H), 2.24 (s, 3H), 1.70-1.71 (m, 2H), 1.46-1.37 (m, 2H), 0.95-0.82 (m, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.13.
3-Methyl-4-(2-((7-nitro-lλT-benzo[(/]imidazol-2-yl)methy lamino)pyridin-4- yl)benzonitrile (569)
1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J= 5.2 Hz, IH), 8.13 (d, J= 8.0 Hz, IH), 8.03 (d, J= 8.0 Hz, IH), 7.54 (s, IH), 7.52 (d, J= 8.0 Hz, IH), 7.35-7.27 (m, IH), 7.24 (s, IH), 6.66 (d, J = 5.2 Hz, IH), 6.44 (s, IH), 4.90 (d, J= 5.6 Hz, 2H), 2.04 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.38.
4-(2-((5-(5-Chloropyridin-2-yl)-lH-pyrazol-3-yl)methylami no)pyridin-4-yl)-3- methylbenzonitrile (570)
1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (t, J= 1.6 Hz, IH), 8.17 (d, J= 5.2 Hz, IH), 7.65 (s, IH), 7.49-7.46 (m, IH), 7.22-7.16 (m, IH), 6.68 (s, IH), 6.51 (d, J= 5.2 Hz, IH), 6.30 (s, IH), 4.58 (d, J= 5.6 Hz, 2H), 2.25 (s, 3H); TLC ^/(CH 2 Cl 2 : MeOH 20:1) = 0.68.
4-(2-((7-Amino-lH-benzo[rf]imidazol-2-yl)methylamino)pyri din-4-yl)-3- methylbenzonitrile (571)
1 H NMR (400 MHz, CD 3 OD) δ 8.08 (d, J= 4.8 Hz, IH), 7.65 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 7.12-7.03 (m, 2H), 6.90 (s, IH), 6.59-6.57 (m, IH), 6.53 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C 2 jH 18 N 6 (M+H) + 354.41, found 354.40.
4-(3-((5-(4-Fluorophenyl)-lJE- r -pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- methylbenzonitrile (572)
1 H NMR (400 MHz, CDCl 3 ) δ 8.73 (s, IH), 7.65-7.53 (m, 5H), 7.22-7.16 (m, IH), 7.05 (t, J= 8.8 Hz, 2H), 6.48 (s, IH), 4.81 (s 2H), 2.46 (s, 3H).
4-(2-((5-(5-Fluoropyridin-2-yl)-lH-pyrazol-3-yl)methylami no)pyridin-4-yl)-3- methylbenzonitrile (573)
1 HNMR (400 MHz, CD 3 OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.96-7.90 (m, IH), 7.73 (s, IH), 7.64 (s, IH), 7.60-7.58 (m, IH), 7.35 (d, J= 8.0 Hz, IH), 6.96-6.93 (m, IH), 6.82 (s, IH), 6.58- 6.53 (m, IH), 6.51 (s, IH), 4.60 (s 2H), 2.27(s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.43.
4-(2-((3H-Imidazo[4,5-6]pyridin-2-yl)methylamino)pyridin- 4-yl)-3-methylbenzoiiitrile
(574)
1 U NMR (400 MHz, CD 3 OD) δ 8.31 (d, J= 3.6 Hz, IH), 8.06 (d, J= 5.2 Hz, IH), 7.93 (d, J= 8.0 Hz, IH), 7.65 (s, IH), 7.60 (d, J= 8.8 Hz, IH), 7.35 (d, J= 8.0 Hz, IH), 7.28-7.25 (m, IH), 6.60-6.58 (m, IH), 4.59 (s, 2H), 2.15 (s, 3H)
4-(2-((5-(2-Chloro-4-fluorophenyl)-ljH r -pyrazol-3-yl)methylamino)pyridin-4-yI)-3- methylbenzonitrile (575)
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J= 5.2 Hz, IH), 7.69-7.66 (m, IH), 7.54 (s, IH), 7.52 (d, J= 7.6 Hz, IH), 7.25-7.19 (m, 2H), 7.06-7.01 (m, IH), 6.61 (s, IH), 6.58-6.56 (m, IH), 6.35 (s, IH), 4.63 (d, J= 5.6 Hz, 2H), 2.32 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.10.
4-(2-((5-(4-Methoxypyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yl)-3- methylbenzonitrile (576)
1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J= 5.2 Hz, IH), 8.20 (d, J= 4.8 Hz, IH), 7.53 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.31-7.22 (m, 2H), 6.77-6.75 (m, IH), 6.72 (s, IH), 6.53 (d, J= 5.2
Hz, IH), 6.37 (s, IH), 4.63 (d, J= 4.4 Hz, 2H), 3.94 (s, 3H), 2.25 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.46.
3-Methyl-4-(2-((5-nitro-l/- r -indazol-3-yl)methylamino)pyridiiι-4-yl)benzonitrile (577)
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.94 (d, J= 2.0 Hz, IH), 8.15-8.12 (m, IH), 8.07 (d, J= 5.2 Hz, IH), 7.78 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.64 (d, J= 9.2 Hz, IH), 7.40-7.32 (m, IH), 6.50-6.48 (m, IH), 4.88 (d, J= 6.4 Hz, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.10.
4-(2-((5-Amino-lJϊ-indazol-3-yl)methyIamino)pyridin-4-yl )-3-methylbenzonitrile (578)
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J= 5.2 Hz, IH), 7.53 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.27-7.25 (m, 2H), 6.99 (t, J= 2.2 Hz, IH), 6.66-6.86 (m, IH), 6.52-6.51 (m, IH), 6.41 (s, IH), 4.84 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 15:1) = 0.39.
4-(3-((l/ir-pyrazolo [3,4-ϋ>] py ridin-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- chlorobenzonitrile (579)
1 H NMR (400 MHz, CD 3 OD) δ 8.91 (s, IH), 8.46 (d, J= 4.8 Hz, IH), 8.29 (bs, IH), 7.98 (s, IH), 7.79 (m, 2H), 7.12 (q, J= 4.4 Hz, IH), 5.03 (s, 2H); TLC ^/(CH 2 Cl 2 :MeOH 20:1) = 0.16.
3-Chloro-4-(3-((6-fluoro-lH-pyrazolo[3,4-6]pyridin-3-yl)m ethylamino)-l,2,4-triazin[-5- yl)benzonitrile (580)
1 H NMR (400 MHz, CD 3 OD) δ 8.91 (s, IH), 8.35 (bs, IH), 7.99 (s, IH), 7.77 (m, 2H), 6.78 (d, J= 8.8 Hz, IH), 5.00 (s, 2H); TLC λ/(CH 2 Cl 2 :Me0H 20:1) = 0.24; LRMS (electrospray) m/z calculated for Ci 7 H n ClFN 8 (M+H) + 381.08, found 381.13.
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-yIamino)methyl )-lJEr-pyrazol-5-yl)-iV- methylfuran-2-carboxamide (581)
1 H NMR (400 MHz, CD 3 OD) δ 8.07 (t, J= 5.4 Hz, IH), 7.66 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.12 (d, J= 3.6 Hz, IH), 6.78 (d, J= 3.6 Hz, IH), 6.65 (s, IH), 6.58 (t, J= 6.4 Hz, IH), 6.51 (d, J= 6.8 Hz, IH), 4.62 (s, 2H), 2.91 (s, 3H), 2.28 (s, 3H); TLC ^ 7 (CH 2 Cl 2 IMeOH 20:1) = 0.19; LRMS (electrospray) m/z calculated for C 23 H 2 iN 6 O 2 (M+H) + 413.17, found 413.38.
3-Chloro-4-(3-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)-l,2,4-triazin-5- yl)benzonitrile (582)
1 H NMR (400 MHz, CD 3 OD) δ 8.97 (s, IH), 8.59 (d, J= 5.6 Hz, IH), 8.17 (d, J= 8.4 Hz, IH), 8.09 (d, J= 8.0 Hz, IH), 8.02 (s, IH), 7.84 (s, 2H), 7.57 (t, J= 6.4 Hz, IH), 6.96 (s, IH), 4.80 (s, 2H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.25; LRMS (electrospray) m/z calculated for C 19 Hi 4 ClN 8 (M+H) + 389.10, found 389.36.
3,5-DimethyI-4-(2-((5-(pyridin-2-yl)-lJϊ-pyrazoI-3-yl)me thylamino)pyridin-4- yl)benzonitrile (583)
1 H NMR (400 MHz, CD 3 OD) δ 8.51 (d, J= 4.8 Hz, IH), 8.08 (d, J- 5.2 Hz, IH), 7.82 (d, J= 5.6 Hz, 2H), 7.43 (s, 2H), 7.29 (q, J= 3.6 Hz, IH), 6.79 (s, IH), 6.36 (dd, J= 5.2, 1.2 Hz, IH), 6.33 (s, IH); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.13; LRMS (electrospray) m/z calculated for C 23 H 21 N 6 (M+H) + 381.18, found 381.41.
3-Methyl-4-(2-(((l-phenyl-lH-l,2,3-triazoI-4-yl)methyl)am ino)pyrimidin-4- yl)benzonitrile (584)
1 K NMR (400 MHz, CD 3 OD) δ 8.41 (d, J= 4.8 Hz, IH), 8.38 (s, IH), 7.80 (d, J= 8.0 Hz, 2H), 7.66 (s, IH), 7.63 (d, J= 8.0 Hz, IH), 7.57 (t, J= 7.0 Hz, 3H), 7.48 (t, J= 7.2 Hz, IH), 6.79 (d, J= 5.2 Hz, IH), 4.78 (s, 2H), 2.38 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.42; LRMS (electrospray) m/z calculated for C 21 Hj 8 N 7 (M+H) + 368.16, found 368.35.
3-Methyl-4-(2-((l-(pyridin-3-yl)-lJϊ-l,2,3-triazol-4-yl) methylamino)pyrimidiii-4- yl)benzonitrile (585)
1 H NMR (400 MHz, CD 3 OD) δ 9.08 (d, J= 2.4 Hz, IH), 8.67 (d, J= 4.8 Hz, IH), 8.53 (s, IH), 8.43 (d, J= 5.2 Hz, IH), 8.31 (d, J= 8.8 Hz, IH), 7.65 (m, 3H), 7.57 (d, J= 8.0 Hz, IH), 6.81 (d, J= 5.2 Hz, IH), 4.80 (s, 2H), 2.39 (s, 3H); TLC JJy(CH 2 Cl 2 =MeOH 20:1) = 0.23; LRMS (electrospray) m/z calculated for C 20 H 17 N 8 (M+H) + 369.16, found 369.37.
4-(2-((l-(4-Methoxyphenyl)-lJH r -l,2,3-triazol-4-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (586)
1 H NMR (400 MHz, CD 3 OD) δ 8.39 (d, J= 5.2 Hz, IH), 8.24 (s, IH), 7.65 (m, 3H), 7.61 (d, J = 8.0 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.06 (d, J= 9.2 Hz, 2H), 6.77 (d, J= 5.2 Hz, IH),
4.55 (s, 2H), 3.84 (s, 3H), 2.35 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:3) = 0.49; LRMS (electrospray) m/z calculated for C 22 H 20 N 7 O(M+H) + 398.17, found 398.41.
3-Methyl-4-(2-((l-(2-nitrophenyl)-lH-l,2,3-triazol-4-yl)m ethylamino)pyrimidin-4- yl)benzonitrile (587)
1 H NMR (400 MHz, CD 3 OD) δ 8.39 (d, J= 5.2 Hz, IH), 8.21 (s, IH), 8.11 (dd, J= 8.2, 1.4 Hz, IH), 7.86 (td, J= 7.8, 1.2 Hz, IH), 7.77 (td, J= 8.0, 1.6 Hz, IH), 7.68 (d, J= 7.6 Hz, IH), 7.64 (s, IH), 7.61 (d, J= 9.2 Hz, IH), 7.54 (d, J= 8.0 Hz, IH), 6.78 (d, J= 4.8 Hz, IH), 4.72 (s, 2H), 2.39 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.13; LRMS (electrospray) m/z calculated for C 21 H 17 N 8 O 2 (M+H) + 413.15, found 413.38.
4-(2-((l-(2-Aminophenyl)-l/r-l,2,3-triazol-4-yl)methylami no)pyrimidin-4-yl)-3- methylbenzonitrile (588)
1 U NMR (400 MHz, CD 3 OD) δ 8.34 (d, J= 4.8 Hz, IH), 8.07 (s, IH), 7.58 (m, 3H), 7.49 (d, J = 8.0 Hz, IH), 7.18 (s, IH), 7.14 (dd, J= 8.6, 2.2 Hz, IH), 6.85 (d, J= 8.8 Hz, IH), 6.73 (d, J = 4.8 Hz, IH), 4.50 (s, 2H), 2.33 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.32; LRMS (electrospray) m/z calculated for C 2 iH 19 N 8 (M+H) + 383.17, found 383.38.
3-Methyl-4-(2-((l-(3-nitrophenyl)-lJϊ-l,2,3-triazol-4-yl )methylamino)pyrimidin-4- yl)benzonitrile (589)
1 U NMR (400 MHz, CD 3 OD) δ 8.70 (s, IH), 8.57 (s, IH), 8.44 (bs, IH), 8.31 (d, J= 8.4 Hz, IH), 8.25 (d, J= 7.2 Hz, IH), 7.81 (t, J= 8.2 Hz, IH), 7.62 (t, J= 7.8 Hz, 2H), 7.54 (d, J= 8.0 Hz, IH), 6.79 (d, J= 4.0 Hz, IH), 4.77 (s, 2H), 2.40 (s, 3H); TLC λ/fø-HexanesiEtOAc
2:3) = 0.40; LRMS (electrospray) m/z calculated for C 21 H 17 N 8 O 2 (M+H) + 413.15, found 413.38.
4-(2-((l-(3-Aminophenyl)-l J H r -l,2,3-triazoI-4-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (590)
1 H NMR (400 MHz, CD 3 OD) δ 8.34 (d, J- 4.8 Hz, IH), 8.17 (s, IH), 7.59 (s, IH), 7.56 (d, J = 8.0 Hz, IH), 7.48 (d, J= 7.6 Hz, IH), 7.15 (t, J= 8.0 Hz, IH), 7.02 (s, IH), 6.90 (d, J= 7.6 Hz, IH), 6.72 (d, J= 5.2 Hz, IH), 6.68 (m, IH), 4.50 (s, 2H), 2.30 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.30; LRMS (electrospray) m/z calculated for C 21 H 19 N 8 (M+H) + 383.17, found 383.38.
3-Methyl-4-(2-((l-(4-nitrophenyl)-lH-l,2,3-triazol-4-yI)m ethylamino)pyrimidin-4- yl)benzonitrile (591)
1 H NMR (400 MHz, CD 3 OD) δ 8.55 (s, IH), 8.42 (d, J= 9.2 Hz, 2H), 8.33 (bs, IH), 8.11 (d, J= 9.2 Hz, 2H), 7.62 (t, J= 7.0 Hz, 2H), 7.53 (d, J= 7.6 Hz, IH), 6.78 (d, J= 4.8 Hz, IH), 4.68 (s, 2H), 2.35 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:3) = 0.42; LRMS (electrospray) m/z calculated for C 21 H 17 N 8 O 2 (M+H) + 413.15, found 413.38.
4-(2-((l-(4-Aminophenyl)-ljH r -l,2,3-triazoI-4-yl)methyIamino)pyrimidin-4-yl)-3- methylbenzonitrile (592)
1 H NMR (400 MHz, CD 3 OD) δ 8.33 (d, J= 5.2 Hz, IH), 8.08 (s, IH), 7.59 (s, IH), 7.56 (d, J = 8.0 Hz, IH), 7.48 (d, J= 7.6 Hz, IH), 7.36 (d, J= 8.8 Hz, 2H), 6.72 (m, 3H), 4.50 (s, 2H),
2.30 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.35; LRMS (electrospray) m/z calculated for C 21 H 19 N 8 (M+H) + 383.17, found 383.38.
3-Methyl-4-(2-((5-(4-nitrophenyl)-lH-pyrazol-3-yl)methyla mino)pyridin-4- yl)benzonitrile (593)
1 H NMR (400 MHz, CD 3 OD) δ 8.25 (d, J= 8.4 Hz, 2H), 8.06 (d, J= 5.6 Hz, IH), 7.95 (m, 2H), 7.63 (s, IH), 7.58 (d, J= 8.0 Hz, IH), 7.33 (d, J= 7.6 Hz, IH), 6.75 (s, IH), 6.55 (d, J= 4.4 Hz, IH), 6.50 (s, IH), 4.61 (s, 2H), 2.26 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.24; LRMS (electrospray) m/z calculated for C 23 H 19 N 6 O 2 (M+H) + 411.16, found 411.47.
4-(2-((5-(4-Aminophenyl)-liϊ-pyrazol-3-yI)methylamino)py ridin-4-yl)-3- methylbenzonitrile (594)
1 H NMR (400 MHz, CD 3 OD) δ 8.05 (d, J= 5.6 Hz, IH), 7.64 (s, IH), 7.59 (dd, J= 7.6, 1.2 Hz, IH), 7.41 (d, J= 8.4 Hz, 2H), 7.34 (d, J= 7.6 Hz, IH), 6.73 (d, J= 8.8 Hz, 2H), 6.55 (dd, J= 5.4, 1.4 Hz, IH), 6.51 (s, IH), 6.41 (s, IH), 4.53 (s, 2H), 2.26 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 10:1) = 0.35; LRMS (electrospray) m/z calculated for C 23 H 21 N 6 (MH-H) + 381.18, found 381.41.
Methyl 5-(3-((5-(4-cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino)me thyl)-ljH r -pyrazol- 5-yl)furan-2-carboxylate (595)
1 H NMR (400 MHz, CD 3 OD) δ 8.78 (s, IH), 7.70 (s, IH), 7.67 (s, 2H), 7.27 (d, J= 3.6 Hz, IH), 6.80 (d, J= 3.6 Hz, IH), 6.64 (s, IH), 4.73 (s, 2H), 3.86 (s, 3H), 2.41 (s, 3H); TLC R f
(CH 2 Cl 2 :Me0H 20:1) = 0.13; LRMS (electrospray) m/z calculated for C 21 H 18 N 7 O 3 (M+H) + 416.15, found 416.37.
5-(3-((5-(4-Cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino )methyl)-lH-pyrazol-5- yl)furan-2-carboxylic acid (596)
1 H NMR (400 MHz, CD 3 OD) δ 9.72 (s, IH), 8.66 (s, IH), 8.62 (d, J= 9.2 Hz, IH), 8.52 (d, J = 8.0 Hz, IH), 8.06 (d, J= 3.6 Hz 5 IH), 7.64 (d, J= 3.6 Hz, IH), 7.34 (s, IH), 4.78 (s, 2H), 3.31 (s, 3H).
5-(3-((5-(4-Cyano-2-methyIphenyl)-l,2,4-triazin-3-ylamino )methyl)-lH-pyrazol-5-yl)-iV- methylfuran-2-carboxamide (597)
1 H NMR (400 MHz, CD 3 OD) δ 8.81 (s, IH), 7.72 (s, IH), 7.69 (s, 2H), 7.12 (d, J= 4.0 Hz, IH), 6.78 (d, J= 3.6 Hz, IH), 6.67 (s, IH), 4.76 (s, 2H), 3.25 (s, 3H), 2.43 (s, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.09; LRMS (electrospray) m/z calculated for C 21 H 19 N 8 O 2 (M+H) + 415.16, found 415.42.
5-(3-((5-(4-Cyano-2-methyIphenyl)-l,2,4-triazin-3-ylamino)me thyl)-ljy r -pyrazol-5-yl)- 7V,iV-dimethylfuran-2-carboxamide (598)
1 H NMR (400 MHz, CD 3 OD) δ 8.80 (s, IH), 7.72 (s, IH), 7.68 (s, 2H), 7.11 (d, J= 4.0 Hz, IH), 6.81 (d, J= 3.6 Hz, IH), 6.64 (s, IH), 4.74 (s, 2H), 3.26 (s, 3H), 3.20 (s, 3H), 2.43 (s, 3H); TLC 22/(CH 2 Cl 2 =MeOH 20:1) = 0.12; LRMS (electrospray) m/z calculated for C 22 H 21 N 8 O 2 (M+H) + 429.18, found 429.43.
4-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl )-li?-pyrazol-5-yl)-iV,iV- dimethylbenzenesulfonamide (599)
1 H NMR (400 MHz, CDCl 3 ) δ 11.32 (bs, IH), 8.24 (d, J= 5.2 Hz, IH), 7.91 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.52 (m, 2H), 7.23 (s, IH), 6.59 (dd, J= 5.4, 1.4 Hz, IH), 6.54 (s, IH), 6.33 (s, IH), 4.98 (m, IH), 4.63 (d, J= 6.0 Hz, 2H), 2.71 (s, 6H), 2.26 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.23; LRMS (electrospray) m/z calculated for C 25 H 25 N 6 O 2 S(M+H) + 473.18, found 473.50.
3-Methyl-4-(3-((5-(4-nitrophenyI)-l J H r -pyrazol-3-yl)methylamino)-l,2,4-triazin-5- yl)benzonitrile (600)
1 H NMR (400 MHz, CD 3 OD) δ 8.68 (s, IH), 8.13 (d, J= 8.8 Hz, 2H), 7.84 (d, J= 8.0 Hz, 2H), 7.79 (s, IH), 7.58 (s, IH), 7.55 (s, IH), 6.66 (s, IH), 4.60 (s, 2H), 2.30 (s, 3H); TLC R 1 (CH 2 Cl 2 :Me0H 20:1) = 0.34; LRMS (electrospray) m/z calculated for C 21 H 17 N 8 O 2 (M+H) + 413.15, found 413.38.
4-(3-((5-(4-Aminophenyl)-lH-pyrazol-3-yl)methylamino)-l,2 ,4-triaziii-5-yl)-3- methylbenzonitrile (601)
1 H NMR (400 MHz, CD 3 OD) δ 8.77 (s, IH), 7.71 (s, IH), 7.68 (s, 2H), 7.40 (d, J= 8.0 Hz, 2H), 6.72 (d, J= 8.4 Hz, 2H), 6.42 (s, IH), 4.69 (s, 2H), 2.44 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.20; LRMS (electrospray) m/z calculated for C 21 Hi 9 N 8 (M+H) + 383.17, found 383.38.
3-MethyI-4-(2-((5-(4-nitrophenyI)-ljBr-pyrazol-3-yl)methy lamino)pyrimidin-4- yl)benzonitrile (602)
1 U NMR (400 MHz, CD 3 OD) δ 8.42 (d, J= 5.2 Hz, IH), 8.27 (d, J= 8.8 Hz, 2H), 7.96 (d, J- 6.4 Hz, 2H), 7.64 (m, 2H), 7.55 (d, J= 8.0 Hz, IH), 6.80 (d, J= 5.2 Hz, IH), 6.74 (s, IH), 4.70 (s, 2H), 2.36 (s, 3H); TLC ^-(CH 2 Cl 2 : MeOH 20:1) = 0.12; LRMS (electrospray) m/z calculated for C 22 H 18 N 7 O 2 (M+H) + 412.15, found 412.36.
4-(2-((5-(2-Chlorophenyl)-l J fiT-pyrazol-3-yl)methylamino)pyridm-4-yl)-3- methylbenzonitrile (603)
1 B. NMR (400 MHz, CD 3 OD) δ 8.06 (d, J= 4.8 Hz, IH), 7.65 (s, IH), 7.59 (d, J= 8.0 Hz, 2H), 7.47 (bs, IH), 7.34 (m, 3H) 5 6.63 (s, IH), 6.56 (d, J= 4.8 Hz, IH), 6.52 (s, IH), 4.60 (s, 2H), 2.27 (s, 3H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.56; LRMS (electrospray) m/z calculated for C 23 H 19 C1N 5 (M+H) + 400.13, found 400.38.
4-(2-((5-(3-Chlorophenyl)-l/7-pyrazol-3-yl)methylamino)py ridin-4-yl)-3- methylbenzonitrile (604)
1 H NMR (400 MHz, CD 3 OD) δ 8.07 (d, J= 5.2 Hz, IH), 7.75 (s, IH), 7.65 (s, 2H), 7.60 (d, J = 8.0 Hz, IH), 7.37 (m, 2H), 7.32 (m, IH), 6.63 (s, IH), 6.57 (d, J= 5.6 Hz, IH), 6.52 (s, IH), 4.60 (s, 2H), 2.32 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.64; LRMS (electrospray) m/z calculated for C 23 H 19 C1N 5 (M+H) + 400.13, found 400.38.
4-(2-((5-(4-Chlorophenyl)-l/f-pyrazol-3-yl)methyIamino)py ridin-4-yl)-3- methylbenzonitrile (605)
1 H NMR (400 MHz, CD 3 OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.72 (bs, 2H), 7.69 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.39 (d, J= 7.2 Hz, 2H), 7.35 (d, J= 8.0 Hz, IH), 6.60 (s, IH), 6.56 (d, J = 4.4 Hz, IH), 6.51 (s, IH), 4.59 (s, 2H), 2.27 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.23; LRMS (electrospray) m/z calculated for C 23 H 19 C1N 5 (M+H) + 400.13, found 400.38.
4-(2-((5-(4-ChIoropyridin-2-yl)-lH-pyrazol-3-yl)methylami no)pyridiii-4-yI)-3- methylbenzonitrile (606)
1 H NMR (400 MHz, CD 3 OD) δ 8.47 (s, IH), 8.07 (d, J= 5.2 Hz, IH), 7.94 (bs, IH), 7.65 (s, IH), 7.59 (dd, J= 8.0, 1.2 Hz, IH), 7.34 (m, 2H), 6.85 (s, IH), 6.57 (m, IH), 6.52 (s, IH), 4.62 (s, 2H), 2.27 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C 22 H 18 C1N 6 (M+H) + 401.13, found 401.47.
4-(2-((5-(6-Chloropyridin-2-yl)-lH-pyrazol-3-yl)methylami no)pyridin-4-yl)-3- methylbenzonitrile (607)
1 H NMR (400 MHz, CD 3 OD) δ 8.03 (d, J= 4.8 Hz, IH), 7.79 (m, 2H), 7.62 (d, J= 6.0 Hz, IH), 7.56 (d, J= 8.0 Hz, IH), 7.29 (m, 2H), 6.81 (s, IH), 6.52 (m, IH), 6.48 (s, IH), 4.57 (s, 2H), 2.24 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C 22 H 18 C1N 6 (M+H) + 401.13, found 401.34.
4-(3-((5-(3-Fluorophenyl)-lfiT-pyrazol-3-yl)methylamino)- l,2,4-triaziii-5-yl)-3- methylbenzonitrile (608)
1 H NMR (400 MHz, CD 3 OD) δ 8.80 (s, IH), 7.72 (s, IH), 7.69 (s, 2H), 7.52 (bs, IH), 7.44 (m, 2H), 7.04 (bs, IH), 6.65 (s, IH), 4.76 (s, 2H), 2.44 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.25; LRMS (electrospray) m/z calculated for C 21 H 17 FN 7 (M+H) + 386.15, found 386.37.
4-(3-((5-(2-Fluorophenyl)-li7-pyrazol-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (609)
1 H NMR (400 MHz, CD 3 OD) δ 8.77 (s, IH), 7.80 (bs, IH), 7.70 (s, IH), 7.67 (s, 2H), 7.32 (bs, IH), 7.20 (m, 2H), 6.64 (s, IH), 4.73 (s, 2H), 2.42 (s, 3H); TLC tf/(CH 2 Cl 2 :Me0H 20:1) = 0.12.
4-(2-((5-(4-(Difluoromethoxy)phenyI)-l£T-pyrazol-3-yl)me thylamiiio)pyridiii-4-yl)-3- methylbenzonitrile (610)
1 H NMR (400 MHz, CD 3 OD) δ 8.06 (d, J= 5.6 Hz, IH), 7.73 (m, 2H), 7.65 (s, IH), 7.59 (d, J = 9.2 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.17 (d, J= 8.0 Hz, 2H), 6.84 (t, J= 74.2 Hz, IH), 6.58 (s, IH), 6.56 (d, J= 5.6 Hz, IH), 6.51 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C 24 H 20 F 2 N 5 O(M+H) + 432.16, found 432.42.
4-(2-((5-(2,5-Dichlorophenyl)-lH-pyrazol-3-yl)methylamino )pyridin-4-yl)-3- methylbenzonitrile (611)
1 H NMR (400 MHz, CD 3 OD) δ 8.08 (d, J= 5.6 Hz, IH), 7.70 (m, IH), 7.67 (s, IH), 7.61 (d, J = 8.0 Hz, IH), 7.47 (m, IH), 7.35 (m, 2H), 6.72 (s, IH), 6.58 (d, J= 5.2 Hz, IH), 6.53 (s, IH), 4.64 (s, 2H), 2.29 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 20:1) = 0.30; LRMS (electrospray) m/z calculated for C 23 H 18 C1 2 N 5 (M+H) + 434.09, found 434.33.
4-(2-((5-(5-Methoxypyridin-2-yl)-lH-pyrazol-3-yl)methyIam mo)pyridin-4-yl)-3- methylbenzonitrile (612)
1 U NMR (400 MHz, CD 3 OD) δ 8.21 (bs, IH), 8.04 (d, J= 5.2 Hz, IH), 7.80 (bs, IH), 7.63 (s, IH), 7.58 (d, J- 7.6 Hz, IH), 7.41 (dd, J= 8.8, 2.8 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 6.70 (s, IH), 6.54 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.57 (s, 2H), 3.88 (s, 3H), 2.25 (s, 3H); TLC R f (CH 2 Cl 2 :Me0H 20:1) = 0.11; LRMS (electrospray) m/z calculated for C 23 H 2 ! N 6 0(M+H) + 397.18, found 397.46.
4-(2-((5-(5-Hydroxypyridin-2-yl)-lH-pyrazol-3-yl)methylam ino)pyridm-4-yl)-3- methylbenzonitrile (613)
1 H NMR (400 MHz, CD 3 OD) δ 8.10 (s, IH), 8.06 (d, J= 5.2 Hz, IH), 7.70 (bs, IH), 7.65 (s, IH), 7.60 (d, J= 7.6 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.24 (dd, J= 8.8, 2.8 Hz, IH), 6.68 (s, IH), 6.55 (d, J= 5.2 Hz, IH), 6.51 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.23.
4-(2-((5-(4-Chloro-3-nitrophenyl)-liϊ-pyrazol-3-yl)methy lamino)pyridin-4-yI)-3- methylbenzonitrile (614)
1 H NMR (400 MHz, CD 3 OD) δ 8.28 (s, IH), 8.07 (t, J= 5.4 Hz, IH), 7.98 (d, J= 8.4 Hz, IH), 7.67 (d, J= 8.8 Hz, 2H), 7.60 (d, J= 9.2 Hz 5 IH), 7.35 (d, J= 8.0 Hz, IH), 6.73 (s, IH), 6.57 (d, J= 5.6 Hz, IH), 6.51 (s, IH), 4.62 (s, 2H), 2.28 (s, 3H); TLC ^(CH 2 Cl 2 MeOH 20:1) = 0.35.
Methyl 5-(3-((4-(4-cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-l //-pyrazol-5- yl)furan-2-carboxy!ate (615)
1 H NMR (400 MHz, CD 3 OD) δ 8.04 (d, J= 5.6 Hz, IH), 7.62 (s, IH), 7.56 (d, J= 8.4 Hz, 1H),7.32 (d, J= 8.0 Hz, IH), 7.25 (d, J= 3.6 Hz, IH), 6.79 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.8 Hz, IH), 6.48 (s, 1H),4.58 (s, 2H), 3.84 (s, 3H), 2.25 (s, 3H); LRMS (electrospray) m/z calculated for C 23 H 20 N 5 O 3 (M+H) + 414.44, found 414.26.
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-yIamino)methyI )-l/T-pyrazoI-5-yl)furan-2- carboxylic acid (616)
1 H NMR (400 MHz, CD 3 OD) δ 7.94 (d, J= 6.8 Hz, IH), 7.71 (s, IH), 7.66 (d, J= 8.0 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.25 (d, J= 3.2 Hz, IH), 7.05 (s, IH), 6.94 (dd, J= 6.8, 1.6 Hz, IH), 6.84 (d, J= 3.6 Hz, IH), 6.74 (s, IH), 4.68 (s, 2H), 3.84 (s, 3H), 2.30 (s, 3H); LRMS (electrospray) m/z calculated for C 23 H 18 N 5 O 3 (M+H) + 400.41, found 400.32.
Isopropyl 5-(3-((4-(4-cyano-2-methylphenyI)pyridin-2-ylamino)methyl)-l H-pyrazol-5- yl)furan-2-carboxylate (617)
1 H NMR (400 MHz, CD 3 OD) δ 8.02 (bs, IH), 7.61 (s, IH), 7.55 (d, J= 9.2 Hz, IH), 7.31 (d, J= 7.6 Hz, IH), 7.21 (bs, IH), 6.77 (bs, IH), 6.59 (s, IH), 6.54-6.53 (m, IH), 6.46 (s, IH), 5.15 (t, J= 7.6 Hz, IH), 4.57 (s, 2H), 2.23 (s, 3H), 1.35-1.30 (m, 6H).
Benzyl 5-(3-((4-(4-cyano-2-methylphenyI)pyridin-2-yIamino)methyl)-l Jϊ-pyrazol-5- yl)furan-2-carboxylate (618)
1 H NMR (400 MHz, CD 3 OD) δ 8.03 (d, J= 5.2 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 9.2 Hz, IH), 7.42-7.40 (m, 2H), 7.36-7.28 (m, 7H), 6.79 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.4 Hz, IH), 6.47 (s, IH), 5.31 (s, 2H), 4.58 (s, 2H), 2.24 (s, 3H); TLC £/(«-Hexanes:EtOAc 1 :2) = 0.58; LRMS (electrospray) m/z calculated for C 29 H 24 N 5 O 3 (MH-H) + 490.19, found 490.37
619
Ethyl 5-(3-((4-(4-cy ano-2-methylphenyl)pyridin-2-ylamino)methyl)-liϊ-pyrazol-5- yl)furan-2-carboxylate (619)
1 U NMR (400 MHz, CD 3 OD) δ 8.03 (d, J= 5.6 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.24 (d, J= 3.6 Hz, IH), 6.78 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.8 Hz, IH), 6.49 (s, IH), 4.58 (s, 2H), 4.34-4.28 (m, 2H), 2.24 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.43; LRMS (electrospray) m/z calculated for C 24 H 22 N 5 O 3 (M+H) + 428.17, found 428.34
N-benzyl-5-(3-((4-(4-cyano-2-methylphenyl)pyridin-2-ylami no)methyl)-lH-pyrazol-5- yl)furan-2-carboxamide (620)
1 H NMR (400 MHz, CD 3 OD) δ 8.03 (d, J= 5.2 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 6.8 Hz, IH), 7.36-7.13 (m, 7H), 6.76-6.75 (m, IH), 6.62 (s, IH), 6.53 (d, J= 5.2 Hz, IH), 6.46 (s, IH), 4.57 (s, 2H), 4.52 (s, 2H), 2.24 (s, 3H); TLC tf/(«-Hexanes:EtOAc 1:2) = 0.42; LRMS (electrospray) m/z calculated for C 29 H 25 N 6 O 2 (M+H) + 489.20, found 489.42.
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl )-lH-pyrazol-5-yl)-7V,iV- diethylfuran-2-carboxamide (621)
1 H NMR (400 MHz, CD 3 OD) δ 8.04 (d, J= 5.6 Hz, IH), 7.62 (s, IH), 7.56 (d, J= 8.0 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 7.07 (d, J= 3.6 Hz, IH), 6.77 (d, J= 3.2 Hz, IH), 6.55-6.53 (m, 2H), 6.48 (s, IH), 4.58 (s, 2H), 4.52 (s, 2H), 3.80-3.40 (m, 4H), 2.24 (s, 3H), 1.25-1.13 (m, 6H); TLC #/(ra-Hexanes:EtOAc 1:2) = 0.23; LRMS (electrospray) m/z calculated for C 26 H 27 N 6 O 2 (M+H) + 455.52, found 455.41.
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl )-lH-pyrazol-5-yl)-7V,iV- dimethylfuran-2-carboxamide (622)
1 R NMR (400 MHz, CD 3 OD) δ 8.02 (bs, IH), 7.61 (s, IH), 7.55 (d, J= 8.0 Hz, IH), 7.31 (d, J= 8.0 Hz, IH), 7.07 (d, J= 3.6 Hz, IH), 6.77 (bs, IH), 6.58 (s, IH), 6.53 (m, IH), 6.47 (s, IH), 4.57 (s, 2H), 3.09 (s, 6H), 2.24 (s, 3H); TLC i?/(EtOAc only) = 0.30; LRMS (electrospray) m/z calculated for for C 24 H 23 N 6 O 2 (M+H) + 427.19, found 427.39.
3-Methyl-4-(2-((5-(5-(morpholine-4-carbonyl)furan-2-yl)-l f/-pyrazol-3- yl)methyIamino)pyridin-4-yl)benzonitrile (623)
1 H NMR (400 MHz, CD 3 OD) δ 8.04 (d, J= 5.6 Hz, IH) 5 7.62 (s, IH), 7.56 (d, J= 7.6 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 7.08 (d, J= 3.6 Hz, IH), 6.77 (d, J= 3.6 Hz, IH), 6.57 (s, IH), 6.53 (d, J= 5.2 Hz, IH), 6.47 (d, J= 5.2 Hz, IH), 4.58 (s, 2H), 3.81-3.69 (m, 4H), 3.59-3.55 (m, 4H), 2.24 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.31; LRMS (electrospray) m/z calculated for C 26 H 25 N 6 O 3 (M+H) + 469.20, found 469.42
4-(3-((5-(5-Bromofuran-2-yl)-lH-pyrazol-3-yl)methylamino) -l,2,4-triazin-5-yl)-3- methylbenzonitrile (624)
1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, IH), 7.52-7.46 (m, 3H), 6.52 (d, J= 3.2 Hz, IH), 6.38 (s, IH), 6.27 (d, J= 3.2 Hz, IH), 4.73 (bs, 2H), 2.38 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.40; LRMS (electrospray) m/z calculated for C 19 H 15 BrN 7 O(M+H) + 436.05, found 438.20
5-(3-((5-(4-Cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino)me thyl)-l J fiT-pyrazoI-5- yI)furan-2-carbonitrile (625)
1 H NMR (400 MHz, CD 3 OD) δ 8.77 (s, IH), 7.68 (s, IH), 7.65-7.64 (m, 2H), 7.33 (d, J= 3.2 Hz, IH), 6.81 (d, J= 3.6 Hz, IH), 6.62 (s, IH), 4.68 (bs, 2H), 2.39 (s, 3H); TLC R f (n- Hexanes:EtOAc 1 :2) = 0.37; LRMS (electrospray) m/z calculated for C 20 H 15 N8O(M+H) + 383.14, found 383.24.
3-Methyl-4-(2-((5-(2-nitrophenyl)-lH-pyrazol-3-yl)methyla mino)pyridin-4- yl)benzonitrile (626)
1 K NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J= 4.8 Hz, IH), 7.71-7.66 (m, 2H), 7.58-7.50 (m, 3H), 7.44 (d, J= 8.4 Hz, IH), 7.23-7.19 (m, IH), 6.57 (d, J= 4.8 Hz, IH), 6.32 (bs, 2H), 5.00 (bs, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.26 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1:2) = 0.60; LRMS (electrospray) m/z calculated for C 23 H 19 N 6 O 2 (M+H) + 411.16, found 411.40.
4-(2-((5-(2-Aminophenyl)-ljH r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (627)
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (bs, IH), 7.53-7.43 (m, 3H), 7.08 (t, J= 7.6 Hz, IH), 6.73-6.72 (m, 2H), 6.57-6.56 (m, IH), 6.48 (s, IH), 6.31 (s, IH), 5.00 (bs, IH), 4.63 (d, J = 8.0 Hz, 2H), 2.26 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.57; LRMS (electrospray) m/z calculated for C 23 H 21 N 6 (M+H) + 381.18, found 381.41.
3-Methyl-4-(2-((5-(3-nitrophenyl)-lH-pyrazol-3-yl)methyla mino)pyridin-4- yl)benzonitrile (628)
1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, J= 2.0 Hz, IH), 8.21 (d, J= 5.6 Hz, IH), 8.12-8.08 (m, 2H), 7.54-7.48 (m, 3H), 7.24-7.21 (m, IH), 6.57-6.55 (m, 2H), 6.33 (s, IH), 4.62 (d, J= 6.0 Hz, 2H), 2.24 (s, 3H); TLC ^(w-Hexanes: EtOAc 1:2) = 0.56; LRMS (electrospray) m/z calculated for C 23 Hi 9 N 6 O 2 (M+H) + 411.16, found 411.40.
4-(2-((5-(3-Aininophenyl)-lH-pyrazoI-3-yl)methylamino)pyr idin-4-yl)-3- methylbenzonitrile (629)
1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J= 5.2 Hz, IH), 7.52-7.49 (m, 2H), 7.17 (t, J= 7.2 Hz, IH), 7.04-7.01 (m, 3H), 6.64 (d, J= 8.4 Hz, IH), 6.54 (d, J= 4.8 Hz, IH), 6.44 (s, IH), 6.32 (s, IH), 5.00 (bs, IH), 4.59 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC .fy(n-Hexanes:EtOAc 1:2) - 0.39 ; LRMS (electrospray) m/z calculated for C 23 H 21 N 6 (M+H) + 381.18, found 381.41.
4-(2-(Benzo[rf]thiazoI-2-ylmethylamino)pyridin-4-yl)-3-me thylbenzonitrile (630)
1 H NMR (400 MHz, CDCl 3 ) 5 8.18 (d, J= 4.8 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.82 (d, J= 8.1 Hz, 1H),7.51-7.44 (m, 3H), 7.35 (t, J= 7.4 Hz, IH), 7.23-7.22 (m, IH), 6.56 (d, J= 4.8 Hz, IH), 6.39 (s, IH), 5.53 (bs, IH), 5.00 (d, J= 6.0 Hz, 2H), 2.21 (s, 3H); TLC R f (n- Hexanes:EtOAc 2:1) = 0.20.
4-(2-(Benzo [d\ oxazol-2-y lmethylamino)pyridin-4-yl)-3-methylbenzonitrile (631)
1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J= 5.2 Hz, IH), 7.68-7.65 (m, IH), 7.52-7.48 (m, 3H), 7.33-7.28 (m, 2H), 7.25-7.23 (m, IH), 6.54 (dd, J= 5.0, 1.4 Hz, IH), 6.45 (s, IH), 5.37 (t, J= 5.4 Hz, IH), 4.89 (d, J= 5.6 Hz, 2H), 2.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.30; LRMS (electrospray) m/z calculated for C 2 iH 17 N 4 O (M+H) + 341.14, found 341.34.
3-Methyl-4-(2-((4-nitrobenzo [d\ oxazol-2-yl)methylamino)pyridin-4-yl)benzonitrile (632)
1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (d, J= 5.2 Hz, IH), 7.87 (d, J= 8.4 Hz, IH), 7.56-7.52 (m, 2H), 7.30 (d, J= 7.6 Hz, IH), 7.22 (d, J= 8.0 Hz, IH), 7.13 (s, IH), 7.01-6.93 (m, 2H), 4.79 (s, 2H), 2.30 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.43; LRMS (electrospray) m/z calculated for C 21 H 16 N 5 O 3 (M+H) + 386.13, found 386.37.
4-(2-((5-(2-Fluorophenyl)-l J fi r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (633)
1 H NMR (400 MHz, CD 3 OD) δ 8.04 (d, J= 5.2 Hz, IH), 7.75 (bs, IH), 7.62 (s, IH), 7.57 (d, J= 8.8 Hz, IH), 7.33 (d, J= 8.0 Hz, 2H), 7.21-7.13 (m, 2H), 6.62 (d, J= 3.2 Hz, IH), 6.53 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.56 (bs, 2H), 2.24 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.62; LRMS (electrospray) m/z calculated for C 23 Hi 9 N 5 (M+H) + 384.16, found 384.40.
4-(2-(((5-(3-Fluorophenyl)-lH-pyrazol-3-yl)methyl)amino)p yridin-4-yl)-3- methylbenzonitrile (634)
1 H NMR (400 MHz, CD 3 OD) δ 8.02 (d, J= 5.2 Hz, IH), 7.60 (s, IH), 7.54 (d, J= 8.0 Hz, IH), 7.50-7.38 (m, 3H), 7.30 (d, J- 7.6 Hz, IH), 6.99-6.98 (m, IH), 6.58 (s, IH), 6.51 (d, J= 4.0 Hz, IH), 6.46 (s, IH), 4.55 (bs, 2H), 2.22 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.66; LRMS (electrospray) m/z calculated for C 23 H 19 N 5 (M+H) + 384.16, found 384.47.
635
4-(2-((4-Bromo-5-(5-bromothiophen-2-yl)-ljH r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (635)
1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J= 5.2 Hz, IH), 7.49-7.45 (m, 2H), 7.36 (d, J= 4.0 Hz, IH), 7.17 (d, J= 8.0 Hz, IH), 6.98 (d, J= 4.0 Hz, IH), 6.51 (d, J= 5.2 Hz, IH), 6.33 (s, IH), 5.59 (bs, IH), 4.53 (d, J= 4.4 Hz, 2H), 2.22 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.21.
636
4-(2-((4-Bromo-5-(thiophen-2-yI)-lH-pyrazol-3-yl)methylam ino)pyridin-4-yl)-3- methylbenzonitrile (636)
1 H NMR (400 MHz, CD 3 OD) δ 7.99 (d, J= 5.2 Hz, IH), 7.56-7.54 (m, 2H), 7.51 (dd, J= 7.8, 1.4 Hz, IH), 7.38-7.37 (m, IH), 7.26 (d, J= 8.0 Hz, IH), 7.05-7.03 (m, IH), 6.48 (dd, J- 5.4, 1.4 Hz, IH), 6.44 (s, IH), 4.50 (s, 2H), 2.19 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.26.
3-Methyl-4-(2-(oxazolo[4,5-6]pyridin-2-ylmethylamino)pyri din-4-yl)benzonitrile (637)
1 H NMR (400 MHz, CD 3 OD) δ 8.40 (d, J= 4.8 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.95 (d, J= 5.6 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 8.4 Hz, IH), 7.36-7.31 (m, 2H), 6.58 (s, IH), 6.52 (d, J - 5.2 Hz, IH), 4.84 (s, 2H), 2.25 (s, 3H); LRMS (electrospray) m/z calculated for C 20 H 16 N 5 O(M+H) + 342.14, found 342.43.
638
4-(2-((5-(2,4-DichlorophenyI)-lH r -pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (638)
1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J= 5.2 Hz, IH), 7.59 (d, J= 8.4 Hz, IH), 7.48-7.46 (m, 2H), 7.41 (d, J= 2.0 Hz, IH), 7.22-7.18 (m, 2H), 6.62 (s, IH), 6.51 (dd, J= 3.2, 2.0 Hz, IH), 6.31 (s, IH), 5.42 (bs, IH), 4.58 (d, J= 5.6 Hz, 2H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.61; LRMS (electrospray) m/z calculated for C 23 Hi 8 Cl 2 N 5 O(M+H) + 434.09, found 434.46.
639
4-(2-((5-(2-Chloro-4-methoxyphenyl)-lH-pyrazol-3-yl)methy lamino)pyridin-4-yl)-3- methylbenzonitrile (639)
1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J= 5.6 Hz, IH), 7.55-7.49 (m, 3H), 7.25-7.24 (m, IH), 6.97 (d, J= 2.4 Hz, IH), 6.85 (dd, J= 8.8, 2.4 Hz, IH), 6.55-6.52 (m, 2H), 6.33 (s, IH), 5.16 (bs, IH), 4.60 (d, J= 5.6 Hz, 2H), 3.81 (s, 3H), 2.25 (s, 3H); TLC i?/(«-Hexanes: EtOAc 1:2) = 0.33; LRMS (electrospray) m/z calculated for C 24 H 2 ,C1N 5 O(M+H) + 430.14, found 430.45.
4-(2-((5-(2-Chloro-4-hydroxyphenyl)-liϊ-pyrazol-3-yl)met hyIamino)pyridin-4-yl)-3- methylbenzonitrile (640)
1 H NMR (400 MHz, CD 3 OD) δ 7.99 (d, J= 5.6 Hz, IH), 7.57 (s, IH), 7.52 (dd, J= 8.0, 1.2 Hz, IH), 7.32-7.26 (m, 2H), 6.83 (d, J= 2.4 Hz, IH), 6.70 (dd, J= 8.4, 2.4 Hz, IH), 6.48 (dd, J= 5.4, 1.4 Hz, IH), 6.45 (d, J= 1.2 Hz, 2H), 4.50 (s, 2H), 2.19 (s, 3H); TLC R f (n- Hexanes:EtOAc 1 :2) = 0.31; LRMS (electrospray) m/z calculated for C 23 H 19 C1N 5 O(M+H) + 416.13, found 416.44.
4-(2-((5-(2-Fluoro-4-methoxyphenyl)-l/T-pyrazol-3-yl)meth ylamino)pyridiii-4-yl)-3- methylbenzonitrile (641)
1 K NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J= 4.8 Hz, IH), 7.63 (t, J= 9.0 Hz, IH), 7.51-7.47 (m, 2H), 7.24-7.22 (m, IH), 6.72 (dd, J= 8.6, 2.6 Hz, IH), 6.66 (dd, J= 13.0, 2.6 Hz, IH), 6.51- 6.50 (m, 2H), 6.33 (s, IH), 4.57 (d, J= 5.6 Hz, 2H), 3.80 (s, 3H), 2.23 (s, 3H); TLC R f (n- Hexanes:EtOAc 1:2) = 0.35; LRMS (electrospray) m/z calculated for C 24 H 21 FN 5 O(M+H) + 414.17, found 414.53.
642
4-(2-((5-(2-Fluoro-4-hydroxyphenyl)-l£r-pyrazol-3-yl)met hylamino)pyridin-4-yl)-3- methylbenzonitrile (642)
1 H NMR (400 MHz, CD 3 OD) δ 8.16 (t, J= 2.8 Hz, IH), 7.62 (t, J= 8.8 Hz, IH), 7.53-7.47 (m, 2H), 7.24 (t, J= 8.0 Hz, IH), 6.74-6.65 (m, 2H), 6.55-6.50 (m, 2H), 6.33 (s, IH), 4.607 (d, J- 8.0 Hz, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes: EtOAc 1 :2) - 0.30; LRMS (electrospray) m/z calculated for C 23 Hi 9 FN 5 O (M+H) + 400.16, found 400.38.
643
4-(2-((5-(3-Chloro-4-fluorophenyI)-ljfir-pyrazol-3-yl)met hylamino)pyridin-4-yl)-3- methylbenzonitrile (643)
1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J= 5.2 Hz, IH), 7.78 (dd, J= 7.0, 2.2 Hz, IH), 7.62- 7.58 (m, IH), 7.53-7.50 (m, 2H), 7.24-7.22 (m, IH), 7.14 (t, J= 8.8 Hz, IH), 6.57 (dd, J= 5.2, 1.2 Hz, IH), 6.42 (s, IH), 6.32 (s, IH), 5.03 (bs, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.25 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.45; LRMS (electrospray) m/z calculated for C 23 H 18 C1FN 5 (M+H) + 418.12, found 418.41.
644
4-(2-((5-(4-Fluoro-3-methoxyphenyl)-lH-pyrazoI-3-yl)methy lamino)pyridin-4-yl)-3- methylbenzonitrile (644)
1 H NMR (400 MHz, CD 3 OD) δ 7.98 (d, J= 5.2 Hz, IH), 7.56 (s, IH), 7.51 (d, J= 7.2 Hz, IH), 7.37-7.35 (m, IH), 7.26 (d, J= 7.6 Hz, IH), 7.18-7.12 (m, IH), 7.04-6.99 (m, IH), 6.50 (s, !H), 6.47 (d, J= 4.8 Hz, IH), 6.43 (s, IH), 4.50 (s, 2H), 3.83 (s, 3H), 2.18 (s, 3H); TLC R f (rc-Hexanes:EtOAc 1 :2) = 0.33; LRMS (electrospray) m/z calculated for C 24 H 21 FN 5 O(MH-H) + 414.17, found 414.53.
645
4-(2-((5-(6-Methoxypyridin-2-yl)-l J H r -pyrazol-3-yI)methylamino)pyridin-4-yl)-3- methylbenzonitrile (645)
1 U NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J= 5.2 Hz, IH), 7.59 (t, J= 7.0 Hz, IH), 7.51-7.48 (m, 2H), 7.25-7.20 (m, 2H), 6.67 (d, J= 4.4 Hz, 2H), 6.51 (d, J= 5.2 Hz, IH), 6.34 (s, IH), 5.28 (bs, IH), 4.60 (d, J= 5.2 Hz, 2H), 3.97 (s, 3H), 2.24 (s, 3H); TLC i?/(n-Hexanes: EtOAc 1:2) = 0.44; LRMS (electrospray) m/z calculated for C 23 H 2 ϊ N 6 0(M+H) + 397.18, found 397.46.
646
4-(2-((5-(2-Bromo-4-fluorophenyl)-lH-pyrazol-3-yl)methyIa mino)pyridin-4-yl)-3- methylbenzonitrile (646)
1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J= 5.2 Hz, IH), 7.55-7.47 (m, 3H), 7.35 (dd, J= 8.2, 2.6 Hz, IH), 7.23 (t, J= 7.9 Hz, IH), 7.04-6.99 (m, IH), 6.56 (s, IH), 6.52 (dd, J= 5.2, 1.2 Hz, IH), 6.33 (s, IH), 5.49 (bs, IH), 4.59 (bs, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.53.
4-(2-((5-(4-FIuoro-3-hydroxyphenyI)-lJE- r -pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (647)
1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (bs, IH), 7.44-7.39 (m, 2H), 7.25-7.24 (m, IH), 7.08-7.02 (m, IH), 6.95-6.93 (m, IH), 6.82-6.79 (m, IH), 6.43 (bs, IH), 6.21 (s, IH), 6.08-6.04 (m, IH), 5.55 (bs, IH), 4.47 (bs, 2H), 2.10 (s, 3H); TLC £/ (CH 2 Cl 2 :MeOH 10:1) = 0.22; LRMS (electrospray) m/z calculated for C 23 H 18 FN 5 O(M+H) + 400.16, found 400.38.
4-(2-((5-(5-Fluoropyridin-2-yl)-lH-pyrazol-3-yl)methylami no)pyridin-4-yl)-3- methylbenzonitrile (648)
1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (bs, IH), 8.16 (d, J= 5.6 Hz, IH), 7.72-7.70 (m, IH), 7.49-7.39 (m, 3H), 7.21 (d, J= 7.6 Hz, IH), 6.67 (s, IH), 6.49 (d, J= 5.2 Hz, IH), 6.34 (s, IH), 5.57 (bs, IH), 4.59 (bs, 2H), 2.21 (s, 3H); LRMS (electrospray) m/z calculated for C 22 H lg FN 6 (M+H) + 385.16, found 385.35.
4-(2-((6-Methoxy-l//-pyrazolo[3,4-£]pyridin-3-yl)methyla mino)pyridin-4-yl)-3- methylbenzonitrile (649)
1 H NMR (400 MHz, CD 3 OD) δ 8.05 (d, J= 5.2 Hz, IH), 8.01 (d, J- 8.4 Hz, IH), 7.62 (s, IH), 7.58-7.56 (m, IH), 7.31 (d, J= 7.6 Hz, IH), 6.55-6.51 (m, 3H), 4.78 (s, 2H), 3.94 (s, 3H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.53.
3-Methyl-4-(2-((6-oxo-6,7-dihydro-l//-pyrazolo[3,4-6]pyri din-3- yl)methylamino)pyridin-4-yl)benzonitrile (650)
1 H NMR (400 MHz, CD 3 OD) δ 8.08 (d, J= 5.6 Hz, IH), 7.90 (d, J= 9.2 Hz, IH), 7.65 (s, IH), 7.59 (t, J= 4.0 Hz, IH), 7.34 (d, J= 8.0 Hz, IH), 6.58-6.56 (m, IH), 6.49 (s, IH), 6.19 (d, J= 9.2 Hz, IH), 4.72 (s, 2H), 2.25 (s, 3H); TLC i?/(CH 2 Cl 2 :Me0H 10:1) = 0.48.
References
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Table 1 :
Compound EC 50 Compound EC 50
Activity ranqe: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1 -5 uM, + indicates > 5 uM
Compound EC, 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC.50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 5Q Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EQ 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC • 50 Compound EC ■ 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC ■ 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC50 Compound EC50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC50 Compound EC50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uNI, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uNl, ++ indicates between 1-5 uNI, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1 -5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 5Q
Activity range: +++ indicates ≤ 1 uWI, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC.50 Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uWI
Compound EC 5Q Compound EC 50
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM
Compound EC 50 Compound EC 5, 0
Activity range: +++ indicates ≤ 1 uWI, ++ indicates between 1-5 uM, + indicates > 5 uM