CN117693511A - Penicillin binding protein inhibitors - Google Patents

Penicillin binding protein inhibitors Download PDF

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Publication number
CN117693511A
CN117693511A CN202280052020.6A CN202280052020A CN117693511A CN 117693511 A CN117693511 A CN 117693511A CN 202280052020 A CN202280052020 A CN 202280052020A CN 117693511 A CN117693511 A CN 117693511A
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alkyl
compound
heterocycloalkyl
cycloalkyl
aryl
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Chinese (zh)
Inventor
克里斯多佛·J·伯恩斯
丹尼斯·戴格尔
楚国华
朱迪·哈姆里克
史蒂文·A·博伊德
阿莉森·L·祖利
斯蒂芬·M·康登
卡伦·L·梅尔斯
徐真荣
上原刚
纳坦·莱恩
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VenatoRx Pharmaceuticals Inc
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VenatoRx Pharmaceuticals Inc
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Priority claimed from PCT/US2022/021883 external-priority patent/WO2022250776A1/en
Publication of CN117693511A publication Critical patent/CN117693511A/en
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Abstract

Described herein are certain boron-containing compounds, compositions, formulations, and uses thereof as modulators of the transpeptidase function of bacterial penicillin binding proteins and as antibacterial agents. In some embodiments, a compound described herein inhibits penicillin binding proteins. In certain embodiments, the compounds described herein are useful for treating bacterial infections.

Description

Penicillin binding protein inhibitors
Cross reference
The present application claims the benefit of U.S. provisional application Ser. No. 63/193,326, filed 5/26 of 2021, and U.S. provisional application Ser. No. 63/284,572, filed 11/30 of 2021, which are incorporated herein by reference in their entireties.
Statement regarding federally sponsored research
The present invention is a federal prize 6ids ep16030-01-02 subcontario 4500003206 awarded by the ministry of health and public service (Health and Human Services Office of the Assistant Secretary for Preparedness and Response, HHS/ASPR) under CARB-X penetrating entity (CARB-X Pass Through Entity) at 1R01AI141239 of the national institutes of health (National Institutes of Health, NIH), 1R01AI160269 of the National Institutes of Health (NIH), and a federal prize 6ids tra117C 0070-01-02 awarded by the national defense threat reduction office (Defense Threat Reduction Agency, DTRA) at the national defense (Department of Defense) and a government-supported under contract 75N93020C00016 awarded by the National Institute of Health (NIH) national allergic and infectious diseases institute (National Institute of Allergy and Infectious Diseases, NIAID). The government has certain rights in this invention.
Background
Antibiotics are the most effective drugs for treating bacterial related infectious diseases clinically. They are a very valuable therapeutic option, and are currently losing effectiveness due to the evolution and expansion of drug-resistant genes leading to multi-drug resistant bacterial organisms. Among the different classes of antibiotics, penicillin binding protein targeting beta-lactams (e.g. penicillins, cephalosporins and carbapenems) are the most widely used antibiotics because of their strong bactericidal effect and low associated toxicity.
Penicillin Binding Proteins (PBPs) are a family of essential bacterial enzymes involved in the synthesis of peptidoglycans, the major structural polymers found in bacterial cell walls. Beta-lactam antibiotics bind to PBP with high affinity and inhibit their transpeptidase function, resulting in disruption of peptidoglycan cell wall synthesis and rapid cell lysis of actively dividing bacteria. PBP represents an ideal target for antibacterial agents, since PBP has no close mammalian homologs and β -lactams are favored for their safety and efficacy.
Disclosure of Invention
Described herein are compounds that inhibit the activity of penicillin binding proteins, which bacterial enzymes are targeted by beta lactam antibiotics and do provide significant antibacterial activity in vitro.
Provided herein is a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl group,C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
R 2 is hydrogen, C 1 -C 6 Alkyl, -C (=o) R 3 、-S(＝O) 2 R 3 、-C(＝O)N(R 4 ) 2 or-S (=o) 2 N(R 4 ) 2 ；
R 3 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a Substitution;
each R 3a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution;
or two R's on the same atom 3a Together forming oxo;
each R 3b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 3b Together forming oxo;
each R 4 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4a Substitution;
each R 4a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4b Substitution;
or two on the same atomR 4a Together forming oxo;
each R 4b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 4b Together forming oxo;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
ring a is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
l is absent OR L is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 3 An alkylene group;
R 6a is-OH, -OR a Or C 1 -C 6 An alkyl group;
R 6b is-OH, -OR a Or C 1 -C 6 An alkyl group;
each R 7 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or two R's on the same atom 7 Together forming oxo;
n is 0 to 4;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or ringAn alkyl group;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 Forms, together with the boron atom to which they are attached, an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ]]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with oneOr multiple oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not
Also provided herein is a compound of formula (IIa) or (IIb), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each Y 1 And Y 2 Is independently-C (=O) -or-C (R) Y ) 2 -；
Each R Y Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
q is 1-3;
p is 1-3;
R 8 is- (W) u -ring B;
each W is independently-C (R W1 ) 2 -、-O-、-NR W2 -、-S-、-S(＝O)-、-S(＝O) 2 -or-C (=o) -;
each R W1 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteration ofAlkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each R W2 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or one R W1 And one R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W1 Forms together cycloalkyl or heterocycloalkyl when present; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
u is 1-10;
ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally being substituted with one or more R B Substitution;
each R B Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R 7a is hydrogen, deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7b is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7c is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or cycloalkyl;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 Forms, together with the boron atom to which they are attached, an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ]]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteration ofAlkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not
Also provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, and a pharmaceutically acceptable excipient.
Also provided herein is a method of treating a bacterial infection in a subject comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof or a pharmaceutical composition disclosed herein. Also disclosed herein is a method of inhibiting a bacterial penicillin binding protein in a human infected with a bacterial infection comprising contacting the bacterial penicillin binding protein with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer or trimer thereof or a pharmaceutical composition disclosed herein. In some embodiments, the bacterial infection is caused by neisseria gonorrhoeae (Neisseria gonorrhoeae). In some embodiments, the bacterial infection is caused by burkholderia melioides (Burkholderia pseudomallei). In some embodiments, the bacterial infection is caused by pseudomonas aeruginosa (Pseudomonas aeruginosa). In some embodiments, the bacterial infection is caused by acinetobacter baumannii (Acinetobacter baumannii). In some embodiments, the bacterial infection is caused by pseudomonas aeruginosa/acinetobacter baumannii. In some embodiments, the bacterial infection is caused by carbapenem-resistant enterobacteria (CRE).
Incorporation by reference
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Detailed Description
In decades of clinical use of beta-lactam antibiotics, bacteria have evolved drug resistance mechanisms that impair the utility of beta-lactams, including the generation of a broad spectrum of beta-lactamases that are readily transferable, and which are capable of efficiently hydrolyzing the beta-lactam ring. These enzymes now include >1300 variants, which have been spread over Enterobacteriaceae (Enterobacteriaceae). This rapid expansion of bacterial drug resistance mechanisms severely limits the β -lactam therapeutic options.
Novel non- β -lactam compounds that inhibit the transpeptidase function of PBP and are not degraded by β -lactamases would represent a significant advance in the treatment of drug resistant bacterial infections, essentially circumventing bacterial evolution for >70 years that protects the function of penicillin binding proteins in cell wall biosynthesis. The present invention is directed to certain boron-based compounds (boric acid and cyclic borates) which are PBP inhibitors and antibacterial compounds. The compounds and pharmaceutically acceptable salts thereof are useful in the treatment of bacterial infections, particularly antibiotic-resistant bacterial infections. Some embodiments include compounds, compositions, pharmaceutical compositions, uses, and preparation thereof.
Definition of the definition
In the following description, certain specific details are set forth in order to provide a thorough understanding of the embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be interpreted in an open, inclusive sense, i.e. as "comprising but not limited to. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
The term "antibiotic" refers to a compound or composition that reduces the viability of a microorganism, or inhibits the growth or proliferation of a microorganism. The phrase "inhibiting growth or proliferation" means increasing the generation time (i.e., the time required for bacterial cell division or population doubling) by at least about 2-fold. Preferred antibiotics are those that can increase the generation time to at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, such as total cell death). As used in this disclosure, antibiotics are further intended to include antimicrobial, bacteriostatic or bactericidal agents. Examples of antibiotics suitable for use in the present invention include penicillin, cephalosporin and carbapenem.
The term "beta-lactam antibiotic" refers to a compound containing beta-lactam functions with antibiotic properties. Non-limiting examples of beta-lactam antibiotics useful for the present invention include penicillin, cephalosporin, carbapenem, and monocyclolactam.
The term "beta-lactamase" refers to a protein capable of inactivating a beta-lactam antibiotic. The beta-lactamase may be an enzyme that catalyzes the hydrolysis of the beta-lactam ring of a beta-lactam antibiotic. Of particular interest herein are microbial beta-lactamases. The beta-lactamase may be, for example, serine beta-lactamase or metallo-beta-lactamase.
The term "penicillin binding protein" ("PBP") refers to an indispensable family of bacterial enzymes responsible for the synthesis of peptidoglycans, an essential structural polymer found only in the cell wall of bacteria. The protein family includes three classes. Class a is a high molecular weight bifunctional enzyme having both glycosyltransferase (GTase) and transpeptidase (TPase) activities, while class B is a monofunctional high molecular weight transpeptidase and class C is a low molecular weight remodelling enzyme, including D, D-carboxypeptidase and D, D-endopeptidase. Penicillin Binding Proteins (PBPs) are targets of β -lactam antibiotics, agents that covalently modify the active site of TPase and block peptidoglycan synthesis and remodeling, leading to rapid bacterial cell lysis of actively dividing cells.
"amino" means-NH 2 A substituent.
"oxo" refers to an =o substituent.
"oxime" means an =n-OH substituent.
"thio" refers to the = S substituent.
"alkyl" refers to a fully saturated linear or branched hydrocarbon chain. The alkyl group may have from 1 to 30 carbon atoms. Alkyl groups comprising up to 30 carbon atoms are referred to as C 1 -C 30 Alkyl, also for example, alkyl comprising up to 12 carbon atoms is C 1 -C 12 An alkyl group. Alkyl groups comprising up to 6 carbons are C 1 -C 6 An alkyl group. Alkyl groups include, but are not limited to, C 1 -C 30 Alkyl, C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl, C 1 -C 8 Alkyl, C 1 -C 6 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 2 -C 8 Alkyl, C 3 -C 8 Alkyl, C 4 -C 8 Alkyl and C 5 -C 12 An alkyl group. In some embodiments, the alkyl group is C 1 -C 6 An alkyl group. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), 2-ethylpropyl, and the like. Representative linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and the like. In some embodiments, the alkyl group is substituted with an optionally substituted aryl group to form an optionally substituted aralkyl group. In some embodiments, the alkyl is substituted with an optionally substituted heteroaryl to form an optionally substituted heteroarylalkyl. In some embodiments, the alkyl is substituted with an optionally substituted cycloalkyl to form an optionally substituted cycloalkylalkyl. In some embodiments, the alkyl is substituted with an optionally substituted heterocycloalkyl to form an optionally substituted heterocycloalkyl. In some embodiments, the alkyl group is optionally substituted with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, the alkyl group is optionally substituted with halo.
"alkenyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. In certain embodiments, alkenyl groups comprise 2 to 12 (C 2 -C 12 Alkenyl) carbon atoms or 2 to 8 carbon atoms (C 2 -C 8 Alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 Alkenyl) or 2 to 4 carbon atoms (C 2 -C 4 Alkenyl). Alkenyl groups may be attached to the remainder of the molecule by single bonds, for example, vinyl, prop-1-enyl (i.e., allyl), but-1-enyl, pent-1, 4-dienyl, and the like. Alkenyl groups may be linked to the remainder of the molecule by a double bond, e.g., =ch 2 、＝CH(CH 2 ) 3 CH 3 . In some embodiments, the alkenyl group is optionally substituted with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally oxo, halogen, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, the alkenyl is optionally oxo, halogen, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, alkenyl is optionally substituted with halo.
"alkynyl" refers to a straight or branched hydrocarbon chain group containing at least one carbon-carbon triple bond. In certain embodiments, the alkynyl group comprises 2 to 12 (C 2 -C 12 Alkynyl) carbon atoms or 2 to 8 carbon atoms (C 2 -C 8 Alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 Alkynyl) or 2 to 4 carbon atoms (C 2 -C 4 Alkynyl). Alkynyl groups may be attached to the remainder of the molecule by single bonds, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. In some embodiments, the alkynyl group is optionally substituted with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, alkynyl is optionally substituted with oxo, halo, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, alkynyl is optionally substituted with halo.
"alkylene" or "alkylene chain" refers to a straight or branched divalent radical that connects the remainder of the molecule to a groupHydrocarbon chains, which are composed of carbon and hydrogen only, contain no unsaturation, and have, for example, from 1 to 12 carbon atoms (C 1 -C 12 Alkylene) such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is linked to the rest of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkylene chain to the remainder of the molecule and the group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, the alkylene group comprises 1 to 8 carbon atoms (C 1 -C 8 Alkylene) or 1 to 5 carbon atoms (C 1 -C 5 Alkylene) or 1 to 4 carbon atoms (C 1 -C 4 Alkylene) or 1 to 3 carbon atoms (C 1 -C 3 Alkylene) or 1 to 2 carbon atoms (C 1 -C 2 An alkylene group). In other embodiments, the alkylene group includes one carbon atom (C 1 Alkylene) or two carbon atoms (C 2 An alkylene group). In certain embodiments, the alkylene group comprises 2 to 5 carbon atoms (e.g., C 2 -C 5 An alkylene group). In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, the alkylene is optionally substituted with halo.
"alkoxy" refers to a group of the formula-O-alkyl, wherein alkyl is as defined herein. Unless specifically stated otherwise in the specification, the alkoxy groups may be optionally substituted as described above for alkyl groups.
"aryl" refers to an aromatic monocyclic hydrocarbon or aromatic polycyclic hydrocarbon ring system in which a hydrogen atom is removed from the ring carbon atoms. Aryl groups may comprise rings having 6 to 18 carbon atoms, wherein at least one ring of the ring system is aromatic, i.e. it contains a cyclic, delocalized (4n+2) pi-electron system according to Huckel's theory. In some embodiments, aryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when substituted with cycloalkyl or heterocycloalkylWhen the base ring is fused, the aryl group is bonded through an aromatic ring atom). In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6 membered aryl. In some embodiments, the aryl is a 10 membered aryl. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. In some embodiments, aryl is optionally substituted with halo, amino, nitrile, nitro, hydroxy, alkyl, haloalkyl, alkoxy, aryl, aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halo, -CN, -Me, -Et, -CF 3 、-OH、-OMe、-NH 2 、-NO 2 Or cyclopropyl substitution. In some embodiments, aryl is optionally substituted with oxo, halogen, -CN, -Me, -Et, -CF 3 -OH, -OMe or cyclopropyl. In some embodiments, aryl is optionally substituted with halo.
"aryloxy" refers to a group of formula-O-aryl bonded through an oxygen atom, wherein aryl is as described above.
"aralkyl" means a compound of formula-R h -aryl groups, wherein R h Is an alkylene chain as defined above, e.g., methylene, ethylene, and the like. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.
"borate" means-B (OR) k ) 2 Wherein each R is k Independently is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, (polyethylene glycol) ethyl or optionally substituted saccharide, provided that they are not all hydrogen. In some embodiments, each R k Is an alkyl group. In some embodiments, two R k Optionally substituted heterocyclic or cyclic borates may be formed together with the atoms to which they are attached. In some embodiments, the cyclic borate is formed from pinanediol, pinacol, 1, 2-ethanediol, 1, 3-propanediol, 1, 2-propanediol Alcohols, 2, 3-butanediol, 1, 2-diisopropylethylene glycol, 5, 6-decanediol, 1, 2-dicyclohexylethylene glycol, diethanolamine, 1, 2-diphenyl-1, 2-ethylene glycol, 2, 6-trimethylbicyclo [3.1.1 ]]Heptane-2, 3-diol or (1 s,2s,3r,5 s) -2, 6-trimethylbicyclo [3.1.1]Heptane-2, 3-diol.
"cycloalkyl" refers to a saturated or partially unsaturated, mono-or polycyclic hydrocarbon. In certain embodiments, cycloalkyl groups include fused ring systems (cycloalkyl groups are bonded through non-aromatic ring atoms when fused to an aryl or heteroaryl ring) or bridged ring systems. In certain embodiments, cycloalkyl groups contain from 3 to 20 carbon atoms (C 3 -C 20 Cycloalkyl) or 3 to 10 carbon atoms (C 3 -C 10 Cycloalkyl) or 3 to 8 carbon atoms (C 3 -C 8 Cycloalkyl) or 3 to 6 carbon atoms (C 3 -C 6 Cycloalkyl). In some embodiments, cycloalkyl is 3 to 6 membered cycloalkyl. In some embodiments, cycloalkyl is 3-to 8-membered cycloalkyl. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo [ 2.2.1)]Heptyl), norbornenyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1 ]Heptyl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, haloalkyl, alkoxy, aryl, aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, -CN, -Me, -Et, -CF 3 、-OH、-OMe、-NH 2 、-NO 2 Or cyclopropyl substitution. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, -CN, -Me, -Et, -CF 3 -OH, -OMe or cyclopropyl. In some embodiments, cycloalkyl is optionally substituted with halo.
"cycloalkylalkyl" means a radical of formula-R h -cycloalkyl groups, wherein R h Is an alkylene chain as defined above. The alkylene chain and cycloalkyl groups are optionally substituted as described above.
"halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, halogen refers to chlorine or fluorine.
"heterocycloalkyl" refers to a saturated or partially unsaturated ring containing 2 to 20 carbon atoms and at least one heteroatom. In certain embodiments, the heteroatoms are independently selected from N, O, si, P, B and S atoms. In certain embodiments, the heteroatoms are independently selected from N, O and S atoms. The heterocycloalkyl group may be selected from a monocyclic or bicyclic ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or a bridged ring system. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. Heterocycloalkyl groups are partially or fully saturated. Any atom of the heterocycloalkyl group (such as any carbon or nitrogen atom of the heterocycloalkyl group) through which the valence allows is attached to the remainder of the molecule. In certain embodiments, heterocycloalkyl comprises from 2 to 20 carbon atoms (C 2 -C 20 Heterocycloalkyl) or 2 to 10 carbon atoms (C 2 -C 10 Heterocycloalkyl) or 2 to 8 carbon atoms (C 2 -C 8 Heterocycloalkyl) or 2 to 6 carbon atoms (C 2 -C 6 Heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 6 membered heterocycloalkyl. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, aziridinyl, dioxolanyl, thienyl [1,3 ]]Dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl), and,1-oxo-thiomorpholinyl and 1, 1-dioxo-thiomorpholinyl. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, haloalkyl, alkoxy, aryl, aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, -CN, -Me, -Et, -CF 3 、-OH、-OMe、-NH 2 、-NO 2 Or cyclopropyl substitution. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, -CN, -Me, -Et, -CF 3 -OH, -OMe or cyclopropyl. In some embodiments, the heterocycloalkyl group is optionally substituted with halo.
"Heterocyclylalkylalkyl" means a compound of formula-R h -a heterocycloalkyl group, wherein R h Is an alkylene chain as defined above. If the heterocycloalkyl group is a nitrogen-containing heterocycloalkyl group, the heterocycloalkyl group is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of the heterocycloalkyl alkyl group is optionally substituted as defined above for the alkylene chain. The heterocycloalkyl moiety of the heterocycloalkyl group is optionally substituted as defined above for the heterocycloalkyl group.
"heteroaryl" refers to a 5 to 14 membered ring system comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is a 5-or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, heteroaryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, heteroaryl is bonded through an aromatic ring atom); and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 10 membered heteroaryl. Examples include, but are not limited to, aza Group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxa->Alkenyl, 1, 4-benzodioxanyl, benzonaphthafuranyl, benzoxazolyl, benzodioxolyl, benzodioxadienyl, benzopyranyl, benzopyronyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benzo [4,6 ]]Imidazo [1,2-a]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-azaA group, oxazolyl, oxiranyl, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. In some embodiments, heteroaryl is optionally substituted with halo, amino, nitrile, nitro, hydroxy, alkyl, haloalkyl, alkoxy, aryl, aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, -CN, -Me, -Et, -CF 3 、-OH、-OMe、-NH 2 、-NO 2 Or cyclopropyl substitution. In some embodiments, heteroaryl is optionally substituted with halogen, -CN, -Me, -Et, -CF 3 -OH, -OMe or cyclopropyl. In some embodiments, heteroaryl groups are optionallyIs substituted by halogen.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g. -CF) 2 CF 3 ) Monosubstituted (e.g. -CH 2 CH 2 F) Or at any level between full substitution and single substitution (e.g., -CH 2 CHF 2 、-CH 2 CF 3 、-CF 2 CH 3 、-CFHCHF 2 Etc.). Those skilled in the art will appreciate that for any group containing one or more substituents, such groups are not intended to introduce any substitution or pattern of substitution that is sterically impractical and/or synthetically infeasible (e.g., substituted alkyl groups include optionally substituted cycloalkyl groups, which in turn are defined to include optionally substituted alkyl groups, possibly infinitely repeated). Thus, any substituent described is generally understood to have a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject in a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.
"treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention that is used to attempt to alter the natural course of the individual or cell. In some embodiments, the treatment comprises administering the pharmaceutical composition at the beginning of a pathological event or after contact with a pathogen, and comprises stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition. In some embodiments, treatment further includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected of having a bacterial infection).
Compounds of formula (I)
Compounds that modulate the activity of penicillin binding proteins are described herein. In some embodiments, a compound described herein inhibits β -lactamase. In certain embodiments, the compounds described herein are useful for treating bacterial infections. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection. In some embodiments, the bacterial infection is an uncomplicated or uncomplicated urinary tract infection, uncomplicated or uncomplicated gonorrhea, upper or lower respiratory tract infection, skin or skin structure infection, intraperitoneal infection, central nervous system infection, blood flow infection, or systemic infection.
Disclosed herein is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
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wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
R 2 is hydrogen, C 1 -C 6 Alkyl, -C (=o) R 3 、-S(＝O) 2 R 3 、-C(＝O)N(R 4 ) 2 or-S (=o) 2 N(R 4 ) 2 ；
R 3 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a Substitution;
each R 3a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl、C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution;
or two R's on the same atom 3a Together forming oxo;
each R 3b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 3b Together forming oxo;
each R 4 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl groups, the rings Alkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4a Substitution;
each R 4a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4b Substitution;
or two R's on the same atom 4a Together forming oxo;
each R 4b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 4b Together forming oxo;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
ring a is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
l is absent OR L is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 3 An alkylene group;
R 6a is-OH, -OR a Or C 1 -C 6 An alkyl group;
R 6b is-OH, -OR a Or C 1 -C 6 An alkyl group;
each R 7 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or two R's on the same atom 7 Together forming oxo;
n is 0 to 4;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or cycloalkyl;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 With boron attached to themTogether, the atoms form an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ]]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
Each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl group-Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not
In some embodiments of the compounds of formula (Ia) or (Ib), R 2 Is C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (Ia) or (Ib)Wherein R is 2 is-C (=O) R 3 or-S (=o) 2 R 3 . In some embodiments of the compounds of formula (Ia) or (Ib), R 2 is-C (=O) R 3 . In some embodiments of the compounds of formula (Ia) or (Ib), R 2 is-S (=O) 2 R 3 . In some embodiments of the compounds of formula (Ia) or (Ib), R 2 is-C (=O) N (R) 4 ) 2 or-S (=o) 2 N(R 4 ) 2 .
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a And (3) substitution.
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a And (3) substitution.
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is optionally substituted with one or more R 3a Substituted heterocycloalkyl.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or the same sourceTwo R on the son 3a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、-Y-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、-Y-C(＝O)R a 、C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3a Not C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom 3b Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 3b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is thatOr->In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is->
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is that
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is->
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is that
In some embodiments of the compounds of formula (Ia) or (Ib), R 3 Is that
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4 Independently hydrogen, C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4a And (3) substitution.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4 Independently hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4a And (3) substitution.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4 Independently hydrogen or heterocycloalkyl, optionally substituted with one or more R 4a And (3) substitution.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4b Substitution; or two R's on the same atom 4a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、-Y-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4b Substitution; or two R's on the same atom 4a Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom 4b Together forming oxo.
In some embodiments of the compounds of formula (Ia) or (Ib), each R 4b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (Ia) or (Ib), the compounds are of formula (Ia-1) or formula (Ib-1):
wherein:
each Y 1 And Y 2 Is independently-C (=O) -or-C (R) Y ) 2 -；
Each R Y Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
q is 1-3;
p is 1-3;
R 5 is-Y-OC (=O) R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a Substitution; and is also provided with
Each R 5a Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 5a Together forming oxo.
In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 1 or 2. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 1. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 2. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 3.
In some embodiments of compounds of formula (Ia-1) or (Ib-1), p is 1 or 2. In some embodiments of compounds of formula (Ia-1) or (Ib-1), p is 1. In some embodiments of compounds of formula (Ia-1) or (Ib-1), p is 2. In some embodiments of compounds of formula (Ia-1) or (Ib-1), p is 3.
In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and each Y 2 is-C (=o) -. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 1; and Y is 2 is-C (=o) -. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and one Y 2 is-C (R) Y ) 2 -and one Y 2 is-C (=o) -. In some embodiments of compounds of formula (Ia-1) or (Ib-1), q is 2; y is a 1 is-C (R) 5 ) 2 -and one Y 1 is-C (=o) -; p is 2; and one Y 2 is-C (R) 5 ) 2 -and one Y 2 is-C (=o) -.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), each R Y Independently hydrogen, halogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), each R Y Is hydrogen.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1),is thatIn some embodiments of the compounds of formula (Ia-1) or (Ib-1), the compound is->In some embodiments of the compounds of formula (Ia-1) or (Ib-1), the compound is->In some embodiments of the compounds of formula (Ia-1) or (Ib-1), the compound is->
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 、-Y-NR b C(＝O)R a -Y-heterocycloalkyl or-Y-aryl; wherein heterocycloalkyl and aryl are optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-S (=O) 2 R a 。
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-NR b C(＝O)R a 。
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), -Y-aryl; wherein aryl is optionally substituted with one or more R 5a And (3) substitution.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 is-Y-heterocycloalkyl; wherein heterocycloalkyl is optionally substituted with one or more R 5a And (3) substitution.
In the compounds of formula (Ia-1) or (Ib-1)In some embodiments, each R 5 Not C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), each R 5a Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom 3b Together forming oxo.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), each R 5a Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 Is methyl, ethyl orIn some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 Is->
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 Is that In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 Is->In one of the compounds of the formula (Ia-1) or (Ib-1)In some embodiments, R 5 Is->
In some embodiments of the compounds of formula (Ia-1) or (Ib-1), R 5 Is that
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is aryl or heteroaryl. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is aryl. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is phenyl.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is heteroaryl. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is a 5-or 6-membered heteroaryl. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), ring A is a 6-membered heteroaryl.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), L is absent. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) OR (Ib-1), L is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 3 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), L is C substituted with one or more halogens 1 An alkylene group.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), R 6a is-OH or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), R 6a is-OH.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), R 6b is-OH or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), R 6b is-OH.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), each R 7 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), each R 7 Independently is halogen or-OH. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), each R 7 Independently halogen.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 1 or 2. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 0 or 1. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 0. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 1. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 2. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib) or (Ib-1), n is 3.
Also disclosed herein is a compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each Y 1 And Y 2 Is independently-C (=O) -or-C (R) Y ) 2 -；
Each R Y Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
q is 1-3;
p is 1-3;
R 8 is- (W) u -ring B;
each W is independently-C (R W1 ) 2 -、-O-、-NR W2 -、-S-、-S(＝O)-、-S(＝O) 2 -or-C (=o) -;
each R W1 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each R W2 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or one R W1 And one R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W1 Forms together cycloalkyl or heterocycloalkyl when present; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
u is 1-10;
ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally being substituted with one or more R B Substitution;
each R B Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups；
R 7a Is hydrogen, deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7b is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7c is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or cycloalkyl;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 Forms, together with the boron atom to which they are attached, an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ]]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not/>
In some embodiments of compounds of formula (IIa) or (IIb), q is 1 or 2. In some embodiments of compounds of formula (IIa) or (IIb), q is 1. In some embodiments of compounds of formula (IIa) or (IIb), q is 2. In some embodiments of compounds of formula (IIa) or (IIb), q is 3.
In some embodiments of compounds of formula (IIa) or (IIb), p is 1 or 2. In some embodiments of compounds of formula (IIa) or (IIb), p is 1. In some embodiments of compounds of formula (IIa) or (IIb), p is 2. In some embodiments of compounds of formula (IIa) or (IIb), p is 3.
In some embodiments of compounds of formula (IIa) or (IIb), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and each Y 2 is-C (=o) -. In some embodiments of compounds of formula (IIa) or (IIb), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 1; and Y is 2 is-C (=o) -. In some embodiments of compounds of formula (IIa) or (IIb), q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and one Y 2 is-C (R) Y ) 2 -and one Y 2 is-C (=o) -. In some embodiments of compounds of formula (IIa) or (IIb), q is 2; y is a 1 is-C (R) 5 ) 2 -and one Y 1 is-C (=o) -; p is 2; and one Y 2 is-C (R) 5 ) 2 -and one Y 2 is-C (=o) -.
In some embodiments of the compounds of formula (IIa) or (IIb), each R Y Independently hydrogen, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R Y Is hydrogen.
In some embodiments of the compounds of formula (IIa) or (IIb),or (b)In some embodiments of the compounds of formula (IIa) or (IIb), the formula (IIa) is>Is thatIn some embodiments of the compounds of formula (IIa) or (IIb), the formula (IIa) is>In some embodiments of the compounds of formula (IIa) or (IIb),
in some embodiments of the compounds of formula (IIa) or (IIb), R 7a Is hydrogen or halogen. In some embodiments of the compounds of formula (IIa) or (IIb), R 7a Is hydrogen.
In some embodiments of the compounds of formula (IIa) or (IIb), R 7b Is halogen.
In some embodiments of the compounds of formula (IIa) or (IIb), R 7c Is halogen.
In some embodiments of compounds of formula (IIa) or (IIb), u is 1-8. In some embodiments of compounds of formula (IIa) or (IIb), u is 1-7. In some embodiments of compounds of formula (IIa) or (IIb), u is 1-6. In some embodiments of compounds of formula (IIa) or (IIb), u is 1-5. In some embodiments of compounds of formula (IIa) or (IIb), u is 3-8. In some embodiments of compounds of formula (IIa) or (IIb), u is 4-8. In some embodiments of compounds of formula (IIa) or (IIb), u is 5-8. In some embodiments of compounds of formula (IIa) or (IIb), u is 4-6. In some embodiments of compounds of formula (IIa) or (IIb), u is 2-6. In some embodiments of compounds of formula (IIa) or (IIb), u is 2-5. In some embodiments of compounds of formula (IIa) or (IIb), u is 2-4. In some embodiments of compounds of formula (IIa) or (IIb), u is 1. In some embodiments of compounds of formula (IIa) or (IIb), u is 2. In some embodiments of compounds of formula (IIa) or (IIb), u is 3. In some embodiments of compounds of formula (IIa) or (IIb), u is 4. In some embodiments of compounds of formula (IIa) or (IIb), u is 5. In some embodiments of compounds of formula (IIa) or (IIb), u is 6. In some embodiments of compounds of formula (IIa) or (IIb), u is 7. In some embodiments of compounds of formula (IIa) or (IIb), u is 8. In some embodiments of compounds of formula (IIa) or (IIb), u is 9. In some embodiments of compounds of formula (IIa) or (IIb), u is 10.
In some embodiments of compounds of formula (IIa) or (IIb), each W is independently-C (R) W1 ) 2 -、-NR W2 -or-C (=o) -. In some embodiments of compounds of formula (IIa) or (IIb), each W is independently-C (R) W1 ) 2 -、-NR W2 -or-S (=o) 2 -. In some embodiments of compounds of formula (IIa) or (IIb), each W is independently-C (R) W1 ) 2 -、-NR W2 -、-S(＝O) 2 -or-C (=o) -. In some embodiments of compounds of formula (IIa) or (IIb), each W is independently-C (R) W1 ) 2 -or-NR W2 -. In some embodiments of compounds of formula (IIa) or (IIb), each W is independently-C (R) W1 ) 2 -。
In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-、-[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -、-[C(R W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -、-[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -、-[C(R W1 ) 2 ] 1-3 -NR W2 -[C(R W1 ) 2 ] 1-3 -、-[C(R W1 ) 2 ] 1-4 -、-S(＝O) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C (=o) -or-S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C (=o) -or- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C (=o) -or- [ C (R) W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-、-[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -、-[C(R W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -or- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C (=o) -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -[C(R W1 ) 2 ] 1-2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -。In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-3 -NR W2 -[C(R W1 ) 2 ] 1-3 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is- [ C (R) W1 ) 2 ] 1-4 -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is-S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C (=o) -. In some embodiments of the compounds of formula (IIa) or (IIb), - (W) u -is-S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -。
In some embodiments of the compounds of formula (IIa) or (IIb), each R W1 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R W1 Independently hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R W1 Is hydrogen.
In some embodiments of the compounds of formula (IIa) or (IIb), each R W2 Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R W2 Independently hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R W2 Is hydrogen. In some embodiments of the compounds of formula (IIa) or (IIb), each R W2 Independently C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IIa) or (IIb), one R W1 And one R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds of formula (IIa) or (IIb), one R W1 And one R W2 Together when present form piperidinyl or pyrrolidinyl; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds of formula (IIa) or (IIb), one R W1 And one R W2 Together when present form a piperidinyl or pyrrolidinyl group. In some embodiments of the compounds of formula (IIa) or (IIb), one R W1 And one R W2 Together when present form a piperidinyl group.
In some embodiments of the compounds of formula (IIa) or (IIb), two R W1 Forms together cycloalkyl or heterocycloalkyl when present; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
In some embodiments of the compounds of formula (IIa) or (IIb), two R W2 Together when present form a heterocycloalkyl group, which is optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
In some embodiments of compounds of formula (IIa) or (IIb), ring B is heterocycloalkyl, aryl, or heteroaryl; each optionally being substituted with one or more R B And (3) substitution.
In some embodiments of compounds of formula (IIa) or (IIb), ring B is aryl or heteroaryl; each optionally being substituted with one or more R B And (3) substitution. In formula (IIa) or (IIa)In some embodiments of the compound of (IIb), ring B is optionally substituted with one or more R B Substituted aryl. In some embodiments of the compounds of formula (IIa) or (IIb), ring B is optionally substituted with one or more R B A substituted phenyl group. In some embodiments of the compounds of formula (IIa) or (IIb), ring B is optionally substituted with one or more R B Substituted heteroaryl groups. In some embodiments of the compounds of formula (IIa) or (IIb), ring B is optionally substituted with one or more R B Substituted 5-or 6-membered heteroaryl.
In some embodiments of the compounds of formula (IIa) or (IIb), each R B Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R B Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R B Independently halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (IIa) or (IIb), each R B Independently halogen or OH.
In some embodiments of the compounds of formula (IIa) or (IIb), R 8 Is that
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), R 1 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), R 1 Is hydrogen.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), R d Is hydrogen.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), each R e Is hydrogen.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), X 1 And X 2 is-OH.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) OR (IIb), each R is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl groups. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) OR (IIb), each R is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), each R is independently deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), each R is independently halogen.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), m is 0 or 1. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), m is 1 or 2. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), m is 0. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), m is 1. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), m is 2.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Z is hydrogen. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Z is R 11 The method comprises the steps of carrying out a first treatment on the surface of the And R is 11 Is C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Z is-R 10 OC(＝O)R 11 or-R 10 OC(＝O)OR 11 ；R 10 is-CH 2 -or-CH (CH) 3 ) -; and R is 11 Is alkyl, cycloalkyl or heterocycloalkyl.
In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is absent. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) OR (IIb), Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is C 1 -C 6 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is C 1 -C 4 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is C 2 -C 6 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is C 2 -C 4 An alkylene group. In some embodiments of the compounds of formula (Ia), (Ia-1), (Ib-1), (IIa) or (IIb), Y is C 1 Alkylene groupA base.
In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 An alkyl group. In some embodiments of the compounds disclosed herein, each R a Independently is-Y-aryl; wherein each aryl is independently optionally substituted with one or more halogens, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently is-Y-aryl; wherein each aryl is independently optionally substituted with one or more halogens, -CN, -OH, -OCH 3 、-NH 2 、-C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently is-Y-aryl; wherein each aryl is independently optionally substituted with one or more halogens or —oh.
In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds disclosed herein, each R b Is hydrogen. In some embodiments of the compounds disclosed herein, each R b Independently C 1 -C 6 An alkyl group.
In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl; wherein each alkyl group,Cycloalkyl and heterocycloalkyl are independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -Y-cycloalkyl or-Y-heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds disclosed herein, each R c And R is d Is hydrogen. In some embodiments of the compounds disclosed herein, each R c And R is d Independently C 1 -C 6 An alkyl group.
In some embodiments of the compounds disclosed herein, R c And R is d Together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution.
In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1-6 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1-5 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1-4 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1-3 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1 or 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 1 substituent as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, when a substituent is optionally substituted with one or more substituents as defined herein, the substituent is optionally substituted with 5 substituents as defined herein.
Other forms of the compounds disclosed herein
Isomers/stereoisomers
In some embodiments, due to the oxophilic nature of the boron atom, the compounds described herein may be converted to or exist in equilibrium with alternative forms, particularly in environments containing water (aqueous solutions, plasma, etc.). Thus, the compounds described herein may exist in equilibrium between the "closed" cyclic forms shown in formulas (Ia), (Ia '), (IIa) and the "open" acyclic forms shown in formulas (Ib), (Ib'), (IIb). Furthermore, the compounds described herein may associate as intramolecular dimers, trimers, and related combinations.
Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis (cis), trans (trans), cis (syn), trans (anti), entgegen (E) and zusammen (Z) isomers, and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereoisomeric, enantiomeric and epimeric forms, as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers derived from a single preparation step, combination, or interconversion may be used in the applications described herein. In some embodiments, a compound described herein is prepared as its individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these distinct points. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered with the resolving agent by any practical method that does not result in racemization. The compounds described herein may be prepared as a single isomer or as a mixture of isomers.
Tautomers
In some cases, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by hydrogen atom migration accompanied by a switch between a single bond and an adjacent double bond. In a bonding arrangement that can be tautomerized, the chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact proportion of tautomers depends on several factors, including temperature, solvent and pH.
Labeling compounds
In some embodiments, the compounds described herein are present in their isotopically-labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include the same A potential labeling compound that is identical to the compounds described herein except that one or more atoms are replaced with an atom having an atomic mass or mass number that is different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as, respectively 2 H、 3 H、 13 C、 14 C、 l5 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds described herein containing the above isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds (e.g., incorporating a radioisotope (such as 3 H and 14 c) Compounds of (c) are useful in drug and/or substrate tissue distribution assays. Tritiated isotopes (i.e 3 H) And a carbon-14 isotope (i.e 14 C) It is particularly preferred because of its ease of preparation and ease of detection. Furthermore, the heavy isotopes (such as deuterium (i.e. 2 H) Substitution) results in certain therapeutic advantages derived from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically-labeled compounds, pharmaceutically-acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof, are prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt formed thereby.
Examples of pharmaceutically acceptable salts include those prepared by reaction of a compound described herein with mineral, organic or inorganic acids, including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorate, camphorsulfonate, caprate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, caprate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate (palmoate), pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluene sulfonate undecanoate and xylene sulfonate.
In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic or organic acids (including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, hydroxy-benzoic acid, salicylic acid, glutamic acid, and stearic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable per se, are used to prepare salts useful as intermediates to obtain the compounds described herein and pharmaceutically acceptable acid addition salts thereof.
In some embodiments, those compounds described herein that include a free acid group are reacted with a suitable base of a pharmaceutically acceptable metal cation (such as hydroxide, carbonate, bicarbonate, sulfate), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium and magnesium salts, aluminum salts, and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl group 4 Etc.
Representative organic amines useful in forming the base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, the water-soluble or oil-soluble or dispersible product is obtained by such quaternization.
Solvates of the formula
In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.
Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared from aqueous/organic solvent mixtures using organic solvents (including, but not limited to, dioxane, tetrahydrofuran, or methanol). Furthermore, the compounds provided herein may exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
Pharmaceutical composition/formulation
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a β -lactam antibiotic. In certain embodiments, the β -lactam antibiotic is a penicillin, a cephalosporin, a carbapenem, a monocyclic lactam, a bridged monocyclic lactam, or a combination thereof.
In some embodiments, the compounds described herein are formulated as pharmaceutical compositions. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the route of administration selected. The summary of the pharmaceutical compositions described herein may be found, for example, in Remington: the Science and Practice of Pharmacy, ninth edition (Easton, pa.: mack Publishing Company, 1995); hoover, john e., remington's Pharmaceutical Sciences, mack Publishing co., easton, pennsylvania 1975; liberman, h.a. and Lachman, l. Editions, pharmaceutical Dosage Forms, marcel Decker, new York, n.y.,1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, seventh edition (Lippincott Williams & Wilkins 1999), such disclosures being incorporated herein by reference.
A pharmaceutical composition as used herein refers to a mixture of a compound described herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients) (e.g., carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, permeation enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combinations thereof). The pharmaceutical compositions facilitate administration of the compounds to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds may be used alone or as a component of a mixture in combination with one or more therapeutic agents.
The pharmaceutical formulations described herein are administered to a subject by suitable routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations and immediate and controlled release mixed formulations.
Combination therapy
The compounds described herein may be used in combination with one or more antibiotics to treat bacterial infections. Such antibiotics may be administered simultaneously or sequentially with the compounds described herein by routes and amounts thus commonly used. Pharmaceutical compositions in unit dosage form containing such other drugs and the compounds of the invention are preferred when the compounds described herein are used in combination with one or more antibiotics. However, combination therapy may also include therapy in which the compounds described herein are administered with one or more antibiotics at different overlapping schedules. It is also contemplated that when used in combination with one or more antibiotics, the antibiotics may be used at a lower dosage than when each antibiotic is used alone.
Accordingly, the pharmaceutical compositions of the present invention also include those containing one or more antibiotics in addition to the compounds described herein. In some embodiments, the pharmaceutical composition comprising a compound described herein further comprises a β -lactam antibiotic. In certain embodiments, the β -lactam antibiotic is a penicillin, a cephalosporin, a carbapenem, a monocyclic lactam, a bridged monocyclic lactam, or a combination thereof.
In some embodiments, the compounds described herein are used in combination with one or more antibiotics to treat bacterial infections. In certain embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection. In some embodiments, the bacterial infection is an uncomplicated or uncomplicated urinary tract infection, uncomplicated or uncomplicated gonorrhea, upper or lower respiratory tract infection, skin or skin structure infection, intraperitoneal infection, central nervous system infection, blood flow infection, or systemic infection.
In some embodiments, the one or more antibiotics are selected from the group consisting of β -lactam antibiotics. Beta-lactam antibiotics include, but are not limited to, penicillins, carbapenems, cephalosporins, monobactams, or combinations thereof. Penicillin includes, but is not limited to, amoxicillin (amoxicillin), ampicillin (ampicillin), azidothicillin (azidocillin), azlocillin (azlocillin), bammoxicillin (bacampicillin), benzathine (benzathine benzylpenicillin), benzathine benzylpenicillin (benzathine epoxypencilin), benzyl penicillin (benzathine pencilin) (G), carbobenicillin (carbicillin), carbodanicillin (carindacilin), clomexicillin (clomexicillin), cloxacillin (cloxacilin), bischlorocilin (dicycloxacilin), epmethicillin (epoxicillin), flucloxacilin), pentacillin (hepacillin) mexillin (mecillinam), methicillin (metamycin), methicillin (meticillin), mezlocillin (mezlocillin), nafcillin (nafcillin), oxacillin (oxacillin), penciclin (penameicillin), non-netillin (phenicillin), phenoxymethyl penicillin (phenamicylin) (V), piperacillin (piperacillin), pivacillin (pivacillin), pivicillin (pivicillin), procalcitonin (procaine benzylpenicillin), phenylpenicillin (proficillin), sulbenicillin (sulbenicillin), phthalamillin (tamicillin), temicillin (temicillin) and ticarcillin (ticarcillin). The penems include, but are not limited to, faropenem (faropenem). Carbapenems include, but are not limited to, biapenem (biapenem), ertapenem (ertapenem), doripenem (doripenem), imipenem (imipenem), meropenem (meropenem), and panipenem (panipeem). Cephalosporins/cephalosporins including, but not limited to, ceftriaxone (cefatrine), cefaclor (cefaclor), cefadroxil (cefdroxil), cefalexin (cefalexin), cefalexin (cefaloxin), cefalonim (cefdinir), cefaloridine (cefaloridine), cefalotin (cefalotin), cefamandole (cefamandole), cefpirane (cefapirin), cefatrizine (cefatrizine), ceftazil (ceftamaking), cefazedone (cefazedone), cefazolin (cefbuperazone), cefprozil (cefcapene), cefdaxime (cefdaxime), cefdinir), cefditoren (cefditoren), cefepime (cefpirane) cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefditime, cefmetazole, cefditime, cefmedicine, and pharmaceutical composition cefonicid, cefoperazone, ceftriadime, cefotaxime, cefotetan, and the like cefotiam (ceftiam), ceftivalin (ceflevetil), cefoxitin (cefoxitin), cefazolin (cefzopran), ceftizol (ceftizopran), ceftizoxime (ceftizoxime), cefpiramide (cefpirome), cefpodoxime (cefpodoxime), cefprozil (cefrozil), cefquinome (cefquinome), cefquinome, ceftazidime, cefteram ceftezole ceftazidime, cefteram, ceftezole, and the like ceftibuten, ceftiofur ceftioline (ceftiolene), ceftizoxime (ceftoxime), cefpirane (ceftobipole), ceftriaxone (ceftriaxone), cefuroxime (cefuroxime), cefazolonam (cefzonam), flomoxef, latamoxef and chlorocarbon cefuroxime (lopocarbef). Monocyclic lactams include, but are not limited to, aztreonam (aztreonam), carumonam (carumonam), nocardine A (nocardicinA), and tigemonam (tigemonam).
Method
The present disclosure also provides methods for inhibiting bacterial growth, such methods comprising contacting a bacterial cell culture or a bacterial infected cell culture, tissue or organism with a penicillin binding protein inhibitor as described herein. Preferably, the bacteria to be inhibited by administration of the penicillin binding protein inhibitors described herein are bacteria resistant to beta-lactam antibiotics. The term "drug resistance" is well known to those of ordinary skill in the art (see, e.g., payne et al, antimicrobial Agents and Chemotherapy, 767-772 (1994), hanaki et al, antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)). In some embodiments, the penicillin binding protein inhibitors described herein are used to treat bacterial infections resistant to beta-lactam antibiotics. In some embodiments, the penicillin binding protein inhibitors described herein are used to treat bacterial infections that have developed beta-lactamase.
These methods can be used in various situations to inhibit bacterial growth. In certain embodiments, the compounds described herein are administered to experimental cell cultures in vitro to prevent the growth of beta-lactam resistant bacteria. In some embodiments, the compounds described herein are administered to a mammal, including a human, to prevent the growth of beta-lactam resistant bacteria in vivo. The method according to this embodiment comprises administering a therapeutically effective amount of a penicillin binding protein inhibitor as described herein to a mammal, including a human, for a therapeutically effective period of time. Preferably, the penicillin binding protein inhibitors described herein are administered in the form of a pharmaceutical composition as described above.
In another aspect, provided herein is a method of treating a bacterial infection, the method comprising administering to a subject a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, and a pharmaceutically acceptable excipient. In some embodiments, a method of treating a bacterial infection in a subject comprises administering to the subject a pharmaceutical composition as described herein. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection. In some embodiments, the bacterial infection is an uncomplicated or uncomplicated urinary tract infection, uncomplicated or uncomplicated gonorrhea, upper or lower respiratory tract infection, skin or skin structure infection, intraperitoneal infection, central nervous system infection, blood flow infection, or systemic infection.
In some embodiments, the infection treated or prevented is caused by bacteria including pseudomonas aeruginosa, pseudomonas fluorescens (Pseudomonas fluorescens), pseudomonas acidovorax (Pseudomonas acidovorans), pseudomonas alcaligenes (Pseudomonas alcaligenes), pseudomonas putida (Pseudomonas putida), stenotrophomonas maltophilia (Stenotrophomonas maltophilia), burkholderia cepacia (Burkholderia cepacia), aeromonas hydrophila (Aeromonas hydrophilia), escherichia coli (Escherichia coli), citrobacter freundii (Citrobacter freundii), salmonella typhimurium (Salmonella typhimurium), salmonella typhi (Salmonella typhi), salmonella paratyphi (Salmonella paratyphi), salmonella enteritidis (Salmonella enteritidis), shigella dysenteriae (Shigella dysenteriae), shigella flexneri (Shigella flexneri), shigella sonnei, enterobacter cloacae (Enterobacter cloacae), enterobacter aerogenes (Enterobacter aerogenes), klebsiella pneumoniae (Klebsiella pneumoniae), klebsiella acidophilus (Klebsiella oxytoca), serratia (Serratia marcescens), salmonella terrestris (Francisella tularensis), salmonella typhimurium (Providencia alcalifaciens), salmonella oxydans (Providencia alcalifaciens), providencia stuartii (atherosclerosis (5282), morganii (2), and providencia stuartii (35) Acinetobacter haemolyticus (Acinetobacter haemolyticus), yersinia enterocolitica (Yersinia enterocolitica), yersinia pestis (Yersinia pestis), yersinia pseudotuberculosis (Yersinia pseudotuberculosis), yersinia intermedia (Yersinia intermedia), pertussis bauterobacterium (Bordetella pertussis), pertussis bauterobacterium parapertussis (Bordetella parapertussis), bordetella bronchiseptica (Bordetella bronchiseptica), haemophilus influenzae (Haemophilus influenzae), haemophilus parainfluenza (Haemophilus parainfluenzae), haemophilus haemolyticus (Haemophilus haemolyticus), haemophilus parahaemolyticus (Haemophilus parahaemolyticus), haemophilus ducreyi (Haemophilus ducreyi), pasteurella multocida (Pasteurella multocida), pasteurella haemolytica (Pasteurella haemolytica), campylobacter catarrhalis (Branhamella catarrhalis), helicobacter pylori (Helicobacter pylori), campylobacter foetidis (Helicobacter pylori), campylobacter jejuni (Helicobacter pylori), campylobacter coli (Helicobacter pylori), borrelia berkohlrabi (Vibrio (Helicobacter pylori), vibrio parahaemolyticus (Helicobacter pylori), haemolyticus (Helicobacter pylori), haemophilus parahaemolyticus (Helicobacter pylori), neisseria angusta (Helicobacter pylori), neisseria (Helicobacter pylori), and neisseria (Helicobacter pylori) and neisseria (5.fragi.group (5) Bacteroides vulgatus (Bacteroides vulgatus), bacteroides ovatus (Bacteroides ovalus), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides simplex (Bacteroides uniformis), bacteroides elmendocina (Bacteroides eggerthii), bacteroides visceri (Bacteroides splanchnicus), clostridium difficile (Clostridium difficile), mycobacterium tuberculosis (Mycobacterium tuberculosis), mycobacterium avium (Mycobacterium avium), mycobacterium intracellulare (Mycobacterium intracellulare), mycobacterium leprae (Mycobacterium leprae), corynebacterium diphtheriae (Corynebacterium diphtheriae), corynebacterium ulcerans (Corynebacterium ulcerans), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus agalactiae (Streptococcus agalactiae), streptococcus pyogenes (Streptococcus pyogenes), enterococcus faecalis (Enterococcus faecalis), enterococcus faecium (Enterococcus faecium), staphylococcus aureus (Staphylococcus aureus), staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus saprophyticus (Staphylococcus saprophyticus), staphylococcus intermedia (Staphylococcus intermedius), staphylococcus suis (Staphylococcus hyicus subsp.hyicus), staphylococcus haemolyticus (Staphylococcus haemolyticus), staphylococcus hominis (Staphylococcus hominis) or staphylococcus saccharolyticus (Staphylococcus saccharolyticus).
In some embodiments, the infection treated or prevented is caused by bacteria including pseudomonas aeruginosa, pseudomonas fluorescens, stenotrophomonas maltophilia, escherichia coli, citrobacter freundii, salmonella typhimurium, salmonella paratyphi, salmonella enteritidis, shigella dysenteriae, shigella flexneri, shigella sonnei, enterobacter cloacae, enterobacter aerogenes, klebsiella pneumoniae, klebsiella oxytoca, serratia viscosa, calcium acetate, haemolyticus, yersinia enterocolitica, plague, yersinia pestis, pseudotuberculosis, yersinia intermedia, haemophilus influenzae, haemophilus haemolyticus, haemophilus parahaemolyticus, helicobacter pylori, campylobacter fetalis, campylobacter jejuni, vibrio cholerae, vibrio parahaemophilus, haemophilus pneumophila, listeria monocytogenes, gonorrhoeae, neisseria, bacteroides, neisseria parahaemophilus, haemophilus parahaemophilus, haemophilus sp.
In some embodiments, the infection treated or prevented is caused by enterobacter (Enterobacterales) bacteria. In some embodiments, the infection treated or prevented is caused by bacteria including Escherichia (Escherichia spp), klebsiella (Klebsiella spp.), enterobacter (Enterobacter spp.), citrobacter (Citrobacter spp.), morganella (Morganella spp.), proteus (Proteus spp.), salmonella spp), serratia (Serratia spp.), shigella spp, or Yersinia spp.
In some embodiments, the compounds disclosed herein are useful for treating or preventing infections associated with non-fermenting bacteria. In some embodiments, the compounds disclosed herein are useful for treating or preventing infections associated with non-fermenting gram-negative bacteria. In some embodiments, the non-fermenting gram-negative bacteria are pseudomonas aeruginosa, acinetobacter (Acinetobacter spp.) (Acinetobacter baumannii/Acinetobacter calcoaceticus), stenotrophomonas maltophilia, alicabo's bacteria (Elizabethkingia spp) (alicabo's bacteria (e.meningosuptaca)/alicabo's bacteria (e.anopheles)), burkholderia cepacia (Burkholderia cepacian complex), burkholderia melitensis, or burkholderia melitensis (Burkholderia mallei).
In some embodiments, the infection treated or prevented is tuberculosis. In some embodiments, the infection treated or prevented is caused by tubercle bacillus. In some embodiments, the treated or prevented infection is caused by a non-TB mycobacterium species bacterium. In some embodiments, the non-TB mycobacterium species is mycobacterium abscessus (m.abscessus), m.canum, mycobacterium bovis (m.bovis), mycobacterium africanus (m.africanum), or mycobacterium caprae (m.caprae).
In some embodiments, the infection treated or prevented is gonorrhea. In some embodiments, the infection treated or prevented is caused by neisseria gonorrhoeae.
In some embodiments, the infection treated or prevented is meningitis and other forms of meningococcal disease such as meningococcal sepsis. In some embodiments, the infection treated or prevented is caused by neisseria meningitidis.
In some embodiments, the infection treated or prevented is caused by a bacterium, which is neisseria gonorrhoeae. In some embodiments, the infection treated or prevented is caused by a bacterium, which is pseudomonas aeruginosa. In some embodiments, the infection treated or prevented is caused by a bacterium that is acinetobacter baumannii. In some embodiments, the infection treated or prevented is caused by a bacterium that is pseudomonas aeruginosa/acinetobacter baumannii. In some embodiments, the infection treated or prevented is caused by a bacterium that is carbapenem-resistant enterobacteria (CRE).
In some embodiments of the methods described herein, the compounds described herein are not administered with a β -lactam antibiotic. In some embodiments of the methods described herein, the compounds described herein are not administered with a β -lactamase inhibitor. In some embodiments of the methods described herein, the compounds described herein are not administered with a combination of a β -lactam antibiotic and a β -lactamase inhibitor.
Examples
General examples for the preparation of compounds.
The starting materials and intermediates for the compounds of the invention may be prepared by applying or adapting the methods described below, obvious chemical equivalents thereof or as described, for example, in the literature (such as The Science of Synthesis, volumes 1-8, e.m. carreira et al, thieme publishers (2001-2008)). The protecting group may be used as described in the method schemes such as Greene's Protective Groups in Organic Synthesis, fifth edition, john Wiley & Sons, inc. 2014.
Certain compounds of formula I (scheme 1) are prepared by treating a borate protected by the corresponding functional group with a lewis acid in a solvent such as dichloromethane at a temperature of-78 ℃ to 0 ℃ followed by aqueous quenching.
Amide intermediate a can be prepared according to the pathway outlined in scheme 2. The chloroborate ester B prepared by the previously described method (see for example WO 2014089365) is reacted with a silylamine base such as lithium hexamethyldisilazide and the intermediate silylamine is treated with carboxylic acid C under amide coupling conditions (such as with carbodiimide dehydration reagents, HATU or other coupling reagents) to provide the protected amide a. Alternatively, the above silylamine intermediate is allowed to react with an acid chloride to provide a. The carboxylic acid (C) or acid chloride (D) may be obtained from commercial sources, prepared according to methods known in the literature, or prepared by several different reaction sequences. The formation of the acid chloride (D) involves treating (C) with a chlorinating agent such as thionyl chloride, phosphorus pentachloride or oxalyl chloride in a solvent such as methylene chloride in the presence of a catalyst such as DMF at around room temperature. In some cases, DMF is also used as a co-solvent. The formation of the acid anhydride (E) involves treating (C) with a sterically hindered acid chloride or chloroformate such as trimethylacetyl chloride or isopropyl chloroformate in an inert solvent such as methylene chloride in the presence of a non-nucleophilic base such as triethylamine or diisopropylethylamine at room temperature or lower. The formation of the activated ester (F) involves treating (C) with an activating reagent system such as EDCI, EDCI/HOBt, DCC/HOBt, HATU, BOP reagent or TBTU in a solvent such as DMF, DMA, NMP or dichloromethane at room temperature or lower (International Journal of Pharmaceutical Sciences Review and Research (2011), 8 (1), 108-119).
The chloroborate ester B can be prepared from aryl halides or aryl triflates K (x=br, I or OTf) in the manner described in scheme 4. Compound K (x=br, I or OTf) can be converted to boric acid L by treatment with an alkyl lithium reagent (e.g. n-butyllithium) and then quenching the intermediate aryl lithium species with a trialkyl borate, followed by water treatment. Boric acid L can be converted to the protected borate M by treatment with a 1, 2-diol, such as (+) -pinanediol or pinacol. Alternatively, the aryl halide K may be prepared by reaction with a diboron compound (e.g., bis [ (+) -pinanediol)]Diboron catalyst and palladium catalyst) to a borate ester M. As previously described, two consecutive Matteson reactions provide a reaction with a broad range of substituents R a 、R b And R is c Is a chloroborate ester B. Another variant consists of the reaction of K with chloromethyl borate J with isopropyl magnesium chloride to directly afford the desired intermediate N.
While there are common topics and strategies in the illustrative examples cited below, the selection of the appropriate reaction sequence (including the protecting group requirements) is determined by the nature and arrangement of the functional groups present in the target molecule, and thus may involve obvious adaptations of the illustrative method for application to a particular situation.
General method a: deprotection with boron trichloride or boron tribromide.
BCl was added dropwise to a solution of protected precursor A (0.4 mmol) in anhydrous DCM (15 mL) at-78deg.C under argon 3 Or BBr 3 (1.0M in DCM, 2.4-4mL,2.4-4mmol,6-10 eq.). The reaction mixture was allowed to slowly warm to 0 ℃ over 1h and stirred for an additional 1-2h at 0-5 ℃ and then quenched with water (2 mL) and methanol (20 mL), the DCM was evaporated off, washed with hexane and concentrated to a volume of about 4-5 mL. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization to give product I.
General method B: deprotection with aluminum chloride.
To a solution of protected precursor A (0.4 mmol) in anhydrous DCM (15 mL) at room temperature was added AlCl in one portion 3 (535 mg,4mmol,10 eq.). The reaction mixture was stirred at room temperature for 24h, then quenched with water (2 mL) and methanol (20 mL), the DCM was removed by evaporation, washed with hexane, and concentrated to a volume of about 4-5 mL. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization to give product I.
General procedure C: the chloroborate is converted into an amide.
LiHMDS (1.0M in THF, 4.5mL,4.5 mmol) was added dropwise to a solution of chloride B (4 mmol) in anhydrous THF (16 mL) at-60 ℃. The reaction mixture was allowed to slowly warm to 0 ℃ over 45min and stirred at room temperature for an additional 2h.
In a separate flask was added carboxylic acid C (4.2 mmol) and anhydrous DMA (20 mL), HATU (1.68 g,4.4 mmol) was added to the mixture followed by 4-methylmorpholine (0.49 mL,4.4 mmol). The reaction mixture was stirred at room temperature for 2h, at which time the solution from the above reaction was added to the flask, and the reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, washed with water, brine, and Na 2 SO 4 Dried, concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (hexane-EtOAc, 20:1-1:1, or hexane-acetone, 10:1-1:1, or DCM-MeOH, 30:1-10:1) to give product a.
Example 1: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (2-fluoro-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of 2- ((tert-Butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetic acid.
7N ammonia in methanol (23 mL) was added to 1g (4 mmol) of 2-fluoro-4-iodobenzaldehyde at 0deg.C, followed by 0.75mL (6 mmol,1.5 eq.) of trimethylcyanosilane, stirred at 45deg.C for 7h, and concentrated in vacuo. The crude product was dissolved in 3N hydrochloric acid in methanol (14 mL), stirred at 70 ℃ for 18h, and concentrated in vacuo to give HCl salt. The reaction was slurried in tetrahydrofuran (20 mL) and cooled at 0deg.C. Triethylamine 1.7mL (12 mmol,3 eq.) was added followed by di-tert-butyl dicarbonate 1.3g (6 mmol,1.5 eq.) at room temperature for 1h and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% ethyl acetate/hexane) to give 1.1g of the desired product. 1.1g (2.71 mmol) of methyl 2- ((tert-butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetate was dissolved in tetrahydrofuran (10 mL)/H 2 O (10 mL), followed by dissolution of lithium hydroxide monohydrate 0.34g (8.14 mmol,3 eq.) and stirring at room temperature for 1h, and concentration. Water with 2N hydrochloric acidThe solution was added dropwise to the solution to obtain pH 2, diluted with dichloromethane, and extracted. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 1.1g of the title compound (68% overall yield). ESI-MS M/z 396 (M+H) + 。
Step 2: synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoate.
By following general procedure C, the chloride (prepared as previously reported, WO 2014/089365) was treated with LiHMDS and then coupled with 2- ((tert-butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetic acid in the presence of HATU and NMM to yield the title compound. ESI-MS M/z 807 (M+H) + 。
Step 3: synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoate.
To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 0.64g (0.79 mmol) of tert-butyl dioxaborolan-2-yl) -2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (28 mL) and the temperature was raised at room temperature for 18h. The reaction was heated at 40 ℃ for 5h and concentrated in vacuo to give 3- ((2R) -2- (2-amino-2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl esterAnd (3) a hydrogen chloride salt. ESI-MS M/z 707 (M+H) + 。
3- ((2R) -2- (2-amino-2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (13 mL) at 0deg.C][1,3,2]To 0.59g (0.8 mmol) of tert-butyl dioxaborolan-2-yl) ethyl) -2-methoxybenzoate hydrochloride was added 0.41mL (2.38 mmol,3 eq.) of N, N-diisopropylethylamine followed by 0.24g (1.2 mmol,1.5 eq.) of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride and the reaction was warmed at room temperature for 30min. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to give the title compound 0.76g, which was taken directly to the next step without further purification. ESI-MS M/z 875 (M+H) + 。
Step 4: synthesis of tert-butyl 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) -2-fluorophenyl) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoate.
To 3- ((2R) -2- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (2-fluoro-4-iodophenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) under argon][1,3,2]To 0.76g (0.86 mmol) of t-butyl dioxaborolan-2-methoxybenzoate was added 0.45mL (2.59 mmol,3 eq.) of diisopropylethylamine, 0.1g (0.09 mmol,10 mol%), 0.38mL (1.73 mmol,2 eq.) of tetrakis (triphenylphosphine) palladium (0.38 mol%), followed by addition of 1-methyl-2-pyrrolidone (15 mL) and deaeration three times. The mixture was stirred at 90 ℃ for 1h, cooled, diluted with ethyl acetate, washed 3 times with water, dried over sodium sulfate, and concentrated to give the title compound, which was directly taken to the next step without further purification. ESI-MS M/z 1009 (M+H) + 。
Step 5: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (2-fluoro-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) -2-fluorophenyl) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (25 mL) at-78deg.C][1,3,2]To 0.87g (0.86 mmol) of tert-butyl dioxaborolan-2-yl) -2-methoxybenzoate was added dropwise 1M boron tribromide in 8.6mL (8.6 mmol,10 eq.) of methylene chloride and the mixture was warmed at room temperature for 30min. The crude mixture was cooled at 0deg.C and taken up with H 2 Quenched with O/MeOH and concentrated. The title compound was purified by reverse phase HPLC. ESI-MS M/z 607 (M+H) + 。
Example 2: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (2-fluoro-5-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 2-fluoro-4-iodobenzaldehyde with 2-fluoro-5-iodobenzaldehyde in step 1. ESI-MS M/z 607 (M+H) + 。
Example 3: synthesis of (3R) -3- (2- (4- (2-aminoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) carbamate instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride in step 3. ESI-MS M/z 604 (M+H) + 。
Example 4: synthesis of (3R) -3- (2, 3-dioxo-4- (2, 2-trifluoroethyl) piperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using 2, 3-dioxo-4- (2, 2-trifluoroethyl) piperazine-1-carbonyl chloride in place of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride in step 3. ESI-MS M/z 643 (M+H) + 。
Example 5: synthesis of (R) -2-hydroxy-3- ((S) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using 3- (methylsulfonyl) -2-oxoimidazolidine-1-carbonyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride in step 3. After purification by reverse phase HPLC in step 5, the title compound was collected at the first elution peak. ESI-MS M/z 611 (M+H) + 。
Example 6: synthesis of (R) -2-hydroxy-3- ((R) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using 3- (methylsulfonyl) -2-oxoimidazolidine-1-carbonyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride in step 3. After purification by reverse phase HPLC in step 5, the title compound was collected at the second elution peak. ESI-MS M/z 611 (M+H) + 。
Example 7: synthesis of (R) -3- ((R) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (3-fluoro-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 3-fluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1. After purification by reverse phase HPLC in step 5, the title compound was collected at the second elution peak. ESI-MS M/z 607 (M+H) + 。
Example 8: synthesis of (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh) 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) and then anhydrous toluene (400 mL) were added and the mixture stirred at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 2- (4- (bis (benzyloxy) phosphoryl) in O (100 mL)Phenyl) -2- ((t-Butoxycarbonyl) amino) acetic acid methyl ester (27 g,51.4 mmol) lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) was added and the mixture stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2, synthesizing 4- (2-chloro-3, 4-dimethoxy benzyl) -2, 3-dioxopiperazine-1-formyl chloride.
Step 2a.
To a solution of 2-chloro-3, 4-dimethoxybenzaldehyde (3.0 g,15 mmol) in MeOH (500 mL) was added tert-butyl (2-aminoethyl) carbamate (2.6 mL,16mmol,1.1 eq). The solution was stirred at room temperature for 2h and then cooled to 0 ℃. Addition of NaBH in portions 4 (2.8 g,75mmol,5.0 eq.) and allowed to warm to room temperature overnight. Concentrating the mixture, followed by addition of H 2 O (200 mL) and DCM (200 mL). The layers were separated and the aqueous layer was extracted with DCM (3X 100 mL). The combined organic layers were dried (Na 2 SO 4 ) Filtered and concentrated.
Step 2b.
HCl (4 m in dioxane, 15 mL) was added to the crude product in MeOH (30 mL) at 0 ℃. The reaction was warmed to room temperature and stirred for 2h, then concentrated in vacuo.
Step 2c.
The crude product was dissolved in EtOH (150 mL) and TEA (6.3 mL,45mmol,3.0 eq.) and diethyl oxalate (2.2 mL,16mmol,1.1 eq.) were added sequentially. The mixture was heated to 90 ℃ overnight and concentrated. The crude product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired intermediate (2.0 g, 45% over 3 steps).
Step 2d.
1- (2-chloro-3, 4-dimethoxybenzyl) piperazine-2, 3-dioneA solution of (2.0 g,6.7 mmol) in DCM (10 mL)/THF (10 mL) was cooled to-40 ℃. TMSCl (0.93 mL,7.4mmol,1.1 eq.) and TEA (1.1 mL,8.0mmol,1.2 eq.) were added sequentially. The mixture was warmed to 0 ℃ for 1h. Triphosgene (795 mg,2.7mmol,0.4 eq.) in THF (10 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil. Addition of Et 2 O (50 mL) and the product was triturated overnight at room temperature and filtered. The resulting solid was treated with Et 2 O (10 mL) was washed and dried in vacuo to afford the title compound (2.0 g, 84%).
Step 3. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid.
Step 3a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid (500 mg,0.98 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3b.
The crude product was dissolved in THF (4.0 mL)/NaHCO 3 (saturated aqueous solution, 4.0 mL) was then added 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride (3838 mg,1.07mmol,1.1 eq.). The reaction was stirred at room temperature for 2h. Will react with H 2 O (5 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (50 mL) was added and the organic layer was taken up with H 2 O (2X 10 mL) and brine (1X 10 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (375 mg, 69% over 2 steps). ESI-MS M/z 737 (M+H) + 。
Step 4. Synthesis of (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 4a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (5.2 g,11 mmol) (example 200 step 7) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (5.8 g, 99%).
Step 4b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To a solution of t-butyl dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate hydrochloride (198 mg,0.340 mmol), 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid (375 mg,0.509mmol,1.5 eq.) and HATU (226 mg,0.595mmol,1.75 eq.) in DMA (3.4 mL) was added NMM (0.11 mL,1.02mmol,3.0 eq.). The reaction was stirred at room temperature for 30min and diluted with EtOAc (30 mL). The mixture was treated with H 2 O (2X 10 mL) and brine (xx mL), and dried (Na 2 SO 4 ) Filtered, and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanoBenzo [ d ] radicals][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (252 mg, 64%) ESI M/z 1166 (M+H) + 。
Step 4c.
To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78deg.C ][1,3,2]To a solution of tert-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate (252 mg,0.216 mmol) in DCM (2.2 mL) was added BBr 3 (1M, 2.2mL,2.2mmol,10 eq.) in DCM. The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid (44 mg, 28%). ESI M/z 735 (M+H) + 。
Example 9: synthesis of (R) -3- ((S) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] in step 2][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester. After purification by reverse phase HPLC in step 5, the title compound was collected at the first elution peak. ESI-MS M/z 607 (M+H) + 。
Example 10: synthesis of (R) -3- ((R) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to that of the examplesThe title compound was synthesized in example 9 and collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 607 (M+H) + 。
Example 11: synthesis of (3R) -3- (2- (3-chloro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 3-chloro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI-MS 645M/z (M+H) + 。
Example 12: synthesis of (3R) -3- (2- (3-fluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 3-fluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI-MS 629M/z (M+H) + 。
Example 13: synthesis of (R) -3- ((R) -2- (2, 3-difluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 2, 3-difluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. After purification by reverse phase HPLC in step 5, the title compound ESI-MS 647M/z (M+H) was collected at the second elution peak + 。
Example 14: (3R) -3- (2-amino-2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in analogy to the synthesis of example 8, using 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid instead of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid in step 4 b. The title compound was isolated by reverse phase HPLC. ESI-MS M/z438 (M+H) + 。
Example 15: synthesis of (R) -3- ((R) -2- (3-fluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 12 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 629 (M+H) + 。
Example 16: synthesis of (R) -3- ((R) -2- (2, 3-difluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 13 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester (in example 1, step 2). ESI-MS M/z 665 (M+H) + 。
Example 17: synthesis of (3R) -2-hydroxy-3- (2- (3-hydroxy-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 3- (benzyloxy) -4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI- MS m/z 627(M+H) + 。
Example 18: synthesis of (R) -3- ((R) -2- (3, 5-difluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 3, 5-difluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. After purification by reverse phase HPLC in step 5, the title compound ESI-MS M/z 647 (M+H) was collected at the second elution peak + 。
Example 19: synthesis of (R) -7-fluoro-3- ((R) -2- (3-fluoro-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 9, substituting 3-fluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde (in example 1 step 1) and collecting the title compound at the second eluting peak after reverse phase HPLC purification. ESI-MS M/z 647 (M+H) + 。
Example 20: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4- (phosphonomethyl) phenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of (4- (2- (((R) -2- (3- (tert-butoxycarbonyl) -2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) amino) -1- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2-oxoethyl) benzyl) phosphonic acid.
3- ((2R) -2- (2- (4- ((diethoxyphosphoryl) methyl) phenyl) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- [. Sup.(3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]To 0.44g (0.54 mmol) of tert-butyl dioxaborolan-2-yl) -2-methoxybenzoate was added dropwise 0.21mL (1.61 mmol,3 eq.) of trimethylbromosilane, warmed at room temperature for 18h, and concentrated in vacuo to give the title compound. ESI-MS M/z 769 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4- (phosphonomethyl) phenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared by following the general deprotection and purification procedure in step 5 of example 1. ESI-MS M/z 603 (M+H) + 。
Example 21: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (3-hydroxy-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 17, substituting 3- (methylsulfonyl) -2-oxoimidazolidine-1-carbonyl chloride with 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride in (example 1 step 3). ESI-MS M/z 605 (M+H) + 。
Example 22: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (3- (phosphonomethyl) phenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 20 using diethyl (3-formylbenzyl) phosphonate instead of diethyl (4-formylbenzyl) phosphonate (example 1, step 1). ESI-MS M/z 603 (M+H) + 。
Example 23: synthesis of (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (3-fluoro-4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was synthesized in a similar manner to example 8 using 3-fluoro-4-iodobenzaldehyde instead of 4-iodobenzaldehyde (example 8, step 1). ESI M/z 753 (M+H) + 。
Example 24: synthesis of (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was synthesized in a manner analogous to example 8 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester (WO 2014/089365) replaces 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (example 8, step 4). ESI M/z 717 (M+H) + 。
Example 25: synthesis of (3R) -3- (2, 6-difluoro-4-phosphonophenyl) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 2, 6-difluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI-MS M/z 625 (M+H) + 。
Example 26: synthesis of (3R) -3- (2-acetamido-2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using acetyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z463 (M+H) + 。
Example 27: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2-propionylamino acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using propionyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z477 (M+H) + 。
Example 28: synthesis of (3R) -2-hydroxy-3- (2-isobutyrylamino-2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using isobutyryl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z491 (M+H) + 。
Example 29: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2-pivaloylaminoacetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using pivaloyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z505 (M+H) + 。
Example 30: synthesis of (3R) -3- (2- (cyclopropanecarboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using cyclopropanecarbonyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 489 (M+H) + 。
Example 31: synthesis of (3R) -3- (2- (cyclohexanecarboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1 using cyclohexane formyl chloride instead of 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 531 (M+H) + 。
Example 32: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (picolinamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting pyridine formyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 526 (M+H) + 。
Example 33: synthesis of (3R) -3- (2- ((R) -1-acetylpyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting acetyl-L-prolyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 560 (M+H) + 。
Example 34: synthesis of (R) -2-hydroxy-3- ((S) -2- ((R) -1- (methylsulfonyl) pyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and example 35: synthesis of (R) -2-hydroxy-3- ((R) -2- ((R) -1- (methylsulfonyl) pyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting (methylsulfonyl) -D-prolyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound after purification by HPLC. ESI-MS M/z 596 (M+H) + 。
Example 36: synthesis of (R) -2-hydroxy-3- ((S) -2- (2-oxopiperidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [39e ] [1,2] oxaborole-8-carboxylic acid and example 37: synthesis of (R) -2-hydroxy-3- ((R) -2- (2-oxopiperidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting 2-oxopiperidine-1-carbonyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound after purification by HPLC. ESI-MS M/z 546 (M+H) + 。
Example 38: synthesis of (3R) -2-hydroxy-3- (2- (3-methyl-2-oxohexahydropyrimidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting 3-methyl-2-oxotetrahydropyrimidine-1 (2H) -carbonyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 561 (M+H) + 。
Example 39: synthesis of (R) -2-hydroxy-3- ((S) -2- (2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and example 40: synthesis of (R) -2-hydroxy-3- ((R) -2- (2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting 2-oxoimidazolidine-1-carbonyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound after purification by HPLC. ESI-MS M/z 533 (M+H) + 。
Example 41: synthesis of (3R) -2-hydroxy-3- (2- (3-methyl-2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting 3-methyl-2-oxoimidazolidine-1-carbonyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 547 (M+H) + 。
Example 42: synthesis of (3R) -3- (2- (3-ethyl-2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting 3-ethyl-2-oxoimidazolidine-1-carbonyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound. ESI-MS M/z 561 (M+H) + 。
Example 43: synthesis of (R) -2-hydroxy-3- ((S) -2- ((S) -1- (methylsulfonyl) pyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and example 44: synthesis of (R) -2-hydroxy-3- ((R) -2- ((S) -1- (methylsulfonyl) pyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 1, substituting (methylsulfonyl) -L-prolyl chloride for 4-ethyl-2, 3-dioxopiperazine-1-carbonyl chloride to give the title compound after purification by HPLC. ESI-MS M/z 596 (M+H) + 。
Example 45: synthesis of (3R) -3- (2- (4- (2-chloro-5-fluoro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
Step 1a.
A solution of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde (8.00 g,47.0 mmol) in toluene (170 mL) was cooled to 0deg.C. Adding (i-Bu) 2 NH (4.00 mL,49.4mmol,1.05 eq.) followed by slow addition of SO 2 Cl 2 (0.82 mL,4.70mmol,0.1 eq.). The mixture was heated to 70 ℃ overnight, then cooled to room temperature and quenched with H 2 O (50 mL) quench. The layers were separated and the aqueous layer was extracted with EtOAc (3X 50 mL). Drying (Na) 2 SO 4 ) The combined organic layers were filtered and concentrated.
Step 1b.
The crude product was dissolved in DMF (120 mL) and Cs was added 2 CO 3 (38.3 g,117mmol,2.5 eq.) followed by MeI (8.8 mL,140mmol,3.0 eq.) was added. The mixture was stirred at room temperature for 1H, diluted with EtOAc (300 mL), and quenched with H 2 O (150 mL) quench. The layers were separated and combined with EtOAc (3X 150 mL)The aqueous layer was extracted. The combined organic layers were treated with H 2 O (3X 75 mL) and brine (75 mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc/hexanes). ESI M/z 219 (M+H) + 。
Step 2. Synthesis of (3R) -3- (2- (4- (2-chloro-5-fluoro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was synthesized in analogy to example 8, using 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde instead of 2-chloro-3, 4-dimethoxybenzaldehyde (example 8, step 2). ESI M/z 753 (M+H) + 。
Example 46: synthesis of (3R) -3- (2- (3- (2-chloro-3, 4-dihydroxybenzyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 3- (2-chloro-3, 4-dimethoxy benzyl) -2-oxo-imidazolidine-1-formyl chloride.
Step 1a.
This reaction was carried out in a manner analogous to example 8, step 2a.
Step 1b.
This reaction was carried out in a manner analogous to example 8, step 2b.
Step 1c.
To a mixture of the crude product (14.95 mmol) in THF (150 mL) was added TEA (6.3 mL,45mmol,3.0 eq.) and CDI (2.7 g,16mmol,1.1 eq.). The reaction was stirred at room temperature overnight and then concentrated. The crude product was purified by silica gel chromatography (70-100% EtOAc/hexanes) to afford the desired intermediate (2.59 g, 64% over 3 steps). ESI M/z 271 (M+H) + 。
Step 1d.
The reaction was carried out in a manner analogous to example 8, step 2d.
Step 2. Synthesis of (3R) -3- (2- (3- (2-chloro-3, 4-dihydroxybenzyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was synthesized in analogy to example 8, using 3- (2-chloro-3, 4-dimethoxybenzyl) -2-oxoimidazolidine-1-carbonyl chloride instead of 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride (example 8 step 2). ESI M/z 707 (M+H) + . Example 47: synthesis of (3R) -3- ((2R) -2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4- (hydroxy (methyl) phosphoryl) phenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting ethyl methylphosphinate for dibenzyl phosphite in step 4. After purification by reverse phase HPLC in step 5, the title compound was collected at the second elution peak. ESI-MS M/z 587 (M+H) + . Example 48: synthesis of (3R) -3- (2- (3-fluoro-2-hydroxy-4-phosphonophenyl) -2- (3- (methylsulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 2- (benzyloxy) -3-fluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and substituting Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI-MS M/z 645 (M+H) + . Example 49: synthesis of (R) -3- ((R) -2- (2-chloro-3, 4-dihydroxybenzoylamino) -2- (4-phosphonophenyl) acetylamino) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh) 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) followed by anhydrous toluene (400 mL) and stirring the mixture at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 To methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2: synthesis of tert-butyl 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoate.
By following general procedure C, the chloride (prepared as previously reported, WO 2014/089365) was treated with LiHMDS and then coupled with 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid in the presence of HATU and NMM to yield the title compound. ESI-MS M/z 923 (M+H) + 。
Step 3: (R) -3- ((R) -2- (2-chloro-3, 4-dihydroxybenzoylamino) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
i) To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]Dioxaborol-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester 1N trifluoroacetic acid in dichloromethane was added and the temperature was raised at room temperature for 6h. The reaction was concentrated in vacuo to give 3- ((2R) -2- (2-amino-2- (4- (bis (benzyloxy) phosphoryl) phenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) ][1,3,2]Dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid-2, 2-trifluoro-1 l 3-eth-1-one (1/1). ESI-MS M/z 767 (M+H) + 。
ii) N, N-diisopropylethylamine was added to the above crude product in dichloromethane at 0℃followed by 2-chloro-3, 4-dimethoxybenzoyl chloride and the reaction was warmed at room temperature for 30min. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to give 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (2-chloro-3, 4-dimethoxybenzoylamino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid was taken directly to the next step without further purification. ESI-MS M/z 965 (M+H) + 。
iii) 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (2-chloro-3, 4-dimethoxybenzoylamino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane at-78deg.C][1,3,2]1M boron tribromide in methylene chloride was added dropwise to dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid and the temperature was raised at room temperature for 30min. The crude mixture was cooled at 0deg.C and taken up with H 2 Quenched with O/MeOH and concentrated. The title compound was purified by reverse phase HPLC. ESI-MS M/z 591 (M+H) + 。
Example 50: synthesis of (R) -3- ((S) -2- (2-aminothiazole-5-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-aminothiazole-5-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using tert-butyl (5- (chlorocarbonyl) thiazol-2-yl) carbamate in place of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 547 (M+H) + 。
Example 51: synthesis of (R) -3- ((S) -2- (2-aminothiazole-4-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-aminothiazole-4-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to example 49 using tert-butyl (4- (chlorocarbonyl) thiazol-2-yl) carbamate instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 547 (M+H) + 。
Example 52: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- ((R) -pyrrolidine-2-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49, substituting D-prolyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 518 (M+H) + 。
Example 53: synthesis of (3R) -2-hydroxy-3- (2- ((R) -5-oxopyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using (R) -5-oxopyrrolidine-2-carbonyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z532 (M+H) + 。
Example 54: synthesis of (R) -2-hydroxy-3- ((S) -2- ((R) -1-methylpyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -2-hydroxy-3- ((R) -2- ((R) -1-methylpyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using methyl-D-prolyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z532 (M+H) + 。
Example 56: synthesis of (3R) -2-hydroxy-3- (2- (2-oxohexahydropyrimidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 49, substituting 3- (chlorocarbonyl) -2-oxotetrahydropyrimidine-1 (2H) -carboxylic acid tert-butyl ester for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 547 (M+H) + 。
Example 57: synthesis of (3R) -2-hydroxy-3- (2- (2-oxopyrrolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting 2-chloro-3, 4-dimethoxybenzoyl chloride with 2-oxopyrrolidine-1-carbonyl chloride in step 3. ESI-MS M/z 532 (M+H) + 。
Example 58: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (sulfamoylamino) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using tert-butyl (chlorosulfonyl) carbamate in place of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 500 (M+H) + 。
Example 59: synthesis of (3R) -2-hydroxy-3- (2- (methylsulfonylamino) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting methanesulfonyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 499 (M+H) + 。
Example 60: synthesis of (3R) -2-hydroxy-3- (2- ((1-methylethyl) sulfonylamino) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting propane-2-sulfonyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 527 (M+H) + 。
Example 61: synthesis of (3R) -3- (2- (cyclopropanesulfonylamino) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting cyclopropanesulfonyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 525 (M+H) + 。
Example 64: synthesis of (3R) -2-hydroxy-3- (2- ((S) -5-oxopyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using (S) -5-oxopyrrolidine-2-carbonyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z532 (M+H) + 。
Example 65: synthesis of (3R) -3- (2- ((S) -1-acetylpyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using acetyl-L-prolyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z560 (M+H) + 。
Example 66: synthesis of (3R) -2-hydroxy-3- (2- ((S) -5-oxopyrrolidine-2-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using methyl-L-prolyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z532 (M+H) + 。
Example 120: synthesis of (3R) -3- (2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid.
Step 1a.
This reaction was carried out in a manner analogous to example 8, step 3a.
Step 1b.
This reaction was carried out in a similar manner to example 8, step 3b, substituting tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) carbamate for 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride. The product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired intermediate (2.73 g, 79% over 2 steps).
Step 1c.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2- ((tert-butoxycarbonyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid (1.14 g,1.64 mmol) in DCM (6.6 mL) was added TFA (1.64 mL) at 0deg.C. The solution was warmed to room temperature for 1h and then concentrated.
Step 1d.
The crude product was dissolved in DCM (16 mL). Triethylamine (1.1 mL,8.2mmol,5.0 eq.) was added followed by 2-chloro-3, 4-dimethoxybenzoyl chloride (424 mg,1.80mmol,1.1 eq.). The mixture was stirred for 1h, then NaHSO was used 4 (1.0M, 10.0 mL) quenching. The layers were separated and the aqueous layer was extracted with DCM (3X 20 mL). Drying (Na) 2 SO 4 ) The combined organic layers were filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/DCM) to give the title compound (1.01 g, 78% over 2 steps).
Step 2 Synthesis of (3R) -3- (2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in a similar manner to the synthesis of example 8 step 4 using (3R) -3- (2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid substitution 2- (4- (bis (benzyloxy)Group) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid. The desired compound was isolated by reverse phase HPLC. ESI-MS M/z 791 (M+H) + 。
Example 160: synthesis of (R) -3- ((R) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh) 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) then anhydrous toluene (400 mL) was added and the mixture stirred at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate and water Washed then with brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
In THF (100 mL)/H 2 Methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((t-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2, synthesizing 4- (2-chloro-3, 4-dimethoxy benzyl) -2, 3-dioxopiperazine-1-formyl chloride.
Step 2a.
To a solution of 2-chloro-3, 4-dimethoxybenzaldehyde (3.0 g,15 mmol) in MeOH (500 mL) was added tert-butyl (2-aminoethyl) carbamate (2.6 mL,16mmol,1.1 eq). The solution was stirred at room temperature for 2h and then cooled to 0 ℃. Addition of NaBH in portions 4 (2.8 g,75mmol,5.0 eq.) and allowed to warm to room temperature overnight. Concentrating the mixture, followed by addition of H 2 O (200 mL) and DCM (200 mL). The layers were separated and the aqueous layer was extracted with DCM (3X 100 mL). The combined organic layers were dried (Na 2 SO 4 ) Filtered and concentrated.
Step 2b.
HCl (4 m in dioxane, 15 mL) was added to the crude product in MeOH (30 mL) at 0 ℃. The reaction was warmed to room temperature and stirred for 2h, then concentrated in vacuo.
Step 2c.
The crude product was dissolved in EtOH (150 mL) and TEA (6.3 mL,45mmol,3.0 eq.) and diethyl oxalate (2.2 mL,16mmol,1.1 eq.) were added sequentially. The mixture was heated to 90 ℃ overnight and concentrated. The crude product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired intermediate (2.0 g, 45% over 3 steps).
Step 2d.
A solution of 1- (2-chloro-3, 4-dimethoxybenzyl) piperazine-2, 3-dione (2.0 g,6.7 mmol) in DCM (10 mL)/THF (10 mL) was cooled to-40 ℃. TMSCl (0.93 mL,7.4mmol,1.1 eq.) and TEA (1.1 mL,8.0mmol,1.2 eq.) were added sequentially. The mixture was warmed to 0 ℃ for 1h. Triphosgene (795 mg,2.7mmol,0.4 eq.) in THF (10 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil. Addition of Et 2 O (50 mL) and the product was triturated overnight at room temperature and filtered. The resulting solid was treated with Et 2 O (10 mL) was washed and dried in vacuo to afford the title compound (2.0 g, 84%).
Step 3. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid.
Step 3a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid (500 mg,0.98 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3b.
The crude product was dissolved in THF (4.0 mL)/NaHCO 3 (saturated aqueous solution, 4.0 mL) followed by 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride (3838 mg,1.07mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (5 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (50 mL) was added and the organic layer was taken up with H 2 O (2X 10 mL) and brine (1X 10 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was chromatographed on silica gel(0-20% MeOH/DCM) to give the title compound (375 mg, 69% over 2 steps). ESI-MS M/z 737 (M+H) + 。
Step 4. Synthesis of (R) -3- ((R) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 4a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (5.2 g,11 mmol) (example 200 step 7) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (5.8 g, 99%).
Step 4b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To a solution of t-butyl dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate hydrochloride (198 mg,0.340 mmol), 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid (375 mg,0.509mmol,1.5 eq.) and HATU (226 mg,0.595mmol,1.75 eq.) in DMA (3.4 mL) was added NMM (0.11 mL,1.02mmol,3.0 eq.). The reaction was stirred at room temperature for 30min and diluted with EtOAc (30 mL). The mixture was treated with H 2 O(2×10mL)And brine (xx mL), dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (252 mg, 64%) ESI M/z 1166 (M+H) + 。
Step 4c.
To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78deg.C][1,3,2]To a solution of tert-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate (252 mg,0.216 mmol) in DCM (2.2 mL) was added BBr 3 (1M, 2.2mL,2.2mmol,10 eq.) in DCM. The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ][1,2]Oxaborole-8-carboxylic acid (44 mg, 28%). ESI M/z 735 (M+H) + . After purification by reverse phase HPLC, the title compound ESI M/z 735 (M+H) was collected at the second elution peak + 。
Example 161: synthesis of (R) -3- ((S) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 160 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] in step 2][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]DioxaborolanAlkenyl-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester. After purification by reverse phase HPLC in step 5, the title compound was collected at the first elution peak. ESI M/z 735 (M+H) + 。
Example 162: synthesis of (R) -3- ((S) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (3-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 8, substituting 3-iodobenzaldehyde for 4-iodobenzaldehyde in step 1 a. The title compound was isolated at the second elution peak by reverse phase HPLC. ESI-MS M/z 734 (M+H) + 。
Example 163: synthesis of (R) -3- ((R) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (3-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 8, substituting 3-iodobenzaldehyde for 4-iodobenzaldehyde in step 1 a. The title compound was isolated at the first elution peak by reverse phase HPLC. ESI-MS M/z 734 (M+H) + 。
Example 164: synthesis of (3R) -3- (2- (4- (2-chloro-5-fluoro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 45 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. The title compound was isolated by reverse phase HPLC. ESI-MS M/z 734 (M+H) + 。
Example 165: synthesis of (R) -3- ((S) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2, 3-difluoro-4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid, and
example 166: synthesis of (R) -3- ((R) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2, 3-difluoro-4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 8, substituting 2, 3-difluoro-4-iodobenzaldehyde for 4-iodobenzaldehyde in step 1 a. The title compound was isolated by reverse phase HPLC. ESI-MS M/z 770 (M+H) + 。
Example 167: synthesis of (R) -3- ((S) -2- (3- ((2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid, and
example 168: synthesis of (R) -3- ((R) -2- (3- ((2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh) 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) followed by anhydrous toluene (400 mL) and stirring the mixture at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 To methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2. Synthesis of tert-butyl (2- ((3-chloro-2-oxoimidazolidin-1-yl) sulfonyl) ethyl) carbamate.
Step 2a.
To a solution of 2-aminoethane-1-sulfonic acid in tetrabutylammonium hydroxide/acetone/water was added (Boc) 2 O. The solution is put inStir at room temperature overnight. The mixture was concentrated, followed by the addition of DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na 2 SO 4 ) Filtered and concentrated to give the crude product.
Step 2b.
BTC was added to the crude in THF at 0deg.C, and the mixture was stirred at room temperature for 30min. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc/hexane (1:1 v/v) and the mixture was filtered through a small amount of silica gel with EtOAc/hexane (1:1, v/v) as the eluent. The mixture was evaporated under reduced pressure to give tert-butyl (2- (chlorosulfonyl) ethyl) carbamate.
Step 2c.
Tert-butyl (2- (chlorosulfonyl) ethyl) carbamate was dissolved in ethane-1, 2-diamine and stirred at room temperature overnight. The combined organic layers were dried (Na 2 SO 4 ) Filtered and concentrated to give the crude tert-butyl (2- (N- (2-aminoethyl) sulfamoyl) ethyl) carbamate.
Step 2d.
A solution of tert-butyl (2- (N- (2-aminoethyl) sulfamoyl) ethyl) carbamate in THF was cooled to 0deg.C. CDI is added. The mixture was warmed to 60 ℃ for 4h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a pale yellow oil. Purification by flash chromatography to afford tert-butyl (2- ((2-oxoimidazolidin-1-yl) sulfonyl) ethyl) carbamate.
Step 2e.
A solution of (3- ((2-oxoimidazolidin-1-yl) sulfonyl) propyl) tert-butyl and TEA in THF was cooled to 0deg.C. Triphosgene in THF was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide the title compound.
Step 3. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- ((tert-butoxycarbonyl) amino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid.
Step 3a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid (5 g,0.98 mmol) in DCM (40 mL) was added TFA (10 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3b.
The crude product was dissolved in THF (40 mL)/NaHCO 3 (saturated aqueous solution, 40 mL) followed by tert-butyl (2- ((3-chloro-2-oxoimidazolidin-1-yl) sulfonyl) ethyl) carbamate (3.8 g,10.7mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (50 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (500 mL) was added and the organic layer was taken up with H 2 O (2X 10 mL) and brine (1X 10 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (5.01 g, 70% over 2 steps). ESI-MS M/z 731 (M+H) + 。
Step 4 Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid
Step 4a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- ((tert-butoxycarbonyl) amino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid (730 mg,1 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0 ℃. The solution was warmed to room temperature for 2h and then concentrated.
Step 4b.
The crude product was dissolved in THF (4.0 mL)/NaHCO 3 (saturated aqueous solution, 4.0 mL) followed by 2-chloro-3, 4-dimethoxybenzoyl chloride (258 mg,1.1mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (5 mL) was diluted and acidified to pH 2 with HCl (2M). Ethyl acetate (50 mL) was added and the organic layer was taken up with H 2 O (2X 10 mL) and brine (1X 10 mL)Washing, drying (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (580 mg, 70% over 2 steps). ESI-MS M/z 829 (M+H) + 。
Step 5. Synthesis of (3R) -3- (2- (3- ((2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 5a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (5.2 g,11 mmol) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (5.8 g, 99%).
Step 5b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (198 mg,0.340 mmol), 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) sulphonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid (428 mg,0.509mmol,1.5 eq.) and HATU (226 mg,0.59 mmol,1.75 eq.) were added NMM (0.11 mL,1.02 mmo) in DMA (3.4 mL)l,3.0 equivalents). The reaction was stirred at room temperature for 30min and diluted with EtOAc (30 mL). The mixture was treated with H 2 O (2X 10 mL) and brine (xx mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid (260 mg, 64%) ESI M/z 1202 (M+H) + 。
Step 5c.
3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78deg.C][1,3,2]To a solution of dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid (260 mg,0.216 mmol) in DCM (2.2 mL) was added BBr 3 (1M, 2.2mL,2.2mmol,10 eq.) in DCM. The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (3- ((2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e][1,2]Oxaborole-8-carboxylic acid (50 mg, 28%). ESI M/z 828 (M+H) + . After purification by reverse phase HPLC, the title compound ESI M/z 828 (M+H) was collected at the second elution peak + 。
Example 169: synthesis of (R) -3- ((S) -2- (3- ((3- (2-chloro-3, 4-dihydroxybenzoylamino) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 168 substituting 3-aminopropane-1-sulfonic acid for 2-aminoethane-1-sulfonic acid in step 2. After purification by reverse phase HPLC, the title compound ESI M/z 842 (M+H) was collected at the first elution peak + 。
Example 170: synthesis of (R) -3- ((R) -2- (3- ((2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 168 and was collected at the first elution peak after reverse phase HPLC purification. ESI-MS M/z 828 (M+H) + 。
Example 171: synthesis of (R) -3- ((R) -2-amino-2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1. After purification by reverse phase HPLC, the title compound was collected at the first elution peak. ESI-MS M/z 421 (M+H) + 。
Example 172: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (2, 2-trifluoroacetamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 2, 2-trifluoroacetyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z517 (M+H) + 。
Example 173: synthesis of (R) -2-hydroxy-3- ((R) -2- (4-phosphonophenyl) -2- ((S) -pyrrolidine-2-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 49, substituting (S) -2- (chlorocarbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 518 (M+H) + 。
Example 174: synthesis of (3R) -2-hydroxy-3- (2- (2-oxo-1, 2-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 2-oxo-1, 2-dihydropyridine-3-carbonyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 542 (M+H) + 。
Example 175: synthesis of (R) -2-hydroxy-3- ((R) -2- (4-oxo-1, 4-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 4-oxo-1, 4-dihydropyridine-3-carbonyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 542 (M+H) + 。
Example 176: synthesis of (3R) -2-hydroxy-3- (2- (6-oxo-1, 6-dihydropyrimidine-5-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 6-oxo-1, 6-dihydropyrimidine-5-carbonyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. ESI-MS M/z 543 (M+H) + 。
Example 177: synthesis of (R) -2-hydroxy-3- ((S) -2- (3-oxo-2, 3-dihydropyridazine-4-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49, in3-oxo-2, 3-dihydropyridazine-4-carbonyl chloride is used to replace 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. After purification by reverse phase HPLC, the title compound ESI M/z 543 (M+H) was collected at the first elution peak + 。
Example 178: synthesis of (R) -2-hydroxy-3- ((R) -2- (3-oxo-2, 3-dihydropyridazine-4-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 178 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 543 (M+H) + 。
Example 179: synthesis of (3R) -3- (2- (4-cyanopyridinecarboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 4-cyanopyridine formyl chloride in place of 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. ESI-MS M/z551 (M+H) + 。
Example 180: synthesis of (R) -3- ((R) -2- (6-cyanopyridinecarboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting 6-cyanopyridine formyl chloride for 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. ESI-MS M/z551 (M+H) + 。
Example 181: synthesis of (R) -2-hydroxy-3- ((S) -2- (1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 49, substituting 1-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC, the title compound ESI M/z 556 (M+H) was collected at the first elution peak + 。
Example 182: synthesis of (R) -2-hydroxy-3- ((R) -2- (1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 181 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 556 (M+H) + 。
Example 183 (3R) -3- (2- (3-chloropyridine formylamino) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid was synthesized.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting 3-chloropyridine formyl chloride for 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. ESI-MS 560M/z (M+H) + 。
Example 184: synthesis of (3R) -3- (2- (5-chloropyridine formylamino) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 substituting 5-chloropyridine formyl chloride for 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. ESI-MS M/z560 (M+H) + 。
Example 186: synthesis of (R) -2-hydroxy-3- ((S) -2- (4-phosphonophenyl) -2- (pyrazolo [1,5-a ] pyrimidine-6-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 49 using pyrazolo [1,5-a ] in step 3]Pyrimidine-6-carbonyl chloride replaces 2-chloro-3, 4-dimethoxy benzoyl chloride. After purification by reverse phase HPLC, the title compound ESI M/z566 (M+H) was collected at the first elution peak + 。
Example 187: synthesis of (R) -2-hydroxy-3- ((R) -2- (4-phosphonophenyl) -2- (pyrazolo [1,5-a ] pyrimidine-6-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 186 and was purified by reverse phase HPLC at the second elution peakThe title compound was collected. ESI-MS M/z566 (M+H) + 。
Example 188: synthesis of (3R) -3- (2- (5-carbamoyl-pyridine-carboxamido) -2- (4-phosphonophenyl) -acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 5-carbamoyl pyridine formyl chloride in place of 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. ESI-MS M/z 569 (M+H) + 。
Example 189: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-sulfophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesizing the neopentyl 4-formyl benzene sulfonate.
To 1g (4.89 mmol) of 4-formylbenzenesulfonyl chloride in chloroform (10 mL) was added 1.2mL (14.7 mmol,3 eq.) of pyridine at 0deg.C, followed by 0.65mL (7.33 mmol,1.5 eq.) of neopentyl alcohol and the reaction was warmed at room temperature for 18h. The mixture was washed with 1N HCl, water, dried over sodium sulfate, and concentrated to dryness to give 0.65g (51%) of the title compound. ESI-MS M/z 257 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-sulfophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 4-formylbenzenesulfonic acid neopentyl ester for 2-fluoro-4-iodobenzaldehyde in step 1. ESI-MS M/z 589 (M+H) + 。
Example 189: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-sulfophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
Step 1: synthesizing the neopentyl 4-formyl benzene sulfonate.
To 1g (4.89 mmol) of 4-formylbenzenesulfonyl chloride in chloroform (10 mL) was added 1.2mL (14.7 mmol,3 eq.) of pyridine at 0deg.C, followed by 0.65mL (7.33 mmol,1.5 eq.) of neopentyl alcohol and the reaction was warmed at room temperature for 18h. The mixture was washed with 1N HCl, water, dried over sodium sulfate, and concentrated to dryness to give 0.65g (51%) of the title compound. ESI-MS M/z 257 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (4-sulfophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 4-formylbenzenesulfonic acid neopentyl ester for 2-fluoro-4-iodobenzaldehyde in step 1. ESI-MS M/z 589 (M+H) + 。
Example 190: synthesis of (R) -3- ((S) -2- (1- (difluoromethyl) -2-oxo-1, 2-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 49, substituting 1- (difluoromethyl) -2-oxo-1, 2-dihydropyridine-3-carbonyl chloride for 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC, the title compound ESI M/z 592 (M+H) was collected at the first elution peak + 。
Example 191: synthesis of (R) -3- ((R) -2- (1- (difluoromethyl) -2-oxo-1, 2-dihydropyridine-3-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 190 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 592 (M+H) + 。
Example 192: synthesis of (R) -2-hydroxy-3- ((S) -2- (4-phosphonophenyl) -2- (5- (trifluoromethyl) pyridine formylamino) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 5- (trifluoromethyl) pyridine carbonyl chloride instead of 2-chloro-3, 4-dimethoxy benzoyl chloride in step 3. After purification by reverse phase HPLC, the title compound ESI M/z 594 (M+H) was collected at the first elution peak + 。
Example 193: synthesis of (R) -2-hydroxy-3- ((R) -2- (4-phosphonophenyl) -2- (5- (trifluoromethyl) pyridine formylamino) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 192 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 594 (M+H) + 。
Example 194: synthesis of (R) -2-hydroxy-3- ((S) -2- (5-oxo-5H-thiazolo [3,2-a ] pyrimidine-6-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 5-oxo-5H-thiazolo [3,2-a ] in step 3 ]Pyrimidine-6-carbonyl chloride. After purification by reverse phase HPLC, the title compound ESI M/z 599 (M+H) was collected at the first elution peak + 。
Example 195: synthesis of (R) -2-hydroxy-3- ((R) -2- (5-oxo-5H-thiazolo [3,2-a ] pyrimidine-6-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the procedure of example 194The title compound was collected at the second elution peak after purification by reverse phase HPLC. ESI-MS M/z 599 (M+H) + 。
Example 196: synthesis of (R) -2-hydroxy-3- ((S) -2- (5-oxo-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 49 using 5-oxo-2, 3-dihydro-5H-thiazolo [3,2-a ] in step 3]Pyrimidine-6-carbonyl chloride. After purification by reverse phase HPLC, the title compound ESI M/z 601 (M+H) was collected at the first elution peak + 。
Example 197: synthesis of (R) -2-hydroxy-3- ((R) -2- (5-oxo-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxamido) -2- (4-phosphonophenyl) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 196 and was collected at the second elution peak after reverse phase HPLC purification. ESI-MS M/z 601 (M+H) + 。
Example 198: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (3-fluoro-2-hydroxy-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesizing 2- (benzyloxy) -3-fluoro-4-iodobenzaldehyde.
To 1g (3.76 mmol) of 3-fluoro-2-hydroxy-4-iodobenzaldehyde in N, N-dimethylformamide (10 mL) was added 0.78g (5.64 mmol,1.5 eq.) of potassium carbonate followed by 0.5mL (4.13 mmol,1.1 eq.) of benzyl bromide and the reaction was stirred at room temperature for 1h. The mixture was diluted with ethyl acetate, washed with water (3 times), dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (5% ethyl acetate/hexanes) to give 1.17g (87%) of the title compound. ESI-MS M/z 357 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (4-ethyl-2, 3-dioxopiperazine-1-carboxamido) -2- (3-fluoro-2-hydroxy-4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 1, substituting 2- (benzyloxy) -3-fluoro-4-iodobenzaldehyde for 2-fluoro-4-iodobenzaldehyde in step 1 and substituting Xantphos Pd G3 for tetrakis (triphenylphosphine) palladium (0) in step 4. ESI-MS M/z 623 (M+H) + 。
Example 200: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (methyl (thiazol-2-ylmethyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing tertiary butyl (4-fluoro-2-methoxyphenoxy) dimethylsilane.
To a solution of 4-fluoro-2-methoxyphenol (5.68 g,40 mmol) in DCM (100 mL) was added TEA (11.2 mL,80 mmol), 4-DMAP (488 mg,4 mmol), followed by TBSCl (7.5 g,49.8 mmol). The reaction mixture was stirred at room temperature overnight, then cooled to 0℃again and Boc was added 2 O (36.7 g,168 mmol). The reaction mixture was stirred at room temperature overnight with NaHCO 3 Washing with aqueous solution, na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane-EtOAc, 50:1-10:1) to give 10g of the title compound. ESI-MS M/z 257 (M+H) + 。
Step 2. Synthesis of tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -6-fluoro-2-methoxybenzoate.
To a solution of diisopropylamine (6.6 mL,46.8 mmol) in anhydrous THF (120 mL) was added nBuLi (2.5M, 18.72mL,46.8 mmol) dropwise under argon at-65 ℃. The reaction mixture was stirred at-60℃to-55℃for 20min. To the reaction mixture was added dropwise the above product (10 g,39 mmol) in THF (15 mL), stirred for 1h, then Boc was added 2 O (28.19 g,129 mmol). The reaction mixture was slowly warmed up to room temperature and stirred at room temperature overnight, quenched with water and extracted with ethyl acetate. The organic extracts were washed with brine, with Na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (DCM-hexane, 1:20-1:1) to give the title compound (8 g) which was purified by some by-products and Boc 2 O pollution. ESI-MS M/z 357 (M+H) + 。
And 3, synthesizing the 6-fluoro-3-hydroxy-2-methoxybenzoic acid tert-butyl ester.
TBAF (1.0M, 50mL,50 mmol) was added to a solution of the above product (8 g,22.5 mmol) in THF (150 mL), the reaction was stirred at room temperature for 1.5h, diluted with EtOAc and saturated NaHCO 3 Washing with aqueous solution, brine, and washing with Na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane-EtOAc, 40:1-2:1) to give 1.4g of the title compound, ESI-MS M/z 243 (M+H) + And 2.6g O-Boc product, ESI-MS M/z 343 (M+H) + . After purification by flash chromatography, the O-Boc product (2.6 g) was treated with excess piperidine in DCM overnight at room temperature to give an additional 1.4g of the title compound.
Step 4. Synthesis of tert-butyl 6-fluoro-2-methoxy-3- (((trifluoromethyl) sulfonyl) oxy) benzoate.
To a solution of the above product (1.4 g,5.8 mmol) in DCM (50 mL) was added PhNTf 2 (2.9 g,8.12 mmol), TEA (2.03 mL,14.5 mmol), and 4-DMAP (71 mg,0.58 mmol). The reaction mixture was stirred at room temperature overnight with saturated NaHCO 3 Washing with aqueous solution, na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane-DCM, 10:1-1:4) to give 1.9g of the title compound. ESI-MS M/z 375 (M+Na) + 。
Step 5. Synthesis of tert-butyl 6-fluoro-2-methoxy-3- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) benzoate.
To the above product (3.85 g,10.3 mmol) in dry DMF (35 mL) was added bis [ (+) -pinanediol ]Diboron (5.7 g,15.9 mmol), KOAc (3.1 g,31.6 mmol) and Pd (dppf) Cl 2 DCM (430 mg,0.53 mmol). The reaction mixture was stirred at 90-100 ℃ overnight, water was added, and extracted with diethyl ether. The ether extract was washed with water, brine, and Na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane-DCM, 10:1-1:10) to give 2.4g of the title compound. ESI-MS m/z831 (2M+Na) + 。
Step 6. Synthesis of tert-butyl 6-fluoro-2-methoxy-3- (((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) methyl) benzoate.
To a solution of chloroiodomethane (3.2 mL,43.9 mmol) in THF (70 mL) was added dropwise over a period of 20min under argon at-78deg.CSolution (1.3M in THF, 16.8mL,21.8 mmol). The resulting solution was stirred at-78 ℃ for 45min, then a solution of the above product (2.38 g,5.89 mmol) in THF (9 mL) was slowly added over a period of 20 min. After the addition was complete, the reaction mixture was stirred for 1.5h. Drop wise addition of ZnCl to the solution 2 The solution (1.0M in diethyl ether, 6.4mL,6.4 mmol) and stirring was continued for 15min after the addition was complete. The cold water bath was removed and the reaction mixture was stirred at room temperature overnight, cooled to-30 ℃, diluted with ether and NH 4 Aqueous Cl, water and brine, washed with Na 2 SO 4 Dried and concentrated, purified by flash chromatography on silica gel (hexane-EtOAc, 20:1-5:1) to give 2.24g of the title compound. ESI-MS M/z 441 (M+Na) + 。
Step 7. Synthesis of tert-butyl 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
Cooled (-100 ℃ C., meOH/N) in THF (15 mL) to DCM (0.82 mL,12.8 mmol) during 20min 2 ) n-BuLi (2.5M in hexane, 3.06mL,7.65 mmol) was added dropwise to the solution along the sides of the flask. The resulting mixture was stirred for 45min, then a solution of the above product (2.24 g,5.36 mmol) in THF (8 mL) was slowly added along the sides of the flask over a period of 20min, and stirring was continued for 45min after the addition was complete. ZnCl is added dropwise to the mixture obtained during 5min 2 (1.0M in diethyl ether, 7.3mL,7.3 mmol). After 15min, the methanol/N was replaced with a dry ice/acetone bath (-10 ℃ C.) 2 Bath and stirring was continued for 1.5h. Diluting the reaction mixture with diethyl ether and using NH 4 Aqueous Cl, water and brine, washed with Na 2 SO 4 Dried, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane-EtOAc, 20:1-4:1) to give 2.1g of the title compound. ESI-MS M/z 489 (M+Na) + 。
And 8, synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
i) To 3-fluoro-5-hydroxy-4-methoxybenzaldehyde (4.6 g,27.1 mmol) in DMF (50 mL) was added N-chlorosuccinimide (4.81 g,36 mmol). The reaction mixture was stirred at room temperature for 4h, diluted with diethyl ether, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product.
ii) to the above crude product (27.1 mmol) in DMF (60 mL) was added Cs 2 CO 3 (20.8 g,63.8 mmol) followed by methyl iodide (5 mL,80 mmol). The reaction mixture was stirred at room temperature overnight, diluted with diethyl ether, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane-EtOAc, 30:1-6:1) to give 1.5g of the title compound. ESI-MS M/z 219/221 (M+H) + /(M+H+2) + 。 1 H NMR(400MHz,CDCl 3 )δ10.36(s,1H),7.48(d,1H),4.1(s,3H),3.19(br s,1H),3.94(s,3H)。
Step 9. Synthesis of 2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid.
i) To 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde (5 g,22.9 mmol) was added NH 7N in methanol (200 mL) at 0deg.C 3 TMSCN (5 mL,40 mmol) was then added. The reaction mixture was stirred at 0 ℃. After 15min, the reaction mixture was warmed to about 45 ℃. After 6h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford the title compound as a yellow oil, which was used without further purification.
ii) the crude product (22.9 mmol) was dissolved in methanol (200 mL) and 4N HCl in dioxane (200 mL) was added. The reaction mixture was heated at 55-60 ℃ for 3 days and then concentrated.
iii) To this crude product in THF (180 mL) and water (180 mL) was added LiOH H 2 O (5 g,119 mmol). The reaction mixture was stirred at room temperature for 1h.
iv) the reaction mixture was neutralized to pH about 9 with 1N HCl followed by addition of saturated NaHCO at 0deg.C 3 Boc in aqueous solution (60 mL) and THF (30 mL) 2 O (8 g,36.7 mmol). The reaction mixture was then stirred at room temperature for 2h, concentrated, and taken up in Et 2 And O extraction. The aqueous solution was acidified to pH 2-3 with 1N HCl and extracted with EtOAc (2 passes). The organic extracts were combined with Na 2 SO 4 Dried and concentrated in vacuo to yield 7.3g of the title acid, which was about 85% based on NMR, which was used directly in the next step without further purification. ESI-MS M/z 364/366 (M+H) + /(M+H+2) + 。
Step 10. Synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The title compound was prepared by following general coupling procedure C from the above-described acid and chloride intermediate from step 7. ESI-MS M/z 793/795 (M+H) + /(M+H+2) + 。
Step 11. Synthesis of tert-butyl 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The above compound (11 g,13.9 mmol) was taken up in Et at about 55 ℃ 2 In O (170 mL,340 mmol)2N HCl and 4N HCl in dioxane (88 mL,352 mmol) were treated for 2h and then concentrated in vacuo to give the crude product as the HCl salt, which was used directly in the next step without further purification. ESI-MS M/z 693/695 (M+H) + /(M+H+2) + 。
Step 12. Synthesis of tert-butyl (2- (2, 3-dioxopiperazin-1-yl) ethyl) (methyl) carbamate.
To ethylenediamine (21.88 g, 264 mmol) was added tert-butyl (2-chloroethyl) (methyl) carbamate (6.984 g,36 mmol) dropwise under argon. The mixture was stirred at room temperature for 27h, then quenched with brine, and quenched with Et 2 O extraction (2 times), with Na 2 SO 4 Dried and evaporated under reduced pressure to give 6.95g of the title compound. ESI-MS M/z 272 (M+H) + 。
Step 13. Synthesis of tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) (methyl) carbamate.
To a solution of tert-butyl (2- (2, 3-dioxopiperazin-1-yl) ethyl) (methyl) carbamate (4 g,14.8 mmol) in DCM (16 mL) and THF (40 mL) was added dropwise TMSCl (2.1 mL,16.5 mmol) followed by TEA (2.5 mL,17.9 mmol) under argon at-15 ℃. The reaction mixture was stirred at-15-0deg.C for 1h. A solution of triphosgene (1.8 g,6.06 mmol) in THF (8 mL) was then added dropwise to the resulting reaction mixture at-15 ℃. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 2h, then filtered and washed with THF. The filtrate was evaporated under reduced pressure and dried in vacuo to give the title compound which was used directly in the next step.
Step 14. Synthesis of 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (2- (methylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid.
i) To the crude product from step 11 (2.92 g,4 mmol) in DCM (100 mL) was added iPr at 0deg.C 2 NEt (3.2 ml,18.4 mmol) followed by tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) (methyl) carbamate (1.56 g,4.66 mmol) from step 13. The reaction mixture was stirred at room temperature for 1.5h, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. ESI-MS M/z 834/836 (M-Boc- t Bu+H) + /(MH-Boc- t Bu+2) + 。
ii) the crude product (4 mmol) was taken up in Et at room temperature 2 2N HCl in O (56 mL,112 mmol) and 4N HCl in dioxane (28 mL,112 mmol) were treated for 4h and then concentrated in vacuo to give the crude product as HCl salt which was used directly in the next step without further purification. ESI-MS M/z 834/836 (M+H) + /(M+H+2) + 。
Step 15. Synthesis of 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (2- (methyl (thiazol-2-ylmethyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid.
To the above crude product (333 mg,0.38 mmol) in DCE (8 mL) was added iPr 2 NEt (0.10 mL,0.57 mmol) followed by thiazole-2-carbaldehyde (114 mg,1 mmol) and NaBH (OAc) 3 (212 mg,1 mmol). The reaction mixture was allowed to stand at room temperatureStirred for 2h, diluted with DCM, washed with brine, and dried over Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. ESI-MS M/z931/933 (M+H) + /(M+H+2) + 。
Step 16. Synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (methyl (thiazol-2-ylmethyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The above product was treated with an excess of BBr at room temperature by following general procedure A 3 Treatment overnight afforded the title compound after purification by reverse phase HPLC. ESI-MS M/z 737/739 (M+H) + /(M+H+2) + 。
Example 201: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (methyl (pyridin-3-ylmethyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 200, using 3-pyridinecarboxaldehyde instead of thiazole-2-carboxaldehyde in step 15 after reverse phase HPLC purification. ESI-MS M/z 731/733 (M+H) + /(M+H+2) + 。
Example 202: synthesis of (3R) -3- (2- (4- (3-benzoylaminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 3-fluoro-4, 5-dihydroxybenzaldehyde.
To DCM at-80 DEG CBBr was added to 50g (294 mmol) of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde in (500 mL) 3 55mL (588 mmol,2 eq.) of solution in DCM (250 mL). The reaction mixture was stirred at room temperature for 6h. The reaction was quenched with MeOH at-30 ℃ and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% MeOH/DCM) to give 40g, 87.3% of the desired product. ESI-MS M/z 157 (M+H) + 。
And 2, synthesizing 3-fluoro-5-hydroxy-4-methoxybenzaldehyde.
Li was added to 40g (256 mmol) of 3-fluoro-4, 5-dihydroxybenzaldehyde in DMF (400 mL) at 0deg.C 2 CO 3 28g (384 mmol,1.5 eq.) followed by MeI40g (284 mmol,1.1 eq.) was added. The reaction mixture was stirred at 40℃for 12h. The reaction was diluted with EA, washed with NaCl (aqueous solution) and with Na 2 SO 4 Dried and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% EA/PE) to give 25g, 57.5% of the desired product. ESI-MS M/z 171 (M+H) + 。
Step 3: synthesizing 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde.
To a solution of 25g (147 mmol) of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde in toluene was added 2.1mL (13 mmol,0.09 eq.) of diisobutylamine. The mixture was heated to 70 ℃ in an oil bath and 14mL (169 mmol,1.15 eq.) of sulfuryl chloride was added at 70 ℃. The reaction mixture was stirred at 70℃for 2h. The resulting mixture was concentrated in vacuo, diluted with water, extracted with EA and taken up in Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 26g, 86.6% of the desired product. ESI-MS M/z 205 (M+H) + 。
Step 4: synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
Cs is added to a solution of 26g (127 mmol) of 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde in DMF at 0 ℃ 2 CO 3 62g (191 mmol,1.5 eq.) followed by MeI 21.6g (152 mmol,1.2 eq.) were added. The mixture was stirred at room temperature for 5h. The reaction mixture was diluted with EA, washed with water, and washed with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 25g, 90.5% of the desired product. ESI-MS M/z 219 (M+H) + 。
Step 5: synthesis of 2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid.
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To 25g (115 mmol) of 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde at 0deg.C was added 7N ammonia in methanol (550 mL) followed by 21.5mL (172.5 mmol,1.5 eq.) of trimethylcyanosilane, stirred at 45deg.C for 7h and concentrated in vacuo. The crude product was dissolved in 3N hydrochloric acid in methanol (450 mL), stirred at 50 ℃ for 18h and concentrated in vacuo to give HCl salt. The reaction was slurried in tetrahydrofuran (500 mL) and cooled at 0deg.C. Triethylamine 48mL (345 mmol,3 eq.) was added followed by di-tert-butyl dicarbonate 37.5g (172.5 mmol,1.5 eq.) at room temperature for 1h and concentrated in vacuo. The product was purified by flash chromatography on silica gel (20-30% ethyl acetate/hexanes) to give 30g of the desired product. 30g (79.5 mmol) of methyl 2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetate was dissolved in tetrahydrofuran (260 mL)/H 2 O (260 mL) was then dissolved in 5g of lithium hydroxide monohydrate (119 mmol,1.5 eq.) and stirred at room temperature for 2h and concentrated. The product was evaporated in vacuo, adjusted to ph=3 with HCl (1M), and taken up in a solventEA extraction with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (40% EA/PE) to give 24g, 83.3% of the desired product. ESI-MS M/z 364 (M+H) + 。
Step 6: synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
By following general procedure C, the chloride (prepared as reported previously, WO 2014/089365) was treated with 4M HCl in LiHMDS and dioxane, followed by coupling of 2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid in the presence of HATU and NMM to give the title compound. ESI-MS M/z 793 (M+H) + 。
Step 7: synthesis of tert-butyl 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 20g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 16g, 91.4% 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S, 6) S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (150 mL) at 0deg.C][1,3,2]To 16g (23 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 12.7mL (69 mmol,3 eq.) of N, N-diisopropylethylamine followed by 11.5g (34.5 mmol,1.5 eq.) of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate and the reaction was warmed at room temperature for 2h. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to 20g, 88.1% 3- ((2R) -2- (2- (4- (3- ((tert-butoxycarbonyl) amino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 990 (M+H) + 。
To 20g (20 mmol) of the above crude product at 0deg.C was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 4h. The reaction was concentrated in vacuo to 16g, 89.4% 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride. ESI-MS M/z 890 (M+H) + 。
Step 8: synthesis of (3R) -3- (2- (4- (3-benzoylaminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) The above crude product 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (8 mL) at 0deg.C][1,3,2]To 0.89g (1 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 0.43mL (3 mmol,3 eq.) of triethylamine followed by 0.15g (1.1 mmol,1.1 eq.) of benzoyl chloride and the reaction mixture was stirred at room temperature for 18h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to give 0.94g, 94.7% of the title compound. ESI-MS M/z 994 (M+H) + 。
ii) the above crude product 3- ((2R) -2- (2- (4- (3-benzoylaminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane at-78deg.C][1,3,2]To 0.94g (0.94 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate was added 14.1mL (14.1 mmol,15 eq.) of 1N boron tribromide in methylene chloride and the temperature was raised at room temperature for 18h. The reaction was quenched with water, concentrated and lyophilized before reverse phase HPLC (5-45% ACN-H 2 O+0.1% trifluoroacetic acid) to yield the title compound. ESI-MS M/z 744 (M+H) + 。
Example 203: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 760 (M+H) + 。
Example 204: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 760 (M+H) + 。
Example 205: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (isonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 202 using isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 745 (M+H) + 。
Example 206: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3- (3-hydroxyphenyl) ureido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 775 (M+H) + 。
Example 207: synthesis of (3R) -3- (2- (4- (2-benzoylaminoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of tert-butyl 3- ((2R) -2- (2- (4- (2-aminoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The title compound was prepared in a similar manner to the synthesis of step 7 in example 202 using tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) carbamate instead of (3- (4- (chloro) ethyl) carbamateCarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamic acid tert-butyl ester. ESI-MS M/z 876 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (4- (2-benzoylaminoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of step 8 in example 202 using 3- ((2R) -2- (2- (4- (2-aminoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) ][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacing 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z730 (M+H) + 。
Example 208: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (((5-hydroxypyridin-3-yl) methyl) (methyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 200, using 5-benzyloxy-pyridine-3-carbaldehyde instead of thiazole-2-carbaldehyde in step 15 after reverse phase HPLC purification. ESI-MS M/z 747/749 (M+H) + /(M+H+2) + 。
Example 209: synthesis of (R) -3- ((R) -2- (4- (2- (((6-aminopyridin-3-yl) methyl) (methyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 200, using tert-butyl (5-formylpyridin-2-yl) carbamate instead of thiazole-2-carbaldehyde in step 15 and adding a few drops of HOAc after purification by reverse phase HPLC. ESI-MS M/z 746/748 (M+H) + /(M+H+2) + 。
Example 210: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (nicotinamide) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 202 using nicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 745 (M+H) + 。
Example 211: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (3- (thiazole-2-carboxamido) propyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using thiazole-2-carbonyl chloride instead of benzoyl chloride. ESI-MS M/z 751 (M+H) + 。
Example 213: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (3- ((S) -pyrrolidine-2-carboxamido) propyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 202 using (t-butoxycarbonyl) -D-proline instead of benzoyl chloride. ESI-MS M/z 737 (M+H) + 。
Example 213: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (3- (pyridin-3-yl) ureido) propyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-isocyanatopyridineReplacement of benzoyl chloride. ESI-MS M/z 760 (M+H) + 。
Example 214: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (4-hydroxybenzoamido) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 746 (M+H) + 。
Example 215: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (3-hydroxybenzoamido) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using 3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 746 (M+H) + 。
Example 216: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (isonicotinamido) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207, using isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 731 (M+H) + 。
Example 217: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (nicotinamide) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207, substituting benzoyl chloride with nicotinoyl chloride. ESI-MS M/z 731 (M+H) + 。
Example 218: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2- (thiazole-2-carboxamido) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using thiazole-2-carbonyl chloride instead of benzoyl chloride. ESI-MS M/z 737 (M+H) + 。
Example 219: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (3- (4-hydroxyphenyl) ureido) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 761 (M+H) + 。
Example 220: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- (3- (3-hydroxyphenyl) ureido) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 761 (M+H) + 。
Example 221: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2- (3- (pyridin-4-yl) ureido) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 208, using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 746 (M+H) + 。
Example 222: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2- (3- (pyridin-3-yl) ureido) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 207 using 3-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 746 (M+H) + 。
Example 223: synthesis of (3R) -3- (2- (4- (2- ((4-carbamoyl-N-methylphenyl) sulfonylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) To the amine intermediate from example 200, step 14 (333 mg,0.36mmol in DCM (100 mL)) was added iPr at 0deg.C 2 NEt (0.32 ml,1.84 mmol) followed by 4-carbamoyl benzenesulfonyl chloride (99 mg,0.45 mmol). The reaction mixture was stirred at room temperature for 1.5h, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification.
ii) the crude product was taken up with an excess of BBr at room temperature by following general procedure A 3 Treatment overnight afforded the title compound after purification by reverse phase HPLC. ESI-MS M/z 823/825 (M+H) + /(M+H+2) + 。
Example 224: synthesis of (3R) -3- (2- (4- (2- ((3-carbamoyl-N-methylphenyl) sulfonylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 223, using 3-carbamoyl benzenesulfonyl chloride instead of 4-carbamoyl benzenesulfonyl chloride after reverse phase HPLC purification. ESI-MS M/z 823/825 (M+H) + /(M+H+2) + 。
Example 225: synthesis of (R) -3- ((R) -2- (4- (2- ((3-carbamoylbenzyl) (methyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamide) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In a similar manner to the synthesis of example 209The title compound was prepared after purification by reverse phase HPLC by substituting 3-formylbenzamide for tert-butyl (5-formylpyridin-2-yl) carbamate. ESI-MS M/z 773/775 (M+H) + /(M+H+2) + 。
Example 226: synthesis of (R) -3- ((R) -2- (4- (2- ((4-carbamoylbenzyl) (methyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamide) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 209, using 4-formylbenzamide instead of tert-butyl (5-formylpyridin-2-yl) carbamate and after purification by reverse phase HPLC. ESI-MS M/z 773/775 (M+H) + /(M+H+2) + 。
Example 227: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3- (4-hydroxyphenyl) ureido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 775 (M+H) + 。
Example 228: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (3- (pyridin-4-yl) ureido) propyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 760 (M+H) + 。
Example 229: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2- ((S) -pyrrolidine-2-carboxamido) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 207 using (t-butoxycarbonyl) -D-pro-rileAcid replaces benzoyl chloride. ESI-MS M/z 723 (M+H) + 。
Example 230: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((4-hydroxyphenyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of 2- (4- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2, 3-dioxopiperazin-1-yl) acetic acid.
i) To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 20g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 16g, 91.4% 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
ii) 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (150 mL) at 0deg.C][1,3,2]To 16g (23 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrogen chloride salt was added 12.7mL (69 mmol,3 eq.) of N, N-diisopropylethylamine followed by 11.3g (34.5 mmol,1.5 eq.) of benzyl 2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) acetate and the reaction was allowed to rise at room temperature The temperature was kept for 2h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to 19g, 84.1% 3- ((2R) -2- (2- (4- (2- (benzyloxy) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z981 (M+H) + 。
iii) 19g (19 mmol) of the above crude product was added to a slurry of Pt/C (1.9 g,10% wt) in MeOH (400 mL). Reaction in H 2 Stirred at room temperature for 12h. The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum to 15g, 88.7% 2- (4- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2, 3-dioxopiperazin-1-yl) acetic acid. ESI-MS M/z 891 (M+H) + 。
Step 8: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((4-hydroxyphenyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The above crude product 2- (4- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)) in dichloromethane (8 mL) at 0deg.C][1,3,2]Dioxaborol-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2, 3-dioxopiperazin-1-yl) acetic acid 0.89g (1 mmol) and 4-methoxyaniline 0.18g (1.5 mmol,1.5 eq) triethylamine 0.43mL (3 mmol,3 eq) were added followed by Mukaiyama reagent 0.51g (2 mmol,2 eq) and the reaction mixture stirred at room temperature for 18h. The product is treated with waterQuench, wash with brine, dry over sodium sulfate and concentrate to give 0.9g, 90.3% of the title compound. ESI-MS M/z 996 (M+H) + 。
The above crude product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (2- ((4-methoxyphenyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in methylene chloride at-78deg.C][1,3,2]To 0.9g (0.9 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate was added 13.5mL (13.5 mmol,15 eq.) of 1N boron tribromide in methylene chloride and the temperature was raised at room temperature for 18h. The reaction was quenched with water, concentrated and lyophilized before reverse phase HPLC (5-45% ACN-H) 2 O+0.1% trifluoroacetic acid) to yield the title compound. ESI-MS M/z 732 (M+H) + 。
Example 231: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((3-hydroxyphenyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using 3-methoxyaniline instead of 4-methoxyaniline. ESI-MS M/z 732 (M+H) + 。
Example 232: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- (phenylamino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using aniline instead of 4-methoxyaniline. ESI-MS M/z 716 (M+H) + 。
Example 233: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- (pyridin-4-ylamino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the procedure of example 230Instead of 4-methoxyaniline, pyridine-4-amine was used. ESI-MS M/z 717 (M+H) + 。
Example 234: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- (pyridin-3-ylamino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using pyridin-3-amine instead of 4-methoxyaniline. ESI-MS M/z 717 (M+H) + 。
Example 235: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- (thiazol-2-ylamino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using thiazol-2-amine instead of 4-methoxyaniline. ESI-MS M/z 723 (M+H) + 。
Example 236: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((4-hydroxybenzyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using (4-methoxyphenyl) methylamine instead of 4-methoxyaniline. ESI-MS M/z 746 (M+H) + 。
Example 237: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((3-hydroxybenzyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using (3-methoxyphenyl) methylamine instead of 4-methoxyaniline. ESI-MS M/z 746 (M+H) + 。
Example 238: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (2- ((3-hydroxybenzyl) amino) -2-oxoethyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using phenylmethylamine instead of 4-methoxyaniline. ESI-MS M/z 730 (M+H) + 。
Example 239: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- ((pyridin-4-ylmethyl) amino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using pyridin-4-ylmethylamine instead of 4-methoxyaniline. ESI-MS M/z 731 (M+H) + 。
Example 240: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- ((pyridin-3-ylmethyl) amino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using pyridin-3-ylmethylamine instead of 4-methoxyaniline. ESI-MS M/z 731 (M+H) + 。
Example 241: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (2-oxo-2- ((thiazol-2-ylmethyl) amino) ethyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 230 using thiazol-2-ylmethylamine instead of 4-methoxyaniline. ESI-MS M/z 737 (M+H) + 。
Example 242: synthesis of (3R) -3- (2- (3- (2-benzoylaminoethyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of tert-butyl 3- ((2R) -2- (2- (3- (2-aminoethyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The title compound was prepared in a similar manner to the synthesis of step 7 in example 202 using tert-butyl (2- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) ethyl) carbamate instead of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate. ESI-MS M/z 848 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (3- (2-benzoylaminoethyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in a similar manner to the synthesis of step 8 in example 202 using 3- ((2R) -2- (2- (3- (2-aminoethyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacing 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z702 (M+H) + 。
Example 243: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (4-hydroxybenzoamido) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 718 (M+H) + 。
Example 244: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (3-hydroxybenzoamido) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 718 (M+H) + 。
Example 245: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (isonicotinamido) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 242 using isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 703 (M+H) + 。
Example 246: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (nicotinamide) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 242 using nicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 703 (M+H) + 。
Example 247: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (2- (thiazole-2-carboxamido) ethyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using thiazole-2-carbonyl chloride instead of benzoyl chloride. ESI-MS M/z 709 (M+H) + 。
Example 248: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (2- ((S) -pyrrolidine-2-carboxamido) ethyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 242 using (t-butoxycarbonyl) -D-proline instead of benzoyl chloride. ESI-MS M/z 695 (M+H) + 。
Example 249: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (3- (3-hydroxyphenyl) ureido) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 733 (M+H) + 。
Example 250: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (2- (3- (pyridin-4-yl) ureido) ethyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 718 (M+H) + 。
Example 251: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (2- (3- (pyridin-3-yl) ureido) ethyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 3-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 718 (M+H) + 。
Example 252: synthesis of (R) -3- ((S) -2- (3- (3-benzoylaminopropyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of tert-butyl 3- ((2R) -2- (2- (3- (3-aminopropyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate
The title compound was prepared in a similar manner to the synthesis of step 7 in example 202 using tert-butyl (3- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) propyl) carbamate instead of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate. ESI-MS M/z 862 (M+H) + 。
Step 2: synthesis of (R) -3- ((S) -2- (3- (3-benzoylaminopropyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in a similar manner to the synthesis of step 8 in example 203 using 3- ((2R) -2- (2- (3- (3-aminopropyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacing 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z716 (M+H) + 。
Example 253: synthesis of (R) -3- ((R) -2- (3- (3-benzoylaminopropyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252. ESI-MS M/z716 (M+H) + 。
Example 254: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (3-hydroxybenzoamido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z732 (M+H) + 。
Example 255: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (3-hydroxybenzoamido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 254. ESI-MS M/z732 (M+H) + 。
Example 256: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (isonicotinamido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 717 (M+H) + 。
Example 258: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (3-hydroxyphenyl) ureido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 747 (M+H) + 。
Example 259: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (3- (pyridin-3-yl) ureido) propyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 3-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 732 (M+H) + 。
Example 260: synthesis of (3R) -3- (2- (3- ((2-benzoylaminoethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of tert-butyl 3- ((2R) -2- (2- (3- ((2-aminoethyl) sulfonyl) -2-oxoimidazolidin-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The title compound was prepared in a manner analogous to the synthesis of step 7 of example 202 using tert-butyl (2- ((3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) sulfonyl) ethyl) carbamate instead of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate. ESI-MS M/z 912 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (3- ((2-benzoylaminoethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
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The title compound was prepared in a similar manner to the synthesis of step 8 in example 202 using 3- (. About.2R) -2- (2- (3- ((2-aminoethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacing 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z766 (M+H) + 。
Example 261: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (3-hydroxybenzoamido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using 3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 782 (M+H) + 。
Example 262: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (nicotinamide) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 261, substituting benzoyl chloride with nicotinoyl chloride. ESI-MS M/z 767 (M+H) + 。
Example 263: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((2- (thiazole-2-carboxamido) ethyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using thiazole-2-carbonyl chloride instead of benzoyl chloride. ESI-MS M/z773 (M+H) + 。
Example 264: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((2- (thiazole-2-carboxamido) ethyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 263. ESI-MS M/z773 (M+H) + 。
Example 265: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((2- ((S) -pyrrolidine-2-carboxamido) ethyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using (tert-butoxycarbonyl) -D-proline instead of benzoyl chloride. ESI-MS M/z 759 (M+H) + 。
Example 266: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (3- (3-hydroxyphenyl) ureido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 261 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 797 (M+H) + 。
Example 267: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((2- (3- (pyridin-3-yl) ureido) ethyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using 3-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 782 (M+H) + 。
Example 268: synthesis of (3R) -3- (2- (3- ((3-benzoylaminopropyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1: synthesis of tert-butyl 3- ((2R) -2- (2- (3- ((3-aminopropyl) sulfonyl) -2-oxoimidazolidin-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The title compound was prepared in a manner analogous to the synthesis of step 7 of example 202 using tert-butyl (3- ((3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) sulfonyl) propyl) carbamate instead of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate. ESI-MS M/z 926 (M+H) + 。
Step 2: synthesis of (3R) -3- (2- (3- ((3-benzoylaminopropyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in a similar manner to the synthesis of step 8 in example 202 using 3- ((2R) -2- (2- (3- ((3-aminopropyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d][1,3,2]Dioxaborole-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester replacing 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z780 (M+H) + 。
Example 269: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (4-hydroxybenzoamido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 796 (M+H) + 。
Example 270: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (3-hydroxybenzoamido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 substituting 3-methoxybenzoyl chloride for benzoyl chloride. ESI-MS M/z 796 (M+H) + 。
Example 271: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (3-hydroxybenzoamido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in the same manner as the synthesis of example 270. ESI-MS M/z796 (M+H) + 。
Example 272: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (isonicotinamido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 substituting isonicotinyl chloride for benzoyl chloride. ESI-MS M/z 781 (M+H) + 。
Example 273: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (nicotinamide) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268, substituting benzoyl chloride with nicotinoyl chloride. ESI-MS M/z 781 (M+H) + 。
Example 274: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((3- (thiazole-2-carboxamido) propyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using thiazole-2-carbonyl chloride instead of benzoyl chloride. ESI-MS M/z 787 (M+H) + 。
Example 275: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((3- ((S) -pyrrolidine-2-carboxamido) propyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 268 using (t-butoxycarbonyl) -D-proline instead of benzoyl chloride. ESI-MS M/z 773 (M+H) + 。
Example 276: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (3- (4-hydroxyphenyl) ureido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 811 (M+H) + 。
Example 277: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((3- (3-hydroxyphenyl) ureido) propyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using 1-isocyanato-3-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 811 (M+H) + 。
Example 278: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((3- (pyridin-3-yl) ureido) propyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using 3-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 796 (M+H) + 。
Example 279: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (2- (3- (4-hydroxyphenyl) ureido) ethyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 242 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 733 (M+H) + 。
Example 280: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (4-hydroxybenzoamido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 732 (M+H) + 。
Example 281: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (nicotinamide) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using nicotinoyl chloride instead of benzoyl chloride. ESI-MS M/z 717 (M+H) + 。
Example 282: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (nicotinamide) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 252 using (t-butoxycarbonyl) -D-proline instead of benzoyl chloride. ESI-MS M/z 709 (M+H) + 。
Example 283: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (3- (4-hydroxyphenyl) ureido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z747 (M+H) + 。
Example 284: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (3- (3- (4-hydroxyphenyl) ureido) propyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in the same manner as in the synthesis of example 283. ESI-MS M/z747 (M+H) + 。
Example 285: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (3- (3- (pyridin-4-yl) ureido) propyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 252 using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 732 (M+H) + 。
Example 286: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (4-hydroxybenzoamido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using 4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z782 (M+H) + 。
Example 287: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (4-hydroxybenzoamido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 286. ESI-MS M/z782 (M+H) + 。
Example 288: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (isonicotinamido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260, substituting isonicotinyl chloride for benzoyl chloride. ESI-MS M/z 767 (M+H) + 。
Example 289: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- ((2- (3- (4-hydroxyphenyl) ureido) ethyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using 1-isocyanato-4-methoxybenzene instead of benzoyl chloride. ESI-MS M/z 797 (M+H) + 。
Example 290: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((2- (3- (pyridin-4-yl) ureido) ethyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 260 using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 782 (M+H) + 。
Example 291: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- ((3- (3- (pyridin-4-yl) ureido) propyl) sulfonyl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 268 using 4-isocyanatopyridine instead of benzoyl chloride. ESI-MS M/z 796 (M+H) + 。
Example 292: synthesis of (3R) -3- (2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) To the crude product from step 11 of example 200 (29 mg,0.4 mmol) in DCM (12 mL) at 0deg.C was added iPr 2 NEt (0.3 ml,1.72 mmol) followed by 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride (162 mg,0.45 mmol). The reaction mixture was stirred at room temperature for 2h, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. ESI-MS M/z 1017/1019/1021 (M+H) + /(M+H+2) + /(M+H+4) + 。
ii) the crude product was taken up with an excess of BBr at room temperature by following general procedure A 3 Treatment overnight afforded the title compound after purification by reverse phase HPLC. ESI-MS M/z739/741/743 (M+H) + /(M+H+2) + /(M+H+4) + 。
Example 293: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of tert-butyl 4- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate.
To a solution of tert-butyl 4- (2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate (4.38 g,14.7 mmol) in DCM (30 mL) and THF (60 mL) under argon was added dropwise TMSCl (2.1 mL,16.5 mmol) followed by TEA (2.5 mL,17.9 mmol). The reaction mixture was stirred at-15-0deg.C for 1h. A solution of triphosgene (1.8 g,6.06 mmol) in THF (8 mL) was then added dropwise to the resulting reaction mixture at-15 ℃. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 2h, then filtered and washed with THF. The filtrate was evaporated under reduced pressure and dried in vacuo to give the title compound which was used directly in the next step.
Step 2. Synthesis of 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2, 3-dioxo-4- (piperidin-4-yl) piperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid.
i) To the crude product from step 11 of example 200 (3.5 g,4.8 mmol) in DCM (100 mL) at 0deg.C was added iPr 2 NEt (3.9 ml,22.4 mmol) followed by tert-butyl 4- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate (2.12 g,5.9 mmol). The reaction mixture was stirred at room temperature for 2h, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. ESI-MS M/z 960/962 (M) t Bu+H) + /(M+H- t Bu+2) + 。
ii) the crude product (4 mmol) was taken up in Et at room temperature 2 2N HCl in O (68 mL,136 mmol) and 4N HCl in dioxane (33 mL,132 mmol) were treated for 5h and then concentrated in vacuo to give the crude product as HCl salt which was used directly in the next step without further purification. ESI-MS M/z 860/862 (M+H) + /(M+H+2) + 。
Step 3 Synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) To the above crude amine intermediate (319 mg,0.4 mmol) in DCM (12 mL) at 0deg.C was added iPr 2 NEt (0.3 ml,1.71 mmol) followed by 3-methoxybenzoyl chloride (79 mg,0.46 mmol). The reaction mixture was stirred at room temperature for 30min, washed with water, brine, and Na 2 SO 4 Dried and concentrated in vacuo to give the crude product, which was used directly in the next step without further purification. ii) the crude product was taken up with an excess of BBr at room temperature by following general procedure A 3 Treatment overnight afforded the title compound after purification by reverse phase HPLC. ESI-MS M/z 786/788 (M+H) + /(M+H+2) + 。
Example 294: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (isonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 202 using isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 745 (M+H) + 。
Example 295: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-chloroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-chloroisonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 780 (M+H) + 。
Example 296: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-hydroxyisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-hydroxyisonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z 761 (M+H) + 。
Example 297: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-methylisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-methylisonicotinoyl chloride instead of benzoyl chloride. ESI-MS M/z 759 (M+H) + 。
Example 298: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-methylisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 2-methylisonicotinoyl chloride instead of benzoyl chloride. ESI-MS M/z 759 (M+H) + 。
Example 299: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 3-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 2, 3-difluoro isonicotinyl chloride instead of benzoyl chloride. ESI-MS M/z781 (M+H) + 。
Example 300: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 3-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 299. ESI-MS M/z781 (M+H) + 。
Example 301: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (5-fluoro-2-methylisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 5-fluoro-2-methylisonicotinoyl chloride instead of benzoyl chloride. ESI-MS M/z 777 (M+H) + 。
Example 302: synthesis of (R) -3- ((S) -2- (4- (3- (2-chloro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 2-chloro-3-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z795 (M+H) + 。
Example 303: synthesis of (R) -3- ((R) -2- (4- (3- (2-chloro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in the same manner as the synthesis of example 302. ESI-MS M/z795 (M+H) + 。
Example 304: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-fluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-fluoro-4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 778 (M+H) + 。
Example 305: synthesis of (3R) -3- (2- (4- (3- (3-chloro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 3-chloro-4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 795 (M+H) + 。
Example 306: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 3-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 2, 3-difluoro-4-methoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 796 (M+H) + 。
Example 307: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 4-dihydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 202 using 2, 4-dimethoxybenzoyl chloride instead of benzoyl chloride. ESI-MS M/z 776 (M+H) + 。
Example 308: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (2, 6-difluoro-3-hydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared after purification by reverse phase HPLC in analogy to the synthesis of example 293 using 2, 6-difluoro-3-methoxybenzoyl chloride (which was prepared by treating 2, 6-difluoro-3-methoxybenzoic acid with excess oxalyl chloride in DCM) instead of 3-methoxybenzoyl chloride in step 3. ESI-MS M/z 822/824 (M+H) + /(M+H+2) + 。
Example 309: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (3, 5-dihydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 3, 5-dimethoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3 after purification by reverse phase HPLC. ESI-MS M/z 802/804 (M+H) + /(M+H+2) + 。
Example 310: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-hydroxy-N-methylbenzamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) (methyl) carbamate.
The title compound was prepared in analogy to the synthesis of tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) (methyl) carbamate described in steps 12 and 13 of example 201 using tert-butyl (3-chloropropyl) (methyl) carbamate instead of tert-butyl (2-chloroethyl) (methyl) carbamate.
Step 2. Synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-hydroxy-N-methylbenzamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using carbamoyl chloride, (tert-butyl 3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) (methyl) carbamate prepared above instead of tert-butyl 4- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate in step 2 after purification by reverse phase HPLC. ESI-MS M/z 774/776 (M+H) + /(M+H+2) + 。
Example 400: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-fluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 3-fluoro-4, 5-dihydroxybenzaldehyde.
BBr is added to 50g (294 mmol) of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde in DCM (500 mL) at-80 ℃ 3 55mL (588 mmol,2 eq.) of solution in DCM (250 mL). The reaction mixture was stirred at room temperature for 6h. The reaction was quenched with MeOH at-30 ℃ and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% MeOH/DCM) to give 40g, 87.3% of the desired product. ESI-MS M/z 157 (M+H) + 。
And 2, synthesizing 3-fluoro-5-hydroxy-4-methoxybenzaldehyde.
Li was added to 40g (256 mmol) of 3-fluoro-4, 5-dihydroxybenzaldehyde in DMF (400 mL) at 0deg.C 2 CO 3 28g (384 mmol,1.5 eq.) followed by MeI40g (284 mmol,1.1 eq.) was added. The reaction mixture was stirred at 40℃for 12h. The reaction was diluted with EA, washed with NaCl (aqueous solution) and with Na 2 SO 4 Dried and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% EA/PE) to give 25g, 57.5% of the desired product. ESI-MS M/z 171 (M+H) + 。
Step 3: synthesizing 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde.
To a solution of 25g (147 mmol) of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde in toluene was added 2.1mL (13 mmol,0.09 eq.) of diisobutylamine. The mixture was heated to 70 ℃ in an oil bath and 14mL (169 mmol,1.15 eq.) of sulfuryl chloride was added at 70 ℃. The reaction mixture was stirred at 70℃for 2h. Mixing the obtained mixtureThe compound was concentrated in vacuo, diluted with water, extracted with EA and taken up in Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 26g, 86.6% of the desired product. ESI-MS M/z 205 (M+H) + 。
Step 4: synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
Cs is added to a solution of 26g (127 mmol) of 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde in DMF at 0 ℃ 2 CO 3 62g (191 mmol,1.5 eq.) followed by MeI 21.6g (152 mmol,1.2 eq.) were added. The mixture was stirred at room temperature for 5h. The reaction mixture was diluted with EA, washed with water, and washed with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 25g, 90.5% of the desired product. ESI-MS M/z 219 (M+H) + 。
Step 5: synthesis of 2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid.
To 25g (115 mmol) of 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde at 0deg.C was added 7N ammonia in methanol (550 mL) followed by 21.5mL (172.5 mmol,1.5 eq.) of trimethylcyanosilane, stirred at 45deg.C for 7h and concentrated in vacuo. The crude product was dissolved in 3N hydrochloric acid in methanol (450 mL), stirred at 50 ℃ for 18h and concentrated in vacuo to give HCl salt. The reaction was slurried in tetrahydrofuran (500 mL) and cooled at 0deg.C. Triethylamine 48mL (345 mmol,3 eq.) was added followed by di-tert-butyl dicarbonate 37.5g (172.5 mmol,1.5 eq.) at room temperature for 1h and concentrated in vacuo. The product was purified by flash chromatography on silica gel (20-30% ethyl acetate/hexanes) to give 30g of the desired product. Will 2- ((tert-butoxy)Carbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid methyl ester 30g (79.5 mmol) was dissolved in tetrahydrofuran (260 mL)/H 2 O (260 mL) was then dissolved in 5g of lithium hydroxide monohydrate (119 mmol,1.5 eq.) and stirred at room temperature for 2h and concentrated. The product was evaporated in vacuo, adjusted to ph=3 with HCl (1M), extracted with EA, extracted with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (40% EA/PE) to give 24g, 83.3% of the desired product. ESI-MS M/z 364 (M+H) + 。
Step 6: synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
By following general procedure C, the chloride (prepared as reported previously, WO 2014/089365) was treated with LiHMDS and 4M dioxane (HCl) followed by coupling of 2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid in the presence of HATU and NMM to give the title compound. ESI-MS M/z 793 (M+H) + 。
Step 7: synthesis of tert-butyl 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 20g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 16g, 91.4% 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) ][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (150 mL) at 0deg.C][1,3,2]To 16g (23 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 12.7mL (69 mmol,3 eq.) of N, N-diisopropylethylamine followed by 11.5g (34.5 mmol,1.5 eq.) of tert-butyl (3- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) propyl) carbamate and the reaction was warmed at room temperature for 2h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to 20g, 88.1% 3- ((2R) -2- (2- (4- (3- ((tert-butoxycarbonyl) amino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 990 (M+H) + 。
To 20g (20 mmol) of the above crude product at 0deg.C was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 4h. The reaction was concentrated in vacuo to 16g, 89.4% 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride. ESI-MS M/z 890 (M+H) + 。
Step 8: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-fluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) The above crude product 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (8 mL) at 0deg.C][1,3,2]To 0.89g (1 mmol) of t-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 0.43mL (3 mmol,3 eq.) of triethylamine followed by 0.175g (1.1 mmol,1.1 eq.) of 3-fluoroisonicotinyl chloride and the reaction mixture was stirred at room temperature for 18h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to give 0.91g, 90% of the title compound. ESI-MS M/z 1013 (M+H) + 。
ii) the above crude product 3- ((2R) -2- (2- (4- (3-benzoylaminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane at-78deg.C ][1,3,2]To 0.91g (0.9 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 13.5mL (13.5 mmol,15 eq.) of 1N boron tribromide in methylene chloride and the temperature was raised at room temperature for 18h. The reaction was quenched with water, concentrated, and lyophilized before reverse phase HPLC (5-45% ACN-H 2 O+0.1% trifluoroacetic acid) to yield the title compound. ESI-MS M/z 763 (M+H) + 。
Example 401: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 6-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 6-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 6-difluoroisonicotinic acid chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 781 (M+H) + 。
Example 402: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3, 5-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3, 5-difluoroisonicotinic acid chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 781 (M+H) + 。
Example 403: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-chloro-5-fluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3-chloro-5-fluoroisonicotinic acid chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 797 (M+H) + 。
Example 404: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (3- (2, 4, 5-trifluoro-3-hydroxybenzoylamino) propyl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2,4, 5-trifluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 814 (M+H) + 。
Example 405: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 5-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 5-difluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 5-difluoroisonicotinic acid chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 781 (M+H) + 。
Example 406: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-fluoro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-fluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 778 (M+H) + 。
Example 407: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-fluoro-5-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-fluoro-5-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 778 (M+H) + 。
Example 408: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-chloro-5-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-5-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 794 (M+H) + 。
Example 409: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (4-fluoro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 4-fluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 778 (M+H) + 。
Example 410: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (3-fluoro-5-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3-fluoro-5-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 778 (M+H) + 。
Example 411: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 4-difluoro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 4-difluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 796 (M+H) + 。
Example 412: synthesis of (3R) -3- (2- (4- (3- (2-chloro-4-fluoro-3-hydroxybenzoamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-4-fluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 812 (M+H) + 。
Example 413: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 6-difluoro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400In step 8, 2, 6-difluoro-3-methoxybenzoyl chloride is used in place of 3-fluoroisonicotinic acid chloride. ESI-MS M/z 796 (M+H) + 。
Example 414: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-chloro-6-fluoro-3-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-6-fluoro-3-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z812 (M+H) + 。
Example 415: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 4-difluoro-3, 5-dihydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 4-difluoro-3, 5-dimethoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z812 (M+H) + 。
Example 416: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (4-fluoro-3, 5-dihydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 4-fluoro-3, 5-dimethoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 794 (M+H) + 。
Example 417: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-fluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-fluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-fluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 778 (M+H) + 。
Example 418: synthesis of (3R) -3- (2- (4- (3- (2-chloro-3-fluoro-4-hydroxybenzoamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-3-fluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 812 (M+H) + 。
Example 419: synthesis of (3R) -3- (2- (4- (3- (3-chloro-2-fluoro-4-hydroxybenzoamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3-chloro-2-fluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 812 (M+H) + 。
Example 420: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 6-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 6-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 6-difluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 796 (M+H) + 。
Example 421: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-chloro-6-fluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-6-fluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 812 (M+H) + 。
Example 422: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3, 5-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3, 5-difluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 796 (M+H) + 。
Example 423: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3, 5-dihydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 3, 5-dimethoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 776 (M+H) + 。
Example 424: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 1-isocyanato-3-methoxybenzene instead of 3-methoxybenzoyl chloride in step 3 after reverse phase HPLC purification. ESI-MS M/z 801/803 (M+H) + /(M+H+2) + 。
Example 425: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (5-hydroxynicotinoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 5- (benzyloxy) nicotinoyl chloride (which was prepared by treating 5- (benzyloxy) nicotinic acid with excess oxalyl chloride in DCM at room temperature) instead of 3-methoxybenzoyl chloride in step 3 after purification by reverse phase HPLC. ESI-MS M/z 787/789 (M+H) + /(M+H+2) + 。
Example 426: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate.
Step 1a.
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (40 g,200 mmol) and tert-butyl (2-aminoethyl) carbamate (38.8 g,200 mmol) in DME (600 mL) was added Na (OAc) in portions at room temperature 3 BH (127.2 g,600 mmol). The reaction mixture was stirred at room temperature overnight. By NaHCO 3 And washing the reaction mixture with brine. The organic phase was evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography (0-10% meoh/DCM) to give the desired intermediate (68.7 g, 90.9%).
Step 1b.
A solution of tert-butyl 4- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) piperidine-1-carboxylate (68.7 g,182 mmol) in MeOH (600 mL) at room temperature Pd/C was added. The reaction mixture was taken up in H 2 Stir overnight. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil (42 g, 94.8%).
Step 1c.
Intermediate (42 g,172.5 mmol) was dissolved in EtOH (1200 mL) and diethyl oxalate (27.6 g,189 mmol) was added. The mixture was refluxed overnight. Concentrating the reaction. The product was purified by flash chromatography on silica gel (0-10% MeOH/DCM) to give the desired intermediate (40 g, 77.9%).
Step 1d.
A solution of tert-butyl 4- (2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate (40 g,134.5 mmol) in DCM (250 mL)/THF (250 mL) was cooled to-40 ℃. TEA (20.2 mL,161.4mmol,1.2 eq.) was added. The mixture was warmed to 0 ℃ for 1h. Triphosgene (16 g,5.38mmol,0.4 eq.) in THF (200 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil. Addition of Et 2 O (1000 mL) and the product was triturated overnight at room temperature and filtered. The resulting solid was treated with Et 2 O (200 mL) was washed and dried in vacuo to afford the title compound (37.3 g, 77%).
Step 2: synthesis of tert-butyl 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The synthesis of 3- ((2R) -2- (2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester was prepared in analogy to the synthesis of example 400 (steps 1 to 6).
At 0 ℃ to 3- ((2R)2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To 20g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 16g, 91.4% 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (150 mL) at 0deg.C ][1,3,2]To 16g (23 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 12.7mL (69 mmol,3 eq.) of N, N-diisopropylethylamine followed by addition of tert-butyl 4- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate (12.4 g,34.5mmol,1.5 eq.) and the reaction was warmed at room temperature for 2h. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to give 18.7g of 80% 4- (4- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ])][1,3,2]Dioxaborolan-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylic acid tert-butyl ester. ESI-MS M/z 1016 (M+H) + 。
To 18.7g (18.4 mmol) of the above crude product was added 1N hydrochloric acid in diethyl ether (400 mL) at 0deg.C and warmed at room temperature for 4h. The reaction was concentrated in vacuo to 16g of 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2, 3-dioxo-4- (piperidin-4-yl) piperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) ][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride, ESI-MS m/z 916(M+H) + 。
Step 3: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) To 4-methoxyaniline (0.16 g,1.3 mmol) in THF (20 mL) was added triethylamine 0.56mL (3.9 mmol,3 eq.) followed by triphosgene (0.154 g,0.52mmol,0.4 eq.) in THF (5 mL) and warmed to room temperature for 1h. It was used in the next step without further purification.
3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2, 3-dioxo-4- (piperidin-4-yl) piperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (8 mL) at 0deg.C ][1,3,2]To t-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate (0.92 g,1 mmol) was added triethylamine (0.43 mL,3mmol,3 eq.) followed by the above solution and the reaction mixture was stirred at room temperature for 18h. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to give 0.74g, 70% of the product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (1- ((4-methoxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 1065 (M+H) + 。
ii) the above crude product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxy) in methylene chloride at-78 ℃ C.)Phenyl) -2- (4- (1- ((4-methoxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To 0.74g (0.7 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate was added 1N boron tribromide in methylene chloride (10.5 mL,10.5mmol,15 eq.) and the temperature was raised at room temperature for 18h. Quenched with water, concentrated, and purified by reverse phase HPLC (5-80% ACN-H 2 O+0.1% trifluoroacetic acid) and collecting the title compound ESI M/z801 (m+h) at the first eluting peak and the second eluting peak + 。
Example 427: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (4-hydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 4-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3 after reverse phase HPLC purification. ESI-MS M/z 786/788 (M+H) + /(M+H+2) + 。
Example 428: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3-hydroxyphenyl) sulfonyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 3-methoxybenzenesulfonyl chloride instead of 3-methoxybenzoyl chloride in step 3 after reverse phase HPLC purification. ESI-MS M/z 822/824 (M+H) + /(M+H+2) + 。
Example 429: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-hydroxyphenyl) sulfonyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In a similar manner to the synthesis of example 293, 4-methoxybenzenesulfonyl chloride was used in place of 3-methoxybenzene in step 3Formyl chloride, after purification by reverse phase HPLC, the title compound was prepared. ESI-MS M/z 822/824 (M+H) + /(M+H+2) + 。
Example 430: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate.
Step 1a.
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (40 g,200 mmol) and tert-butyl (2-aminoethyl) carbamate (32 g,200 mmol) in DME (600 mL) was added Na (OAc) in portions at room temperature 3 BH (127.2 g,600 mmol). The reaction mixture was stirred at room temperature overnight. By NaHCO 3 And washing the reaction mixture with brine. The organic phase was evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography (0-10% meoh/DCM) to give the desired intermediate (61.8 g, 90%).
Step 1b.
The intermediate above (61.8 g,180 mmol) was dissolved in THF (1200 mL) and tert-BuOK (72.8 g, 650) was added. The mixture was stirred at 55 ℃ overnight. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (0-10% MeOH/DCM) to give the desired intermediate (45.7 g, 94%).
Step 1c.
Tert-butyl 4- (2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (45.7 g,169 mmol) in DCM (200 mL)/THF (2)00 mL) was cooled to-40 ℃. TEA (25.4 mL,203mmol,1.2 eq.) was added. The mixture was warmed to 0 ℃ for 1h. Triphosgene (20 g,67.6mmol,0.4 eq.) in THF (200 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil. Addition of Et 2 O (1000 mL) and the product was triturated overnight at room temperature and filtered. The resulting solid was treated with Et 2 O (200 mL) was washed and dried in vacuo to afford the title compound (44.8 g, 80%).
Step 2: synthesis of tert-butyl 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
The synthesis of 3- ((2R) -2- (2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester was prepared in analogy to the synthesis of example 400 (steps 1 to 6).
To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 20g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 16g, 91.4% 3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
At 0 ℃ to3- ((2R) -2- (2-amino-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (150 mL) ][1,3,2]To 16g (23 mmol) of tert-butyl dioxaborolan-2-methoxybenzoate hydrochloride was added 12.7mL (69 mmol,3 eq.) of N, N-diisopropylethylamine followed by the addition of tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (11.5 g,34.5mmol,1.5 eq.) and the reaction was warmed at room temperature for 2h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to give 20g, 87.9% 4- (3- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester. ESI-MS M/z 988 (M+H) + 。
To 20g (20 mmol) of the above crude product at 0deg.C was added 1N hydrochloric acid in diethyl ether (400 mL) and warmed at room temperature for 4h. The reaction was concentrated in vacuo to 16g of 3- ((2R) -2- (2- (4- (3-aminopropyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride, ESI-MS M/z 888 (M+H) + 。
Step 3: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) The above crude product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (8 mL) at 0deg.C][1,3,2]To tert-butyl dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate hydrochloride (0.89 g,1 mmol) was added triethylamine (0.43 mL,3mmol,3 eq.) followed by 3-methoxybenzoyl chloride (0.187 g,1.1mmol,1.1 eq.) and the reaction mixture was stirred at room temperature for 18h. The product was quenched with water, washed with brine, dried over sodium sulfate and concentrated to give 0.92g, 90% 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (3- (1- (3-methoxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] ][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 1022 (M+H) + 。
ii) the above crude product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (3- (1- (3-methoxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane at-78deg.C][1,3,2]To tert-butyl dioxaborolan-2-yl) 6-fluoro-2-methoxybenzoate (0.92 g,0.9 mmol) was added 1N boron tribromide in methylene chloride (13.5 mL,13.5mmol,15 eq.) and warmed at room temperature for 18h. The reaction was quenched with water, concentrated and purified by reverse phase HPLC (5-80% ACN-H 2 O+0.1% trifluoroacetic acid) and collecting the title compound ESI M/z 758 (M+H) at the first and second elution peaks + 。
Example 431: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-fluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 776 (M+H) + 。
Example 432: synthesis of (R) -3- ((S) -2- (3- (1- (2-chloro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (3- (1- (2-chloro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-chloro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 792 (M+H) + 。
Example 433: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-fluoro-5-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 776 (M+H) + 。
Example 434: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-chloro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-chloro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-chloro-5-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 792 (M+H) + 。
Example 435: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 4-fluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 776 (M+H) + 。
Example 436: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-fluoro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-fluoro-5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 3-fluoro-5-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 776 (M+H) + 。
Example 437: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 4-difluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 4-difluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2, 4-difluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 794 (M+H) + 。
Example 438: synthesis of (R) -3- ((R) -2- (3- (1- (2-chloro-4-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-chloro-4-fluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. ESI M/z 810 (M+H) + 。
Example 439: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 6-difluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 6-difluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2, 6-difluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 794 (M+H) + 。
Example 440: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-chloro-6-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-chloro-6-fluoro-3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido-7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2-chloro-6-fluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 810 (M+H) + 。
Example 441: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (2, 4, 5-trifluoro-3-hydroxybenzoyl) piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (2, 4, 5-trifluoro-3-hydroxybenzoyl) piperidin-4-yl) imidazolidine-1-carboxamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2,4, 5-trifluoro-3-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 812 (M+H) + 。
Example 442: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 3, 5-dimethoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 774 (M+H) + 。
Example 443: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-fluoro-3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-fluoro-3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 4-fluoro-3, 5-dimethoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 792 (M+H) + 。
Example 444: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 4-difluoro-3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2, 4-difluoro-3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 2, 4-difluoro-3, 5-dimethoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 810 (M+H) +
Example 445: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
i) To 3-methoxyaniline (0.16 g,1.3 mmol) in THF (20 mL) was added triethylamine 0.56mL (3.9 mmol,3 eq.) followed by triphosgene (0.154 g,0.52mmol,0.4 eq.) in THF (5 mL) and warmed to room temperature for 1h. It was used in the next step without further purification.
3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2, 3-dioxo-4- (piperidin-4-yl) piperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) in dichloromethane (8 mL) at 0deg.C][1,3,2]To t-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate (0.92 g,1 mmol) was added triethylamine (0.43 mL,3mmol,3 eq.) followed by the above solution and the reaction mixture was stirred at room temperature for 18h. The product was quenched with water, washed with brine, dried over sodium sulfate, and concentrated to give 0.851g, 80% of the product 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (1- ((3-methoxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z1065 (M+H) + 。
ii) at-78deg.C to dichloromethaneThe crude 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (4- (1- ((3-methoxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) of the alkane][1,3,2]To 0.851g (0.8 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N boron tribromide in methylene chloride (12 mL,12mmol,15 eq.) and the temperature was raised at room temperature for 18h. The reaction was quenched with water, concentrated and purified by reverse phase HPLC (5-80% ACN-H 2 O+0.1% trifluoroacetic acid) and collecting the title compound. ESI M/z 773 (M+H) + 。
Example 446: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2-fluoro-3-methoxyaniline instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 791 (M+H) + 。
Example 447: synthesis of (R) -3- ((R) -2- (3- (1- ((2-chloro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2-chloro-3-methoxyaniline instead of 3-methoxyaniline. ESI M/z 807 (M+H) + 。
Example 448: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-chloro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-chloro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2-chloro-5-methoxyaniline instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 807 (M+H) + 。
Example 449: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((4-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((4-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 4-fluoro-3-methoxyaniline instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 791 (M+H) + 。
Example 450: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((3-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((3-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 3-fluoro-5-methoxyaniline instead of 3-Methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 791 (M+H) + 。
Example 451: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2-fluoro-5-methoxyaniline instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 791 (M+H) + 。
Example 452: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2, 4-difluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2, 4-difluoro-3-methoxyaniline instead of 3-methoxyaniline. ESI M/z 809 (M+H) + 。
Example 454: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2, 6-difluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2, 6-difluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 445 using 2, 6-diFluoro-3-methoxyaniline replaces 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 809 (M+H) + 。
Example 455: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-chloro-6-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((2-chloro-6-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido-7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 2-chloro-6-fluoro-3-methoxyaniline instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first and second elution peaks. ESI M/z 825 (M+H) + 。
Example 456: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((3, 5-dihydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 3, 5-dimethoxyaniline instead of 3-methoxyaniline. ESI M/z 789 (M+H) + 。
Examples 459-a and 459-B: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- ((2, 4, 5-trifluoro-3-hydroxyphenyl) carbamoyl) piperidine-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid and (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- ((2, 4, 5-trifluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) imidazolidine-1-carboxamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Preparation of the title compoundIn a similar manner to the synthesis of example 445, 2,4, 5-trifluoro-3-methoxyaniline was used instead of 3-methoxyaniline. After reverse phase HPLC purification, the title compound was collected at the first eluting peak (a) and the second eluting peak (B). ESI M/z 827 (M+H) + 。
Example 460: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1-nicotinoylpiperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid.
In analogy to the synthesis of the intermediate of step 2, example 293, the tert-butyl 4- (2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylate was replaced with tert-butyl 4- (2, 3-dioxoimidazolidin-1-yl) piperidine-1-carboxylate in step 1 and the title compound was prepared as HCl salt which was used directly in the next step without further purification. ESI-MS M/z 832/834 (M+H) + /(M+H+2) + 。
Step 2. Synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1-nicotinoylpiperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Following the same reaction conditions as described in example 293, step 3, the above intermediate was converted to the title compound using nicotinamide instead of 3-methoxybenzoyl chloride and the title compound was purified by reverse phase HPLC.ESI-MS m/z 743/745(M+H) + /(M+H+2) + 。
Example 461: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1-isonicotinylpiperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 460, using isonicotinic acid chloride instead of nicotinoyl chloride in step 2 after reverse phase HPLC purification. ESI-MS M/z 822/824 (M+H) + /(M+H+2) + 。
Example 462: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 430 using 4-methoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3. After purification by reverse phase HPLC, the title compound was collected at the first elution peak. ESI M/z 758 (M+H) + 。
Example 463: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 462. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI M/z 758 (M+H) + 。
Example 464: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (5-hydroxynicotinoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In a similar manner to the synthesis of example 460, 5- (benzyloxy) nicotinoyl chloride (which was prepared by treating 5- (benzyloxy) nicotinic acid with excess oxalyl chloride in DCM at room temperature) was used in step 2 to replace the smokeThe title compound was prepared after purification by reverse phase HPLC. ESI-MS M/z 759/761 (M+H) + /(M+H+2) + 。
Example 465: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (2-oxo-1, 2-dihydropyridine-4-carbonyl) piperidine-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared after purification by reverse phase HPLC in analogy to the synthesis of example 460 using 2- (benzyloxy) isonicotinic acid chloride (which was prepared by treating 2- (benzyloxy) isonicotinic acid with excess oxalyl chloride in DCM at room temperature) instead of nicotinyl chloride in step 2. ESI-MS M/z 759/761 (M+H) + /(M+H+2) + 。
Example 466: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2-fluoroisonicotinamido) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-fluoroisonicotinic acid chloride instead of 3-fluoroisonicotinic acid chloride in step 8. ESI-MS M/z 763 (M+H) + 。
Example 467: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 445 using 4-methoxyaniline instead of 3-methoxyaniline. After purification by reverse phase HPLC, the title compound was collected at the first elution peak. ESI M/z 773 (M+H) + 。
Example 468: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((4-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
PreparationThe title compound was synthesized in a similar manner to example 467. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI M/z 773 (M+H) + 。
Example 469: synthesis of (3R) -3- (2- (3- (1- (1H-benzo [ d ] [1,2,3] triazole-5-carbonyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In a similar manner to the synthesis of example 460, 1H-benzo [ d ] is used in step 2][1,2,3]Triazole-5-carbonyl chloride was substituted for nicotinyl chloride and the title compound was prepared after purification by reverse phase HPLC. ESI-MS M/z 783/785 (M+H) + /(M+H+2) + 。
Example 470: synthesis of (R) -3- ((S) -2- (4- (3- (2-chloro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2-chloro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. After purification by reverse phase HPLC, the title compound was collected at the first elution peak. ESI-MS M/z 794 (M+H) + 。
Example 471: synthesis of (R) -3- ((R) -2- (4- (3- (2-chloro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 470. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 794 (M+H) + 。
Example 472: synthesis of (R) -3- ((S) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 5-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 400 using 2, 5-difluoro-4-methoxybenzoyl chloride instead of 3-fluoroisonicotinic acid chloride in step 8. After purification by reverse phase HPLC, the title compound was collected at the first elution peak. ESI-MS M/z 796 (M+H) + 。
Example 473: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (3- (2, 5-difluoro-4-hydroxybenzoylamino) propyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 472. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 796 (M+H) + 。
Example 474: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (2- (3-hydroxyphenyl) acetyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 2- (3-methoxyphenyl) acetyl chloride instead of 3-methoxybenzoyl chloride in step 3 after purification by reverse phase HPLC. ESI-MS M/z 800/802 (M+H) + /(M+H+2) + 。
Example 475: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- ((1- (3-hydroxybenzoyl) piperidin-4-yl) methyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 293, using 4- ((2, 3-dioxopiperazin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester instead of 4- (2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylic acid tert-butyl ester in step 1 after reverse phase HPLC purification. ESI-MS M/z 800/802 (M+H) + /(M+H+2) + 。
Example 476: (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- (2, 4-dihydroxybenzoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in analogy to the synthesis of example 293, using 2, 4-dimethoxybenzoyl chloride instead of 3-methoxybenzoyl chloride in step 3 after purification by reverse phase HPLC. ESI-MS M/z 802/804 (M+H) + /(MH+2) + 。
Example 477: (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- ((1- ((3-hydroxyphenyl) carbamoyl) piperidin-4-yl) methyl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in analogy to the synthesis of example 424, using 4- ((2, 3-dioxopiperazin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester instead of 4- (2, 3-dioxopiperazin-1-yl) piperidine-1-carboxylic acid tert-butyl ester in step 1 after reverse phase HPLC purification. ESI-MS M/z 815/817 (M+H) + /(MH+2) + 。
Example 478: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((2-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2-fluoro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 819 (M+H) + 。
Example 479: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((2-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2-fluoro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 819 (M+H) + 。
Example 480: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((4-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 4-fluoro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 819 (M+H) + 。
Example 481: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 3-fluoro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 819 (M+H) + 。
Example 482: synthesis of (R) -3- ((R) -2- (4- (1- ((2-chloro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2-chloro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 835 (M+H) + 。
Example 483: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((2-chloro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2-chloro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 835 (M+H) + 。
Example 484: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3-chloro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 3-chloro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 835 (M+H) + 。
Example 485: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3-hydroxybenzyl) sulfonyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in analogy to the synthesis of example 293, using (3-methoxyphenyl) methanesulfonyl chloride instead of 3-methoxybenzoyl chloride in step 3 after purification by reverse phase HPLC. ESI-MS M/z 836/838 (M+H) + /(M+H+2) + 。
Example 486: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((2, 4-difluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2, 4-difluoro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 837 (M+H) + 。
Example 487: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((2, 6-difluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2, 6-difluoro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 837 (M+H) + 。
Example 488: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (4- (1- ((3, 4-difluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 3, 4-difluoro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 837 (M+H) + 。
Example 489: synthesis of (3R) -3- (2- (4- (1- ((4-chloro-2-fluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 4-methoxy aniline with 4-chloro-2-fluoro-3-methoxy aniline in step 3. ESI M/z 853 (M+H) + 。
Example 490: synthesis of (3R) -3- (2- (4- (1- ((2-chloro-4-fluoro-5-hydroxyphenyl) carbamoyl) piperidin-4-yl) -2, 3-dioxopiperazine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2-chloro-4-fluoro-5-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 853 (M+H) + 。
Example 491: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2, 3-dioxo-4- (1- ((2, 4, 5-trifluoro-3-hydroxyphenyl) carbamoyl) piperidin-4-yl) piperazine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 426 substituting 2,4, 5-trifluoro-3-methoxyaniline for 4-methoxyaniline in step 3. ESI M/z 855 (M+H) + 。
Example 492: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (pyridin-3-ylmethyl) piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Following the same reaction conditions described in step 15 and step 16 of example 200, thiazole-2-carbaldehyde was replaced with 3-pyridinecarbaldehyde, which was purified by reverse phase HPLC from the intermediate of step 1 of example 460 to the title compound. ESI-MS M/z729/731 (M+H) + /(M+H+2) + 。
Example 493: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (pyridin-4-ylmethyl) piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 492, using 4-pyridinecarboxaldehyde instead of 3-pyridinecarboxaldehyde after reverse phase HPLC purification. ESI-MS M/z729/731 (M+H) + /(M+H+2) + 。
Example 494: synthesis of (R) -3- ((R) -2- (3- (1- (2-chloro-3, 4-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine 20.2g,156mmol,3 eq.) Pd (PPh 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) followed by anhydrous toluene (400 mL) and stirring the mixture at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 To methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2. Synthesis of tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate.
Step 2a.
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (40 g,200 mmol) and tert-butyl (2-aminoethyl) carbamate (32 g,200 mmol) in DME (600 mL) was added Na (OAc) in portions at room temperature 3 BH (127.2 g,600 mmol). The reaction mixture was stirred at room temperature overnight. By NaHCO 3 And brine wash. The organic phase was evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel (0-10% MeOH/DCM) to give the desired intermediate (61.8 g, 90%).
Step 2b.
The intermediate (61.8 g,180 mmol) was dissolved in THF (1200 mL) and tert-BuOK (72.8 g, 650) was added. The mixture was stirred at 55 ℃ overnight. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (0-10% MeOH/DCM) to give the desired intermediate (45.7 g, 94%).
Step 2c.
A solution of tert-butyl 4- (2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (45.7 g,169 mmol) in DCM (200 mL)/THF (200 mL) was cooled to-40 ℃. TEA (25.4 mL,203mmol,1.2 eq.) was added. The mixture was warmed to 0 ℃ for 1h. Triphosgene (20 g,67.6mmol,0.4 eq.) in THF (200 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil. Addition of Et 2 O (1000 mL) and the product was triturated overnight at room temperature and filtered. The resulting solid was treated with Et 2 O (200 mL) was washed and dried in vacuo to afford the title compound (44.8 g, 80%).
Step 3 Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- (1- (2-chloro-3, 4-dimethoxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetic acid
Step 3a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid (2.1 g,4 mmol) in DCM (16.0 mL) was added TFA (4.0 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3b.
The crude product was dissolved in THF (40.0 mL)/NaHCO 3 (saturated aqueous solution, 40.0 mL) followed by tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (1.46 g,4.4mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (50 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (200 mL) was added and the organic layer was taken up with H 2 O (2X 50 mL) and brine (1X 50 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (1.4 g, 56% over 2 steps). ESI-MS M/z 721 (M+H) + 。
Step 3c.
To a solution of tert-butyl 4- (3- ((1- (4- (bis (benzyloxy) phosphoryl) phenyl) -2-methoxy-2-oxoethyl) carbamoyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (1.4 g,1.94 mmol) in DCM (16.0 mL) was added TFA (4.0 mL) at 0 ℃. The solution was warmed to room temperature for 2h and then concentrated.
And 3d, performing step 3d.
The crude product was dissolved in THF (40.0 mL)/NaHCO 3 (saturated aqueous solution, 40.0 mL) followed by 2-chloro-3, 4-dimethoxybenzoyl chloride (0.5 g,2.1mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (50 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (200 mL) was added and the organic layer was taken up with H 2 O (2X 50 mL) and brine (1X 50 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (660 mg, 45% over 2 steps). ESI-MS M/z 820 (M+H) + 。
And 3e, step 3.
To THF (10 mL)/H 2 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- (1- (2-chloro-3, 4-dimethoxybenzoyl) piperidine) in O (10 mL)To methyl-4-yl) -2-oxoimidazolidine-1-carboxamido) acetate (660 mg,0.8 mmol) was added lithium hydroxide monohydrate (23 mg,0.96mmol,1.2 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound (400 mg, 61%) as a white solid. ESI-MS M/z 806 (M+H) + 。
Step 4. Synthesis of (R) -3- ((R) -2- (3- (1- (2-chloro-3, 4-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 4a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (5.2 g,11 mmol) (example 200 step 7) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (5.8 g, 99%).
Step 4b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride(198mg, 0.340 mmol), (3R) -3- (2- (3- (1- (2-chloro-3, 4-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]To a solution of oxaborole-8-carboxylic acid (400 mg,0.50mmol,1.5 eq.) and HATU (226 mg,0.595mmol,1.75 eq.) in DMA (3.4 mL) was added NMM (0.11 mL,1.02mmol,3.0 eq.). The reaction was stirred at room temperature for 30min and diluted with EtOAc (30 mL). The mixture was treated with H 2 O (2X 10 mL) and brine (xx mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- (1- (2-chloro-3, 4-dimethoxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (330 mg, 53%) ESI M/z 1234 (M+H) + 。
Step 4c.
To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- (1- (2-chloro-3, 4-dimethoxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78 DEG C][1,3,2]To a solution of tert-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate (330 mg,0.26 mmol) in DCM (2.2 mL) was added BBr 3 (1M, 2.2mL,2.2mmol,10 eq.) in DCM. The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (3- (1- (2-chloro-3, 4-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e][1,2]Oxaborole-8-carboxylic acid (33.7 mg). ESI M/z 804 (M+H) + 。
Example 495: synthesis of (R) -3- ((R) -2- (3- (1- (2-chloro-5-fluoro-3, 4-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 494 using 2-chloro-5-fluoro-3, 4-dimethoxybenzoyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC in step 4, the title compound was collected at the second elution peak. ESI-MS M/z 822 (M+H) + 。
Example 496: synthesis of (R) -3- ((R) -2- (3- (1- (3-chloro-4, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 494 using 3-chloro-4, 5-dimethoxybenzoyl chloride instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC in step 4, the title compound ESI-MS M/z 804 (M+H) was collected + 。
Example 497: synthesis of (R) -3- ((R) -2- (3- (1- ((2-chloro-3, 4-dihydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 494 using 2-chloro-1-isocyanato-3, 4-dimethoxybenzene instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC in step 4, the title compound was collected at the second elution peak. ESI-MS M/z 819 (M+H) + 。
Example 498: synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (pyrazolo [1,5-a ] pyridine-6-carboxamide) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh) 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) followed by anhydrous toluene (400 mL) and stirring the mixture at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate/hexanes) to give the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 To methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The crude product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g,60％)。ESI-MS m/z 512(M+H) + 。
step 2. Synthesis of (3R) -3- (2-amino-2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 2a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (4.9 g,11 mmol) (example 200 step 7) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester hydrochloride (5.5 g, 99%).
Step 2b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To a solution of t-butyl dioxaborolan-2-yl) ethyl) -2-methoxybenzoate hydrochloride (1.7 g,3.40 mmol), 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((t-butoxycarbonyl) amino) acetic acid (3 g,5.09mmol,1.5 eq.) and HATU (2.26 g,5.95mmol,1.75 eq.) in DMA (34 mL) was added NMM (1.1 mL,10.2mmol,3.0 eq.). The reaction was stirred at room temperature for 30min. And diluted with EtOAc (300 mL). The mixture was treated with H 2 O (2X 100 mL) and brine (300 mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl group)Phenyl) -2- ((tert-Butoxycarbonyl) amino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester (2 g, 64%) ESI M/z 923 (M+H) + 。
Step 2c.
To a solution of tert-butyl 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -2-methoxybenzoate (2 g,2.16 mmol) in DCM (16.0 mL) was added TFA (4.0 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3 Synthesis of (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (pyrazolo [1,5-a ] pyridine-6-carboxamide) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 3a.
To 3- ((2R) -2- (2-amino-2- (4- (bis (benzyloxy) phosphoryl) phenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester (340 mg,0.34 mmol), pyrazolo [1,5-a]To a solution of pyridine-6-carboxylic acid (284 mg,0.509mmol,1.5 eq.) and HATU (226 mg,0.595mmol,1.75 eq.) in DMA (3.4 mL) was added NMM (1.1 mL,1.02mmol,3.0 eq.). The reaction was stirred at room temperature for 30min and diluted with EtOAc (30 mL). The mixture was treated with H 2 O (2X 10 mL) and brine (30 mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (pyrazolo [1, 5-a)]Pyridine-6-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester An ester. (197mg, 60%) ESI M/z 967 (M+H) + 。
Step 3b.
To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (pyrazolo [1, 5-a) at-78 DEG C]Pyridine-6-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]To a solution of tert-butyl dioxaborolan-2-yl) ethyl-2-methoxybenzoate (197mg, 0.2 mmol) in DCM (2 mL) was added BBr 3 (1M, 2mL,2.2mmol,10 eq.) in DCM. The reaction was warmed to room temperature overnight and then concentrated. The crude product obtained was purified by reverse phase HPLC to give (3R) -2-hydroxy-3- (2- (4-phosphonophenyl) -2- (pyrazolo [1, 5-a)]Pyridine-6-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e][1,2]Oxaborole-8-carboxylic acid (14.9 mg). ESI M/z565 (M+H) + 。
Example 499: synthesis of (R) -2-hydroxy-3- ((R) -2- (4-phosphonophenyl) -2- (pyrrolo [1,2-a ] pyrimidine-3-carboxamido) acetamido) -3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 498 using pyrrolo [1,2-a ] in step 3]Pyrimidine-3-carboxylic acid substituted pyrazolo [1,5-a ]]Pyridine-6-carboxylic acid. After purification by reverse phase HPLC in step 4, the title compound was collected at the second elution peak. ESI-MS M/z565 (M+H) +
Example 500: synthesis of (R) -3- ((R) -2- (3- (1- ((3-chloro-4, 5-dihydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 494 using 2-chloro-5-fluoro-1-isocyanato-3, 4-dimethoxybenzene instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC in step 4, the title compound was collected at the second elution peak. ESI-MS M/z 837 (M+H) + 。
Example 501: synthesis of (R) -3- ((R) -2- (3- (1- ((3-chloro-4, 5-dihydroxyphenyl) carbamoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 494 using 3-chloro-1-isocyanato-4, 5-dimethoxybenzene instead of 2-chloro-3, 4-dimethoxybenzoyl chloride in step 3. After purification by reverse phase HPLC in step 4, the title compound was collected at the second elution peak. ESI-MS M/z 819 (M+H) + 。
Example 502: synthesis of (R) -3- ((R) -2- (4- (2-chloro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (3, 5-difluoro-4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was synthesized in a similar manner to example 8 using 3, 5-difluoro-4-iodobenzaldehyde instead of 4-iodobenzaldehyde (example 8, step 1). ESI M/z 770 (M+H) + 。
Example 503: synthesis of (R) -3- ((R) -2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2- (2-chloro-3, 4-dimethoxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid.
Step 1a.
This reaction was carried out in a manner analogous to example 8, step 3a.
Step 1b.
This reaction was carried out in a similar manner to example 8, step 3b, substituting tert-butyl (2- (4- (chlorocarbonyl) -2, 3-dioxopiperazin-1-yl) ethyl) carbamate for 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride. The product was purified by silica gel chromatography (0-5% meoh/DCM) to give the desired intermediate (2.73 g, 79% over 2 steps).
Step 1c.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2- ((tert-butoxycarbonyl) amino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid (1.14 g,1.64 mmol) in DCM (6.6 mL) was added TFA (1.64 mL) at 0deg.C. The solution was warmed to room temperature for 1h and then concentrated.
Step 1d.
The crude product was dissolved in DCM (16 mL). Triethylamine (1.1 mL,8.2mmol,5.0 eq.) was added followed by 2-chloro-3, 4-dimethoxybenzoyl chloride (424 mg,1.80mmol,1.1 eq.). The mixture was stirred for 1h, then NaHSO was used 4 (1.0M, 10.0 mL) quenching. The layers were separated and the aqueous layer was extracted with DCM (3X 20 mL). Drying (Na) 2 SO 4 ) The combined organic layers were filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% meoh/DCM) to give the title compound (1.01 g, 78% over 2 steps).
Step 2 Synthesis of (3R) -3- (2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
The title compound was prepared in a similar manner to the synthesis of example 8 step 4 using (3R) -3- (2- (4- (2- (2-chloro-3, 4-dihydroxybenzoylamino) ethyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ]][1,2]Oxaborole-8-carboxylic acid replaces 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) acetic acid. The desired compound was isolated by reverse phase HPLC. ESI-MS M/z 792 (M+H) + 。
Example 504: synthesis of (R) -3- ((R) -2- (4- (2-chloro-5-fluoro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
Step 1a.
A solution of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde (8.00 g,47.0 mmol) in toluene (170 mL) was cooled to 0deg.C. Adding (i-Bu) 2 NH (4.00 mL,49.4mmol,1.05 eq.) followed by slow addition of SO 2 Cl 2 (0.82 mL,4.70mmol,0.1 eq.). The mixture was heated to 70 ℃ overnight, then cooled to room temperature and quenched with H 2 O (50 mL) quench. The layers were separated and the aqueous layer was extracted with EtOAc (3X 50 mL). Drying (Na) 2 SO 4 ) The combined organic layers were filtered and concentrated.
Step 1b.
The crude product was dissolved in DMF (120 mL) and Cs was added 2 CO 3 (38.3 g,117mmol,2.5 eq.) followed by MeI (8.8 mL,140mmol,3.0 eq.) was added. The mixture was stirred at room temperature for 1H, diluted with EtOAc (300 mL) and with H 2 O (150 mL) quench. The layers were separated and the aqueous layer was extracted with EtOAc (3X 150 mL). The combined organic layers were treated with H 2 O (3X 75 mL) and brine (75 mL), and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc/hexanes). ESI M/z 219 (M+H) + 。
Step 2. Synthesis of (3R) -3- (2- (4- (2-chloro-5-fluoro-3, 4-dihydroxybenzyl) -2, 3-dioxopiperazine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was synthesized in a similar manner to example 8 using 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde instead of 2-chloro-3, 4-dimethoxybenzaldehyde (example 8 step 2), using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester(example 8, step 4), ESI M/z 735 (M+H) + 。
Example 505: synthesis of (3R) -3- (2- (3- ((2-chloro-3, 4-dihydroxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid.
Step 1a.
To 4-iodobenzaldehyde (46.2 g,200 mmol) was added 7N ammonia in methanol (600 mL) at 0deg.C followed by trimethylcyanosilane (29.8 g,300mmol,1.5 eq.). The mixture was stirred at 45 ℃ for 24h and concentrated in vacuo.
Step 1b.
The crude product was dissolved in 3N hydrochloric acid in methanol (400 mL), stirred at 50 ℃ for 36h and concentrated in vacuo.
Step 1c.
To the crude product in DCM (400 mL) was added triethylamine (30.3 g,300mmol,3 eq.) followed by di-tert-butyl dicarbonate (65.4 g,300mmol,1.5 eq.) at 0deg.C. The reaction was warmed to room temperature for 12h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give the desired intermediate (51 g, 66% over 3 steps).
Step 1d.
To methyl 2- ((tert-butoxycarbonyl) amino) -2- (4-iodophenyl) acetate (20 g,52 mmol) was added N, N-diisopropylethylamine (20.2 g,156mmol,3 eq.) Pd (PPh 3 ) 4 (11.8 g,10.2mmol,20 mol%), dibenzyl phosphite (26.7 g,102mmol,2 eq.) followed by anhydrous toluene (400 mL) and stirring the mixture at room temperature under argon for 5-7h. The reaction was diluted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, and concentrated. The product was purified by flash chromatography on silica gel (35-50% ethyl acetate Ethyl acetate/hexanes) to afford the desired intermediate (27 g, 99%).
Step 1e.
To THF (100 mL)/H 2 To methyl 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetate (27 g,51.4 mmol) in O (100 mL) was added lithium hydroxide monohydrate (6.48 g,154mmol,3 eq.) and the mixture was stirred at room temperature for 1h. 2N hydrochloric acid was added dropwise to obtain pH 2 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 20g of crude product. The product was purified by flash chromatography on silica gel (10-20% MeOH/DCM) to give the title compound as a white solid (15.8 g, 60%). ESI-MS M/z 512 (M+H) + 。
Step 2 Synthesis of 3- ((2-chloro-3, 4-dimethoxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carbonyl chloride
Step 2a.
To a solution of tert-butyl (2-aminoethyl) carbamate (3.9 mL,24mmol,1.1 eq.) in DCM (200 mL) was added 2-chloro-3, 4-dimethoxy-cyclohexane-2, 4-diene-1-sulfonyl chloride (6.1 g,22 mmol) and TEA (6 mL,44.0mmol,2 eq.) in sequence. The solution was stirred at room temperature for 2h. The mixture was concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired intermediate (8.1 g, 92%)
Step 2b.
To the crude product in THF (30 mL) was added HCl (4 m in dioxane, 30 mL) at 0 ℃. The reaction was warmed to room temperature and stirred for 2h, then concentrated in vacuo.
Step 2c.
The crude product was dissolved in THF (400 mL) and TEA (6.3 mL,45 mmol) and CDI (3.6 g,22mmol,1.1 eq.) were added sequentially. The mixture was heated to 60 ℃ overnight and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired intermediate (5.1 g, 87.5% over 3 steps).
Step 2d.
A solution of 1- ((2-chloro-3, 4-dimethoxyphenyl) sulfonyl) imidazolidin-2-one (3.5 g,10.9 mmol) and TEA (6 mL,44mmol,4 eq.) in THF (150 mL) was cooled to 0deg.C. Triphosgene (1.3 g,4.36mmol,0.4 eq.) in THF (40 mL) was added and warmed to room temperature for 1h. The heterogeneous mixture was filtered through celite and concentrated in vacuo to provide a viscous brown oil.
Step 3. Synthesis of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2-chloro-3, 4-dimethoxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid.
Step 3a.
To a solution of 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- ((tert-butoxycarbonyl) amino) acetic acid (3 g,5.86 mmol) in DCM (30.0 mL) was added TFA (7.5 mL) at 0deg.C. The solution was warmed to room temperature for 2h and then concentrated.
Step 3b.
The crude product was dissolved in THF (40 mL)/NaHCO 3 (saturated aqueous solution, 40 mL) followed by 4- (2-chloro-3, 4-dimethoxybenzyl) -2, 3-dioxopiperazine-1-carbonyl chloride (2.47 g,6.45mmol,1.1 eq.) was added. The reaction was stirred at room temperature for 2h. Will react with H 2 O (5 mL) was washed and acidified to pH 2 with HCl (2M). Ethyl acetate (200 mL) was added and the organic layer was taken up with H 2 O (2X 50 mL) and brine (1X 50 mL), and dried (Na 2 SO 4 ) And concentrated. The crude product was purified by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (2.8 g, 62% over 2 steps). ESI-MS M/z 758 (M+H) + 。
Step 4 Synthesis of (3R) -3- (2- (3- ((2-chloro-3, 4-dihydroxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid
Step 4a.
A solution of 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (5.2 g,11 mmol) (example 200 step 7) in THF (45 mL) was cooled to-78 ℃. LiHMDS (1M in THF, 11mL,11mmol,1.0 eq.) was added dropwise and the mixture warmed to room temperature for 1h. The solution was cooled to 0deg.C and HCl (4M in dioxane, 11mL,44mmol,4.0 eq.) was added dropwise. The reaction was warmed to room temperature for 1h and then concentrated. Hexane (200 mL) was added and stirred at room temperature overnight. The solid was filtered, washed with hexane (2X 100 mL) and dried to give the desired intermediate 3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester hydrochloride (5.8 g, 99%).
Step 4b.
3- ((R) -2-amino-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]To a solution of t-butyl dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate hydrochloride (2.15 g,3.7 mmol), 2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2-chloro-3, 4-dimethoxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetic acid (2.8 g,3.7mmol,1 eq.) and HATU (2.46 g,6.5mmol,1.75 eq.) in DMA (37 mL) was added NMM (1.2 mL,11.1mmol,3.0 eq.). The reaction was stirred at room temperature for 30min. And diluted with EtOAc (120 mL). The mixture was treated with H 2 O (2X 100 mL) and brine, and dried (Na 2 SO 4 ) Filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to give the desired 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2-chloro-3, 4-dimethoxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester (1.8 g, 41%) ESI M/z 1187 (M+H) + 。
Step 4c.
To 3- ((2R) -2- (2- (4- (bis (benzyloxy) phosphoryl) phenyl) -2- (3- ((2-chloro-3, 4-dimethoxyphenyl) sulphonyl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78 DEG C ][1,3,2]To a solution of tert-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate (1.8 g,1.5 mmol) in DCM (15 mL) was added BBr 3 (1M in DCM, 15mL,2.2mmol,10 eq.). The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (3- ((2-chloro-3, 4-dihydroxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e][1,2]Oxaborole-8-carboxylic acid (150 mg). ESI M/z 757 (M+H) + 。
Example 506: synthesis of (R) -3- ((R) -2- (3- ((2-chloro-3, 4-dihydroxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 505, diastereoisomeric separation was carried out by reverse phase HPLC purification. ESI-MS M/z 757 (M+H) + 。
Example 509: synthesis of (R) -3- ((R) -2- (3- ((2-chloro-3, 4-dihydroxyphenyl) sulfonyl) -2-oxoimidazolidine-1-carboxamido) -2- (4-phosphonophenyl) acetamido) -2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 505 using 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] in step 4a][1,3,2]Dioxaborolin-2-yl) ethyl) -2-methoxybenzoic acid tert-butyl ester replacement 3- ((S) -2-chloro-2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborol-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester was purified by reverse phase HPLC purification. ESI-MS M/z 738 (M+H) + 。
Example 600: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((3, 5-dihydroxyphenyl) sulfonyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 460, using 3, 5-dimethoxybenzenesulfonyl chloride instead of nicotinoyl chloride in step 2 after purification by reverse phase HPLC. ESI-MS M/z 810/812 (M+H) + /(M+H+2) + 。
Example 601: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (pyridazin-4-ylmethyl) piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 492 using pyridazine-4-carbaldehyde instead of 3-pyridinecarbaldehyde after reverse phase HPLC purification. ESI-MS M/z 730/732 (M+H) + /(M+H+2) + 。
Example 602: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (2-oxo-3- (1- (pyrimidin-4-ylmethyl) piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 492 using pyrimidine-4-carbaldehyde instead of 3-pyridinecarbaldehyde after reverse phase HPLC purification. ESI-MS M/z 730/732 (M+H) + /(M+H+2) + 。
Example 603: synthesis of (R) -3- ((R) -2- (3- (1- (3- (aminomethyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 1, synthesizing 3-fluoro-4, 5-dihydroxybenzaldehyde.
BBr is added to 50g (294 mmol) of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde in DCM (500 mL) at-80 ℃ 3 55mL (588 mmol,2 eq.) of solution in DCM (250 mL). The reaction mixture was stirred at room temperature for 6h. The reaction was quenched with MeOH at-30 ℃ and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% MeOH/DCM) to give 40g, 87.3% of the desired product. ESI-MS M/z 157 (M+H) + 。
And 2, synthesizing 3-fluoro-5-hydroxy-4-methoxybenzaldehyde.
Li was added to 40g (256 mmol) of 3-fluoro-4, 5-dihydroxybenzaldehyde in DMF (400 mL) at 0deg.C 2 CO 3 28g (384 mmol,1.5 eq.) followed by MeI40g (284 mmol,1.1 eq.) was added. The reaction mixture was stirred at 40℃for 12h. The reaction was diluted with EA, washed with NaCl (aqueous solution) and with Na 2 SO 4 Dried and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% EA/PE) to give 25g, 57.5% of the desired product. ESI-MS M/z 171 (M+H) + 。
Step 3: synthesizing 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde.
To a solution of 25g (147 mmol) of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde in toluene was added 2.1mL (13 mmol,0.09 eq.) of diisobutylamine. The mixture was heated to 70 ℃ in an oil bath and 14mL (169 mmol,1.15 eq.) of sulfuryl chloride was added at 70 ℃. The reaction mixture was stirred at 70℃for 2h. The resulting mixture was concentrated in vacuo, diluted with water, extracted with EA and taken up in Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 26g, 86.6% of the desired product. ESI-MS M/z 205 (M+H) + 。
Step 4: synthesizing 2-chloro-5-fluoro-3, 4-dimethoxy benzaldehyde.
Cs is added to a solution of 26g (127 mmol) of 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde in DMF at 0 ℃ 2 CO 3 62g (191 mmol,1.5 eq.) followed by MeI 21.6g (152 mmol,1.2 eq.) were added. The mixture was stirred at room temperature for 5h. The reaction mixture was diluted with EA, washed with water, and washed with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EA/PE) to give 25g, 90.5% of the desired product. ESI-MS M/z 219 (M+H) + 。
Step 5: synthesis of 2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid.
To 25g (115 mmol) of 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde at 0deg.C was added 7N ammonia in methanol (550 mL) followed by 21.5mL (172.5 mmol,1.5 eq.) of trimethylcyanosilane, stirred at 45deg.C for 7h and concentrated in vacuo. The crude product was dissolved in 3N hydrochloric acid in methanol (450 mL), stirred at 50 ℃ for 18h and concentrated in vacuo to give HCl salt. The reaction was slurried in tetrahydrofuran (500 mL) and cooled at 0deg.C. Triethylamine 48mL (345 mmol,3 eq.) was added followed by di-tert-butyl dicarbonate 37.5g (172.5 mmol,1.5 eq.) at room temperature for 1h and concentrated in vacuo. The product was purified by flash chromatography on silica gel (20-30% ethyl acetate/hexanes) to give 30g of the desired product. 30g (79.5 mmol) of methyl 2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetate was dissolved in tetrahydrofuran (260 mL)/H 2 O (260 mL) was then dissolved in 5g of lithium hydroxide monohydrate (119 mmol,1.5 eq.) and stirred at room temperature for 2h and concentrated. The product was evaporated in vacuo, usingHCl (1M) was adjusted to ph=3, extracted with EA, extracted with Na 2 SO 4 Dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel (40% EA/PE) to give 24g, 83.3% of the desired product. ESI-MS M/z 364 (M+H) + 。
Step 6: synthesis of tert-butyl 3- ((2R) -2- (2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
By following general procedure C, the chloride (prepared as reported previously, WO 2014/089365) was treated with 4M HCl in LiHMDS and dioxane, followed by coupling of 2- ((tert-butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetic acid in the presence of HATU and NMM to give the title compound. ESI-MS M/z 793 (M+H) + 。
Step 7: synthesis of tert-butyl 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoate.
Step 7a.
To 3- ((2R) -2- (2- ((tert-Butoxycarbonyl) amino) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0 DEG C][1,3,2]To 40g (25 mmol) of tert-butyl dioxaborolan-2-yl) -6-fluoro-2-methoxybenzoate was added 1N hydrochloric acid in diethyl ether (400 mL) and the temperature was raised at room temperature for 18h. The reaction was concentrated in vacuo to give 32g, 91.4% 3- ((2R) -2- (2-ammonia)1-2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolin-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl chloride. ESI-MS M/z 693 (M+H) + 。
Step 7b.
The crude product was dissolved in DCM, followed by the addition of tert-butyl 4- (3- (chlorocarbonyl) -2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (1.1 eq) and TEA (3 eq). The reaction was stirred at room temperature for 2h. Will react with H 2 And (3) washing. DCM was added and the organic layer was taken up with H 2 O (2X 50 mL) and brine (1X 50 mL), and dried (Na 2 SO 4 ) And concentrated. ESI-MS M/z 988 (M+H) + 。
Step 7c.
To 4- (3- ((2- (((R) -2- (3- (tert-butoxycarbonyl) -4-fluoro-2-methoxyphenyl) -1- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at 0deg.C ][1,3,2]Dioxaborole-2-yl) ethyl) amino) -1- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2-oxoethyl) carbamoyl) -2-oxoimidazolidin-1-yl piperidine-1-carboxylic acid tert-butyl ester 1N hydrochloric acid in diethyl ether was added and warmed at room temperature for 18h. The reaction was concentrated in vacuo to give 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 888 (M+H) + 。
Step 8: synthesis of (R) -3- ((R) -2- (3- (1- (3- (aminomethyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Step 8a.
3- ((2R) -2- (2-)Chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ]][1,3,2]Dioxaborol-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester was dissolved in DCM and tert-butyl (3- (chlorocarbonyl) benzyl) carbamate (1.1 eq) and TEA (3 eq) were added. The reaction was stirred at room temperature for 2h. Will react with H 2 And (3) washing. DCM was added and the organic layer was taken up with H 2 O (2X 50 mL) and brine (1X 50 mL), and dried (Na 2 SO 4 ) And concentrated to give 3- ((2R) -2- (2- (3- (1- (3- (((tert-butoxycarbonyl) amino) methyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z1121 (M+H) + 。
Step 8b.
To 3- ((2R) -2- (2- (3- (1- (3- (((t-butoxycarbonyl) amino) methyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78deg.C][1,3,2]Adding BBr to a solution of t-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate in DCM 3 (10 equivalents). The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (3- (1- (3- (aminomethyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ][1,2]Oxaborole-8-carboxylic acid. ESI M/z 771 (M+H) + 。
Example 604: synthesis of 3R) -3- (2- (3- (1- (4- (aminomethyl) benzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Preparation of the title compoundIn analogy to the synthesis of example 603, tert-butyl (3- (chlorocarbonyl) benzyl) carbamate was replaced in step 8 by tert-butyl (4- (chlorocarbonyl) benzyl) carbamate. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 771 (M+H) + 。
Example 605: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The procedure is analogous to that of example 603 (steps 1 to 7) except for preparing intermediate 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 as,4s,6s,7 ar) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d ] [1,3,2] dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester.
Step 8a.
To 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (2-oxo-3- (piperidin-4-yl) imidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborol-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester and 3-methoxybenzaldehyde (1.1 eq.) in DCE was then added NaBH (OAc) 3 (3 equivalents). The reaction was stirred at room temperature overnight. Will react with H 2 And (3) washing. DCM was added and taken up in H 2 The organic layer was washed with O and brine, dried (Na 2 SO 4 ) And concentrated to give 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (3- (1- (3-methoxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d)][1,3,2]Dioxaborolan-2-yl) ethyl) -6-fluoro-2-methoxybenzoic acid tert-butyl ester. ESI-MS M/z 1008 (M+H) + 。
Step 8b.
To 3- ((2R) -2- (2- (2-chloro-5-fluoro-3, 4-dimethoxyphenyl) -2- (3- (1- (3-methoxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -2- ((3 aS,4S,6S,7 aR) -3a, 5-trimethylhexahydro-4, 6-methanobenzo [ d) at-78deg.C ][1,3,2]Adding BBr to a solution of t-butyl dioxaborolan-2-yl) ethyl-6-fluoro-2-methoxybenzoate in DCM 3 (10 equivalents). The reaction was warmed to room temperature overnight and then concentrated. The resulting crude product was purified by reverse phase HPLC to give (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e][1,2]Oxaborole-8-carboxylic acid. ESI M/z 744 (M+H) + 。
Example 606: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-fluoro-3-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 4-fluoro-3-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 762 (M+H) + 。
Example 607: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-fluoro-5-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 3-fluoro-5-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 762 (M+H) + 。
Example 608: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-5-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 2-fluoro-5-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 762 (M+H) + 。
Example 609: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (4-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 4-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 744 (M+H) + 。
Example 610: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3-fluoro-4-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 3-fluoro-4-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 762 (M+H) + 。
Example 611: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (2-fluoro-4-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 2-fluoro-4-methoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 762 (M+H) + 。
Example 612: synthesis of (3R) -3- (2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3, 5-dihydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 3, 5-dimethoxybenzaldehyde instead of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 760 (M+H) + 。
Example 613: synthesis of (R) -3- ((R) -2- (3- (1- (3- (aminomethyl) benzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using tert-butyl (3-formylbenzyl) carbamate in place of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 757 (M+H) + 。
Example 614: synthesis of (R) -3- ((R) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) -2- (3- (1- ((5-hydroxypyridin-3-yl) methyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using 5-methoxy nicotinaldehyde instead of 3-methoxy benzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 745 (M+H) + 。
Example 615: synthesis of (R) -3- ((R) -2- (3- (1- (3- (aminomethyl) -5-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a similar manner to the synthesis of example 603 using tert-butyl (3- (chlorocarbonyl) -5-methoxybenzyl) carbamate in step 8Replacement of tert-butyl (3- (chlorocarbonyl) benzyl) carbamate. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 787 (M+H) + 。
Example 616: synthesis of (3R) -3- (2- (3- (1- (4- (aminomethyl) -3-hydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 603 using tert-butyl (4- (chlorocarbonyl) -2-methoxybenzyl) carbamate in place of tert-butyl (3- (chlorocarbonyl) benzyl) carbamate in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 787 (M+H) + 。
Example 617: synthesis of (R) -3- ((R) -2- (3- (1- (3- (aminomethyl) -5-hydroxybenzyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using tert-butyl (3-formyl-5-methoxybenzyl) carbamate in place of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z773 (M+H) + 。
Example 618: synthesis of (R) -3- ((R) -2- (3- (1- ((6-aminopyridin-3-yl) methyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in a manner analogous to the synthesis of example 605 using tert-butyl (5-formylpyridin-2-yl) carbamate in place of 3-methoxybenzaldehyde in step 8. After purification by reverse phase HPLC, the title compound was collected at the second elution peak. ESI-MS M/z 744 (M+H) + 。
Example 619: synthesis of (R) -3- ((R) -2- (3- (1- ((2-aminopyridin-4-yl) methyl) piperidin-4-yl) -2-oxoimidazolidine-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
The title compound was prepared in analogy to the synthesis of example 492, using tert-butyl (4-formylpyridin-2-yl) carbamate instead of 3-pyridinecarbaldehyde after reverse phase HPLC purification. ESI-MS M/z 744/746 (M+H) + /(M+H+2) + 。
Example 620: synthesis of (R) -3- ((S) -2- (3- (1- ((1H-benzo [ d ] [1,2,3] triazol-5-yl) sulfonyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid, and
example 621: synthesis of (R) -3- ((R) -2- (3- (1- ((1H-benzo [ d ] [1,2,3] triazol-5-yl) sulfonyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) -2- (2-chloro-5-fluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In a similar manner to the synthesis of example 460, step 2 utilizes 1H-benzo [ d ]][1,2,3]Triazole-5-sulfonyl chloride was used in place of nicotinoyl chloride to prepare example 620 and example 621 after reverse phase HPLC purification, which were collected at the first and second elution peaks, respectively. ESI-MS M/z819/821 (M+H) + /(MH+2) + 。
Example 622: synthesis of (R) -3- ((R) -2- (3- (1- ((1H-benzo [ d ] [1,2,3] triazol-5-yl) sulfonyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) -2- (2, 5-difluoro-3, 4-dihydroxyphenyl) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
In an analogous manner to the synthesis of example 621, example 622 was prepared after reverse phase HPLC purification using commercially available 2, 5-difluoro-3, 4-dimethoxybenzaldehyde instead of 2-chloro-5-fluoro-3, 4-dimethoxybenzaldehyde for the Strecker reaction to prepare 2- ((tert-butoxycarbonyl) amino) -2- (2, 5-difluoro-3, 4-dimethoxyphenyl) acetic acid. ESI-MS M/z 803/805 (M+H) + /(M+H+2) + 。
Example 623: synthesis of (R) -3- ((R) -2- (2, 5-difluoro-3, 4-dihydroxyphenyl) -2- (3- (1- (3, 5-dihydroxybenzoyl) piperidin-4-yl) -2-oxoimidazolidin-1-carboxamido) acetamido) -7-fluoro-2-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] oxaborole-8-carboxylic acid.
Substitution of 1H-benzo [ d ] with 3, 5-Dimethoxybenzoyl chloride in a similar manner to the Synthesis of example 622][1,2,3]Triazole-5-sulfonyl chloride was purified by reverse phase HPLC to prepare the title compound. ESI-MS M/z 758/760 (M+H) + /(M+H+2) + 。
The compounds of the examples are shown in tables 1-4.
Table 1.
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Table 2. Example compounds can be prepared in analogy to the procedure of examples 1-198.
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Table 3.
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Table 4.
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Example A1: parenteral compositions
To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100mg of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, is dissolved in DMSO and then admixed with 10ml of a 0.9% sterile saline solution. The mixture is incorporated into a dosage unit suitable for administration by injection.
Example A2: oral compositions
To prepare a pharmaceutical composition for oral delivery, 400mg of the disclosed compound was intimately mixed with the following ingredients and compressed into single scored tablets.
Tablet formulation
The following ingredients were intimately mixed and filled into hard shell gelatin capsules.
Capsule preparation
Biological examples
Example I: experimental methods for penicillin binding protein binding assays with Bocilin-FL via fluorescence polarization.
To determine the ability of the boronic acid-based test PBP inhibitors to bind Penicillin Binding Proteins (PBP), bocillin-FL (fluorescently labeled penicillin V; thermoFisher Scientific) was used in a Fluorescence Polarization (FP) competitive binding assay to assess binding of inhibitors to PBP3 from escherichia coli (K-12), PBP3 from pseudomonas aeruginosa (PAO 1), PBP1a and PBP3 from acinetobacter baumannii (ATCC 19606), and PBP2 from neisseria gonorrhoeae (FA 19). PBP was cloned and purified as previously described (E.coli PBP3, king, D.T et al ACS Infectious Diseases 2015,1,175-184; P.aeruginosa PBP3, han et al PNAS2010,107 (51), 22002-22007; A. Baumannii PBP, penwell et al, antimicrob. Agents chemther. 2015,59 (3), 1680-1689; N.gonorrhoeae PBP2, singh et al J.biol. Chem.2019,294 (38), 14020-14032). In order to establish the assay conditions for competitive binding, an enzyme titration/saturation binding assay is first performed. Bocilin-FL was prepared at 0.2. Mu.M in a buffer consisting of 50mM Hepes (pH 8.0), 300mM NaCl and 10% (v/v) glycerol for reaction with E.coli, P.aeruginosa and N.gonorrhoeae PBP, and Bocilin-FL was prepared at 0.2. Mu.M in a buffer consisting of 25mM Tris (pH 8.0), 200mM NaCl, 10% (v/v) glycerol and 0.005% (v/v) Tween 20 for reaction with A. Baumannii PBP. Saturation binding was performed by mixing 40. Mu.l of PBP solution ranging in concentration from 0 to 24. Mu.M and 40. Mu.l of 0.2. Mu.M Bocilin-FL solution in individual wells of a black 384 well microplate. FP (excitation wavelength, 490nm; emission wavelength, 520nm g factor, 0.96 And continuously measured for up to 120 minutes. The FP reactions of pseudomonas aeruginosa and acinetobacter baumannii PBP3 were stable after 15min, the FP reactions of escherichia coli PBP3 and acinetobacter baumannii PBP1a were stable after 30min, and the FP reactions of neisseria gonorrhoeae PBP2 were stable after less than 1 min. In all cases, the FP signal showed a dose dependence on PBP concentration. Competition binding assays (80 μl final volume) were validated using β -lactam and final concentrations of PBP as follows: coli PBP3 at 1.5 μm; pseudomonas aeruginosa PBP3 at 0.75 μm; acinetobacter baumannii PBP1a is 1 mu M; acinetobacter baumannii PBP3 is 0.2 mu M; neisseria gonorrhoeae PBP2 at 0.25. Mu.M. Bocilin-FL is 0.1. Mu.M (0.05. Mu.M when reacted with Acinetobacter baumannii PBP1 a) and the beta-lactam concentration ranges from 0-1,000. Mu.M. Coli PBP3 was incubated with increasing concentrations of ampicillin in black 384 well microplates (Corning) for 30 minutes. Pseudomonas aeruginosa PBP3 was incubated with ammonia Qu Nawen for 15min, while Acinetobacter baumannii PBP1a and PBP3 were incubated with meropenem for 15min, followed by the addition of Bocilin-FL followed by up to 60 min FP measurements. For neisseria gonorrhoeae PBP2 assay, cefixime, ceftriaxone were mixed with Bocillin-FL, then enzyme was added and FP was measured immediately for up to 30 minutes. Beta-lactam potency was reported as the concentration of beta-lactam (EC) required to reduce the amount of PBP-bound Bocilin-FL by 50% 50 ). EC of ampicillin against E.coli PBP3 50 Measured at 1.4. Mu.M. EC of aztreonam on Pseudomonas aeruginosa PBP3 50 Measured as<0.5. Mu.M. EC of meropenem and Acinetobacter baumannii PBP1a and PBP3 50 Respectively as follows<0.5. Mu.M and 0.23. Mu.M. EC of cefixime and ceftriaxone and neisseria gonorrhoeae PBP2 50 The values were 0.26. Mu.M and 0.27. Mu.M, respectively. Binding assays for boronic acid PBP inhibitors each PBP was performed in exactly the same manner.
Representative results of binding to E.coli PBP3 are shown in Table 5, where A represents a potency > 250. Mu.M, B represents a potency between 50. Mu.M and 250. Mu.M (containing 50. Mu.M and 250. Mu.M), C represents a potency between 10. Mu.M and 50. Mu.M (containing 10. Mu.M and 50. Mu.M), and D represents a potency < 10. Mu.M. Nt=no test.
Table 5. Binding affinity of example compounds to E.coli PBP3 in a fluorescence polarization competition binding assay using Bocilin-FL.
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Representative results of binding to P.aeruginosa PBP3 are shown in Table 6, where A represents efficacy > 250. Mu.M, B represents efficacy between 50. Mu.M and 250. Mu.M (containing 50. Mu.M and 250. Mu.M), C represents efficacy between 10. Mu.M and 50. Mu.M (containing 10. Mu.M and 50. Mu.M), and D represents efficacy < 10. Mu.M. Nt=no test.
Table 6. Binding affinity of example compounds to P.aeruginosa PBP3 in a fluorescence polarization competition binding assay using Bocilin-FL.
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Representative results of binding to acinetobacter baumannii PBP1B and PBP3 are shown in table 7, wherein a represents efficacy >250 μm, B represents efficacy between 50 μm and 250 μm (containing 50 μm and 250 μm), C represents efficacy between 10 μm and 50 μm (containing 10 μm and 50 μm), and D represents efficacy <10 μm. Nt=no test.
Table 7 binding affinities of example compounds for Acinetobacter baumannii PBP1a and PBP3 in a fluorescence polarization competition binding assay using Bocilin-FL.
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Representative results of binding to neisseria gonorrhoeae FA19 PBP2 are shown in table 8, wherein a represents efficacy >250 μm, B represents efficacy between 50 μm and 250 μm (containing 50 μm and 250 μm), C represents efficacy between 10 μm and 50 μm (containing 10 μm and 50 μm), and D represents efficacy <10 μm. Nt=no test.
Table 8 binding affinity of example compounds to Neisseria gonorrhoeae FA19 PBP2 in a fluorescence polarization competition binding assay using Bocilin-FL.
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Example II: experimental methods for penicillin binding protein binding assay with Bocilin-FL via gel filtration.
Affinity for acinetobacter baumannii PBP1a and PBP2 was assessed by a competition balance binding assay using Bocillin-FL as a reporter molecule. The enzyme was pre-incubated with increasing concentrations of inhibitor, followed by addition of Bocillin and further incubation for 15 minutes. PBP binding to Bocilin-FL was isolated by gel filtration using a 96-well Zeba Spin-size exclusion plate and fluorescence was measured. Inhibitor affinity (reported as EC) was determined by plotting the fraction of PBP bound to Bocillin-FL at each inhibitor concentration versus inhibitor concentration and fitting the data to the following equation 50 )：
Where y is the binding fraction at a given inhibitor concentration, y min Is the binding fraction, y, when the enzyme is completely inactivated max Is the maximum (uninhibited) binding fraction, n is the Hill coefficient, and x is the inhibitor concentration.
Representative results of binding to acinetobacter baumannii PBP1a and PBP2 are shown in table 9, where a represents efficacy >250 μm, B represents efficacy between 50 μm and 250 μm (containing 50 μm and 250 μm), C represents efficacy between 10 μm and 50 μm (containing 10 μm and 50 μm), and D represents efficacy <10 μm. Nt=no test.
Table 9 binding affinities of example compounds to Acinetobacter baumannii PBP1a and PBP2 in a competitive binding assay using Bocilin-FL via gel filtration.
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Example III: in vitro antimicrobial test.
To determine the ability of test compounds to inhibit bacterial strain growth, classical cell-based liquid medium microdilution Minimal Inhibitory Concentration (MIC) assays were used. MIC tests were performed according to the CLSI method (CLSI, 2018 and CLSI, 2019) unless otherwise indicated. Coli ATCC 25922; coli AG100 as a wild-type parent strain; high permeability E.coli 901C and E.coli D22; and the E.coli AG100A strain lacking the acrAB efflux pump encoding gene was used to determine the ability of the PBP inhibitor to penetrate the outer membrane of gram-negative bacteria and to inhibit bacterial growth. Three additional klebsiella pneumoniae challenge isolates (klebsiella pneumoniae 848844 producing SHV-11 and KPC-2, klebsiella pneumoniae UMM producing SHV-5 and KPC-2, and klebsiella pneumoniae SI-117 producing VIM-1) were used to further evaluate antibacterial activity in enterobacteria and demonstrate the activity of PBP inhibitors regardless of the beta-lactamase content of these organisms. Pseudomonas aeruginosa ATCC 27853 and Acinetobacter baumannii ATCC 19606, as well as highly permeable Pseudomonas aeruginosa ATCC 35151 and Pseudomonas aeruginosa engineered efflux pump impaired strain (ΔmexAB-oprM) were used to determine the ability of PBP inhibitors to penetrate the outer membranes of Pseudomonas aeruginosa and Acinetobacter baumannii, and to evaluate antibacterial activity against these important gram-negative organisms. Finally, BSL-2-type burkholderia melitensis Δpurm adenine auxotrophic strain Bp82 was used to evaluate potential utility against this biological weapon pathogen.
Briefly, frozen bacterial cultures of the challenge strains were streaked for isolation on appropriate agar media (in this case cation-adjusted Mueller Hinton agar (Enterobacter, pseudomonas aeruginosa, and Acinetobacter baumannii)) or cation-adjusted Mueller Hinton agar supplemented with 0.6mM adenine (Burkholderia-like Bp 82). After incubation, colonies were allowed to grow, the plates were sealed with a sealing film and refrigerated for up to two weeks. To prepare the test inoculum and ensure low variability, at least 5 colonies were picked from the agar plates with an inoculating loop and aseptically transferred into culture tubes containing 3mL of cation-adjusted Mueller Hinton liquid medium (camdb) for enterobacteria, pseudomonas aeruginosa and acinetobacter baumannii or 3mL of cation-adjusted Mueller Hinton liquid medium supplemented with 0.6mM adenine for burkholderia melioides Bp 82. The liquid medium culture was grown at 37℃for 3-5 hours under shaking (E.coli, P.aeruginosa and Acinetobacter baumannii) or at 37℃in a fixed ambient air incubator (Burkholderia meliotidis Bp 82). At the same time, 2-fold serial dilutions of the test compound were made in 96-well plates with a final volume of 50 μl per well at 2-fold final desired concentration. After setting up the dilution plate, the growth culture was then diluted in a cuvette containing camdb and the optical density measured at 600 nm. The inoculum was diluted so that when 50 μl of this culture in camdb (for burkholderia-like Bp82, supplemented with 2x 0.6mm adenine) was added to the dilution plate, it resulted in an initial bacterial concentration of 2-8 x 10 5 CFU/mL. At 37 ℃ to make enterobacteria and pseudomonas aeruginosaFor 16-20 hours, acinetobacter baumannii and Burkholderia-like gangrene were incubated for 20-24 hours. MIC values were visually read as the lowest concentration wells with no bacterial growth.
Representative results of the enterobacter MIC test are shown in Table 10, wherein A represents MIC.gtoreq.128. Mu.g/mL, and B represents MIC of 32 to 64. Mu.g/mL; c represents MIC from 8 to 16 μg/mL; d represents MIC from 2 to 4 μg/mL; e represents MIC.ltoreq.1. Mu.g/mL. Nt=no test.
Table 10: inhibition of bacterial growth. Minimal inhibitory concentration of the compounds of the examples against E.coli in CAMHB.
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Representative test results for Pseudomonas aeruginosa and Acinetobacter baumannii strains are shown in Table 12, wherein A represents MIC.gtoreq.128. Mu.g/mL, B represents MIC from 32 to 64. Mu.g/mL, C represents MIC from 8 to 16. Mu.g/mL, D represents MIC from 2 to 4. Mu.g/mL, and E represents MIC.ltoreq.1. Mu.g/mL. Nt=no test.
Table 12: inhibition of bacterial growth. The compounds of the examples have minimal inhibitory concentration on pseudomonas aeruginosa and acinetobacter baumannii strains in camdb.
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Representative results of tests in Burkholderia-like Bp82 are shown in Table 11, wherein A represents MIC.gtoreq.128. Mu.g/mL, B represents MIC from 32 to 64. Mu.g/mL, C represents MIC from 8 to 16. Mu.g/mL, D represents MIC from 2 to 4. Mu.g/mL, and E represents MIC.ltoreq.1. Mu.g/mL. Nt=no test.
Table 11: inhibition of bacterial growth. The compounds of the examples have minimal inhibitory concentration on Burkholderia melioides Bp82 in CAPHB.
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Example III: in vitro antimicrobial tests were performed in iron depleted cation conditioned Mueller-Hinton liquid medium.
To determine the ability of test compounds to inhibit bacterial strain growth under iron depletion conditions, a classical cell-based liquid medium microdilution Minimal Inhibitory Concentration (MIC) assay was used. MIC tests were performed according to the CLSI method (CLSI, 2018 and CLSI, 2019) unless otherwise indicated. The reference strain E.coli ATCC 25922 was used to determine the ability of the PBP inhibitor to inhibit the growth of E.coli. Wild type pseudomonas aeruginosa ATCC 27853, acinetobacter baumannii ATCC 17978 and acinetobacter baumannii ATCC 19606, as well as high permeability pseudomonas aeruginosa ATCC 35151, engineered efflux pump impaired pseudomonas aeruginosa strain (Δmexab-oprM) were used to determine the ability of PBP inhibitors to penetrate the outer membrane of pseudomonas aeruginosa and to evaluate antibacterial activity against these important gram negative organisms. Furthermore, four challenge isolates of P.aeruginosa (P.aeruginosa CDC-0054 producing VIM-4, OXA-50 and PDC; P.aeruginosa CDC-0090 producing KPC-5, OXA-50 and PDC; P.aeruginosa CDC-0095 producing OXA-50 and PDC), as well as five challenge isolates of P.baumannii (P.baumannii 1258916 producing ADC-33, OXA-23 and OXA-82; P.baumannii CDC-0033 producing NDM-1 and OXA-94; P.baumannii CDC-0036 producing OXA-65 and OXA-24; P.baumannii CDC-0045 producing TEM-1D, OXA-23 and OXA-69; and P.baumannii CDC-0083 producing NDM-1, PER-7, XA-3 and OXA-69) were used to further demonstrate the activity against the enzyme beta-inhibitors in the non-fermentor non-fermenters without consideration of the activity of these enzymes. In addition, two burkholderia bioweapon pathogen substitution strains (burkholderia thailans (b. Thailandensis) ATCC 700388 and hanpridi Du Bake haldsis (b. Hunptydooensis) ATCC BAA-2767) were used to evaluate potential biodefense applications.
Briefly, frozen bacterial cultures of the challenge strains were streaked for isolation on an appropriate agar medium (in this case cation-adjusted Mueller Hinton agar). After incubation colonies were allowed to grow, the plates were sealed with a sealing film and refrigerated for up to two weeks. To prepare the test inoculum and ensure low variability, at least 5 colonies were picked from the agar plates with an inoculating loop and aseptically transferred to culture tubes containing 3mL of iron-depleted cation-conditioned Mueller Hinton liquid medium (IDM) -IDM preparation see below. The liquid medium culture was grown at 37℃for 3-5 hours with shaking at 200 rpm. At the same time, 2-fold serial dilutions of the test compound were made in 96-well plates, with a final volume of 50 μl per well at 2-fold final desired concentration. After setting the dilution plate, the growth culture was then diluted in a cuvette containing IDM and the optical density was measured at 600 nm. The inoculum was diluted such that when 50 μl of this culture in IDM was added to the dilution plate, it resulted in an initial bacterial concentration of 2-8×10 5 CFU/mL. Plates of Enterobacter and Pseudomonas aeruginosa were incubated at 37℃for 16-20 hours, plates of Acinetobacter baumannii were incubated for 20-24 hours. MIC values were visually read as the lowest concentration wells with no bacterial growth.
Method for preparing iron depleted cation conditioned Mueller Hinton liquid medium (IDM):
cation-adjusted Mueller Hinton liquid medium was prepared and autoclaved according to the manufacturer's recommendations.
100g/L Chelex 100 resin was added, covered with foil and incubated for 2 hours with stirring
The Chelex 100 resin was removed by filtration using a 0.45 μm filter flask
The following were added back to the medium:
οCaCl 2 dihydrate: 82.5mg/L
οMgCl 2 Hexahydrate: 94.1mg/L
οZnSO 4 ：10μM
The pH of the medium was adjusted to 7.3 with 5N HCl
Sterilizing on 0.22 μm filter flask
Representative results of testing compounds under conditions of iron depleted media are shown in tables 13, 14 and 15, wherein A represents MIC.gtoreq.128. Mu.g/mL, B represents MIC from 32 to 64. Mu.g/mL, C represents MIC from 8 to 16. Mu.g/mL, D represents MIC from 2 to 4. Mu.g/mL, and E represents MIC.ltoreq.1. Mu.g/mL. Nt=no test.
Table 13: inhibition of bacterial growth. Minimum inhibitory concentration of the example compounds on pseudomonas aeruginosa strains in iron depleted CAMHB (IDM).
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Table 14: inhibition of bacterial growth. Minimal inhibitory concentration of the example compounds on Acinetobacter baumannii strains in iron-depleted CAMHB (IDM).
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Table 15: inhibition of bacterial growth. Minimum inhibitory concentration of the example compounds against burkholderia strains in iron-depleted CAMHB (IDM).
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Example IV: in vitro antibacterial test of neisseria gonorrhoeae strains.
Additional antimicrobial tests of this series were performed in 8 neisseria gonorrhoeae reference strains (ATCC 49226, FA1090, MS11, WHO G, WHO L, WHO M, WHO K, WHO X, WHO Z, WHO Q, CDC-0197). ATCC 49226, FA1090, MS11, WHO G, WHO L and WHO M produce wild-type or wild-like PBP2.WHO K, WHO X, WHO Z, WHO Q and CDC-0197 produced chimeric PBP2. The liquid medium based assay was used for antibacterial testing of PBP inhibitors in neisseria gonorrhoeae. Briefly, frozen bacterial cultures of clinical strains were streaked to separate on chocolate agar (72 g/L (2 x) GC agar base (BD # 228950) and 2% (2 x) heme, which was autoclaved at 121 ℃ for 20 minutes to disinfect once cooled to about 50 ℃, 2x GC agar base and 2x heme solutions were combined and 1% isovitalx enrichment (BD # 211876) was added to the solution). 24 hours before inoculum preparation, the strain was exposed to 36℃and 5% CO 2 Incubate under to allow colony growth. Serial 2-fold dilutions of the test compounds were performed in 96-well plates with a final volume of 75 μl/well at 2-fold final desired concentration in fasting liquid medium (remel#r 07664). To prepare the test inoculum, a direct suspension was prepared by aseptically wiping 10-15 colonies from an agar plate into a culture tube containing 2mL of fresh sterile saline. After the dilution plate is set, the direct suspension is then diluted in a cuvette containing sterile saline And the optical density was measured at 600 nm. The inoculum was diluted so that when 75 μl of this culture in causticized liquid medium was added to the dilution plate, it resulted in a starting bacterial concentration of 5×10 5 CFU/mL. The plates were incubated at 36℃and 5% CO 2 Incubate for about 24 hours. MIC was visually read as the lowest concentration well that completely inhibited bacterial growth.
Representative test results for N.gonorrhoeae strains are shown in Table 16, wherein A represents MIC.gtoreq.64 μg/mL, B represents MIC from 16 to 32 μg/mL, C represents MIC from 4 to 8 μg/mL, D represents MIC from 1 to 2 μg/mL, and E represents MIC.ltoreq.1 μg/mL. Nt=no test.
Table 16: inhibition of bacterial growth. The compounds of the examples have minimal inhibitory concentrations on neisseria gonorrhoeae strains.
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While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims are intended to define the scope of the invention and their equivalents and methods and structures within the scope of these claims are therefore covered thereby.

Claims (125)

1. A compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
R 2 is hydrogen, C 1 -C 6 Alkyl, -C (=o) R 3 、-S(＝O) 2 R 3 、-C(＝O)N(R 4 ) 2 or-S (=o) 2 N(R 4 ) 2 ；
R 3 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a Substitution;
each R 3a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkylThe heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo;
each R 3b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 3b Together forming oxo;
each R 4 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4a Substitution;
each R 4a Is independently deuterium, halogen, -Y-CN, -Y-NO 2 、-Y-OH、-Y-OR a 、-Y-OC(＝O)R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 4b Substitution;
or two R's on the same atom 4a Together forming oxo;
each R 4b Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 4b Together forming oxo;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
ring a is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
l is absent OR L is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 3 An alkylene group;
R 6a is-OH, -OR a Or C 1 -C 6 An alkyl group;
R 6b is-OH, -OR a Or C 1 -C 6 An alkyl group;
each R 7 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or two R's on the same atom 7 Together forming oxo;
n is 0 to 4;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or cycloalkyl;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 Forms, together with the boron atom to which they are attached, an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ]]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached, form a heterocycloalkyl group, optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not
2. The compound of claim 1, wherein R 2 Is C 1 -C 6 An alkyl group.
3. The compound of claim 1, wherein R 2 is-C (=O) R 3 or-S (=o) 2 R 3 。
4. The compound of claim 1, wherein R 2 is-C (=O)R 3 。
5. The compound of claim 1, wherein R 2 is-C (=O) N (R) 4 ) 2 or-S (=o) 2 N(R 4 ) 2 。
6. The compound of any one of claims 1-4, wherein R 3 Is C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a And (3) substitution.
7. The compound of any one of claims 1-4 or 6, wherein R 3 Is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3a And (3) substitution.
8. The compound of any one of claims 1-4 or 6 or 8, wherein R 3 Is optionally substituted with one or more R 3a Substituted heterocycloalkyl.
9. The compound of any one of claims 1-8, wherein each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
10. The compound of any one of claims 1-8, wherein each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl;wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
11. The compound of any one of claims 1-8, wherein each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、-Y-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
12. The compound of any one of claims 1-8, wherein each R 3a Independently halogen, -Y-CN, -Y-OH, -Y-OR a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、-Y-C(＝O)R a 、C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 3b Substitution; or two R's on the same atom 3a Together forming oxo.
13. The compound of any one of claims 1-8, whereinEach R 3a Not C 1 -C 6 An alkyl group.
14. The compound of any one of claims 1-13, wherein each R 3b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom 3b Together forming oxo.
15. The compound of any one of claims 1-13, wherein each R 3b Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
16. The compound of any one of claims 1-15, wherein the compound is of formula (Ia-1) or formula (Ib-1):
Wherein:
each Y 1 And Y 2 Is independently-C (=O) -or-C (R) Y ) 2 -；
Each R Y Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
q is 1-3;
p is 1-3;
R 5 is-Y-OC (=O) R a 、-Y-OC(＝O)OR b 、-Y-OC(＝O)NR c R d 、-Y-SH、-Y-SR a 、-Y-S(＝O)R a 、-Y-S(＝O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a Substitution; and is also provided with
Each R 5a Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom 5a Together forming oxo.
17. The compound of claim 16, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and each Y 2 is-C (=o) -.
18. The compound of claim 16, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 1; and Y is 2 is-C (=o) -.
19. The compound of claim 16, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and one Y 2 is-C (R) Y ) 2 -and one Y 2 is-C (=o) -.
20. The compound of claim 16, wherein q is 2; y is a 1 is-C (R) 5 ) 2 -and one Y 1 is-C (=o) -; p is 2; and one isY 2 is-C (R) 5 ) 2 -and one Y 2 is-C (=o) -.
21. The compound of any one of claims 16-20, wherein each R Y Independently hydrogen, halogen or C 1 -C 6 An alkyl group.
22. The compound of any one of claims 16-21, wherein each R Y Is hydrogen.
23. The compound of any one of claims 16-22, whereinIs that
24. The compound of any one of claims 16-23, whereinIs->
25. The compound of any one of claims 16-23, whereinIs->
26. The compound of any one of claims 16-25, wherein R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
27. The compound of any one of claims 16-25, wherein R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)NR c R d 、-Y-NR b C(＝O)R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b C(＝O)R a 、-Y-NR b C(＝O)OR b 、-Y-NR b S(＝O) 2 R a 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 R a 、-Y-NR b S(＝O) 2 NR c R d 、-Y-S(＝O) 2 (C 1 -C 6 Alkylene) NR b S(＝O) 2 NR c R d 、-Y-C(＝O)R a 、-Y-C(＝O)OR b 、-Y-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
28. The compound of any one of claims 16-25, wherein R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
29. The compound of any one of claims 16-25, wherein R 5 is-Y-S (=O) 2 R a 、-Y-S(＝O) 2 NR c R d 、-Y-NR c R d 、-Y-NR b C(＝O)R a 、-Y-NR b S(＝O) 2 R a 、C 1 -C 6 Haloalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5a And (3) substitution.
30. The compound of any one of claims 16-25, wherein each R 5 Not C 1 -C 6 An alkyl group.
31. The compound of any one of claims 16-30, wherein each R 5a Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom 3b Together forming oxo.
32. The compound of any one of claims 16-31, wherein each R 5a Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-C(＝O)R a 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
33. The compound of any one of claims 1-32, wherein ring a is aryl or heteroaryl.
34. The compound of any one of claims 1-33, wherein ring a is aryl.
35. The compound of any one of claims 1-34, wherein L is absent.
36. The compound of any one of claims 1-34, wherein L is optionally substituted with one OR more deuterium, halogen, -CN, -OH, OR-OR a Substituted C 1 -C 3 An alkylene group.
37. The compound of any one of claims 1-34, which isWherein L is C substituted by one or more halogens 1 An alkylene group.
38. The compound of any one of claims 1-37, wherein R 6a is-OH or C 1 -C 6 An alkyl group.
39. The compound of any one of claims 1-38, wherein R 6a is-OH.
40. The compound of any one of claims 1-39, wherein R 6b is-OH or C 1 -C 6 An alkyl group.
41. The compound of any one of claims 1-40, wherein R 6b is-OH.
42. The compound of any one of claims 1-41, wherein each R 7 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
43. The compound of any one of claims 1-42, wherein each R 7 Independently is halogen or-OH.
44. The compound of any one of claims 1-43, wherein n is 1 or 2.
45. The compound of any one of claims 1-43, wherein n is 0 or 1.
46. A compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:
wherein:
R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each Y 1 And Y 2 Is independently-C (=O) -or-C (R) Y ) 2 -；
Each R Y Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
q is 1-3;
p is 1-3;
R 8 is- (W) u -ring B;
each W is independently-C (R W1 ) 2 -、-O-、-NR W2 -、-S-、-S(＝O)-、-S(＝O) 2 -or-C (=o) -;
each R W1 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
each R W2 Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group;
or one R W1 And one R W2 Together when present form a heterocycloalkyl group, optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W1 Forms together cycloalkyl or heterocycloalkyl when present; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or two R W2 Together when present form a heterocycloalkyl group, optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
u is 1-10;
ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally being substituted with one or more R B Substitution;
each R B Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-NR b S(＝O) 2 NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R 7a is hydrogen, deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7b is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
R 7c is deuterium, halogen, -OH, -OR a 、-NR c R d Or C 1 -C 6 An alkyl group;
each R is independently deuterium, halogen, -CN, -OH, -OR a 、-SH、-SR a 、-NR c R d 、-NR c C(＝O)R b 、-C(＝O)NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl or-Y-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
m is 0 to 3;
R d is hydrogen or C 1 -C 6 An alkyl group;
each R e Independently hydrogen, -CN, -OH, C 1 -C 6 Alkyl or cycloalkyl;
X 1 and X 2 independently-OH, -OR X or-F; or alternatively
X 1 And X 2 Forms, together with the boron atom to which they are attached, an optionally substituted cyclic borate;
R X is C 1 -C 6 Alkyl or cycloalkyl;
z is hydrogen, R 11 、-(R 10 ) w OR 11 、-(R 10 ) w O(R 10 ) w OR 11 、-R 10 OC(＝O)R 11 、-R 10 OC(＝O)OR 11 、-R 10 OC(＝O)NHR 11 、-R 10 OC(＝O)N(R 11 ) 2 Alkoxyalkyl, acyloxyalkyl or alkyl- [1,3 ] ]Dioxol-2-one;
each R 10 Is independently-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -or 1,1' -cyclopropylene;
each R 11 Independently C 1 -C 6 Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or alternatively
Two R 11 Together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, which is optionally substituted with C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
w is 2-4;
y is absent OR Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH OR-OR a Substituted C 1 -C 6 An alkylene group;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; and is also provided with
Each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, or-Y-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached, form a heterocycloalkyl group, optionally substituted with one or more oxo, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)N(CH 3 ) 2 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl substitution; provided that the compound is not/>
47. The compound of claim 46, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and each Y 2 is-C (=o) -.
48. The compound of claim 46, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 1; and Y is 2 is-C (=o) -.
49. The compound of claim 46, wherein q is 2; each Y 1 is-C (R) Y ) 2 -; p is 2; and one Y 2 is-C (R) Y ) 2 -and one Y 2 is-C (=o) -.
50. The compound of claim 46, wherein q is 2; y is a 1 is-C (R) 5 ) 2 -and one Y 1 is-C (=o) -; p is 2; and one Y 2 is-C (R) 5 ) 2 -and one Y 2 is-C (=o) -.
51. The compound of any one of claims 46-50, wherein each R Y Independently hydrogen, halogen or C 1 -C 6 An alkyl group.
52. The compound of any one of claims 46-51, wherein each R Y Is hydrogen.
53. The compound of any one of claims 46-52, whereinIs that
54. The compound of any one of claims 46-53, whereinIs->
55. The compound of any one of claims 46-53, whereinIs->
56. The compound of any one of claims 46-55, wherein R 7a Is hydrogen or halogen.
57. The compound of any one of claims 46-56, wherein R 7a Is hydrogen.
58. The compound of any one of claims 46-57, wherein R 7b Is halogen.
59. The compound of any one of claims 46-58, wherein R 7c Is halogen.
60. The compound of any one of claims 46-59, wherein u is 1-8.
61. The compound of any one of claims 46-59, wherein u is 1-7.
62. The compound of any one of claims 46-59, wherein u is 1-6.
63. The compound of any one of claims 46-59, wherein u is 1-5.
64. The compound of any one of claims 46-59, wherein u is 3-8.
65. The compound of any one of claims 46-59, wherein u is 4-8.
66. The compound of any one of claims 46-59, wherein u is 5-8.
67. The compound of any one of claims 46-59, wherein u is 4-6.
68. The compound of any of claims 46-67, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-、-[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -、-[C(R W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -、-[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -、-[C(R W1 ) 2 ] 1-3 -NR W2 -[C(R W1 ) 2 ] 1-3 -、-[C(R W1 ) 2 ] 1-4 -、-S(＝O) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C (=o) -or-S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -。
69. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-。
70. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-[C(R W1 ) 2 ] 1-2 -。
71. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -S(＝O) 2 -。
72. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -。
73. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-3 -NR W2 -[C(R W1 ) 2 ] 1-3 -。
74. The compound of any of claims 46-68, wherein- (W) u -is- [ C (R) W1 ) 2 ] 1-4 -。
75. The compound of any of claims 46-68, wherein- (W) u -is-S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-。
76. The compound of any of claims 46-68, wherein- (W) u -is S (=o) 2 -[C(R W1 ) 2 ] 1-4 -NR W2 -C(＝O)-NR W2 -。
77. The compound of any one of claims 46-76, wherein each R W1 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
78. The compound of any one of claims 46-77, wherein each R W1 Independently hydrogen or C 1 -C 6 An alkyl group.
79. The compound of any one of claims 46-78, wherein each R W1 Is hydrogen.
80. The compound of any one of claims 46-79, wherein each R W2 Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
81. The compound of any one of claims 46-80, wherein each R W2 Independently hydrogen or C 1 -C 6 An alkyl group.
82. The compound of any one of claims 46-81, wherein each R W2 Is hydrogen.
83. The compound of any one of claims 46-81, wherein each R W2 Independently C 1 -C 6 An alkyl group.
84. The compound of any one of claims 46-76, wherein one ofR W1 And one R W2 Together when present form a heterocycloalkyl group, optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
85. The compound of any one of claims 46-76, wherein two R W1 Forms together cycloalkyl or heterocycloalkyl when present; each optionally being substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
86. The compound of any one of claims 46-76, wherein two R W2 Together when present form a heterocycloalkyl group, optionally substituted with one or more C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
87. The compound of any one of claims 46-86, wherein ring B is heterocycloalkyl, aryl, or heteroaryl; each optionally being substituted with one or more R B And (3) substitution.
88. The compound of any one of claims 46-87, wherein ring B is aryl or heteroaryl; each optionally being substituted with one or more R B And (3) substitution.
89. The compound of any one of claims 46-88, wherein ring B is optionally substituted with one or more R B Substituted aryl.
90. The compound of any one of claims 46-88, wherein ring B is optionally substituted with one or more R B Substituted heteroaryl groups.
91. The compound of any one of claims 46-90, wherein each R B Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group.
92. The compound of any one of claims 46-91, wherein each R B Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 A heteroalkyl group.
93. The compound of any one of claims 46-92, wherein each R B Independently halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
94. The compound of any one of claims 46-93, wherein each R B Independently halogen or OH.
95. As claimed inThe compound of any one of claims 1-94, wherein R 1 Is hydrogen or C 1 -C 6 An alkyl group.
96. The compound of any one of claims 1-95, wherein R 1 Is hydrogen.
97. The compound of any one of claims 1-96, wherein R d Is hydrogen.
98. The compound of any one of claims 1-97, wherein each R e Is hydrogen.
99. The compound of any one of claims 1-98, wherein X 1 And X 2 is-OH.
100. The compound of any one of claims 1-99, wherein each R is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR a 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Aminoalkyl groups.
101. The compound of any one of claims 1-100, wherein each R is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
102. The compound of any one of claims 1-101, wherein each R is independently deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
103. The compound of any one of claims 1-102, wherein each R is independently halogen.
104. The compound of any one of claims 1-103, wherein m is 0 or 1.
105. The compound of any one of claims 1-103, wherein m is 1 or 2.
106. The compound of any one of claims 1-105, wherein Z is hydrogen.
107. The compound of any one of claims 1-105, wherein Z is R 11 The method comprises the steps of carrying out a first treatment on the surface of the And R is 11 Is C 1 -C 6 An alkyl group.
108. The compound of any one of claims 1-105, wherein Z is-R 10 OC(＝O)R 11 or-R 10 OC(＝O)OR 11 ；R 10 is-CH 2 -or-CH (CH) 3 ) -; and R is 11 Is alkyl, cycloalkyl or heterocycloalkyl.
109. The compound of any one of claims 1-108, wherein Y is absent.
110. The compound of any one of claims 1-108, wherein Y is optionally substituted with one OR more deuterium, halogen, -CN, -OH, OR-OR a Substituted C 1 -C 6 An alkylene group.
111. The compound of any one of claims 1-108, wherein Y is C 1 -C 6 An alkylene group.
112. The compound of any one of claims 1-108, wherein Y is C 1 -C 4 An alkylene group.
113. The compound of any one of claims 1-108, wherein Y is C 2 -C 6 An alkylene group.
114. The compound of any one of claims 1-108, wherein Y is C 2 -C 4 An alkylene group.
115. The compound of any one of claims 1-108, wherein Y is C 1 An alkylene group.
116. A compound selected from the group consisting of the compounds of table 1, table 2, table 3, or table 4, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof.
117. A pharmaceutical composition comprising a compound of any one of claims 1-116, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, and a pharmaceutically acceptable excipient.
118. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-116, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, or a pharmaceutical composition of claim 117.
119. A method of inhibiting a bacterial penicillin binding protein in a human infected with a bacterial infection comprising contacting the bacterial penicillin binding protein with an effective amount of the compound of any one of claims 1-116 or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof or the pharmaceutical composition of claim 117.
120. The method of claim 118 or 119, wherein the bacterial infection is caused by neisseria gonorrhoeae.
121. The method of claim 118 or 119, wherein the bacterial infection is caused by burkholderia melitensis.
122. The method of claim 118 or 119, wherein the bacterial infection is caused by pseudomonas aeruginosa.
123. The method of claim 118 or 119, wherein the bacterial infection is caused by acinetobacter baumannii.
124. The method of claim 118 or 119, wherein the bacterial infection is caused by pseudomonas aeruginosa/acinetobacter baumannii.
125. The method of claim 118 or 119, wherein the bacterial infection is caused by carbapenem-resistant enterobacteria (CRE).
CN202280052020.6A 2021-05-26 2022-03-25 Penicillin binding protein inhibitors Pending CN117693511A (en)

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US63/193,326 2021-05-26
US202163284572P 2021-11-30 2021-11-30
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PCT/US2022/021883 WO2022250776A1 (en) 2021-05-26 2022-03-25 Penicillin-binding protein inhibitors

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