HK1190699A

HK1190699A - Inhibitors of influenza viruses replication

Info

Publication number: HK1190699A
Application number: HK14103715.2A
Authority: HK
Inventors: P．S．查里夫森; M．P．克拉克; U．K．班达拉格; I.戴维斯; J．P．达菲; 高淮; J.冯; J.梁; J.M.肯尼迪; M．W．莱德波尔; B．莱德福; F．马尔泰斯; E．佩罗拉
Original assignee: 沃泰克斯药物股份有限公司
Priority date: 2010-12-16
Filing date: 2011-12-16
Publication date: 2014-07-11

Description

Inhibitors of influenza virus replication

Cross Reference to Related Applications

The present application claims priority under 35u.s.c. § 119 from us provisional application No.61/527,273 entitled "INHIBITORS OF INFLUENZA virus REPLICATION" filed on 25/8/2011 and us provisional application No.61/423,943 entitled "INHIBITORS OF INFLUENZA virus REPLICATION" filed on 16/2010, 12/2010, the entire contents OF both OF which are incorporated herein by reference.

Background

Influenza spreads worldwide in seasonal epidemics, causing hundreds of thousands of deaths annually-millions in pandemic illness. For example, three influenza pandemics occurred in the 20 th century, resulting in the death of tens of millions of people, each pandemic arising from the emergence of new virus strains in humans. Typically, these new strains result from the transmission of existing influenza viruses from other animal species to humans.

Influenza is transmitted from person to person primarily by large virus-bearing droplets produced when an infected person coughs or sneezes; these large droplets may then settle on the mucosal surfaces of the upper respiratory tract of susceptible individuals who are close to infected individuals (e.g., within about 6 feet). Transmission may also occur by direct or indirect contact with respiratory secretions, such as touching a surface contaminated with influenza virus, then touching the eyes, nose or mouth. An adult may be able to transmit influenza to others from 1 day before symptoms appear to about 5 days after symptoms begin. Children and immunocompromised people may be contagious 10 or more days after the onset of symptoms.

Influenza viruses are RNA viruses of the Orthomyxoviridae family (Orthomyxoviridae) which include five genera: influenza a, influenza B, influenza C, salmon anemia (isavus), and torulo (thogo viruses).

One influenza a virus belongs to the genus influenza a. Wild waterfowl is the natural host for many influenza types a. Sometimes, the virus spreads to other species and can then cause devastating outbreaks in poultry or cause pandemics of human influenza. Of the three influenza types, influenza a is the most virulent human pathogen and causes the most serious disease. Influenza a viruses can be subdivided into different serotypes based on the antibody response to these viruses. Serotypes that have been identified in humans, ordered by known numbers of human pandemic deaths, are: H1N1 (causing spanish influenza in 1918), H2N2 (causing asian influenza in 1957), H3N2 (causing hong kong influenza in 1968), H5N1 (pandemic threat in the 2007-08 flu season), H7N7 (with rare zoonotic potential), H1N2 (endemic disease in humans and pigs), H9N2, H7N2, H7N3 and H10N 7.

One type of influenza B virus belongs to the group of influenza B viruses. Influenza B almost exclusively infects humans and is less common than influenza a. The only other animal known to be susceptible to influenza B infection is seal. This type of influenza mutates at a rate 2-3 times slower than type a and is therefore less genetically diverse, with only one influenza B serotype. Due to this lack of antigenic diversity, a certain degree of influenza B immunity is usually acquired in the early years. However, influenza B mutations are sufficient to make persistent immunity impossible. This reduced rate of antigen change, coupled with a limited host range (inhibiting cross species antigen transition), can ensure that influenza B pandemics do not occur.

Influenza C virus belongs to one species, i.e., influenza C virus, which infects humans and pigs and can cause severe disease and endemic epidemics. However, influenza C is less common than other types of influenza and often appears to cause mild disease in children.

A. Influenza B and C viruses are very similar in structure. The virus particles are 80-120nm in diameter and are generally approximately spherical, but filamentous forms may occur. Unusual for viruses, nucleic acids whose genomes are not single fragments; instead, it contains a segmented antisense RNA of 7 or 8 segments. The influenza a genome encodes 11 proteins: hemagglutinin (HA), Neuraminidase (NA), Nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2, and PB 2.

HA and NA are large glycoproteins outside the virion. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into target cells, while NA is involved in the release of progeny virus from infected cells by cleaving sugars that bind to mature viral particles. Therefore, these proteins have been targets for antiviral drugs. In addition, they are antigens against which antibodies can be raised. Influenza a viruses are divided into subtypes based on antibody responses to HA and NA, forming the basis for H to N discrimination in, for example, H5N1 (see above).

Influenza incurs direct costs due to lost productivity and associated medical care as well as indirect costs for preventive measures. Influenza is responsible for over 100 billion dollars of total cost per year in the united states, and it is estimated that future pandemics can cause billions of dollars of direct and indirect costs. The prevention cost is also high. Governments around the world have spent billions of dollars in preparing and planning for a possible H5N1 avian influenza pandemic, costs associated with purchasing medications and vaccines and developing strategies for disaster drilling and improving border controls.

Current influenza treatment options include vaccination and chemotherapy or chemoprevention with antiviral drugs. Vaccination against influenza is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes or heart disease. However, it is possible to have vaccinated but still obtain flu. Vaccines are reformulated for a few specific influenza strains each season, but it is unlikely that all strains actively infecting humans in the world for that season will be included. The manufacturer takes about 6 months to formulate and produce millions of doses needed to combat seasonal epidemics; sometimes, new or overlooked strains become prominent and infect people during this period, even though these people have been vaccinated (e.g. 2003-. It may also be infected just prior to vaccination and ill just because of the viral strain that the vaccine should prevent, since the vaccine takes about two weeks to become effective.

In addition, the efficacy of these influenza vaccines can vary. Because of the high mutation rate of viruses, certain influenza vaccines typically provide protection for no more than a few years. Since influenza viruses change rapidly over time and different virus strains become dominant, a vaccine formulated for the current year may be ineffective in the next year.

In addition, the RNA-dependent RNA polymerase of influenza vRNA generates a nucleotide insertion error approximately every 1 ten thousand nucleotides (which is the approximate length of influenza vRNA) due to the lack of RNA proofreading enzyme. Thus, almost every newly manufactured influenza virus is mutant-antigenic drift. If more than one virus line infects a single cell, the genome is separated into 8 individual vRNA fragments to allow for vRNA mixing or reassortment. The resulting rapid changes in the virus genetics can produce antigenic changes and enable the virus to infect new host species and rapidly overcome protective immunity.

Antiviral drugs may also be used to treat influenza, where neuraminidase inhibitors are particularly effective, but the virus may develop resistance to standard antiviral drugs.

Thus, there remains a need for agents that treat influenza infection, for example, agents that have an expanded therapeutic window and/or reduced sensitivity to viral titers.

Disclosure of Invention

The present invention relates generally to methods of treating influenza, methods of inhibiting influenza virus replication, methods of reducing the amount of influenza virus, compounds and compositions useful in these methods.

In one embodiment, the present invention relates to compounds represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

x is-H, -Cl, -Br, -F, -CN or optionally substituted by one or more J¹Substituted C₁-C₆An aliphatic group;

ring T is optionally further substituted by one or more J^TSubstituted C₃-C₁₀A carbocyclic ring or a 4-10 membered heterocyclic ring;

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-、-B(O)₂-or- (CR)^tR^s)_p–Y¹–；

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-B(O)₂-or-CO₂SO₂-; and

R¹comprises the following steps: i) -H; ii) optionally substituted by one or more J^ASubstituted C₁-C₆An aliphatic group; iii) C₃-C₁₀A carbocyclic group or a 4-10 membered heterocyclic group, each optionally and independently substituted with one or more J^BSubstitution; or iv)6-10 membered aryl or 5-10 membered heteroaryl, each optionally and independently substituted with one or more J^CSubstitution;

optionally, R¹Together with R' and the nitrogen to which they are attached, form an optionally substituted one or more J²A substituted 4-8 membered heterocyclic group; or

Optionally, -Q¹-R¹Together with ring T, form optionally substituted one or more J⁴A substituted 4-10 membered non-aromatic spirocyclic ring; and is

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-B(O)₂-or-CO₂SO₂-; and is

R²is-H, -OR, -CO₂R, -NRR ', -CONRR', or optionally substituted with one or more J¹Substituted C₁-C₆An aliphatic group;

R³is-H, -F, -Cl, -CN, -NO₂、–OR、–CO₂R, -CONRR' orOptionally with one or more J¹Substituted C₁-C₆An aliphatic group;

J^A、J^Band J^TEach independently oxo or J^C；

J^CEach and independently selected from halogen, cyano, M, R^aOr R^a-M；

M is independently selected from-OR^b、–SR^b、-S(O)R^a、–SO₂R^a、–NR^bR^c、–C(O)R^a、-C(=NR)R^c、-C(=NR)NR^bR^c、-NRC(=NR)NR^bR^c、–C(O)OR^b、–OC(O)R^b、–NRC(O)R^b、–C(O)NR^bR^c、–NRC(O)NR^bR^c、–NRC(O)OR^b、–OCONR^bR^c、-C(O)NRCO₂R^b、-NRC(O)NRC(O)OR^b、-C(O)NR(OR^b)、-OSO₂NR^bR^c、–SO₂NR^cR^b、-NRSO₂R^b、-NRSO₂NR^cR^b、-P(O)(OR^b)₂、-OP(O)(OR^b)₂、-P(O)₂OR^band-CO₂SO₂R^b(ii) a Or

Optionally, two J^TTwo J^ATwo J^BAnd two J^CIndependently form, optionally substituted by one or more J, taken together with the atoms to which they are attached⁴A substituted 4-10 membered ring; and is

R^aIndependently are:

i) c optionally substituted by one or more substituents selected from₁-C₆Aliphatic group: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl), optionally substituted with one or more J²Substituted C₃-C₈Carbocyclic group, optionally substituted by one or more J²A substituted 4-to 8-membered heterocyclic group, optionally substituted with one or more J³Substituted 5-10 membered heteroaryl and optionally substituted with one or more J³Substituted 6-10 membered aryl;

ii)C₃-C₈a carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J ²Substitution; or

iii) a 5-10 membered heteroaryl or 6-10 membered aryl, each of which is optionally and independently substituted with one or more J³Substitution; and is

R^bAnd R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTogether with the nitrogen atom to which they are attached, each independently form an optionally substituted J or J²A substituted 4-8 membered heterocyclic group;

R^tand R^sEach independently-H, halogen or optionally substituted by one or more J¹Substituted C₁-C₆Alkyl or optionally R^tAnd R^sTaken together with the carbon atom to which they are attached to form a cyclopropane ring optionally substituted with one or more methyl groups;

r and R' are each independently-H or optionally and independently substituted with one or more J¹Substituted C₁-C₆Alkyl, or optionally, R and R' taken together with the nitrogen to which they are attached form optionally substituted by one or more J²A substituted 4-8 membered heterocyclic group;

each J¹Independently selected from halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl) and phenyl;

each J²Independently selected from halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C ₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

J³and J⁴Each independently selected from halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

p is 1, 2, 3 or 4; and is

k is 1, 2, 3 or 4; and is

Provided that Q is¹-R¹Not at the same carbon atom to which the-NH group attached to the pyrimidine ring of formula (I) is attached.

In some embodiments, p is independently 1 or 2; and k is independently 1 or 2.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by structural formula (I), (II), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, adjuvant, or vehicle (vehicle).

In another embodiment, the invention relates to a method of inhibiting influenza virus replication in a biological sample or patient comprising the step of administering to the biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by structural formula (I), (II), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof).

In another embodiment, the invention relates to a method of reducing the amount of influenza virus in a biological sample or patient comprising administering to the biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by structural formula (I), (II), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof).

In another embodiment, the invention relates to a method of treating influenza in a patient comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound represented by structural formula (I), (II), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof).

The invention also provides the use of a compound described herein to inhibit influenza virus replication in a biological sample or patient, to reduce the amount of influenza virus in a biological sample or patient, or to treat influenza in a patient.

Also provided herein is the use of a compound described herein for the manufacture of a medicament for treating influenza in a patient, for reducing the amount of influenza virus in a biological sample or patient, or for inhibiting influenza virus replication in a biological sample or patient.

Also provided herein are compounds represented by structural formula (XX):

or a pharmaceutically acceptable salt thereof. Without being bound by a particular theory, the compounds of structural formula (XX) may be used in the synthesis of compounds of formula (I). The variables of the formula (XX) are each andindependently as defined herein. And G is trityl (i.e., C (Ph)₃Wherein Ph is phenyl).

The present invention also provides a method for preparing a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises the steps of: i) reacting a compound A: With compound (B):reacting to form a compound represented by structural formula (XX); and

ii) deprotecting the G group of the compound of formula (XX) under suitable conditions to form a compound of formula (I), wherein: the variables for structural formulae (I) and (XX) and compounds (a) and (B) are each independently as defined herein. L is²Is halogen (e.g., Cl, Br, or I); and each G is independently trityl. In another embodiment, the method comprises the steps of: i) reacting compound (K) or (L):with compound (D):reacting under suitable conditions to form a compound represented by structural formula (XX); and

ii) deprotecting the G group of the compound of formula (XX) under suitable conditions to form a compound of formula (I), wherein: the variables for structural formulae (I) and (XX) and compounds (K), (L) and (D) are each and independently as defined herein; and each G is independently trityl. In another embodiment, the method comprises the steps of: i) reacting compound (G) with compound (D):

reacting under suitable conditions to form a compound represented by structural formula (XX); and ii) deprotecting the G group of the compound of formula (XX) under suitable conditions to form a compound of formula (I), wherein: the variables for structural formulae (I) and (XX) and compounds (G) and (D) are each and independently as defined herein; l is ¹Is halogen (e.g., Cl, Br, or I); and each G is independently trityl.

Detailed Description

The compounds of the invention are as described in the claims. In some embodiments, the compounds of the present invention are represented by any one of structural formulae (I), (II), (IIIA), and (IIIB), or a pharmaceutically acceptable salt thereof, wherein the variables are each and independently as described herein. In some embodiments, the compounds of the present invention are represented by any of the formulae depicted in table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present invention are represented by any of the formulae depicted in table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present invention are represented by any one of structural formulae (I), (II), (IIIA), and (IIIB), or a pharmaceutically acceptable salt thereof, wherein the variables are each and independently as depicted in the chemical formulae in table 1. In some embodiments, the compounds of the present invention are represented by any one of structural formulae (I), (II), (IIIA), and (IIIB), or a pharmaceutically acceptable salt thereof, wherein the variables are each and independently as depicted in the chemical formulae in table 2.

In one embodiment, the compounds of the present invention are represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein a first set of variable values of structural formula (I) are as follows:

X is-H, -Cl, -Br, -F, -CN, -O (C)_1-4Alkyl) or optionally substituted by one or more J¹Substituted C₁-C₆An aliphatic group. Typically, X is-Cl, -Br, -F, -CN, -O (C)_1-4Alkyl) or optionally substituted C₁-C₆An aliphatic group. More typically, X is-Cl, -Br, -F, -CN, -O (C)_1-4Alkyl) or optionally substituted C₁-C₆An alkyl group. More typically, X is-Cl, -Br, -F, -CN or optionally substituted C₁-C₆An alkyl group. More typically, X is-Cl, -Br, -F, -CN, C₁-C₄Alkyl or C₁-C₄A haloalkyl group. More typically, X is-Cl, -Br, -F, -CN or C₁-C₄A haloalkyl group. More typically, X is-Cl, -F, -Br, -CN or-CF₃. More typically, X is-Cl, -F, -CN, or-CF₃. More typically, X is-Cl or-F.

Ring T is optionally further substituted by one or more J^TSubstituted C₃-C₁₀Carbocyclic or 4-10 membered heterocyclic. Typically, ring T is optionally substituted C₅-C₁₀A carbocyclic group or an optionally substituted 5-10 membered heterocarbocyclic group. In one aspect, ring T is an optionally substituted bridging C₅-C₁₀A carbocyclic group. In another aspect, ring T is an optionally substituted monocyclic ring C₅-C₈A carbocyclic group.

Typical examples of the ring T include:wherein X is 0, 1 or 2. In a specific example, rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently forming an optionally substituted 4-10 membered bridged ring. Further typical examples of the ring T include: Wherein q is 0, 1 or 2; and r is1 or 2. Further typical examples of the ring T include:

and

further typical examples of the ring T include:

wherein q is 0, 1 or 2; and

r is 1 or 2.

Ring A (including ring A1-A6) is optionally further substituted with one or more J^TA substituted 5-10 membered carbocyclic group; or optionally, rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming optionally further substituted J or J^TSubstituted 5-10 membered bridged carbocycles. In one aspect, ring a is optionally and independently further substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming one or more substitutions optionally and independently selected fromBridged carbocyclic group substituted with a group: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups). In another aspect, rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently, an optionally substituted bridged carbocyclic group is formed.

Each ring a1-a5 is independently a 5-10 membered bridged carbocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups). Ring a6 is independently a 5-10 membered bridged heterocyclic ring optionally further substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups). Typically, each of rings a1-a6 is independently and optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Z is-O-, -S-or-NR^g-, wherein R^gis-H or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

Each of rings A8-a11 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-or- (CR)^tR^s)_p–Y¹-. Generally, Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-B(O)₂-or- (CR)^tR^s)_p–Y¹-. More generally, Q¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-、-B(O)₂-or- (CR)^tR^s)_p–Y¹-. More generally, Q¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-or- (CR)^tR^s)_p–Y¹-. More generally, Q¹is-C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CR)^tR^s)_1,2–Y¹–。Q¹is-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)_1,2-Y-. Even more typically, Q¹Independently is-C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)_1,2-Y-. Even more typically, Q¹is-C (O) O-, -NRC (O) -, -C (O) NR-or-NRC (O) NR' -. Q¹Specific examples of (A) include-C (O) O-, -NHC (O) -or-C (O) NH-.

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–,–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-B(O)₂-or-CO₂SO₂-. In general, Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-B(O)₂-or-NRSO₂NR' -. More typically, Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂-or-NRSO₂NR' -. More typically, Y¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-or-CO₂SO₂-. More typically, Y¹is-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-or-NRC (O) NR' -. More typically, Y¹is-C (O) O-, -NRC (O) -, -C (O) NR-or-NRC (O) NR' -. Y is¹Specific examples of (C) include-C (O) O-, -NHC (O) -, -C (O) NH-or-NHC (O) NH-.

R¹Comprises the following steps: i) -H; ii) optionally substituted by one or more J^ASubstituted C₁-C₆An aliphatic group; iii) C₃-C₁₀A carbocyclic group or a 4-10 membered heterocyclic group, each optionally and independently substituted with one or more J^BSubstitution; or iv)6-10 membered aryl or 5-10 membered heteroaryl, each optionally and independently substituted with one or more J^CSubstitution; or

Optionally, -Q¹-R¹Together with ring T, form optionally substituted one or more J⁴Substituted 4-10 membered non-aromatic spirocyclic rings.

In one aspect, R¹Independently i) -H; ii) optionally substituted by one or more J^ASubstituted C₁-C₆-an aliphatic group; iii) C₃–C₈Carbocyclic group or 4-8 membered heterocyclic groupClusters, each of them optionally and independently being substituted by one or more J^BSubstitution; iv) phenyl or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more J^CSubstitution; optionally, R¹Taken together with R' and the nitrogen to which they are attached, to form an optionally substituted 4-8 membered heterocyclic group; or optionally, -Q¹-R¹Taken together with ring T to form an optionally substituted 4-10 membered non-aromatic spirocyclic ring.

In another aspect, R¹Independently i) -H; ii) optionally substituted by one or more J ^ASubstituted C₁-C₆-an aliphatic group; iii) C₃–C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J^BSubstitution; iv) phenyl or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more J^CSubstitution; or optionally, R¹Taken together with R' and the nitrogen to which they are attached, to form an optionally substituted 4-8 membered heterocyclic group;

in another aspect, R¹Independently are: i) -H; ii) C optionally substituted with one or more substituents independently selected from₁-C₆Aliphatic group: halogen, cyano, hydroxy, oxo, -O (C)₁–C₄Alkyl), -NH₂、–NH(C₁–C₄Alkyl), -N (C)₁–C₄Alkyl radical)₂、-C(O)(C₁–C₄Alkyl), -OC (O) (C)₁–C₄Alkyl), -C (O) O (C)₁–C₄Alkyl), -CO₂H、C₃-C₈Carbocyclic groups, 4-8 membered heterocyclic groups, phenyl groups, and 5-6 membered heteroaryl groups; iii) C₃–C₇A carbocyclic group; iv) a 4-7 membered heterocyclic group; v) phenyl; or vi)5-6 membered heteroaryl; or optionally, R¹Taken together with R' and the nitrogen to which they are attached, to form an optionally substituted 4-8 membered heterocyclic group; and

with R¹Is represented by and is used for R¹Is represented by C₁-C₆Aliphatic radicalThe carbocyclic group, phenyl, heterocyclic group and heteroaryl of the substituents of (a), and R¹Said heterocyclic group formed with R', each of which is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

In another aspect, R¹Independently is-H or optionally substituted C₁-C₆Aliphatic radicals, e.g. H or optionally substituted C_1-6An alkyl group.

In another aspect, R¹Independently a 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl, wherein the heterocyclic group, phenyl, and heteroaryl are each independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or optionally, R¹And R' taken together with the nitrogen atom to which they are attached form an optionally substituted 4-8 membered heterocyclic group.

R²is-H, -OR, -CO₂R, -NRR ', -CONRR', or optionally substituted with one or more J¹Substituted C₁-C₆An aliphatic group. In general, R²is-H, -O (C)₁-C₄Alkyl), -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group. More typically, R²is-H, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group. More typically, R²is-H.

R³is-H, -F, -Cl, -CN, -NO ₂、–OR、–CO₂R, -CONRR' or optionally substituted by one or more J¹Substituted C₁-C₆An aliphatic group. In general, R³is-H, -F, -Cl, -CN, -NO₂、-O(C₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group. More typically, R³is-H, -F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group. More typically, R³is-F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group. More typically, R³is-F, -Cl, -CN or C₁-C₄A haloalkyl group. More typically, R³is-F, -Cl, -CN or CF₃. More typically, R³is-F or-Cl.

R¹²、R¹³And R¹⁴Each of which is independently-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups). In general, R¹²、R¹³And R¹⁴Each independently of the others is-H, halogen, cyano, hydroxy, -O (C)₁-C₆Alkyl) or optionally substituted C₁-C₆An alkyl group. More typically, R¹²、R¹³And R¹⁴Each independently of the others is-H, halogen, hydroxy, C ₁-C₆Alkyl radical, C₁-C₆Haloalkyl or-O (C)₁-C₆Alkyl groups).

Each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups). In general, R¹⁵is-H or optionally substituted C₁-C₆An alkyl group. More typically, R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

In one aspect, R¹²、R¹³And R¹⁴Each independently of the others is-H, halogen, cyano, hydroxy, -O (C)₁-C₆Alkyl) or optionally substituted C₁-C₆An alkyl group; and R is¹⁵is-H orOptionally substituted C₁-C₆An alkyl group.

In another aspect, R¹²And R¹³Each independently is-H, halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl or-O (C)₁-C₆Alkyl groups); and R is¹⁴And R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

R²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, -OH, C₁-C₆Alkoxy or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C) ₁-C₄Alkyl groups). In general, R²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

J^A、J^BAnd J^TEach independently oxo or J^C(ii) a And J^CEach and independently selected from halogen, cyano, M, R^aOr R^a-M. Optionally, two J^TTwo J^ATwo J^BAnd two J^CIndependently form, optionally substituted by one or more J, taken together with the atoms to which they are attached⁴Substituted 4-to 10-membered rings (e.g., 5-to 7-or 5-to 6-membered).

M is independently selected from-OR^b、–SR^b、-S(O)R^a、–SO₂R^a、–NR^bR^c、–C(O)R^a、-C(=NR)R^c、-C(=NR)NR^bR^c、-NRC(=NR)NR^bR^c、–C(O)OR^b、–OC(O)R^b、–NRC(O)R^b、–C(O)NR^bR^c、–NRC(O)NR^bR^c、–NRC(O)OR^b、–OCONR^bR^c、-C(O)NRCO₂R^b、-NRC(O)NRC(O)OR^b、-C(O)NR(OR^b)、-OSO₂NR^bR^c、–SO₂NR^cR^b、-NRSO₂R^b、-NRSO₂NR^cR^b、-P(O)(OR^b)₂、-OP(O)(OR^b)₂、-P(O)₂OR^band-CO₂SO₂R^b。

In general, J^CSelected from halogen, cyano, R^a、–OR^b、–SR^b、-S(O)R^a、–SO₂R^a、–NHR^c、–C(O)R^b、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、-NHC(O)NHC(O)OR^b、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、–OCON(CH₃)R^c、-C(O)NHCO₂R^b、-C(O)N(CH₃)CO₂R^b、-N(CH₃)C(O)NHC(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b(ii) a Or two J^CTaken together with the atoms to which they are attached, independently form an optionally substituted 4-10 membered non-aromatic ring.

In one aspect, J^A、J^B、J^CAnd J^TEach independently selected from halogen, cyano, R^a、–OR^b、–NHR^c、–C(O)R^b、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b(ii) a Or

Optionally, two J^TTwo J^ATwo J^BAnd two J^CTaken together with the atoms to which they are attached, independently form a 4-10 membered (or 5-7 membered or 5-6 membered) ring optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

In general, J ^AIs halogen, cyano, hydroxy, oxo, -O (C)₁–C₄Alkyl), -NH₂、–NH(C₁–C₄Alkyl), -N (C)₁–C₄Alkyl radical)₂、-C(O)(C₁–C₄Alkyl), -OC (O) (C)₁–C₄Alkyl), -C (O) O (C)₁–C₄Alkyl), -CO₂H、C₃-C₈A carbocyclic group, a 4-8 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein each of the carbocyclic group, phenyl group, heterocyclic group, and heteroaryl group is independently and optionally substituted with one or more substituents independently selected fromGeneration: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups). Optionally, two J^ATaken together with the atoms to which they are attached, form an optionally substituted 4-10 membered (or 5-7 membered or 5-6 membered) ring.

In general, J^BAnd J^CEach and independently is halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl or-O (C)₁-C₄Alkyl groups). Optionally, two J^BAnd two J^CTaken together with the atoms to which they are attached, independently form an optionally substituted 4-10 membered (or 5-7 membered or 5-6 membered) ring.

In general, J^TIs halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical) ₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl or-O (C)₁-C₄Alkyl groups). More generally, J^TIs halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups). Optionally, two J^TTaken together with the atoms to which they are attached to form an optionally substituted 4-to 10-membered (or 5-to 7-membered or5-6 membered) ring.

Usually, with two J' s^TTwo J^ATwo J^BAnd two J^CThe rings formed are independently optionally substituted non-aromatic rings, such as carbocyclic or heterocyclic rings. More typically, the ring is an optionally substituted carbocyclic ring.

R^aIndependently are:

ii)C₃-C₈a carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J²Substitution; or

iii) a 5-10 membered heteroaryl or 6-10 membered aryl, each of which is optionally and independently substituted with one or more J ³Substitution; and

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTogether with the nitrogen atom to which they are attached, each independently form an optionally substituted J or J²A substituted 4-8 membered heterocyclic group.

In one aspect, R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl radical: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl), optionally substituted C₃-C₈A carbocyclic group, an optionally substituted 4-8 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, and an optionally substituted phenyl group; ii) optionally substituted C₃-C₈A carbocyclic group; iii) an optionally substituted 4-8 membered heterocyclic group; iv) optionally substituted 5-6 membered heteroaryl; v) or optionally substituted phenyl; and

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form an optionally substituted 4-8 membered heterocyclic group.

In another aspect, R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical) ₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl group), C₃-C₈Carbocycle, 4-8 membered heterocycle, 5-6 membered heteroaryl and phenyl; ii) C₃-C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or iii)5-6 membered heteroaryl or phenyl, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); and

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form a 4-8 membered heterocyclic group optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

R^tAnd R^sEach independently-H, halogen or optionally substituted by one or more J ¹Substituted C₁-C₆Alkyl or optionally R^tAnd R^sTaken together with the carbon atoms to which they are attached, form a cyclopropane ring optionally substituted with one or more methyl groups. In general, R^tAnd R^sEach independently is-H, halogen, C₁-C₆Alkyl or C₁-C₆A haloalkyl group. More typically, R^tAnd R^sEach independently is-H or C₁-C₆An alkyl group.

R and R' eachIndependently is-H or optionally and independently is substituted with one or more J¹Substituted C₁-C₆Alkyl, or optionally, R and R' taken together with the nitrogen to which they are attached form optionally substituted by one or more J²A substituted 4-8 membered heterocyclic group. Typically, R and R' are each and independently-H or C_1-4An alkyl group; or optionally, R¹Taken together with R' and the nitrogen to which they are attached, form an optionally substituted 4-8 membered heterocyclic group. More typically, R and R' are each and independently-H or-CH₃(ii) a Or optionally, R¹Taken together with R' and the nitrogen to which they are attached, form an optionally substituted 4-8 membered heterocyclic group. More typically, R and R' are each and independently-H or-CH₃。

Each J¹Independently selected from halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl) and phenyl.

Each J²Independently selected from halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

J³and J⁴Each of which is independently selected from halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Each p is independently 1, 2, 3, or 4, and each k is independently 1, 2, 3, or 4. Typically, each of p and k is independently 1 or 2.

A second set of variable values for structural formula (I) is as follows:

x is-Cl, -Br, -F, -CN or optionally substituted C₁-C₆An alkyl group.

The remaining variables of structural formula (I) are each and independently as described above in the first set of variable values of structural formula (I).

A third set of variable values for structural formula (I) is as follows:

x is-Cl, -Br, -F, -CN or optionally substituted C₁-C₆An alkyl group.

R²is-H, -O (C)₁-C₄Alkyl), -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group.

The values of the fourth set of variables for structural formula (I) are as follows:

x and R²Are each and independently as described above in the second or third set of variable values of structural formula (I).

R³is-H, -F, -Cl, -CN, -NO₂、-O(C₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group.

A fifth set of variable values for structural formula (I) is as follows:

X、R²and R³Are each and independently as described above in any of the first through fourth sets of variable values of structural formula (I).

p and k are each and independently 1 or 2.

R^tAnd R^sEach independently is-H, halogen or C₁-C₄An alkyl group.

A sixth set of variable values for structural formula (I) is as follows:

R²、R³、R^t、R^sthe values of p and k are each and independently as described above in any of the first through fifth sets of variable values of structural formula (I).

X is-Cl, -Br, -F, -CN, C_1-4Alkyl or C₁-C₄A haloalkyl group.

A seventh set of variable values for structural formula (I) is as follows:

X、R³、R^t、R^sthe values of p and k are each and independently as described above in any of the first through sixth sets of variable values of structural formula (I).

R²is-H, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄HalogenatedAn alkyl group.

An eighth set of variable values for structural formula (I) is as follows:

X、R²、R^t、R^sthe values of p and k are each and independently as set forth above in any of the first through seventh sets of variable values of structural formula (I).

R³is-H, -F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

A ninth set of variable values for structural formula (I) is as follows:

X、R¹、R²、R³、R^t、R^sthe values of p and k are each and independently as set forth above in any of the first through eighth sets of variable values of structural formula (I).

Ring T is optionally substituted C₅-C₁₀A carbocyclic group or an optionally substituted 5-10 membered heterocarbocyclic group.

A tenth set of variable values for structural formula (I) is as follows:

x, ring T, R¹、R²、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through ninth sets of variable values of structural formula (I).

R³is-F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

An eleventh set of variable values for structural formula (I) is as follows:

Ring T, R¹、R²、R³、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through tenth sets of variable values of structural formula (I).

X is-Cl, -F, -Br, -CN, -CH₃or-CF₃。

A twelfth set of variable values for structural formula (I) is as follows:

ring T, X, R¹、R²、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through eleventh sets of variable values of structural formula (I).

R³is-F, -Cl, -CN or C₁-C₄A haloalkyl group.

A thirteenth set of variable values for structural formula (I) is as follows:

ring T, X, R¹、R²、R³、R^t、R^sP and k are each and independently as described above in any one of the first to twelfth sets of variable values of structural formula (I).

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-B(O)₂-or- (CR)^tR^s)_p–Y¹–。

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-B(O)₂-or-NRSO₂NR’-。

A fourteenth set of variable values for structural formula (I) is as follows:

ring T, X, R¹、R²、R³、R^t、R^sThe values for p and k are each and independently as set forth above in any one of the first through thirteenth sets of variable values of structural formula (I).

Q¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-or- (CR)^tR^s)_p–Y¹–。

Y¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-or-CO₂SO₂-。

A fifteenth set of variable values for structural formula (I) is as follows:

ring T, X, Q¹、Y¹、R²、R³、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through fourteenth sets of variable values of structural formula (I).

R¹Independently i) -H; ii) optionally substituted by one or more J^ASubstituted C₁-C₆-an aliphatic group; iii) C₃–C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J^BSubstitution; iv) phenyl or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more J^CSubstitution; or

Optionally, R¹Together with R' and the nitrogen to which they are attached, form an optionally substituted one or more J²A substituted 4-8 membered heterocyclic group.

J^AAnd J^BEach independently is oxo or J^C(ii) a And

J^Cselected from halogen, cyano, R^a、–OR^b、–SR^b、-S(O)R^a、–SO₂R^a、–NHR^c、–C(O)R^a、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、-NHC(O)NHC(O)OR^b、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、–OCON(CH₃)R^c、-C(O)NHCO₂R^b、-C(O)N(CH₃)CO₂R^b、-N(CH₃)C(O)NHC(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b(ii) a Or

Optionally, two J^ATwo J^BAnd two J^CTaken together with the atoms to which they are attached, independently form an optionally substituted 4-10 membered non-aromatic ring.

A sixteenth set of variables for structural formula (I) is as follows:

ring T, X, Q¹、Y¹、R¹、R²、R³、J^A、J^B、J^C、R、R'、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through fifteenth sets of variable values of structural formula (I).

R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl), optionally substituted C₃-C₈A carbocyclic group, an optionally substituted 4-8 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, and an optionally substituted phenyl group; ii) optionally substituted C₃-C₈A carbocyclic group; iii) an optionally substituted 4-8 membered heterocyclic group; iv) optionally substituted 5-6 membered heteroaryl; v) or optionally substituted phenyl;

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form an optionally substituted 4-8 membered heterocyclic group; and

r and R' are each and independently-H or C_1-4Alkyl, or optionally, R and R 'taken together with the nitrogen to which they are attached form an optionally substituted 4-8 membered heterocyclic group, or optionally, R' and R¹And the nitrogen to which they are attached, together form an optionally substituted 4-8 membered heterocyclic group.

A seventeenth set of variable values for structural formula (I) is as follows:

ring T, Q¹、Y¹、R¹、R²、R³、J^A、J^B、J^C、R、R'、R^a、R^b、R^c、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through sixteenth sets of variable values of structural formula (I).

X is-Cl, -F, -CN or-CF₃。

An eighteenth set of variable values for structural formula (I) is as follows:

ring T, Q¹、Y¹、R¹、R²、R³、J^A、J^B、J^C、R、R'、R^a、R^b、R^c、R^t、R^sThe values of p and k are each and independently as set forth above in any of the first through seventeenth sets of variable values of structural formula (I).

X is-Cl or-F.

The nineteenth set of variable values for structural formula (I) are as follows:

X、Q¹、Y¹、R¹、R²、R³、J^A、J^B、J^C、R、R'、R^a、R^b、R^c、R^t、R^sthe values for p and k are each and independently as set forth above in any of the first through eighteenth sets of variable values of structural formula (I).

Ring T is optionally substituted, bridging C₅-C₁₀A carbocyclic group.

The twenty-first set of variable values for structural formula (I) is as follows:

Ring T is an optionally substituted monocyclic ring C₅-C₈A carbocyclic group.

A twenty-second set of values for the variables of structural formula (I) is as follows:

The ring T is:

and wherein:

ring A is a 5-10 membered carbocyclic group or a 5-10 membered heterocyclic group, each of which is optionally further substituted with one or more J^TSubstitution; or optionally, rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming optionally further substituted J or J^TA substituted 4-10 membered bridged ring; and

R¹²、R¹³and R¹⁴Each of which is independently-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C) ₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups); and

x is 0, 1 or 2.

A twenty-third set of variable values for structural formula (I) is as follows:

ring T, X, Q¹、Y¹、R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R、R'、R^a、R^b、R^c、R^t、R^sThe values of p, k and x are each and independently as described above in any of the first through twenty sets of variable values of structural formula (I).

J^A、J^B、J^CAnd J^TEach independently selected from halogen, cyano, R^a、–OR^b、–NHR^c、–C(O)R^b、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b(ii) a Or

Optionally, two J^TTwo J^ATwo J^BAnd two J^CTaken together with the atoms to which they are attached, independently form a 4-10 membered ring optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

The values of the twenty-fourth set of variables for structural formula (I) are as follows:

ring T, J^A、J^B、J^C、J^T、X、Q¹、Y¹、R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R、R'、R^t、R^sThe values for p, k and x are each and independently as described above in any of the first through twenty third sets of variable values of structural formula (I).

R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl group), C₃-C₈Carbocycle, 4-8 membered heterocycle, 5-6 membered heteroaryl and phenyl; ii) C₃-C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or iii)5-6 membered heteroaryl or phenyl, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); and

R^band R^cEach independently is R^aor-H; or optionally, R ^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form a 4-8 membered heterocyclic group optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

The values of the twenty-fifth set of variables for structural formula (I) are as follows:

ring T, J^A、J^B、J^C、J^T、X、R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R^a、R^b、R^cThe values of, R, R', p, k and x are each and independently as described above in Structure (I)Any one of the first through twenty-third sets of variable values.

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂-, -OC (O) NR' -, or- (CR)^tR^s)_p–Y¹–。

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂-or-OC (O) NR' -.

A twenty-sixth set of variable values for structural formula (I) is as follows:

ring T is as described above in the twenty-second set of variable values for structural formula (I).

R¹²、R¹³And R¹⁴Each independently of the others is-H, halogen, cyano, hydroxy, -O (C)₁-C₆Alkyl) or optionally substituted C₁-C₆An alkyl group.

R¹⁵is-H or optionally substituted C ₁-C₆An alkyl group.

R^tAnd R^sEach independently is-H, halogen, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

Q¹、Y¹、J^A、J^B、J^C、J^T、X、R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R^a、R^b、R^cThe values of R, R', p and k are each and independently as above in the structural formulae(I) Any one of the first through twenty-fifth sets of variable values of (a).

A twenty-seventh set of variable values for structural formula (I) is as follows:

Ring X, Q¹、Y¹、R¹、R²、R³、R^a、R^b、R^c、R、R'、J^A、J^B、J^COr J^TThe values of p and k are each and independently as described above in any of the first through twenty-fifth sets of variable values of structural formula (I).

R¹²And R¹³Each independently is-H, halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl or-O (C)₁-C₆Alkyl groups).

R¹⁴And R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

R^tAnd R^sEach independently is-H or C₁-C₆An alkyl group.

The twenty-eighth set of variable values for structural formula (I) are as follows:

ring T, X, Q¹、Y¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^B、J^COr J^TP, k and xThe values are each and independently as described above in any one of the first to twenty-seventh sets of variable values of structural formula (I).

R¹Independently are: i) -H; ii) C optionally substituted with one or more substituents independently selected from₁-C₆Aliphatic group: halogen, cyano, hydroxy, oxo, -O (C)₁–C₄Alkyl), -NH₂、–NH(C₁–C₄Alkyl), -N (C)₁–C₄Alkyl radical)₂、-C(O)(C₁–C₄Alkyl), -OC (O) (C)₁–C₄Alkyl), -C (O) O (C)₁–C₄Alkyl), -CO₂H、C₃-C₈Carbocyclic groups, 4-8 membered heterocyclic groups, phenyl groups, and 5-6 membered heteroaryl groups; iii) C₃–C₇A carbocyclic group; iv) a 4-7 membered heterocyclic group; v) phenyl; or vi)5-6 membered heteroaryl; or

Optionally, R¹Taken together with R' and the nitrogen to which they are attached, to form an optionally substituted 4-8 membered heterocyclic group; and

with R¹Is represented by and is used for R¹Is represented by C₁-C₆Said carbocyclic group, phenyl, heterocyclic and heteroaryl group being substituents of aliphatic groups, and R¹Said heterocyclic group formed with R', each of which is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

A twenty-ninth set of variables for structural formula (I) are as follows:

Ring T is as described above in the twenty-second set of values for variables of structural formula (I), wherein ring a is a carbocyclic or heterocyclic group, each of which is optionally and independently further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming a bridged carbocyclic group or a bridged heterocyclic group, each of which is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

X、Q¹、Y¹、R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^B、J^CThe values of p, k and x are each and independently as described above in any of the first to twenty-eighth sets of variable values of structural formula (I).

A thirtieth set of variable values for structural formula (I) is as follows:

Ring T is as described above in the twenty-second set of variables of Structure (I), wherein rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently forming an optionally substituted 4-10 membered bridged ring.

A thirty-first set of variable values for structural formula (I) is as follows:

X、Q¹、Y¹、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^B、J^Cthe values of p and k are each and independently as described above in any of the first to twenty-eighth sets of variable values of structural formula (I).

The ring T is:

wherein:

each ring a1-a5 is independently a 5-10 membered bridged carbocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

ring a6 is a 5-10 membered bridged heterocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

each R¹⁴Independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C) ₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl radical)and-O (C)₁-C₄Alkyl groups);

each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

R²¹、R²²、R²³、R²⁴and R²⁵Each independently is-H, halogen, -OH, C₁-C₆Alkoxy or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

z is-O-, -S-or-NR^g-；

R^gis-H or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C) ₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

q is 0, 1 or 2; and

r is 1 or 2.

A thirty-second set of variable values for structural formula (I) is as follows:

the values of ring T are each and independently as described above in the thirty th set of variable values of structural formula (I), wherein R¹⁴And each R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and R is²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

A thirty-third set of variable values for structural formula (I) is as follows:

the values of ring T are each and independently as described above in the thirtieth set of variable values of structural formula (I), wherein:

R¹⁴、R¹⁵、R²¹、R²²、R²³、R²⁴and R²⁵Each independently as described above in the thirty-first or thirty-second set of variable values of structural formula (I);

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

The values of the thirty-fourth set of variables for structural formula (I) are as follows:

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

X、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^BAnd J^CAre each and independently as described above in any of the first through twenty-eighth sets of variable values of structural formula (I).

Q¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)_1,2–Y¹-; to be provided withAnd

Y¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

The values of the thirty-fifth set of variables for structural formula (I) are as follows:

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

Q¹independently-C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

A thirty-sixth set of values for variables of structural formula (I) is as follows:

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

X、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、J^A、J^BAnd J^CAre each and independently as described above in any of the first through twenty-eighth sets of variable values of structural formula (I).

Q¹independently-C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

R and R' are each and independently-H or-CH₃。

A seventeenth set of variable values for structural formula (I) is as follows:

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

Q¹independently-C (O) O-, -NHC (O) -, -C (O) NH-or-NHC (O) NH-.

The thirty-eighth set of variable values for structural formula (I) are as follows:

the ring T is:

wherein each of rings a1-a6 is independently and optionally further substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

R¹⁴、R¹⁵、R²¹、R²²、R²³、R²⁴And R²⁵Are each and independently as described above in the thirty-first or thirty-second set of variable values of structural formula (I).

Z and R^gAre each and independently as described above in the thirty third set of variable values of structural formula (I).

X、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^BAnd J^CEach and independently varies as above in the first to the second eighteen groups of structural formula (I)Magnitude as described in any one of the groups.

A thirty-ninth set of variables for structural formula (I) is as follows:

ring T, Z and R^gEach and independently as described above in the eighteenth thirty sets of variable values of structural formula (I).

R¹⁴And each R¹⁵Each independently is-H or C_1-6An alkyl group; and

R²¹、R²²、R²³、R²⁴and R²⁵Independently is-H or C_1-6An alkyl group.

The fortieth set of variable values for structural formula (I) are as follows:

ring T, Z and R^gAre each and independently as described above in the thirty-eighth set of variable values for structural formula (I)

R¹⁴、R¹⁵、R²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H.

X、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^BAnd J^CAre each and independently as described above in any one of the first to twenty-eighth sets of variables of structural formula (I).

The fortieth set of variable values for structural formula (I) is as follows:

ring T is selected from:

wherein:

each of rings A8-a11 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Each R¹⁴Independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups). And

each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

X、Q¹、Y¹、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^BAnd J^CAre each and independently as described above in any one of the first to twenty-eighth sets of variables of structural formula (I).

The values of the fortieth set of variables for structural formula (I) are as follows:

ring T, R¹⁴、R¹⁵Each and independently as described above in the fortieth set of variable values of structural formula (I).

Q¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)_1,2–Y¹–。

Y¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

A forty-third set of variables for structural formula (I) are as follows:

ring T is as described above in the fortieth set of variable values of structural formula (I), wherein each of rings A8-a11 is independently and optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

R¹⁴And each R¹⁵Each independently is-H or C_1-6An alkyl group.

X、Q¹、Y¹、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、R、R'、J^A、J^BAnd J^CAre each and independently as described above in any of the first through twenty-eighth and forty-fourth sets of variables of structural formula (I).

A forty-third set of variables for structural formula (I) are as follows:

ring T, R¹⁴And R¹⁵Each and independently as described above in the forty-first or forty-third set of variable values of structural formula (I).

R and R' are each and independently-H or-CH₃。

X、R¹、R²、R³、R^s、R^t、R^a、R^b、R^c、J^A、J^BAnd J^CAre each and independently as described above in any of the first through twenty-eighth and forty-fourth sets of variables of structural formula (I).

Q¹independently-NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

R and R' are each and independently-H or-CH₃。

The values of the forty-fifth set of variables for structural formula (I) are as follows:

X、R²、R³、R^s、R^t、R^a、R^b、R^c、J^A、J^BAnd J^CAre each and independently as described above in any of the first through twenty-eighth and forty-fourth sets of variables of structural formula (I).

R and R' are each and independently-H or-CH₃(ii) a And

R¹independently a 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl, wherein each of the heterocyclic, phenyl, and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or

Optionally, R¹And R' taken together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl, each of which is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C) ₁-C₄Alkyl groups).

In another embodiment, the compounds of the present invention are represented by structural formula (II):

wherein the variable values of formula (II) are each and independently as described above in any one of the first to forty-five sets of variable values of formula (I).

The forty-sixth set of variables for structural formula (II) are as follows:

X is-Cl, -F, -Br, -CN, -CH₃or-CF₃。

R²is-H, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

In one aspect, R³is-F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group. In another aspect, R³is-F, -Cl, -CN or C₁-C₄A haloalkyl group.

p and k are each and independently 1 or 2.

R^tAnd R^sEach independently is-H, halogen or C₁-C₄An alkyl group.

The remaining variables are each and independently as described above in the first set of variable values of structural formula (I).

The values of the seventeenth set of variables for structural formula (II) are as follows:

ring T, X, R²、R³、R^t、R^sP and k are each and independently as above at forty-th of formula (II) Six sets of variable values.

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR' -or- (CR)^tR^s)_p–Y¹–。

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂-or-NRSO₂NR’-。

The fourteenth and eighth sets of variable values for structural formula (II) are as follows:

ring T, X, R²、R³、R^t、R^sThe values for p and k are each and independently as described above in the forty-sixth set of variable values for structural formula (II).

The values of the nineteenth variable set of structural formula (II) are as follows:

Q¹And Y¹Are each and independently as described above in the forty-seventeen or forty-eight sets of variable values of structural formula (II).

R¹Independently i) -H; ii) optionally substituted by one or more J^ASubstituted C₁-C₆-an aliphatic group; iii) C₃–C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J^BSubstitution; iv) phenyl or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more J ^CSubstitution; or

Optionally, R¹Together with R' and the nitrogen to which they are attached, form an optionally substituted one or more J²A substituted 4-8 membered heterocyclic group; and

J^A、J^Band J^TEach independently is oxo or J^C(ii) a And

J^Cselected from halogen, cyano, R^a、–OR^b、–SR^b、-S(O)R^a、–SO₂R^a、–NHR^c、–C(O)R^a、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、-NHC(O)NHC(O)OR^b、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、–OCON(CH₃)R^c、-C(O)NHCO₂R^b、-C(O)N(CH₃)CO₂R^b、-N(CH₃)C(O)NHC(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b；

Optionally, two J^TTwo J^ATwo J^BAnd two J^CTaken together with the atoms to which they are attached, independently form an optionally substituted 4-10 membered non-aromatic ring.

The fifty-group variable values for structural formula (II) are as follows:

R¹、J^A、J^B、J^CAnd J^TAre each and independently as described above in the forty-seventeen or forty-eight sets of variable values of structural formula (II).

R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO ₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl), optionally substituted C₃-C₈A carbocyclic group, an optionally substituted 4-8 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, and an optionally substituted phenyl group; ii) optionally substituted C₃-C₈A carbocyclic group; iii) an optionally substituted 4-8 membered heterocyclic group; iv) optionally substituted 5-6 membered heteroaryl; v) or optionally substituted phenyl;

In another embodiment, the compounds of the present invention are represented by structural formula (IIIA) or (IIIB):

wherein the variable values of formula (II) are each and independently as described above in any one of the first to forty-fifth sets of variable values of formula (I) or the forty-sixteenth to fifty sets of variable values of formula (II).

The fifty-group of variable values for structures (IIIA) and (IIIB) are as follows:

X is-Cl, -F, -Br, -CN, -CH₃or-CF₃。

p and k are each and independently 1 or 2.

R^tAnd R^sEach independently is-H, halogen or C₁-C₄An alkyl group.

J^A、J^BAnd J^TEach independently is oxo or J^C(ii) a And

R^aIndependently are: i) c optionally substituted by one or more substituents selected from ₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl), optionally substituted C₃-C₈A carbocyclic group, an optionally substituted 4-8 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, and an optionally substituted phenyl group; ii) optionally substituted C₃-C₈A carbocyclic group; iii) an optionally substituted 4-8 membered heterocyclic group; iv) optionally substituted 5-6 membered heteroaryl; v) or optionally substituted phenyl;

R^band R^cEach independently is Ra or-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form an optionally substituted 4-8 membered heterocyclic group; and

The fifty-second set of variable values for structures (IIIA) and (IIIB) is as follows:

ring T, R¹、R^t、R^s、R^a、R^b、R^c、R、R'、Q¹、Y¹、J^A、J^B、J^C、J^TThe values for p and k are each and independently as described above in the fifty-th set of variable values for structural formulae (IIIA) and (IIIB).

In one aspect, X is-Cl, -F, -CN, or-CF₃. In another aspect, X is-Cl or-F.

The fifty-third set of variable values for structures (IIIA) and (IIIB) are as follows:

in one aspect, ring T is an optionally substituted bridging C₅-C₁₀A carbocyclic group. In another aspect, ring T is an optionally substituted monocyclic ring C₅-C₈A carbocyclic group.

X is-Cl or-F.

R¹、R^t、R^s、R^a、R^b、R^c、R、R'、Q¹、Y¹、J^A、J^B、J^C、J^TThe values for p and k are each and independently as described above in the fifty-th set of variable values for structural formulae (IIIA) and (IIIB).

The values of the fifty-fourth set of variables for structures (IIIA) and (IIIB) are as follows:

X is-Cl or-F.

The ring T is:

and wherein:

ring A is a 5-10 membered carbocyclic group or a 5-10 membered heterocyclic group, each of which is optionally further substituted with one or more J^TSubstitution; or optionally, rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming optionally further substituted J or J ^TSubstituted 4-10 membered bridged rings.

In one aspect: r¹²、R¹³And R¹⁴Each of which is independently-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more groups selected fromSubstituent group substitution: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups); each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups); and X is 0, 1 or 2.

In another aspect: r¹²、R¹³And R¹⁴Each independently of the others is-H, halogen, cyano, hydroxy, -O (C)₁-C₆Alkyl) or optionally substituted C₁-C₆An alkyl group; r¹⁵is-H or optionally substituted C₁-C₆An alkyl group; and X is 0, 1 or 2.

In yet another aspect: r¹²And R¹³Each independently is-H, halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl or-O (C)₁-C₆Alkyl groups); r¹⁴And R¹⁵Each independently is-H, C ₁-C₆Alkyl or C₁-C₆A haloalkyl group; and X is 0, 1 or 2.

The fifty-fifth set of variables for structures (IIIA) and (IIIB) are as follows:

R¹、R^t、R^s、R^a、R^b、R^c、R、R'、Q¹、Y¹the values for p and k are each and independently as described above in the fifty-th set of variable values for structural formulae (IIIA) and (IIIB).

Ring T, R¹²、R¹³、R¹⁴、R¹⁵And x are each and independently as described above in the fifty-fourth set of variable values for structural formulae (IIIA) and (IIIB).

X is-Cl or-F.

The values of the fifty-sixth set of variables for structures (IIIA) and (IIIB) are as follows:

R¹、R^t、R^s、R、R'、Q¹、Y¹the values for p and k are each and independently as described above in the fifty-th set of variable values for structural formulae (IIIA) and (IIIB).

J^A、J^B、J^CAnd J^TAre each and independently as described above in the fifty-fifth set of variable values for structural formulae (IIIA) and (IIIB).

X is-Cl or-F.

R^aIndependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl group), C₃-C₈Carbocycle, 4-8 membered heterocycle, 5-6 membered heteroaryl and phenyl; ii) C₃-C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or iii)5-6 membered heteroaryl or phenyl, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C) ₁-C₄Alkyl groups); and

The values of the seventeenth group of variables for structural formulae (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

R^a、R^bAnd R^cAre each and independently as described above in the fifty-fifth set of variable values for structural formulae (IIIA) and (IIIB).

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂-, -OC (O) NR' -, or- (CR) ^tR^s)_p–Y¹–。

The values of the fifty-eighth group variables for structural formulas (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

Q¹And Y¹Are each and independently as described above in the seventeenth set of variable values of structural formulae (IIIA) and (IIIB).

R¹Independently are: i) -H; ii) C optionally substituted with one or more substituents independently selected from₁-C₆Aliphatic group: halogen, cyano, hydroxy, oxo, -O (C)₁–C₄Alkyl), -NH₂、–NH(C₁–C₄Alkyl), -N (C)₁–C₄Alkyl radical)₂、-C(O)(C₁–C₄Alkyl), -OC (O) (C)₁–C₄Alkyl), -C (O) O (C)₁–C₄Alkyl), -CO₂H、C₃-C₈Carbocyclic groups, 4-8 membered heterocyclic groups, phenyl groups, and 5-6 membered heteroaryl groups; iii) C ₃–C₇A carbocyclic group; iv) a 4-7 membered heterocyclic group; v) phenyl; or vi)5-6 membered heteroaryl; or

The values of the nineteenth variable groups of structural formulae (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

Ring T is as described above, wherein J^TIs halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl or-O (C)₁-C₄Alkyl groups); j. the design is a square ²Is halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl or-O (C)₁-C₄Alkyl groups).

The values of R, R', p, and k are each and independently as described above in the fifty-th set of variable values for structural formulas (IIIA) and (IIIB).

R¹²、R¹³、R¹⁴、R¹⁵And x are each and independently as described above in the fifty-fourth set of variable values for structural formulae (IIIA) and (IIIB).

R¹、R^tAnd R^sAre each and independently as described above in the fifty-eighth set of variable values for structural formulae (IIIA) and (IIIB).

The sixty-group variable values for structures (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

The ring T is:

wherein:

each of rings a1-a5 is independently a 5-10 membered bridged carbocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);and

ring a6 is a 5-10 membered bridged heterocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Each R¹⁴Independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

Each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C₁-C₄Alkyl groups).

R²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, -OH, C ₁-C₆Alkoxy or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

Z is-O-, -S-or-NR^g-。

R^gis-H or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

q is 0, 1 or 2.

r is 1 or 2.

R¹、R^tAnd R^sEach and independently as above in structural formula (III)A) And (IIIB).

The sixty-group of variable values for structures (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

Ring T is as described above in the sixty-group of variables for structures (IIIA) and (IIIB), where R ¹⁴And each R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and R is²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

The sixty-second set of variable values for structures (IIIA) and (IIIB) is as follows:

x is-Cl or-F.

In one aspect, Q¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)₁,₂–Y¹-; and Y is¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -. In another aspect, Q¹independently-C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

Ring T is as described above in the sixty-group of variables for structures (IIIA) and (IIIB), where R ¹⁴And each R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; r²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; z is-O-or-NR^g-; and R is^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

R¹The values of (c) are as described above in the fifty-eighth set of variable values for structural formulae (IIIA) and (IIIB).

The sixty-third set of variable values for structures (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

The ring T is:

wherein each of rings a1-a6 is independently and optionally further substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); z is-O-or-NR^g-；R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and the values of the other variables are each and independently as described above in the sixty-set of values for structural formulae (IIIA) and (IIIB).

Q¹independently-C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

R¹Independently are: i) -H; ii) C optionally substituted with one or more substituents independently selected from₁-C₆Aliphatic group: halogen, cyano, hydroxy, oxo, -O (C) ₁–C₄Alkyl), -NH₂、–NH(C₁–C₄Alkyl), -N (C)₁–C₄Alkyl radical)₂、-C(O)(C₁–C₄Alkyl), -OC (O) (C)₁–C₄Alkyl), -C (O) O (C)₁–C₄Alkyl), -CO₂H、C₃-C₈Carbocyclic groups, 4-8 membered heterocyclic groups, phenyl groups, and 5-6 membered heteroaryl groups; iii) C₃–C₇A carbocyclic group; iv) a 4-7 membered heterocyclic group; v) phenyl; or vi)5-6 membered heteroaryl; or

In one aspect, R¹⁴And each R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and R is²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group. In another aspect, R¹⁴And each R¹⁵Each independently is-H or C_1-6An alkyl group; and R is ²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H or C_1-6An alkyl group. In another aspect, R¹⁴、R¹⁵、R²¹、R²²、R²³、R²⁴And R²⁵Each independently is-H.

R and R' are each and independently-H or-CH₃。

q is 0, 1 or 2; and

r is 1 or 2.

The values of the sixty-fourth variables for structures (IIIA) and (IIIB) are as follows:

x is-Cl or-F.

Ring T is selected from:

in one aspect: each of rings A8-A11 is independent and arbitraryOptionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); each R¹⁴Independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups); and each R¹⁵independently-H, halogen, cyano, hydroxy or C optionally and independently substituted with one or more substituents selected from ₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups).

In another aspect: ring A8-a11 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, halogen,Hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); and R is¹⁴And each R¹⁵Each independently is-H or C_1-6An alkyl group.

Optionally, R¹Taken together with R' and the nitrogen to which they are attached to form an optionally substituted 4-8 membered heterocyclic group; and

with R¹Is represented by and is used for R¹Is represented by C₁-C₆Said carbocyclic group, phenyl, heterocyclic and heteroaryl group being substituents of aliphatic groups, and R¹Said heterocyclic group formed with R', each of which is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

p and k are each and independently 1 or 2.

R^tAnd R^sEach independently is-H, halogen or C₁-C₄An alkyl group.

The values of the sixty-five variable groups of structural formulae (IIIA) and (IIIB) are as follows:

x, ring T, R¹The values for R and R' are each and independently as described above in the sixty-fourth set of variable values for structures (IIIA) and (IIIB).

Q¹is-NRC (O) -, -C (O) NR-or-NRC (O) NR' -.

The sixteenth set of variable values for structures (IIIA) and (IIIB) is as follows:

the values of X and ring T are each and independently as described above in the sixty-fourth set of variable values for structures (IIIA) and (IIIB).

Q¹is-NRC (O) -, -C (O) NR-or-NRC (O) NR' -.

R and R' are each and independently-H or-CH₃(ii) a And

Optionally, R¹And R' taken together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl, each of which is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

In a further embodiment, the compounds of the invention are represented by any one of structural formulae (I), (II), (IIIA) and (IIIB) or a pharmaceutically acceptable salt thereof, wherein the variable values of structural formulae (I), (II), (IIIA) and (IIIB) are each and independently variable As described above in any of the embodiments, with the proviso that Q¹-R¹Not at the same carbon atom to which the-NH group attached to the pyrimidine ring of each formula is attached.

Specific examples of the compound represented by the structural formula (I) include:

and

pharmaceutically acceptable salts thereof.

Further specific examples of the compound represented by the structural formula (I) include:

and pharmaceutically acceptable salts thereof.

In some embodiments, the compounds of the present invention are selected from any of the compounds depicted in tables 1 and 2, or pharmaceutically acceptable salts thereof.

As used herein, reference to a compound of the invention (e.g. a compound of structural formula (I) or a compound according to claim 1) is intended to include pharmaceutically acceptable salts thereof.

The compounds of the invention described herein may be prepared by any suitable method known in the art. For example, they may be prepared according to the procedures described in WO2005/095400, WO2007/084557, WO2010/011768, WO2010/011756, WO2010/011772, WO2009/073300 and PCT/US2010/038988 filed on 6/17/2010. For example, the compounds shown in tables 1 and 2, as well as the specific compounds depicted above, may be prepared by any suitable method known in the art, e.g., WO2005/095400, WO2007/084557, WO2010/011768, WO2010/011756, WP2010/011772, WO2009/073300, and PCT/US2010/038988, as well as by the exemplary syntheses described below under "examples".

The present invention provides a process for preparing compounds represented by structural formulae (I), (II), (IIIA) and (IIIB). In one example, the compounds of the present invention may be prepared as depicted in general schemes 1-4. Any suitable conditions known in the art may be used in the present invention for each step depicted in the scheme.

In a specific embodiment, as shown in general scheme 1, the method comprises the steps of: reacting compound (A) with compound (B) under suitable conditions to form a compound of formula (XX), wherein L¹And L²Each of which is independently halogen (F, Cl, Br or I), G is trityl and the remaining variables of compounds (a), (B) and structural formula (XX) are each and independently as described herein. L is¹And L²Each and independently is Cl or Br. The method further comprises the step of deprotecting the G group under suitable conditions to form a compound of formula (I). Any suitable conditions known in the art may be used in the present invention for each step depicted in the scheme. For example, any suitable conditions described in WO2005/095400 and WO2007/084557 for coupling dioxolane (dioxaborolan) with chloropyrimidine may be used for the reaction between compounds (a) and (B). Specifically, the reaction between the compound (A) and the compound (B) may be carried out in Pd (PPh) ₃)₄Or Pd₂(dba)₃(dba is dibenzylidene acetone). For example, the detritylation step can be carried out under acidic conditions (e.g., trifluoroacetic acid (TFA)) under, for example, Et₃In the presence of SiH (Et is ethyl). Specific exemplary conditions are described in the "examples" below.

Optionally, the method further comprises the step of preparing compound (a) by reacting compound (E) with compound (D). Any suitable conditions known in the art may be used for this step, and compounds (E) and (D) may be prepared by any suitable method known in the art. Specific exemplary conditions are described in the "examples" below.

General scheme 1

In another specific embodiment, as shown in general scheme 2, the method comprises the step of reacting compound (G) with compound (D) under suitable conditions to form a compound of formula (XX), wherein L¹And L²Each of (a) is independently halogen (F, Cl, Br, or I), G is trityl, and the remaining variables of compounds (G), (D), and structural formula (XX) are each and independently as described herein. L is¹And L²Each and independently is Cl or Br. The method further comprises the step of deprotecting the G group under suitable conditions to form a compound of formula (I). Any suitable conditions known in the art may be used in the present invention for each step depicted in the scheme. For example, any suitable amination conditions known in the art may be used in the present invention for the reaction of compound (G) with compound (D), and any suitable conditions for deprotecting the Tr group may be used in the deprotection step in the present invention. For example, the amination step may be carried out in a base such as NEt ₃Or N (ⁱPr)₂In the presence of Et. For example, the detritylation step can be carried out under acidic conditions (e.g., trifluoroacetic acid (TFA)) under, for example, Et₃In the presence of SiH (Et is ethyl). Additional specific exemplary conditions are described in the "examples" below.

Optionally, the method further comprises the step of preparing compound (G) by reacting compound (F) with compound (B). Any suitable conditions known in the art may be employed in this step. For example, for the reaction between compound (F) and compound (B), any suitable conditions described in WO2005/095400 and WO2007/084557 for the coupling of dioxolane with chloropyrimidine can be employed. Specifically, the reaction between the compound (F) and the compound (B) may be carried out in Pd (PPh)₃)₄Or Pd₂(dba)₃(dba is dibenzylidene acetone). Specific exemplary conditions are described in the "examples" below.

General scheme 2

In another specific embodiment, as shown in general scheme 3, the method comprises the step of reacting compound (K) with compound (D) under suitable conditions to form a compound of structural formula (XX), wherein G is trityl and the remaining variables of compounds (K), (D) and structural formula (XX) are each and independently as described herein. The method further comprises the step of deprotecting the G group under suitable conditions to form a compound of formula (I). Any suitable conditions known in the art may be used in the present invention for each step depicted in the scheme. For example, any suitable reaction conditions known in the art, for example in WO2005/095400 and WO2007/084557 for coupling an amine with a sulfinyl group, may be used for the reaction of compound (K) with compound (D). For example, compound (D) and compound (K) can be reacted in a base such as NEt ₃Or N (ⁱPr)₂(Et). For example, the detritylation step can be carried out under acidic conditions (e.g., trifluoroacetic acid (TFA)) under, for example, Et₃In the presence of SiH (Et is ethyl). Additional specific exemplary conditions are described in the "examples" below.

Optionally, the process further comprises the step of preparing compound (K) by oxidizing compound (J), for example by treatment with m-chloroperbenzoic acid.

Optionally, the method further comprises a step of preparing compound (J) by reacting compound (H) with compound (B). Any suitable conditions known in the art may be employed in this step. For example, any suitable conditions described in WO2005/095400 and WO2007/084557 for coupling dioxolane and chloropyrimidine may be used for the reaction between compound (H) and compound (B). Specifically, the reaction between the compound (H) and the compound (B) may be carried out in Pd (PPh)₃)₄Or Pd₂(dba)₃(dba is dibenzylidene acetone). Specific exemplary conditions areDescribed in the "examples" below.

General scheme 3

In another specific embodiment, as shown in general scheme 4, the method comprises the step of reacting compound (L) with compound (D) under suitable conditions to form a compound of structural formula (XX), wherein G is trityl and the remaining variables of compounds (L), (D) and structural formula (XX) are each and independently as described herein. The method further comprises the step of deprotecting the G group under suitable conditions to form a compound of formula (I). Any suitable conditions known in the art may be used in the present invention for each step depicted in the scheme. For example, any suitable reaction conditions known in the art, for example in WO2005/095400 and WO2007/084557 for coupling an amine to a sulfonyl group, may be used for the reaction of compound (L) with compound (D). For example, compound (D) and compound (L) can be reacted in a base such as NEt ₃Or N (ⁱPr)₂(Et). For example, the detritylation step can be carried out under acidic conditions (e.g., trifluoroacetic acid (TFA)) under, for example, Et₃In the presence of SiH (Et is ethyl). Additional specific exemplary conditions are described in the "examples" below.

Optionally, the process further comprises the step of preparing compound (L) by oxidizing compound (J), for example by treatment with m-chloroperbenzoic acid.

Optionally, the method further comprises a step of preparing compound (J) by reacting compound (H) with compound (B). The reaction conditions are as described above for general scheme 3.

General scheme 4

Compounds (a) - (K) may be prepared by any suitable method known in the art. Specific exemplary synthetic methods for these compounds are described in the "examples" below. In one example, compounds (a), (G), (J), (K), and (L) can be prepared as described in general schemes 1-4.

In some embodiments, the invention relates to compounds represented by structural formula (XX), wherein the variables of structural formula (XX) are each and independently as described herein and G is trityl. Specific examples of the compound represented by the structural formula (XX) include:

and pharmaceutically acceptable salts thereof, wherein Tr is trityl. Additional specific examples include:

And pharmaceutically acceptable salts thereof.

Definitions and general terms

For the purposes of the present invention, chemical Elements are identified according to the Periodic Table of the Elements of the CAS version of the Handbook of Physics,75th Ed, 75th edition, Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics. In addition, in "Organic Chemistry", Thomas Sorrell, Soxhlet university science Books, Saproluto, university science Books: 1999 and "March's Advanced Organic Chemistry (March Advanced Organic Chemistry)", 5th edition, eds: the general principles of organic chemistry are described in Smith, M.B. and March, J., New York John Wiley parent-child publishing company (John Wiley & Sons, New York):2001, the entire contents of which are hereby incorporated by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those generally set forth below or exemplified by specific classes, subclasses, and species of the invention. It is to be understood that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of one or more hydrogen radicals in a given structure with a radical designated as a substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents at each position can be the same or different. When the term "optionally substituted" precedes a list, the term refers to all subsequent substitutable groups in the list. A substituent group or structure is unsubstituted if it is not identified or defined as "optionally substituted". For example, if X is optionally substituted C ₁-C₃Alkyl or phenyl; x can beOptionally substituted C₁-C₃Alkyl or optionally substituted phenyl. Likewise, if the term "optionally substituted" follows a list, the term also refers to all substitutable groups in the preceding list, unless otherwise indicated. For example: if X is C₁-C₃Alkyl or phenyl, wherein X is optionally and independently J^XSubstituted, then C₁-C₃Both alkyl and phenyl groups may optionally be substituted by J^XAnd (4) substitution.

The phrase "at most" as used herein refers to 0 or any integer equal to or less than the number following the phrase. For example, "up to 3" means any of 0, 1, 2, and 3. As described herein, a specified range of numbers of atoms includes any integer therein. For example, a group having 1-4 atoms can have 1, 2, 3, or 4 atoms.

The choices of substituents and combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein means that the compound is not substantially altered when subjected to conditions that allow its production, detection, and particularly its recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stabilizing compound or chemically feasible compound is a compound that does not substantially change when held at 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions. Only those substituent choices and combinations that result in stable structures are contemplated. These options and combinations will be apparent to those of ordinary skill in the art and can be determined without undue experimentation.

The term "aliphatic radical" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, but which is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl, and acetylene.

The term "alkyl" as used herein means a saturated straight or branched chain hydrocarbon. The term "alkenyl" as used herein means a straight or branched chain hydrocarbon containing one or more double bonds. The term "alkynyl" as used herein means a straight or branched chain hydrocarbon containing one or more triple bonds. Each of "alkyl", "alkenyl", or "alkynyl" as used herein may be optionally substituted as described below. In some embodiments, "alkyl" is C ₁-C₆Alkyl or C₁-C₄An alkyl group. In some embodiments, "alkenyl" is C₂-C₆Alkenyl or C₂-C₄An alkenyl group. In some embodiments, "alkynyl" is C₂-C₆Alkynyl or C₂-C₄Alkynyl.

The term "alicyclic" (or "carbocycle" or "carbocyclyl" or "carbocyclic") refers to a ring system containing only non-aromatic carbons, which may be saturated or contain one or more units of unsaturation, having from three to fourteen ring carbon atoms. In some embodiments, the number of carbon atoms is 3 to 10. In other embodiments, the number of carbon atoms is 4 to 7. In still other embodiments, the number of carbon atoms is 5 or 6. The term includes monocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclic ring systems. The term also includes polycyclic ring systems in which the carbocycle may be "fused" to one or more non-aromatic carbocycles or heterocycles or one or more aromatic rings or combinations thereof, wherein the group or point of attachment is on the carbocycle. A "fused" bicyclic ring system includes two rings that share two contiguous ring atoms. Bridged bicyclic groups include two rings that share three or four adjacent ring atoms. The spiro-fused bicyclic ring systems share a common ring atom. Examples of alicyclic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term "heterocycle" (or "heterocyclyl" or "heterocyclic" or "non-aromatic heterocycle") as used herein refers to a non-aromatic ring system that may be saturated or contain one or more units of unsaturation, having from three to fourteen ring atoms in which one or more ring carbons is replaced with a heteroatom such as N, S or O and each ring in the system contains from 3 to 7 members. In some embodiments, the non-aromatic heterocycle comprises up to three heteroatoms selected from N, S and O within the ring. In other embodiments, the non-aromatic heterocyclic ring contains up to two heteroatoms selected from N, S and O within the ring system. In yet other embodiments, the non-aromatic heterocyclic ring contains up to 2 heteroatoms selected from N and O within the ring system. The term includes monocyclic, bicyclic or polycyclic, fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazacyclocycloheptyl, azocinyl, diazacyclooctanyl, triazacyclooctanyl (triazacyclocanyl), triazacyclooctanyl (triazocanyl), Oxazolidinyl, isoOxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl (oxazocanyl), oxazepan-yl, thiazepan-yl, thiazocanyl (thiazocanyl), benzimidazolonyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl (including, for example, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinylA group, a 1-tetrahydropiperazinyl group, a 2-tetrahydropiperazinyl group, a 3-tetrahydropiperazinyl group, a 1-piperidinyl group, a 2-piperidinyl group, a 3-piperidinyl group, a 1-pyrazolinyl group, a 3-pyrazolinyl group, a 4-pyrazolinyl group, a 5-pyrazolinyl group, a 1-piperidinyl group, a 2-piperidinyl group, a 3-piperidinyl group, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiophenyl (benzothiazolyl), benzodithianyl, 3- (1-alkyl) -benzimidazol-2-one, and 1, 3-dihydro-imidazol-2-one.

The term "aryl" (or "aromatic ring" or "aryl group") used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", "aryloxyalkyl", or "heteroaryl" refers to carbocyclic aromatic ring systems. The term "aryl" is used interchangeably with the terms "aromatic ring" or "aryl group".

A "carbocyclic aromatic ring" group has only carbon ring atoms (typically six to fourteen) and includes monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to each other. Examples include 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl. Also included within the scope of the term "carbocyclic aromatic ring" or "carbocyclic aromatic" as used herein are groups in which an aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), for example in indanyl, phthalimidyl, naphthalimide, phenanthridinyl or tetrahydronaphthyl, where the group or point of attachment is on an aromatic ring.

The terms "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group", "aromatic heterocycle" or "heteroaromatic group", used alone or as part of a larger moiety in "heteroaralkyl", "heteroarylalkoxy", refer to heteroaromatic ring groups having five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which the monocyclic aromatic ring is fused to one or more other aromatic rings. Heteroaryl groups have one or more ring heteroatoms. And also comprises Within the scope of the term "heteroaryl" as used herein are groups in which an aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the group or point of attachment is on the aromatic ring. For example, a bicyclic 6,5 heteroaromatic ring as used herein is a six membered heteroaromatic ring fused to a second five membered ring wherein the group or point of attachment is on the six membered ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, and the like,Azolyl radical, isoAzolyl group,Oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl groups, including, for example, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isothiazolylAzolyl, 4-isoAzolyl, 5-isoAzolyl, 2-Oxadiazole group, 5-Oxadiazole group, 2-Azolyl, 4-Azolyl, 5-Oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzothiophenyl Azolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, benzisoxazolylAzolyl, isothiazolyl, 1,2,3-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,2,4-An oxadiazole group, a 1,2, 3-triazolyl group, a 1,2, 3-thiadiazolyl group, a 1,3, 4-thiadiazolyl group, a 1,2, 5-thiadiazolyl group, a purinyl group, a pyrazinyl group, a 1,3, 5-triazinyl group, a quinolyl group (e.g., a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group), and an isoquinolyl group (e.g., a 1-isoquinolyl group, a 3-isoquinolyl group, or a 4-isoquinolyl group).

As used herein, "ring," "cyclic group," or "cyclic portion" includes monocyclic, bicyclic, and tricyclic ring systems, including alicyclic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which is previously defined.

As used herein, a "bicyclic ring system" includes an 8-12 (e.g., 9, 10, or 11) membered structure forming two rings, wherein the two rings share at least one atom (e.g., share 2 atoms). Bicyclic ring systems include bicyclic aliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatics, bicyclic carbocyclic aryl, and bicyclic heteroaryl.

As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system, wherein the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl, and 2, 6-dioxa-tricyclo [3.3.1.03,7] nonyl. The bridged bicyclic ring system may be optionally substituted with one or more substituents, for example, alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, (carbocyclic aryl) oxy, heteroaryloxy, aralkoxy, heteroarylalkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, (carbocyclic aryl) carbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Acyl, mercapto, alkylsulfanyl (alkylsulfanyl), sulfoxy (sulfoxy), urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

The term "bridge" as used herein refers to a bond or atom or unbranched chain of atoms connecting two different parts of a molecule. Two atoms (typically, but not always, two tertiary carbon atoms) connected by a bridge are denoted as a "bridgehead".

The term "spiro" as used herein refers to a ring system having one atom (usually a quaternary carbon atom) as the only common atom between two rings.

The term "ring atom" is an atom such as C, N, O or S in the ring of an aromatic group, a cycloalkyl group or a non-aromatic heterocyclic ring.

A "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen may optionally be replaced by a suitable substituent group. Thus, the term "substitutable ring atom" does not include a ring nitrogen or carbon atom that is common when two rings are fused. In addition, when the structure depicts that a ring carbon or nitrogen atom has been attached to a moiety other than hydrogen, then "substitutable ring atoms" do not include such ring carbon or nitrogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; or a heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺(as in N-substituted pyrrolidinyl)).

Optionally substituted aralkyl groups as used herein may be substituted on both the alkyl and aryl moieties. As used herein, unless otherwise indicated, an optionally substituted aralkyl is optionally substituted on the aryl moiety.

In some embodiments, the aliphatic or heteroaliphatic group or the non-aromatic heterocycle may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic group or heterocycle are selected from those listed above. Other suitable substituents include those listed as suitable for the unsaturated carbon of the carbocyclic aryl or heteroaryl group, and additionally include the following substituents: = O, = S, = NNHR^*、=NN(R^*)₂、=NNHC(O)R^*、=NNHCO₂(alkyl group) = NNHSO₂(alkyl) or = NR^*Wherein each R is^*Independently selected from hydrogen or optionally substituted C_1-6An aliphatic group. R^*Is selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical) in which R is as defined above^*C of (A)_1-4Each of the aliphatic groups is unsubstituted.

In some embodiments, optional substituents on the nitrogen of the heterocycle include those used above. Other suitable substituents include-R ⁺、-N(R⁺)₂、-C(O)R⁺、-CO₂R⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-SO₂R⁺、-SO₂N(R⁺)₂、-C(=S)N(R⁺)₂、-C(=NH)-N(R⁺)₂or-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6Aliphatic group, optionally substituted phenyl group, optionally substituted-O (Ph), optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph); optionally substituted-CH = CH (ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or, two independent R on the same substituent or different substituents⁺And each R⁺The atoms to which groups are bonded are taken together to form a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. R⁺Is selected from NH or an optional substituent on the phenyl ring₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1- ₄Aliphatic group) or halo (C)_1-4Aliphatic radical) in which R is as defined above⁺C of (A)_1-4Each of the aliphatic groups is unsubstituted.

In some implementationsIn examples, an aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atoms of the carbocyclic aryl or heteroaryl group are selected from those listed above. Other suitable substituents include: halogen; -R °; -OR °; -SR °; 1, 2-methylenedioxy; 1, 2-ethylenedioxy; phenyl (Ph) optionally substituted with R °; -o (ph) optionally substituted with R °; - (CH) optionally substituted by R DEG ₂)_1-2(Ph); -CH = CH (ph) optionally substituted with R °; -NO₂；-CN；-N(R°)₂；-NR°C(O)R°；-NR°C(S)R°；-NR°C(O)N(R°)₂；-NR°C(S)N(R°)₂；-NR°CO₂R°；-NR°NR°C(O)R°；-NR°NR°C(O)N(R°)₂；-NR°NR°CO₂R°；-C(O)C(O)R°；-C(O)CH₂C(O)R°；-CO₂R°；-C(O)R°；-C(S)R°；-C(O)N(R°)₂；-C(S)N(R°)₂；-OC(O)N(R°)₂；-OC(O)R°；-C(O)N(OR°)R°；-C(NOR°)R°；-S(O)₂R°；-S(O)₃R°；-SO₂N(R°)₂；-S(O)R°；-NR°SO₂N(R°)₂；-NR°SO₂R°；-N(OR°)R°；-C(=NH)-N(R°)₂(ii) a Or- (CH)₂)_0-2NHC (O) R °; wherein each independent R DEG is selected from hydrogen, optionally substituted C_1- ₆Aliphatic, unsubstituted 5-6 membered heteroaryl or heterocyclic, phenyl, -O (Ph) or-CH₂(Ph) or, on the same or different substituents, two independent R ° taken together with the atom to which each R ° group is bonded form a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. The optional substituents on the aliphatic radical of R DEG are selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group) or halogeno C_1-4Aliphatic radical, CHO, N (CO) (C)_1-4Aliphatic group), C (O) N (C)_1-4Aliphatic radical) in which R.degree.C₁–₄Each of the aliphatic groups is unsubstituted.

Non-aromatic nitrogen-containing heterocycles that are substituted on the ring nitrogen and attached to the rest of the molecule at a ring carbon atom are said to be N-substituted. For example, an N-alkylpiperidinyl group is attached to the rest of the molecule at the 2, 3 or 4 position of the piperidinyl ring and is substituted with an alkyl group at the ring nitrogen. Non-aromatic nitrogen-containing heterocycles, such as pyrazinyl, substituted on the ring nitrogen and attached to the rest of the molecule at the second ring nitrogen atom, are referred to as N' -substituted N-heterocycles. For example, the N' acyl N-pyrazinyl group is attached to the rest of the molecule at one ring nitrogen atom and is substituted with an acyl group at a second ring nitrogen atom.

The term "unsaturated" as used herein means a moiety having one or more units of unsaturation.

As described in detail above, in some embodiments, two independent R ° (or R °)⁺Or any other variable similarly defined herein) may be taken together with the atom to which each variable is bonded to form a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring, or a 3-8 membered cycloalkyl ring. When two are independent of each other R (or R)⁺Or any other variable similarly defined herein) together with the atom to which each variable is bonded include, but are not limited to, the following: a) two independent R (or R) bonded to the same atom and taken together with the atom to form a ring⁺Or any other variable similarly defined herein), e.g., N (R °)₂Wherein the two R DEG radicals, taken together with the nitrogen atom, form a piperidin-1-yl, piperazin-1-yl or morpholin-4-yl radical; and b) two independent R (or R) bonded to different atoms and taken together with those two atoms to form a ring⁺OR any other variable similarly defined herein), for example where the phenyl group is substituted by two OR degreesTwo of themR ° taken together with the oxygen atoms to which they are bonded form a fused 6-membered oxygen containing ring: It is understood that when two are independent of each other R (or R)⁺Or any other variable similarly defined herein) may form a variety of other rings when taken together with the atom to which each variable is bonded, and the examples detailed above are not intended to be limiting.

The terms "hydroxyl", "hydroxy" or "alcohol moiety" refer to-OH.

As used herein, "alkoxycarbonyl", which is encompassed by the term carboxy, alone or in combination with another group, refers to a group such as (alkyl-O) -C (O) -.

As used herein, "carbonyl" refers to-C (O) -.

As used herein, "oxo" means = O.

The term "alkoxy" as used herein or "alkylthio" as used herein refers to an alkyl group as previously defined attached to the molecule through an oxygen ("alkoxy", e.g., -O-alkyl) or sulfur ("alkylthio", e.g., -S-alkyl) atom.

The terms "halogen", "halo" and "halo" as used herein mean F, Cl, Br or I.

The term "cyano" or "nitrile" as used herein refers to-CN or-C.ident.N.

The terms "alkoxyalkyl", "alkoxyalkenyl", "alkoxyaliphatic" and "alkoxyalkoxy" mean an alkyl, alkenyl, aliphatic or alkoxy group, as the case may be, which may be substituted by one or more alkoxy groups.

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" are intended to mean alkyl, alkenyl, aliphatic or alkoxy groups, as the case may be, which may be substituted with one or more halogen atoms.The term includes perfluorinated alkyl groups, e.g., -CF₃and-CF₂CF₃。

The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic" and "cyanoalkoxy" mean an alkyl, alkenyl, aliphatic or alkoxy group which may be substituted as the case may be by one or more cyano groups. In some embodiments, cyanoalkyl is (NC) -alkyl-.

The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic" and "aminoalkoxy" mean an alkyl, alkenyl, aliphatic or alkoxy group, as the case may be, substituted with one or more amino groups, wherein amino is as defined above. In some embodiments, the aminoaliphatic group is substituted with one or more-NH groups₂A C1-C6 aliphatic group substituted with a group. In some embodiments, aminoalkyl refers to the structure (R)^XR^Y) N-alkyl-, wherein R^XAnd R^YEach is independently as defined above. In some embodiments, aminoalkyl is substituted with one or more-NH ₂A C1-C6 alkyl group substituted with a group. In some embodiments, aminoalkenyl is substituted with one or more-NH₂A group substituted C1-C6 alkenyl. In some embodiments, the aminoalkoxy group is-O (C1-C6 alkyl), wherein the alkyl group is substituted with one or more-NH groups₂And (4) substituting the group.

The terms "hydroxyalkyl", "hydroxyaliphatic" and "hydroxyalkoxy" mean an alkyl, aliphatic or alkoxy group which may be substituted as the case may be by one or more-OH groups.

The terms "alkoxyalkyl", "alkoxyaliphatic" and "alkoxyalkoxy" mean an alkyl, aliphatic or alkoxy group, as the case may be, which may be substituted by one or more alkoxy groups. For example, "alkoxyalkyl" refers to an alkyl group such as (alkyl-O) -alkyl-, wherein alkyl is as defined above.

The term "carboxyalkyl" means an alkyl group substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.

As used herein, the terms "protecting group" and "protecting group" are used interchangeably to refer to a reagent used to temporarily block one or more desired functional groups in a compound having multiple reactive sites. In certain embodiments, the protecting group has one or more, or particularly all, of the following characteristics: a) selectively adding to the functional group in good yield to produce a protected substrate; b) stable to reactions occurring at one or more other reactive sites; and c) can be selectively removed in good yield with reagents that do not attack the regenerated, deprotected functional group. One skilled in the art will appreciate that in some cases, the reagent does not attack other reactive groups in the compound. In other cases, the reagent may also react with other reactive groups in the compound. Examples of protecting groups are described in detail in the following documents: greene, t.w., Wuts, P.G, entitled "protective groups in Organic Synthesis", third edition, John Wiley father publishing company, New York (John Wiley & Sons, New York):1999 (and other versions of the book), hereby incorporated by reference in its entirety. The term "nitrogen protecting group" as used herein refers to a reagent used to temporarily block one or more desired nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen protecting Groups also have the characteristics exemplified above for the protecting Groups, and certain exemplary nitrogen protecting Groups are also detailed by Greene, T.W., Wuts, P.G in chapter 7 of "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, New York, 1999, the entire contents of which are hereby incorporated herein by reference.

The term "displaceable moiety" or "leaving group" as used herein refers to a group which is associated with an aliphatic or aromatic group as defined herein and which is displaced by nucleophilic attack by a nucleophile.

Unless otherwise indicated, structures depicted herein are also intended to beAll isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational and rotational) forms of the structure are included. For example, the R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers of each asymmetric center are included in the present invention unless only one of the isomers is specifically drawn. One skilled in the art will appreciate that the substituents may rotate freely about any rotatable bond. For example, draw asThe substituents also represent

Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational and rotational mixtures of the compounds of the present invention are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention except that deuterium or tritium is substituted for hydrogen or enriched ¹³C-or¹⁴Carbon-substituted compounds of C are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in bioassays. Such compounds, and in particular deuterium analogues, are also useful therapeutically.

The terms "bond" and "absent" are used interchangeably to indicate that a group is absent.

The compounds of the present invention are defined herein by their chemical structure and/or chemical name. When a compound is referred to by both chemical structure and chemical name, and the chemical structure and chemical name conflict, the identity of the compound is determined by the chemical structure.

Pharmaceutically acceptable salts, solvates, clathrates, prodrugs and other derivatives

The compounds described herein may be present in free form or, where appropriate, as a salt. Those pharmaceutically acceptable salts are of particular interest because they are useful for administering the compounds described below for medical purposes. Pharmaceutically unacceptable salts are useful in manufacturing processes for isolation and purification purposes, and in some cases, for isolating stereoisomeric forms of the compounds of the invention or intermediates thereof.

The term "pharmaceutically acceptable salt" as used herein refers to salts of compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue adverse side effects such as toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences (journal of pharmaceutical science), 1977, 66, 1-19, by s.m. berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

Where the compounds described herein contain basic groups or sufficiently basic biological isosteres, acid addition salts may be prepared by: 1) reacting the purified compound in free base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, acid addition salts may be in a more convenient form to use, and the use of such salts is equivalent to the use of the free base form.

Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or salts of amino groups formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, glycolates, gluconates, glycolates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates (palmoates), Pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

When the compounds described herein contain a carboxyl group or a sufficiently acidic bioequivalence, base addition salts can be prepared by: 1) reacting the purified compound in acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. In practice, it may be more convenient to use a base addition salt, and the use of this salt form is essentially equivalent to the use of the free acid form. Salts derived from suitable bases include alkali metal (e.g., sodium, lithium, and potassium) salts, alkaline earth metal (e.g., magnesium and calcium) salts, ammonium salts, and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-or oil-soluble or dispersible products can be obtained by this quaternization.

Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium and potassium salts are generally preferred. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine base addition salts are prepared from amines which are frequently used in pharmaceutical chemistry because of their low toxicity and medical acceptability. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylmethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, and the like.

Although other acids and bases are not pharmaceutically acceptable per se, they may be used to prepare salts which are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

It is to be understood that the present invention encompasses mixtures/combinations of different pharmaceutically acceptable salts and also mixtures/combinations of the compound in free form and a pharmaceutically acceptable salt.

In addition to the compounds described herein, pharmaceutically acceptable solvates (e.g., hydrates) and clathrates of these compounds can also be employed in compositions for the treatment or prevention of the conditions identified herein.

The term "pharmaceutically acceptable solvate" as used herein is a solvate formed by association of one or more pharmaceutically acceptable solvent molecules with one of the compounds described herein. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

The term "hydrate" as used herein means a compound described herein or a salt thereof that also includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "clathrate," as used herein, means a compound described herein or a salt thereof in a crystal lattice containing spaces (e.g., channels) in which guest molecules (e.g., solvent or water) are entrapped.

In addition to the compounds described herein, pharmaceutically acceptable derivatives or prodrugs of these compounds may also be employed in compositions for the treatment or prevention of the conditions identified herein.

"pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable ester, salt of an ester, or other derivative or salt thereof of a compound described herein, which upon administration to a recipient is capable of providing, directly or indirectly, a compound described herein or an inhibitory active metabolite or residue thereof. Particularly popular derivatives or prodrugs are those that increase the bioavailability of such compounds when administered to a patient (e.g., by making the orally administered compound more readily absorbed into the blood) or enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

As used herein and unless otherwise indicated, the term "prodrug" means a compound derivative that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compounds described herein. Prodrugs may become active when so reacted under biological conditions, or they may be active in their unreacted form. Examples of prodrugs contemplated in the present invention include, but are not limited to, analogs or derivatives of the compounds of the present invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other example packages of prodrugs Including compounds described herein including-NO, -NO₂-ONO or-ONO₂Derivatives of moieties. Prodrugs can generally be prepared using well known methods, for example, as described in BURGER 'S MEDICINALCHEMISTRY AND DRUG DISCOVERY (Burger's pharmaceutical chemistry and DRUG DISCOVERY (1995)172-178,949-982 (edited by Manfred E.Wolff, 5 th edition).

A "pharmaceutically acceptable derivative" is an adduct or derivative that, when administered to a patient in need thereof, is capable of directly or indirectly providing a compound as otherwise described herein or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters. Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, amino acid esters, phosphate esters, metal salts, and sulfonate esters.

Use of the disclosed compounds

One aspect of the present invention relates generally to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising such a compound or a pharmaceutically acceptable salt thereof, for inhibiting influenza virus replication in a biological sample or in a patient, for reducing the amount of influenza virus in a biological sample or in a patient (reducing viral titer), or for treating influenza in a patient.

In one embodiment, the present invention relates generally to the use of a compound represented by structural formula (I), (II), (IIIA) or (IIIB), or a pharmaceutically acceptable salt thereof, for any of the uses specified above.

In another embodiment, the present invention relates to the use of any one compound selected from the compounds depicted in tables 1 and 2, or a pharmaceutically acceptable salt thereof, for any one of the above uses.

In some embodiments, the compound is represented by any of structural formulae (I), (II), (IIIA), or (IIIB), and the variables are each independently as depicted in the compounds of tables 1 and 2.

In yet another embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce viral titer (e.g., viral titer in the lungs of a patient) in a biological sample (e.g., infected cell culture) or in a human.

As used herein, the terms "influenza virus mediated disorder," "influenza infection," or "influenza" are used interchangeably to mean a disease caused by infection with an influenza virus.

Influenza is an infectious disease caused by influenza viruses that affects birds and mammals. Influenza viruses are RNA viruses of the orthomyxoviridae family, which includes 5 genera: influenza A virus, influenza B virus, influenza C virus, salmon anemia virus and Togao soil virus. Influenza a virus belongs to 1 species, i.e. influenza a virus, which can be subdivided into different serotypes based on the antibody response to these viruses: H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N 7. Influenza B virus belongs to 1 species, i.e. influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza a. Influenza C virus belongs to 1 species, i.e., influenza C virus, which infects humans and pigs and can cause severe disease and endemic epidemics. However, influenza C viruses are less common than other types of influenza and often appear to cause mild disease in children.

In some embodiments of the invention, the influenza or influenza virus is associated with an influenza a or B virus. In some embodiments of the invention, the influenza or influenza virus is associated with influenza a virus. In some embodiments of the invention, the influenza a virus is H1N1, H2N2, H3N2, or H5N 1.

In humans, the common symptoms of influenza are chills, fever, pharyngitis, muscle pain, severe headache, cough, weakness and general malaise. In more severe cases, influenza causes pneumonia which can be fatal, especially in young children and the elderly. Although often confused with the common cold, influenza is a more serious disease and is caused by different types of viruses. Influenza can cause nausea and vomiting, particularly in children, but these symptoms are more typical of unrelated gastroenteritis, sometimes referred to as "stomach flu" or "24 hour flu".

One to two days after infection, symptoms of influenza can begin quite suddenly. The first symptom is usually chills or intolerance of cold, but fever is also common in the early stages of infection, with body temperatures ranging from 38-39 ℃ (approximately 100-. Many people are seriously ill for several days in bed, have general pain and are more serious in the back and legs. Symptoms of influenza may include: physical pain, especially in joints and throat, extreme cold and fever, fatigue, headache, irritative lacrimation, redness of the eyes, skin (especially the face), mouth, throat and nose, abdominal pain (in children with influenza B). Symptoms of influenza are nonspecific, overlapping with many pathogens ("influenza-like" diseases). Often, laboratory data is required in order to confirm a diagnosis.

The terms "disease," "disorder," and "condition" are used interchangeably herein to refer to an influenza virus-mediated medical or pathological condition.

As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird or mammal such as a chicken, quail, or turkey), particularly a "mammal," including a non-primate (e.g., cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., monkey, chimpanzee, and human), and more particularly a human. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a "human".

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

The term "multiplicity of infection" or "MOI" as used herein is the ratio of infectious agent (e.g., phage or virus) to infectious target (e.g., cell). For example, when referring to a group of cells seeded with infectious viral particles, the multiplicity of infection or MOI is the ratio defined by the number of infectious viral particles deposited in a well divided by the number of target cells present in that well.

The term "inhibition of influenza virus replication" as used herein includes both reducing the amount of virus replication (e.g., by at least 10%) and completely preventing virus replication (i.e., 100% reducing the amount of virus replication). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

Influenza virus replication can be measured by any suitable method known in the art. For example, influenza virus titers (e.g., pulmonary virus titers in patients) in biological samples (e.g., infected cell cultures) or in humans can be measured. More specifically, for cell-based assays, in each case, cells are cultured in vitro, virus is added to the culture in the presence or absence of test agent, and the virus-dependent endpoint is evaluated after an appropriate length of time. For a typical assay, motor-Darby canine kidney cells (MDCK) and a standard tissue culture adapted influenza strain A/Puerto Rico/8/34 can be used. The first type of cellular assay that can be used in the present invention relies on the death of infected target cells, a process known as cytopathic effect (CPE), where viral infection causes depletion of cellular resources and eventual lysis of cells. In the first type of cell assay, a small fraction of cells (typically 1/10 to 1/1000) in a well of a microtiter plate are infected, the virus is allowed to replicate for several rounds over a 48-72 hour period, and the amount of cell death is then measured using the reduction in cellular ATP content compared to uninfected controls. The second type of cellular assay that can be employed in the present invention relies on the proliferation of virus-specific RNA molecules in infected cells, where RNA levels are measured directly using the branched-chain DNA hybridization method (bDNA). In the second type of cell assay, a small number of cells are initially infected in the wells of a microtiter plate, the virus is allowed to replicate in the infected cells and spread to several additional rounds of cells, the cells are then lysed and viral RNA levels are measured. Early cessation of the assay, usually after 18-36 hours, leaves all target cells alive. Viral RNA is quantified by hybridization to specific oligonucleotide probes immobilized on the wells of the assay plate, followed by amplification of the signal by hybridization to additional probes linked to a reporter enzyme.

As used herein, "viral titer (or titer)" is a measure of viral concentration. Titer testing can employ serial dilutions to obtain approximate quantitative information from an assay procedure that evaluates essentially only positively or negatively. Titer corresponds to the highest dilution factor that still produced a positive reading; for example, a positive reading in the first 8 consecutive two-fold dilutions converted to a titer of 1: 256. A specific example is virus titer. To determine titre, several dilutions are prepared, e.g. 10^-1、10^-2、10^-3、...、10^-8. The lowest virus concentration that still infects cells is the virus titer.

The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and/or duration of an influenza virus-mediated disorder, or ameliorating one or more symptoms (particularly one or more discernible symptoms) of an influenza virus-mediated condition as a result of administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In particular embodiments, the therapeutic treatment comprises ameliorating at least one measurable physical parameter of an influenza virus-mediated condition. In other embodiments, the therapeutic treatment comprises physically inhibiting the progression of the influenza virus-mediated condition, for example, by stabilizing discernible symptoms, physiologically, for example, by stabilizing physical parameters, or both. In other embodiments, the therapeutic treatment comprises reducing or stabilizing an influenza virus-mediated infection. Antiviral drugs can be used in a community setting to treat people already suffering from influenza to reduce the severity of symptoms and reduce their number of days of illness.

The term "chemotherapy" refers to the use of drugs, such as small molecule drugs (rather than "vaccines"), to treat a disorder or disease.

The terms "prevention", "prophylactic use" and "prophylactic treatment" as used herein refer to any medical or public health procedure aimed at preventing, rather than treating or curing, a disease. The term "preventing" as used herein refers to reducing the risk of acquiring or developing a given condition, or reducing or inhibiting the recurrence of said condition in a subject who is not ill but has or may be in close proximity to a patient. The term "chemoprevention" refers to the use of drugs, such as small molecule drugs (rather than "vaccines"), to prevent a disorder or disease.

Prophylactic use as used herein includes use in the event that an outbreak has been detected to prevent infection or spread where many people at high risk of serious influenza complications come into close contact with each other living (e.g., in hospital wards, day-care centers, prisons, nursing homes, etc.). Also included are uses in the following groups: influenza protection is required but is not protected after vaccination (e.g. due to weak immune system), or when they are unable to obtain a vaccine, or when they are unable to vaccinate due to side effects. Also included is use within two weeks after vaccination, as the vaccine is still ineffective during this period. Prophylactic use may also include treating persons who do not have influenza or are not considered to be at high risk for complications, to reduce the chance of contracting the influenza and passing it to high risk persons (e.g., healthcare workers, nursing home staff, etc.) in close proximity thereto.

According to the american centers for disease control and prevention, an influenza "outbreak" is defined as a sudden increase in acute febrile respiratory disease (AFRI) in 48 to 72 hours in a group of people in close proximity to each other (e.g., in the same area of a assisted living facility, in the same household, etc.) above the normal background incidence or when any subject in the analyzed group tests positive for influenza. One influenza case confirmed by any test method is considered an outbreak.

"Cluster" is defined as a group of three or more cases of AFRI occurring within 48 to 72 hours in a group of people in close proximity to each other (e.g., in the same area of an assisted living facility, in the same household, etc.).

As used herein, an "indicated case," "primary case," or "patient zero (patient zero)" is the initial patient in a population sample of an epidemiological survey. The term is not capitalized when used generically in epidemiological surveys to refer to such patients. When the term is used in a report on a particular survey to refer to a particular person in place of that person's name, the term capitalizes on Patient Zero (Patient Zero). Scientists often look for the cases of indications to determine how the disease spreads and what the source of the disease (reservoir) between outbreaks will be holding the disease. Note that the indicated case is the first patient to indicate the presence of an outbreak. Earlier cases can be found and labeled as first, second, third, etc.

In one embodiment, the method of the invention is a prophylactic or "pre-emergent" measure for patients (particularly humans) susceptible to complications due to influenza virus infection. The term "first-out," as used herein, as used, for example, in first-out use, "first-out" and the like, is prophylactic use in situations where "indication of a case" or "outbreak" has been confirmed, to prevent spread of infection in the rest of the community or population.

In another embodiment, the method of the invention may be used as a "pre-emergence" measure against members of a community or group, particularly humans, to prevent the spread of infection.

As used herein, an "effective amount" refers to an amount sufficient to elicit a desired biological response. In the present invention, the desired biological response is to inhibit influenza virus replication, to reduce the amount of influenza virus or to reduce or ameliorate the severity, duration, progression or onset of influenza virus infection, to prevent the spread of influenza virus infection, to prevent the recurrence, progression, onset or progression of symptoms associated with influenza virus infection, or to enhance or enhance the prophylactic or therapeutic effect of another therapy used against influenza infection. The precise amount of the compound administered to a subject will depend on the mode of administration, the type and severity of the infection and on the characteristics of the subject, such as general health, age, sex, weight and tolerance to drugs. The skilled artisan will be able to determine the appropriate dosage based on these and other factors. When co-administered with other antiviral agents, such as anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages of approved agents are known and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated, and the amount of the compound described herein being used. In the case where amounts are not explicitly specified, an effective amount should be assumed. For example, a compound described herein can be administered to a subject at a dosage range of about 0.01 to 100 mg/body weight/day for therapeutic or prophylactic treatment.

In general, the dosage regimen will be selected in accordance with a variety of factors, including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound employed; renal and hepatic function of the subject; the particular compound or salt thereof employed, the duration of treatment; drugs used in conjunction or concomitantly with the specific compound employed and like factors well known in the medical arts. The skilled artisan can readily determine and prescribe the effective amount of a compound described herein required to treat, prevent, inhibit (fully or partially), or arrest the progress of the disease.

The dosage range of the compounds described herein is from about 0.01 to about 100 mg/body weight/day, from about 0.01 to about 50 mg/body weight/day, from about 0.1 to about 50 mg/body weight/day, or from about 1 to about 25 mg/body weight/day. It is understood that the total amount per day may be administered in a single dose or may be administered in multiple doses, such as 2 times daily (e.g., every 12 hours), 3 times daily (e.g., every 8 hours), or 4 times daily (e.g., every 6 hours).

For therapeutic treatment, the compounds described herein can be administered to a patient within, for example, 48 hours (or within 40 hours or less than 2 days or less than 1.5 days, or within 24 hours) of the onset of symptoms (e.g., nasal congestion, sore throat, cough, pain, fatigue, headache, and chills/sweating). Therapeutic treatment may be continued for any suitable period of time, e.g., 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, the compounds described herein can be administered to a patient, for example, within 2 days of the onset of symptoms in the indicated case, and can continue for any suitable time, e.g., 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Various types of application methods can be employed in the present invention and are described in detail below under the section entitled "application methods".

Combination therapy

An effective amount may be achieved in a method or pharmaceutical composition of the invention using a compound of the invention, including pharmaceutically acceptable salts or solvates (e.g., hydrates), alone or in combination with another suitable therapeutic agent, such as an antiviral agent or a vaccine. When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of the invention and a second amount of an additional suitable therapeutic agent (e.g., an antiviral agent or vaccine).

In another embodiment of the invention, the compound of the invention and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount that would be therapeutically effective when administered alone). In another embodiment, the compound of the invention and the additional therapeutic agent are each administered in an amount that alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, a compound of the invention may be administered in an effective amount, while an additional therapeutic agent is administered in a sub-therapeutic dose. In yet another embodiment, a compound of the invention may be administered at a sub-therapeutic dose, while an additional therapeutic agent, such as a suitable cancer therapeutic agent, is administered in an effective amount.

The terms "combination" or "co-administration" as used herein are used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of this term does not limit the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and second amounts of the simultaneously administered compound in a substantially simultaneous manner, e.g., in a single pharmaceutical composition, e.g., a capsule or tablet with a fixed ratio of the first and second amounts, or in separate capsules or tablets. In addition, such co-administration also encompasses the sequential use of each compound in either order.

In one embodiment, the invention relates to a combination therapy using a compound or pharmaceutical composition of the invention to inhibit influenza virus replication or to treat or prevent influenza virus infection in a biological sample or patient. Accordingly, the pharmaceutical compositions of the present invention also include those comprising an influenza virus replication inhibitor of the present invention in combination with an antiviral compound that exhibits anti-influenza virus activity.

Methods of use of the compounds and compositions of the invention also include combining chemotherapy with a compound or composition of the invention, or with a combination of a compound or composition of the invention with another antiviral agent and vaccination against influenza.

When co-administration involves administering a first amount of a compound of the invention and a second amount of an additional therapeutic agent, respectively, the compounds are administered close enough in time to have the desired therapeutic effect. For example, the time between each administration that can result in the desired therapeutic effect can range from a few minutes to a few hours, and can be determined taking into account the properties of each compound, such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, the compound of the invention and the second therapeutic agent may be administered within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other, in any order.

More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject.

It is understood that co-administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent may result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from administration of the first amount of the compound of the invention and the second amount of the additional therapeutic agent alone.

The term "synergistic" as used herein refers to a combination of a compound of the invention and another therapy (e.g., prophylactic or therapeutic agent) that is more effective than the additive effects of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can allow for the use of lower doses of one or more therapies and/or less frequent administration of the therapies to a subject. Being able to utilize lower doses of a therapy (e.g., a prophylactic or therapeutic agent) and/or less frequently administer the therapy, toxicity associated with administering the therapy to a subject can be reduced without reducing the efficacy of the therapy in the prevention, management, or treatment of a disorder. In addition, synergistic effects may lead to increased efficacy of the agent in the prevention, management or treatment of a disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

When the combination therapy with the compounds of the present invention is in combination with an influenza vaccine, the two therapeutic agents can be administered such that the time between each administration can be longer (e.g., days, weeks, or months).

Methods suitable for assessing drug interactions can be used to determine the presence of a synergistic effect. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin.Pharmacokinet. ("clinical pharmacokinetics") 6:429-453 (1981)), the Loewe addition equation (equalisation of Loewe addition) (Loewe, S. and Muischnek, H., Arch.Exp.Pathol Pharmacol.114:313-326 (1926)), and the median-effect equation (Chou, T.C. and Talalay, P., adv.enzyme Regul. ("Adv.Enzyme Regul.) (22: 27-55 (1984)). Each of the above mentioned equations can be applied together with experimental data to generate a corresponding graph to help assess the effect of a drug combination. The corresponding plots associated with the above mentioned formulas are the concentration-effect curve, the isobologram curve and the combined index curve, respectively.

Specific examples of compounds that can be co-administered with the compounds described herein include neuraminidase inhibitors (e.g., oseltamivir) And zanamivirViral ion channel (M2 protein) blockers (e.g., amantadine)And rimantadineAnd anti-viral drugs described in WO2003/015798, including T-705 developed by the Nippon Fushan chemical company of Japan (Toyama chemical of Japan). (see also Ruruta et al, AntiviralraseThe term "antiviral study" is used herein to describe the concept of "arch (82: 95-102 (2009)", "T-705 (flavipiral) and dried compounds: Novel broad-spectrum inhibitors of RNA viral infections" (T-705 (flavipiral) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections). In some embodiments, the compounds described herein may be co-administered with a traditional influenza vaccine.

Pharmaceutical composition

The compounds described herein may be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as described above and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers appropriately selected for the intended form of administration and in accordance with conventional pharmaceutical practice.

An "effective amount" includes both a "therapeutically effective amount" and a "prophylactically effective amount". The term "therapeutically effective amount" refers to an amount effective for treating and/or ameliorating influenza virus infection in a patient infected with influenza. The term "prophylactically effective amount" refers to an amount effective for preventing and/or substantially reducing the chance or extent of an outbreak of an influenza virus infection. Specific examples of effective amounts are described above in the section entitled "uses of the disclosed compounds".

Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other undesirable reactions or side effects when administered to a patient. Standard pharmaceutical formulation techniques may be employed.

Pharmaceutically acceptable carriers, adjuvants or vehicles as used herein include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate to the particular dosage form desired. Remington's Pharmaceutical Sciences (reishi institute of pharmacy), sixteenth edition, e.w. martin (mack publishing co., Easton, Pa.,1980), discloses various carriers for use in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Any conventional carrier medium is contemplated as being within the scope of the present invention unless incompatible with the compounds described herein, e.g., by producing any undesirable biological effect or interacting in a deleterious manner with any other component of a pharmaceutically acceptable composition. The phrase "side effects" as used herein encompasses unwanted and adverse effects of a therapy (e.g., prophylactic or therapeutic agents). Side effects are always unwanted, but unwanted effects are not necessarily disadvantageous. Adverse effects from therapy (e.g., prophylactic or therapeutic agents) can be harmful or uncomfortable or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, toxic kidney damage, nephrotoxicity (including conditions such as renal papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, myelosuppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, drowsiness, pain (including muscle pain, bone pain, and headache), hair loss, weakness, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

Some examples of substances that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., twin80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium sorbitol, sodium stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., twi, Ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffer, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), and coloring agents, detackifiers, coatings, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

Application method

The above compounds and pharmaceutically acceptable compositions can be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, as an oral spray or nasal spray, etc., depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injections, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, U.S. p. ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are, in particular, suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, Solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also have a composition such that they release the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more of the above excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. As is conventional, such dosage forms may also contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have a composition such that they release the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

Topical or transdermal administration forms of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of allowing controlled delivery of the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions described herein may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the compositions described herein can be an aqueous or oleaginous suspension. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, for example olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, for example, carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as tweens, spans, and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions described herein may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For tablets intended for oral use, carriers that are commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the agent with a non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions described herein may also be administered topically, particularly when the target of treatment includes topical administration of an easily accessible area or organ (including ocular, skin, or lower intestinal tract diseases). Suitable topical formulations for each of these areas or organs are readily prepared.

Topical application to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or specifically as solutions in isotonic, pH adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or for one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage forms may be the same or different for each dose.

Example

Synthesis of Compounds of the invention

The compounds disclosed herein can be prepared by any suitable method known in the art, for example, in WO2005/095400, WO2007/084557, WO2010/011768, WO2010/011756, WP2010/011772, WO2009/073300, and PCT/US2010/038988 filed on 6/17/2010. For example, the compounds shown in tables 1 and 2 may be prepared by any suitable method known in the art, e.g., in WO2005/095400, WO2007/084557, WO2010/011768, WO2010/011756, WP2010/011772, WO2009/073300, and PCT/US2010/038988, as well as by the exemplary syntheses described under "examples" below. In general, the compounds of the invention may be prepared as shown in those syntheses, optionally with any suitable modification as required.

Synthesis and characterization of Compounds

The synthesis of certain exemplary compounds of the invention is described below. NMR and mass spectral data for certain specific compounds are summarized in tables 1 and 2. The term rt (min) as used herein refers to the LCMS retention time in minutes associated with a compound.

Synthesis scheme 1

(a)(CO)₂Cl₂、DMF/CH₂Cl₂、NH₄OH；(b)Et₃N、TFAA、CH₂Cl₂(c)N₂H₄·H₂O, nBuOH, refluxing; (d) tBuNO₂、Br₃CH，60-90℃；(e)Ph₃CCl、K₂CO₃DMF (f) KOAc, 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan, Pd (dppf)₂Cl₂、DMF

Formation of 2-chloro-5-fluoropyridine-3-carboxamide (1)

To a suspension of 2-chloro-5-fluoropyridine-3-carboxylic acid (37.0g,210.8mmol) in dichloromethane (555mL) under nitrogen was added oxalyl chloride (56.2g,442.7 mmol). DMF (1.54g,21.08mmol) was slowly added to the reaction mixture. The mixture was stirred at room temperature for 2 hours and the dichloromethane was removed under reduced pressure. The residue was dissolved in THF (300mL) and cooled to 0 ℃ by an ice bath. Ammonium hydroxide (28-30%,113.0mL,1.8mmol) was added in one portion. The mixture was stirred for a further 15 minutes. The mixture was diluted into ethyl acetate (300mL) and water (300mL) and the phases were separated. The organic layer was washed with brine and Na₂SO₄Dried, filtered and concentrated in vacuo to give 29.8g of the desired product as a white solid: ¹H NMR (300MHz, DMSO) δ 8.53(d, J =3.0Hz,1H),8.11(s,1H),8.00(dd, J =8.0,3.0Hz,1H),7.89(s, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.11 min, (M + H) 175.02.

Formation of 2-chloro-5-fluoropyridine-3-carbonitrile (2)

To a suspension of 2-chloro-5-fluoropyridine-3-carboxamide 1(29.8g,170.4mmol) in dichloromethane (327mL) was added triethylamine (52.3mL,374.9 mmol). The mixture was cooled to 0 ℃. Trifluoroacetic anhydride (26.1mL,187.4mmol) was added slowly over 15 minutes. The mixture was stirred at 0 ℃ for 90 minutes. The mixture was diluted into dichloromethane (300mL) and NaHCO was used₃The resulting organic phase was washed with saturated aqueous solution (300mL) and brine (300 mL). The organic layer was washed with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by silica gel chromatography (40% to 60% ethyl acetate/hexane) to give 24.7g of the product as a white solid:¹H NMR(300MHz,CDCl₃) δ 8.50(d, J =3.0Hz,1H),7.77(dd, J =6.8,3.0Hz, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.50 min, (M + H) 157.06.

5-fluoro-1H-pyrazolo [3,4-b]Formation of pyridin-3-Amines (3)

To a mixture of 2-chloro-5-fluoropyridine-3-carbonitrile 2(29.6g,157.1mmol) in n-butanol (492mL) was added hydrazine hydrate (76.4mL,1.6 mol). The mixture was heated to reflux for 4.5 hours and cooled. N-butanol was removed under reduced pressure and water (300mL) was added to give a yellow precipitate. The suspension was filtered and washed twice with water, then with MTBE. The yellow solid was dried in a vacuum oven to give 18g of the desired product: ¹H NMR (300MHz, d6-DMSO) δ 12.08(s,1H),8.38(dd, J =2.7,1.9Hz,1H),7.97(dd, J =8.8,2.7Hz,1H),5.56(s, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.25 min, (M + H) 152.95.

3-bromo-5-fluoro-1H-pyrazolo [3,4-b]Formation of pyridine (4)

To 5-fluoro-1H-pyrazolo [3,4-b]A mixture of pyridin-3-amine 3(0.88g,5.79mmol) in tribromomethane (8.8mL) was added tert-butyl nitrite (1.38mL,11.57 mmol). The mixture was heated to 61 ℃ for 1 hour, then to 90 ℃ for another 1 hour. The mixture was cooled to room temperature and the tribromomethane was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 970mg of the desired product as a white solid:¹h NMR (300MHz, DMSO) δ 14.22(s,1H),8.67(dd, J =2.7,1.9Hz,1H),8.07(dd, J =8.2,2.7Hz, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.42 min, (M + H) 216.11.

3-bromo-5-fluoro-1-trityl-1H-pyrazolo [3,4-b]Formation of pyridine (5)

Reacting 3-bromo-5-fluoro-1H-pyrazolo [3,4-b]Pyridine 4(0.97g,4.49mmol) and K₂CO₃A mixture of (1.86g,13.47mmol) in DMF (9.7mL) was cooled to 0 ℃. Chlorodiphenylmethylbenzene (1.38g,4.94mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with 40mL ethyl acetate and washed with 30mL water. The organic layer was washed with brine and Na ₂SO₄Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexane) to give 1.68g of the desired product as a white solid:¹h NMR (300MHz, d6-DMSO) δ 8.45-8.38 (m,1H),8.04(dd, J =8.0,2.7Hz,1H), 7.35-7.16 (m, 15H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.03 min, (M + H) 459.46.

5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyri-dine Azolo [3,4-b]Formation of pyridine (6)

Reacting 3-bromo-5-fluoro-1-trityl-pyrazolo [3,4-b]Pyridine 5(3.43g,7.48mmol), KOAc (2.20g,22.45mmol) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan-2-ylA solution of the heterocyclopentanylborane (2.85g,11.23mmol) in DMF (50ml) was degassed for 40 min. To the mixture was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane (0.610g,0.748 mmol). The reaction mixture was heated at 100 ℃ for 90 minutes. The reaction mixture was filtered through a pad of celite. To the resulting filtrate was added diethyl ether and brine. The organic phase was washed with MgSO₄Dried, filtered and concentrated in vacuo to give 4.0g of crude product, which was used in the next step without further purification (note that the product decomposed if purification by silica gel chromatography was attempted).

Synthesis scheme 2

(a)CHCl₃；(b)NaOMe、MeOH；(c)DPPA、Et₃N、BnOH；(d)H₂Pd/C; (e)2, 4-dichloro-5-fluoropyrimidine, N-diisopropylethylamine and DMF

Formation of endo-tetrahydro-4, 7-ethanoisobenzofuran-1, 3-dione (7)

Maleic anhydride (210.0g,2142.0mmol) in CHCl was added over 50 minutes₃A cold (0 ℃ C.) solution in (2.3L) was slowly added cyclohexa-1, 3-diene (224.5mL,2356.0 mmol). The reaction was allowed to warm to room temperature and stirred overnight in the dark. After removal of the solvent under reduced pressure, 2.1L of MeOH was added to the mixture and the mixture was heated to 50 ℃ for 10 minutes and then cooled to 0 ℃. The resulting precipitate was filtered and dried in an oven at 45 ℃ overnight to give 283g of a white solid. The resulting endo (meso) Diels-Alder cycloaddition product was used without further purification.

(+/-) -trans-3- (methoxycarbonyl) bicyclo [2.2.2]Formation of oct-5-ene-2-carboxylic acid (8)

A solution of internal- (+/-) -tetrahydro-4, 7-ethanoisobenzofuran-1, 3-dione 7(74.5g,418.1mmol) was stirred in NaOMe (764.9 mL of a 25% w/w solution in MeOH, 3.3 mol). The reaction mixture was stirred at room temperature for 4 days, thereby obtaining a white suspension. The reaction mixture was concentrated in vacuo to remove approximately 300mL of MeOH. In a separate flask, 300mL of HCl in water (315.9 mL, 36.5% w/w, 3763.0 mmol) was cooled to 0 ℃. The reaction mixture was slowly added to the HCl solution and a white solid precipitated out. The remaining methanol was removed under reduced pressure. The mixture was cooled to 0 ℃ and stirred for 30 minutes. The precipitate was filtered and washed 3 times with water to give an off-white solid. The remaining water was removed under reduced pressure to give 82g of a white solid.

(+/-) -trans-3- (((benzyloxy) carbonyl) amino) bicyclo [2.2.2]Process for producing octyl-5-ene-2-carboxylic acid methyl ester (9) Form a

To rac-trans-3-methoxycarbonylbicyclo [2.2.2]To a solution of oct-5-ene-2-carboxylic acid 8(100.0g,475.7mmol) in toluene (1.0L) were added diphenyl azide phosphate (112.8mL,523.3mmol) and triethylamine (72.9mL,523.3 mmol). The reaction mixture was heated to 90 ℃ for 2 hours. Then, benzyl alcohol (49.2mL,475.7mmol) was added and the mixture was heated to 90 ℃ for 3 days. The mixture was cooled to room temperature and quenched with EtOAc (500mL) and NaHCO₃And (4) diluting with a saturated aqueous solution. The organic phase was washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (100% dichloromethane) to give 115g of oil.¹H NMR showed it to contain BnOH (about 0.05 equiv.). The product was used without further purification:¹H NMR(300MHz,CDCl₃)δ7.40-7.24(m,5H),6.41(t,J=7.4Hz,1H),6.21-6.04(m,1H),5.15-4.94(m,2H),4.63-4.45(m,1H),4.30-4.18(m,1H),3.70(s,2H),3.49(s,1H),2.81(br s,1H),2.68(br s,1H),2.08(s,1H),1.76-1.56(m,1H),1.52-1.35(m,1H),1.33-1.14(m,1H),1.12-0.87(m,1H)。

(+/-) -trans-3-aminobicyclo [2.2.2]Formation of methyl octane-2-carboxylate (10)

To racemic trans-3- (((benzyloxy) carbonyl) amino) -bicyclo [2.2.2]A solution of methyl oct-5-ene-2-carboxylate 9(115.0g,364.7mmol) in THF (253mL) and MeOH (253mL) was added Pd/C and the resulting mixture was placed under an atmosphere of hydrogen at 40psi overnight. A somewhat exothermic reaction was observed. ¹HNMR showed the reaction was complete and BnOH was present. The reaction mixture was filtered through celite (celite) and washed with MeOH. The filtrate was concentrated in vacuo to give 69g of oil:¹H NMR(400MHz,CDCl3)δ3.63(d,J=5.6Hz,3H),3.30(d,J=6.7Hz,1H),2.11(d,J=6.6Hz,1H),1.91(t,J=7.3Hz,1H),1.80–1.64(m,1H),1.63–1.38(m,6H),1.36–1.23(m,2H)。

(+/-) -trans-3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester (11) Formation of

To rac-trans-3-aminobicyclo [2.2.2]To a solution of octane-2-carboxylic acid methyl ester 10(1.30g,7.09mmol) and 2, 4-dichloro-5-fluoro-pyrimidine (1.77g,10.64mmol) in DMF (20mL) was added N, N-diisopropylethylamine (4.94mL,28.38 mmol). The reaction mixture was stirred at room temperature for 100 minutes. Diluting the mixture into NH₄Cl in saturated aqueous solution and extracted with EtOAc. The combined organic phases were washed three times with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. Chromatography on silica gel (0-10% MeOH/CH)₂Cl₂Gradient) the crude residue was purified to give 1.41g of the desired product: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN retention time =1.14 min (M + H) 314.11.

The following compounds were prepared by methods analogous to those described above:

(+/-) -trans- (2,3) -3- ((2, 5-dichloropyrimidin-4-yl) amino) bicyclo- [2.2.2]Octane-2-carboxylic acid methyl ester Formation of ester (37)

To rac-trans- (2,3) -3-aminobicyclo [2.2.2 ] at room temperature ]Octane-2-carboxylic acid methyl ester10(2.0g,10.9mmol) in THF (15.6mL) was added 2,4, 5-trichloropyrimidine (2.2g,1.4mL,12.0mmol) followed by N, N-diisopropylethylamine (2.3mL,13.1 mmol). The vessel was sealed and heated to 60 ℃. After 2.5 h, the solution was diluted with EtOAc, washed twice with half-saturated brine and then Na₂SO₄Dried, filtered through a short column of silica and concentrated in vacuo. Flash chromatography (SiO)₂0-30% EtOAc-hexanes, gradient elution) gave the desired product (3.09 g, 85% yield):¹HNMR(400MHz,MeOD)δ8.04(s,1H),4.53(d,J=6.5Hz,1H),3.71(s,3H),2.77(d,J=6.6Hz,1H),1.99(d,J=2.1Hz,1H),1.84(d,J=2.1Hz,1H),1.81-1.69(m,3H),1.69-1.54(m,3H),1.54-1.38(m,2H)。

synthesis scheme 3: preparation of Compound I-31

(a)X-phos、Pd₂(dba)₃、K₃PO₄、2-MeTHF，120℃；(b)Et₃SiH、TFA、CH₂Cl₂(c) SFC chromatographic resolution of (d) LiOH.H₂O、THF、H₂O

(+/-) trans-3- (5-fluoro-2- (5-fluoro-1-trityl-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidine- 4-ylamino) bicyclo [2.2.2]Formation of methyl octane-2-carboxylate (12)

Reacting rac-trans-3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino]Bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester 11(0.94g,3.00mmol) and 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b]Pyridine 6(1.67g,3.30mmol) and K₃PO₄(2.54g,12.00mmol) in 2-methyl THF (30mL) and H₂The solution in O (6mL) was degassed under a stream of nitrogen for 1 hour. Adding dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl to the mixture ]Phosphane (0.17g,0.36mmol) and 1, 5-diphenylpenta-1, 4-dien-3-one; palladium (0.07g, 0.0)8 mmol). The reaction mixture was heated in a pressure bottle at 120 ℃ for 2 hours. The reaction mixture was filtered through Florisil (Florisil) and Celite (celite), then washed with brine and MgSO₄Drying and concentrating the solvent in vacuo. The crude residue was purified by silica gel chromatography (30% EtOAc/hexanes):¹H NMR(300MHz,CDCl₃) δ 8.50(dd, J =8.4,2.9Hz,1H),8.11(dd, J =20.6,17.2Hz,2H), 7.35-7.16 (m,16H),5.07(d, J =6.1Hz,1H),4.81(t, J =7.2Hz,1H),3.60(s,3H),2.38(d, J =6.6Hz,1H),2.07(d, J =10.6Hz,1H), 1.85-1.35 (m, 10H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.42 min, (M + H) 657.28.

(+/-) trans-3- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bis Ring [2.2.2]Formation of methyl octane-2-carboxylate (13)

Racemic 3- [ [ 5-fluoro-2- (5-fluoro-1-trityl-pyrazolo [3,4-b ]]Pyridin-3-yl) pyrimidin-4-yl]Amino group]Bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester 12(2.40g,3.66mmol) in CH₂Cl₂Et (52mL) solution added₃SiH (5.84mL,36.55mmol) and then trifluoroacetic acid (5.63mL,73.10mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Adding CH to the reaction mixture ₂Cl₂And NaHCO₃A saturated aqueous solution. The organic phase was washed with brine, over MgSO₄Dry, filter and remove the solvent under reduced pressure. By CH₂Cl₂And MeOH the crude product was purified by silica gel chromatography to give 780mg of a racemic mixture of azaindazole 13: 1H NMR (300MHz, CDCl)₃) δ 12.96(s,1H), 8.69-8.47 (m,2H),8.26(d, J =3.0Hz,1H),4.91(t, J =6.3Hz,1H),3.70(s,3H),2.46(dd, J =22.4,6.6Hz,1H),2.14(dd, J =15.9,13.2Hz,3H),1.93(d, J =13.8Hz,1H), 1.83-1.64 (m,5H),1.52(dd, J =24.2,9.5Hz, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.93 min, (M + H) 414.89. The racemic mixture was resolved by SFC chromatography on a chiral support to give the individual enantiomers 14 and 15. The (S, S) -enantiomer (15) was taken and subjected to the next step.

(2S,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclic rings [2.2.2]Formation of octane-2-carboxylic acid-sodium salt (I-31)

To rac-3- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester 15(0.130g,0.296mmol) in THF (10mL) was added 3mL of lithium hydroxide hydrate (0.037g,0.889mmol) in H₂And (4) O solution. The reaction mixture was heated at 60 ℃ for 5 hours. The solvent was removed under reduced pressure. Dissolving the residue in CH ₂Cl₂And MeOH, then with CH₂Cl₂And 76% chloroform, 20% MeOH, and 4% NH₄OH was purified by silica gel chromatography. With 76% chloroform, 20% MeOH, and 4% NH₄OH eluted the product to give 50mg of the ammonium salt of the desired product. To the suspension of the 50mg ammonium salt in MeOH was added 119.9uL of 1 NNaOH. The suspension became clear and the solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give 50mg of the sodium salt of the desired product.¹H NMR (300.0MHz, MeOD) δ 8.71(d, J =6.1Hz, H),8.50(s,1H),8.05(d, J =4.0Hz,1H),4.98(d, J =6.7Hz,1H),4.89(s,1H),3.31(m,1H),2.53(d, J =6.8Hz,1H),2.12-1.99(m,3H),1.87-1.81(m,3H),1.76-1.58(m,2H) and 1.46(dd, J =21.8Hz, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN RT =2.26 min (M + H) 401.3.

The following compounds can be prepared in a similar manner using the procedure described above:

(+/-) -trans-3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclic rings -[2.2.2]Octane-2-carboxylic acid

¹H NMR(300MHz,DMSO)δ13.97(s,1H),12.35(s,1H),8.81(d,J=8.1Hz,1H),8.56(s,1H),8.29(d,J=3.6Hz,1H),7.77(s,1H),7.32(s,1H),4.74(s,1H),2.89(d,J=6.3Hz,1H),2.08(s,1H),1.98(d, J =24.8Hz,2H), 1.83-1.32 (m, 6H); LCMS gradient 10-90%, formic acid, 5 min, C18/ACN, retention time =2.40 min (M + H) 383.06.

Synthesis scheme 4

(a)DPPA、Et₃N, toluene, 110 ℃; ii BnOH, 85 ℃ (b) Pd/C (wet Degussa), hydrogen, EtOH (C)2, 4-dichloro-5-fluoropyrimidine, Degussa, ⁱPr₂NEt, THF, reflux (d) LiOH, THF/water, 50 ℃ (e) DPPA, Et₃N, THF, then pyrrolidine, 85 deg.C

Formation of (1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid

The (1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid starting material can be prepared according to the procedures described in the following documents: barnett, c.j., Gu, r.l., Kobierski, m.e., WO-2002024705, Stereoselective process for preparing cyclohexamine derivatives (chiral selection method for preparing cyclohexylamine derivatives).

Formation of ethyl (1R,3S) -3-benzyloxycarbonylaminocyclohexanecarboxylate (17)

(1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid 16(10.0g,49.9mmol) was dissolved in toluene (100mL) and treated with triethylamine (7.6mL,54.9mmol) and DPPA (12.2mL,54.9 mmol). The resulting solution was heated to 110 ℃ and stirred for 1 hour. After cooling to 70 ℃, benzyl alcohol (7.7mL,74.9mmol) was added and the mixture was heated to 85 ℃ overnight. The resulting solution was cooled to room temperature, poured into EtOAc (150mL) and water (150mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2X 75mL) and the combined organic extracts were washed with water (100mL) and brine (100mL), Na₂SO₄Dried and concentrated in vacuo. The crude was purified by silica gel chromatography (0% to 50% EtOAc in hexanes) Material to give 17 (15.3 g, containing about 25% benzyl alcohol) which was used in the next step without further purification.

Formation of ethyl (1R,3S) -3-aminocyclohexanecarboxylate (18)

To a solution of (1R,3S) -3- (benzyloxycarbonylamino) cyclohexanecarboxylic acid ethyl ester 17(14.0g,45.9mmol) in ethanol (3mL) was added Pd/C (wet, degussa (2.4g,2.3 mmol). the mixture was evacuated and then stirred under nitrogen at room temperature overnight.

Formation of ethyl (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylate (19)

To a solution of (1R,3S) -3-aminocyclohexanecarboxylic acid ethyl ester 18(5.1g,24.1mmol) and 2, 4-dichloro-5, -fluoropyrimidine (6.0g,36.0mmol) in THF (60mL) was added diisopropylethylamine (9.6mL,55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to give 6.7g of ethyl (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylate as a white solid: LCMS retention time =3.1(M + H) 302.2.

Formation of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (20)

To a solution of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ethyl ester 19(20.0g,66.3mmol) in THF (150mL) was added a solution of LiOH hydrate (8.3g,198.8mmol) in 100mL of water. The reaction mixture was stirred at 50 ℃ overnight, to which was added HCl (16.6 mL, 12M solution, 198.8mmol) and EtOAc. The organic phase was washed with brine and MgSO₄Drying and removal of the solvent under reduced pressure gave 17.5g of product, which was purified without further purificationThe following steps are used:¹H NMR(300MHz,CDCl₃)δ7.91(d,J=2.7Hz,2H),5.24(d,J=7.3Hz,2H),4.19–4.03(m,3H),3.84–3.68(m,3H),2.59(ddd,J=11.5,8.2,3.6Hz,2H),2.38(d,J=12.4Hz,2H),2.08(d,J=9.6Hz,6H),1.99–1.76(m,5H),1.63–1.34(m,6H),1.32–1.15(m,4H)。

process for preparing N- ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexyl) -pyrrolidine-1-carboxamide (21) Form a

A solution of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid 20(8.2g,30.0mmol), (azido (phenoxy) phosphoryl) oxybenzene (9.7mL,45.0mmol) and triethylamine (5.8mL,42.0mmol) in THF (200mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85 ℃ for 30 minutes. Pyrrolidine (7.5mL,90.0mmol) was added to the reaction mixture and the reaction was heated at 85 ℃ for an additional 15 minutes. The mixture was diluted into brine and extracted with EtOAc. The organic phase was separated and MgSO ₄And (5) drying. The product was isolated by filtration after partial removal of the solvent under vacuum (6.25 g):¹H NMR(300MHz,CDCl₃)δ7.87(d,J=2.8Hz,2H),5.04(d,J=8.1Hz,2H),4.09(ddd,J=26.9,13.4,5.6Hz,4H),3.91–3.71(m,2H),3.32(t,J=6.5Hz,7H),2.45(d,J=11.5Hz,2H),2.08(dd,J=22.1,12.0Hz,4H),1.96–1.82(m,9H),1.54(dd,J=18.6,8.5Hz,2H),1.22–1.01(m,6H)。

synthesis scheme 5: preparation of Compounds 1-14

(a)X-phos、Pd₂(dba)₃、K₃PO₄、2-MeTHF，120℃；(b)Et₃SiH、TFA、CH₂Cl₂

N- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1-trityl-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidines -4-ylamino) cyclohexyl) cyclopentanecarboxamide(22) Formation of

Reacting 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b ]]Pyridine 6(0.178g,0.352mmol) and N- [ (1R,3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino]Cyclohexyl radical]Pyrrolidine-1-carboxamide 21(0.100g,0.293mmol) in 2-methyl THF (8mL) and H₂The solution in O (0.8mL) was degassed under a stream of nitrogen for 30 minutes. Adding 1, 5-diphenylpenta-1, 4-dien-3-one to the mixture; palladium (0.007g,0.007mmol), dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl]Phosphane (0.017g,0.035mmol) and K₃PO₄(0.249g,1.174mmol) and the mixture degassed for an additional 15 minutes. The reaction mixture was heated in a sealable tube at 115 ℃ for 1 hour. The aqueous phase was removed and the organic phase was filtered through a pad of celite. The mixture was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to give 100mg of the desired product:¹H NMR(300MHz,CDCl₃) δ 8.45(dd, J =8.4,2.9Hz,1H),8.14(dd, J =3.7,1.7Hz,2H), 7.36-7.25 (m,15H),4.95(d, J =5.8Hz,1H),4.20(d, J =10.9Hz,1H),4.05(d, J =7.4Hz,1H),3.86(dd, J =11.4,4.2Hz,1H),3.33(t, J =6.6Hz,4H),2.46(d, J =11.4Hz,1H), 2.32-2.10 (m,2H),1.90(dt, J =13.8,5.1Hz,5H),1.55(dd, J =26.4,12.8, 1H),1.14(dd, J = 24.24, 12.5 Hz, 3.5H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.59 min, (M + H) 685.37.

N- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino Cyclohexyl) Cyclopentanecarboxamide (I-14) formation

To N- [ (1R,3S) -3- [ [ 5-fluoro-2- (5-fluoro-1-trityl-pyrazolo [3,4-b ]]Pyridin-3-yl) pyrimidin-4-yl]Amino group]Cyclohexyl radical]A solution of pyrrolidine-1-carboxamide 22(0.100g,0.146mmol) in dichloromethane (5mL) was added triethylsilane (0.350mL,2.190mmol) followed by trifluoroacetic acid (0.337mL,4.380 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted into 30ml of CH₂Cl₂And NaHCO₃In a saturated aqueous solution. The organic phase was washed with brine, over MgSO₄Dried and the solvent removed under reduced pressure.Chromatography on silica gel (12% MeOH and 88% CH)₂Cl₂) The crude residue was purified to give 64mg of the desired product:¹H NMR(300MHz,CDCl₃) δ 8.42(dd, J =2.7,1.4Hz,1H),7.90(d, J =3.2Hz,1H),7.51(dd, J =8.6,2.7Hz,1H),5.15(d, J =5.5Hz,1H),4.26(d, J =7.9Hz,1H), 3.99-3.79 (m,1H),3.38(d, J =3.2Hz,4H),3.09(d, J =6.6Hz,1H),2.82(d, J =11.3Hz,1H), 2.16-2.05 (m,1H), 2.01-1.85 (m,5H),1.78(d, J =13.2Hz,1H), 1.32-1.04 (m,4H),0.92(dd, J =21.7,11.8, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.31 min, (M + H) 443.34.

Compounds I-1, I-3, I-4, I-5, I-12, I-15, I-16, I-17, I-18, I =19, I- 21. Preparation of I-22, I-23 and I-25

The following compounds were prepared in a manner analogous to that described above for compound I-14.

N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexanes Yl) pyrrolidine-1-carboxamide

¹H NMR(300MHz,CDCl₃) δ 13.85(s,1H),8.56(dd, J =4.5,1.6Hz,1H),8.36(dd, J =8.1,1.4Hz,1H),8.06(d, J =3.1Hz,1H),7.00(dd, J =8.1,4.6Hz,1H),5.07(t, J =15.4Hz,1H),4.17(d, J =7.9Hz,1H), 3.89-3.69 (m,1H),3.35(t, J =6.4Hz,4H),2.77(d, J =11.4Hz,1H),2.11(dd, J =29.5,11.4Hz,2H), 1.93-1.79 (m,5H),1.44(dd, J =26.4,13.3, 1H), 1.91, 0.91, 0H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.12 min (M + H) 425.67.

N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) Cyclohexyl) morpholine-4-carboxamide

¹H NMR (300MHz, MeOD) δ 8.46(s,1H),8.30(dd, J =8.5,2.7Hz,1H),8.04(d, J =3.8Hz,1H),4.13(t, J =11.6Hz,1H),3.81(td, J =8.5,4.2Hz,1H), 3.67-3.57 (m,3H), 3.40-3.33 (m,3H),3.31(dd, J =3.3,1.6Hz,1H),2.32(t, J =14.1Hz,1H),2.16(d, J =11.9Hz,1H), 2.04-1.84 (m,2H), 1.66-1.36 (m,2H), 1.35-1.11 (m, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.76 min (M + H) 459.17.

(R) -3-fluoro-N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidine- 4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

¹H NMR (300MHz, MeOD) δ 8.47(s,4H),8.34(dd, J =8.5,2.8Hz,4H),8.06(t, J =3.2Hz,4H), 5.37-5.11 (m,4H),4.16(dd, J =15.4,7.6Hz,4H),3.82(td, J =8.6,4.4Hz,4H),3.65(t, J =12.9Hz,3H), 3.60-3.34 (m,15H),3.31(dt, J =3.2,1.6Hz,6H),2.33(t, J =10.7Hz,4H), 2.26-2.07 (m,9 ddh), 1.95(dd, J =15.0, 13.6,9.2, 10H), 1.67-1.38.8H, 1.8 (m,8H), 1.8H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.87 min (M + H) 461.68.

(S) -N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) -amino) Cyclohexyl) -2-methylpyrrolidine-1-carboxamide

¹H NMR(300MHz,d6-DMSO)δ9.02(s,1H),8.69(dd,J=4.8,3.3Hz,2H),8.48(d,J=5.0Hz,1H),7.52(dd,J=7.9,4.8Hz,3H),5.87(d,J=8.2Hz,1H),4.23(s,1H),3.90-3.70(m,2H),3.31-3.21(m,1H),3.19-3.01(m,1H),2.76(s,1H),2.20(d,J=11.4Hz,1H),2.01-1.67(m,5H),1.55-1.20(m,5H),1.05(d,J=6.2Hz,2H)。

3, 3-difluoro-N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) Amino) cyclohexyl) pyrrolidine-1-carboxamide

¹H NMR(300MHz,d6-DMSO)δ8.99(s,1H),8.75(d,J=8.4Hz,1H),7.54(s,1H),7.35(s,1H),6.26(d,J=7.9Hz,2H),4.22(s,1H),3.74(s,1H),3.62(t,J=13.4Hz,2H),3.43(t,J=7.3Hz,2H),2.35(dd,J=22.3,14.9Hz,2H),2.24(d,J=22.1Hz,2H),2.09-1.16(m,7H)。

N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) -rings Hexyl) piperidine-1-carboxamide

¹H NMR(300MHz,d6-DMSO)δ13.93(s,1H),8.80-8.64(m,1H),8.56(s,1H),8.27(d,J=3.8Hz,1H),7.70(d,J=7.4Hz,1H),6.23(d,J=7.9Hz,1H),3.68(s,1H),3.28-3.19(m,3H),3.17(d,J=5.2Hz,3H),2.16(d,J=11.5Hz,1H),1.94(d,J=13.4Hz,1H),1.82(s,1H),1.58-1.09(m,11H)。

(S) -N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) -amino) Cyclohexyl) -3-methylpyrrolidine-1-carboxamide

¹H NMR(300MHz,d6-DMSO)δ13.86(s,1H),8.83-8.69(m,1H),8.58(d,J=3.7Hz,1H),8.29(t,J=3.6Hz,1H),7.73(d,J=6.2Hz,1H),7.38(dd,J=8.0,3.9Hz,1H),4.15(s,1H),3.68(d,J=7.6Hz,1H),3.16(d,J=8.4Hz,1H),2.73(t,J=7.3Hz,1H),2.52(s,1H),2.18(d,J=9.0Hz,2H),2.06-1.72(m,5H),1.54-1.12(m,6H),0.98(dd,J=6.4,3.5Hz,3H)。

(S) -3-fluoro-N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b) ]Pyridin-3-yl) pyrimidin-4-yl) Amino) cyclohexyl) pyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.69 min (M + H)443.53[10-90%, formic acid, 5 min, C18/ACN ]

(R) -N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) Cyclohexyl) -2-methylpyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.87 min (M + H)439.56[10-90%, formic acid, 5 min, C18/ACN ]

(R) -3-fluoro-N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) Amino) cyclohexyl) pyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.68 min (M + H)443.53[10-90%, formic acid, 5 min, C18/ACN ]

N- ((1R,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) Cyclohexyl) morpholine-4-carboxamide

¹H NMR (300MHz, MeOD) δ 8.73(s,1H),8.64(s,1H),8.29(d, J =4.8Hz,1H),4.43(m,1H),3.83(m,1H),3.65-3.62(m,4H),3.35 (buried multiplet, 4H),2.38(d, J =12.1Hz,1H),2.23(d, J =9.5Hz,1H),2.03(br m,2H) and 1.70-1.29 (complex multiplet, 4H) ppm; LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.3 min, (M + H) 475.56.14.

N- ((1R,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) Cyclohexyl) pyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.52 min, (M + H) 459.61.

(S) -N- ((1R,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) cyclohexyl) -2- (hydroxymethyl) pyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.33 min, (M + H) 489.65.

N- ((1R,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) Cyclohexyl) -3-methoxypyrrolidine-1-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.38 min, (M + H) 489.6.

Synthesis scheme 6: preparation of Compound I-24

(a) 1-methylimidazole-4-carboxylic acid, HATU,ⁱPr₂NEt, THF (b)3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [5,4-b ]]Pyridine (45), X-phos, Pd₂(dba)₃、K₃PO₄、2-MeTHF，120℃；(c)Et₃SiH、TFA、CH₂Cl₂

N- ((1R,3S) -3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxylic acid methyl ester Formation of amide (24)

To a solution of 1-methylimidazole-4-carboxylic acid (0.113g,0.899mmol) and HATU (0.342g,0.899mmol) in THF (0.009mL) was added (1S,3R) -N1- (2-chloro-5-fluoro-pyrimidin-4-yl) cyclohexane-1, 3-diamine (0.200g,0.817mmol) at room temperature followed by N, N-diisopropylethylamine (0.214mL,1.226 mmol). The reaction was stirred at room temperature for 4 hours. The mixture was diluted with water (20mL) and extracted with ethyl acetate. The organic phase was washed with brine (20mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (50-100% ethyl acetate in hexanes) to afford the desired product: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.67 min (M + H) = 353.44.

N- ((1R,3S) -3- ((5-fluoro-2- (1-trityl-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidine-4- Yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide (25) formation

To 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [5,4-b ]]Pyridine 45(0.259g,0.532mmol) and N- [ (1R,3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino]Cyclohexyl radical](iii) -1-methyl-imidazole-4-carboxamide 24(0.150g,0.425mmol) in 2-Me-THF (7.1mL) and water (1.4mL) addition of K₃PO₄(0.316g,1.488 mmol). The solution was degassed under a stream of nitrogen for 10 minutes. Addition of Pd₂(dba)₃(0.027g,0.030mmol) and dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) -phenyl]Phosphane (0.030g,0.064mmol) and the solution degassed again under a stream of nitrogen. The reaction tube was sealed and heated to 80 ℃ for 2 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The organic phase was extracted with ethyl acetate and washed with brine (10 mL). The crude product was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (0-7% MeOH [2N NH ] in ethyl acetate₃]) Purifying the crude residue to obtain the desired compound: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.78 min (M + H) = 678.73.

N- ((1R,3S) -3- ((5-fluoro-2- (1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexanes Formation of 1-methyl-1H-imidazole-4-carboxamide (I-24)

At room temperature towards N-[ (1R,3S) -3- [ [ 5-fluoro-2- (1-tritylpyrazolo [3,4-b ]]Pyridin-3-yl) pyrimidin-4-yl]Amino group]Cyclohexyl radical](iii) -1-methyl-imidazole-4-carboxamide 25(0.235g,0.347mmol) in dichloromethane (6.90mL) Et was added₃SiH (1.661mL,10.40mmol) followed by addition of TFA (0.401mL,5.200 mmol). The reaction mixture was stirred for 1 hour. The mixture was diluted with dichloromethane and Na₂CO₃And (4) quenching by saturated aqueous solution. The organic phase was extracted with ethyl acetate and washed with brine (10mL), dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (0-7% MeOH [2N NH ] in ethyl acetate₃]) The crude residue was purified to give the desired product: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.46 min (M + H) = 436.62.

Preparation of Compound I-27

The following compounds were prepared in a manner analogous to that described above for compound I-24.

N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) Cyclohexyl) -1-methyl-1H-imidazole-5-carboxamide

LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.61 min (M + H) 454.34.

Synthesis scheme 7

(a) i: diisopropylamine, n-butyllithium, THF, -78 ℃, then ii: morpholine-4-carbaldehyde; (b) refluxing pinacol, pTsOH and toluene; (c) hydrazine,ⁱPr₂NEt, IPrOH, 60 ℃; (d)6NHCl, EtOH, 45 ℃; (e) NIS, DCE, 60 ℃; (f) trityl-Cl, Na₂CO₃DMF; (g) bis (pinacolborane), Pd (dppf)₂Cl₂、KOAc、DMF

Formation of 5-chloro-2-fluoronicotinaldehyde (27)

To a cold (0 ℃ C.) solution of diisopropylamine (12.8mL,91.2mmol) in THF (100mL) was added butyllithium (31.9 mL, 2.5M, 79.8 mmol) over 5 minutes. After 5 minutes, the reaction was cooled to-78 ℃ for 15 minutes. Then 5-chloro-2-fluoro-pyridine (10.0g,76.0mmol) was added slowly over 5 minutes. The reaction was held at-78 ℃ for an additional 1.5 hours. Morpholine-4-carbaldehyde (17.5g,152.1mmol) was then added rapidly. The mixture was stirred for an additional 2 minutes and quenched with 10% citric acid and the mixture allowed to warm to room temperature. The pH was adjusted to 5-6 with additional citric acid solution. The mixture was extracted with dichloromethane (3X 200mL) and the combined organic layers were taken up with Na₂SO₄Dried, filtered and concentrated. Flash chromatography (SiO)₂0-25% EtOAc-hexanes gradient elution) afforded the desired product as an off-white crystalline solid (8.95 g, 74% yield). LC-MS shows the mass of the desired product and corresponding hydrate: ¹H NMR(300MHz,CDCl₃) δ 10.28(d, J =8.4Hz,1H),8.41(t, J =1.4Hz,1H) and 8.25(dd, J =2.7,7.8Hz,1H) ppm; LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.45 min, (M + H) 159.91.

Formation of 5-chloro-2-fluoro-3- (4,4,5, 5-tetramethyl-1, 3-dioxolan-2-yl) pyridine (28)

A flask equipped with a Dean-Stark trap was charged with a solution of 5-chloro-2-fluoro-nicotinaldehyde 27(8.95g,56.10mmol) and 2, 3-dimethylbutane-2, 3-diol (8.00g,67.70mmol) and p-toluenesulfonic acid monohydrate (0.54g,2.81mmol) in toluene (250mL) and heated to vigorous reflux for 3 hours. The mixture was cooled, diluted with EtOAc and washed with NaHCO₃(2x) and brine (1 x). The organic phase is treated with Na₂SO₄Dried, filtered through a silica column and concentrated in vacuo. Form crystals when standingSolid (14.47 g):¹H NMR(300.0MHz,CDCl₃) δ 8.12(s,1H),7.97(dd, J =2.7,7.8Hz,1H),6.08(s,1H),1.33(s,3H) and 1.26(s,3H) ppm.

5-chloro-1H-pyrazolo [3,4-b]Formation of pyridine (30)

To a solution of 5-chloro-2-fluoro-3- (4,4,5, 5-tetramethyl-1, 3-dioxolan-2-yl) pyridine 28(14.5g,55.8mmol) and N, N-diisopropylethylamine (19.5mL,112.0mmol) in isopropanol (200mL) was added hydrazine (12.0mL,382.3 mmol). The mixture was heated to 65 ℃ overnight. LC-MS indicated the formation of the desired hydrazine compound and the mixture was concentrated in vacuo. The crude residue was taken up in 300mL of water and 120mL of EtOH followed by 50mL of 6N HCl. The resulting mixture was allowed to warm to 45 ℃ overnight. Once LC-MS indicated completion of the reaction, the mixture was neutralized with 6N NaOH and the pH was adjusted to 8. The mixture was concentrated in vacuo to remove volatile EtOH and extracted with EtOAc (3 ×). The combined organic layers were washed with Na ₂SO₄Dried, filtered through a short column of silica and concentrated in vacuo. Trituration with 10% aqueous acetonitrile afforded the desired product (6.15g, 72% yield, approximately 90% purity by NMR):¹H NMR(300.0MHz,CDCl₃) δ 11.43(s,1H),8.55(d, J =2.2Hz,1H),8.10(d, J =2.2Hz,1H) and 8.08(s,1H) ppm; LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.05 min (M + H) 153.91.

5-chloro-3-iodo-1H-pyrazolo [3,4-b]Formation of pyridine (31)

Reacting 5-chloro-1H-pyrazolo [3, 4-b)]A mixture of pyridine 30(6.15g,40.10mmol) and N-iodosuccinimide (9.46g,42.1mmol) in DCE was heated to 50 deg.C overnight. After 16 hours, the reaction was allowed to cool to room temperature and stirred overnight for 48 hours. An additional 0.20 equivalents of N-iodosuccinimide (1.80g,8.01mmol) was added and the mixture was heated overnight. The mixture was then cooled and Et₂O dilution with aqueous NaHCO₃Washed with sodium thiosulfate solution, water and brine. The aqueous primary wash was back extracted with EtOAc. The combined organic layers were washed with brine, washed with Na₂SO₄Dried, filtered through silica and concentrated in vacuo. With very small amounts of dichloromethane and Et₂The resulting solid was triturated to give the desired product as an off-white solid. (2.02 g, 96% yield), pure enough for the next reaction: ¹H NMR(300MHz,CDCl₃) δ 11.28(s,1H),8.55(d, J =2.2Hz,1H) and 7.86(d, J =2.2Hz,1H) ppm; LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.76 min, (M + H) 280.06.

5-chloro-3-iodo-1-trityl-1H-pyrazolo [3,4-b]Formation of pyridine (32)

To 5-chloro-3-iodo-1H-pyrazolo [3,4-b]Pyridine 31(11.6g,38.5mmol) and Na₂CO₃(12.2g,115mmol) in N, N-dimethylformamide (200mL) trityl chloride (11.8g,42.4mmol) was added. The mixture was stirred at room temperature overnight. After 16 h, additional trityl chloride (1.61g,5.78mmol) was added. The mixture was heated to 60 ℃ for 45 minutes. The mixture was cooled and Et₂Diluted with O, washed with water (2X), brine (2X), Na₂SO₄Dried, filtered and concentrated in vacuo. Flash chromatography (SiO)₂0-40% EtOAc-hexanes gradient elution) afforded the desired product as a colorless material which was purified by flash chromatography (SiO)₂100% DCM, isocratic elution) further purified:¹H NMR(300MHz,CDCl₃) δ 8.15(d, J =2.3Hz,1H),7.70(d, J =2.3Hz,1H) and 7.23-7.18(m,15H) ppm.

5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyri-dine Azolo [3,4-b]Formation of pyridine (33)

A dry flask was charged with 5-chloro-3-iodo-1-trityl-1H-pyrazolo [3,4-b ]Pyridine 32(3.00g,5.75mmol), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (1.90g,7.48mmol) and potassium acetate (2.26g,23.0mmol) and DMF (50mL) was added. The mixture was degassed with a stream of nitrogen for 30 minutes. Then, Pd (dppf) was added₂Cl₂(0.14g,0.17mmol), the vessel was sealed and heated to 90 ℃ for 16 hours. The mixture was cooled and Et 450mL₂And (4) diluting with oxygen. The organic layer was washed with water (3X) and brine (2X), over Na₂SO₄Dried and filtered through a thin bed of neutral alumina under mild vacuum. The resulting clear yellow solution was concentrated in vacuo to obtain the crude desired product in sufficient purity (technical grade) for subsequent coupling reactions: LCMS retention time =2.76 min (M + H) 440.43.

Synthesis scheme 8: preparation of Compounds I-9 and I-10

(a)i.Pd₂(dba)₃、X-Phos、K₃PO₄、MeTHF-H₂O，125℃，ii.Et₃SiH、TFA、DCM，0℃；(b)NaOH、THF-MeOH-H₂O; (c) chiral SFC separation.

(+/-) -trans- (2,3) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) bicyclo [2.2.2]Formation of methyl octane-2-carboxylate (34)

Reacting racemic trans- (7,8) -7- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino]Bicyclo [2.2.2]Octane-8-carboxylic acid methyl ester 11(0.30g,0.96mmol) and 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b ]Pyridine 33(0.75g,1.43mmol) and K₃PO₄A mixture of (0.64g,3.00mmol) in water (1.5mL) and 2-Me-THF (8.5mL) was degassed with a stream of nitrogen for 5-10 minutes. Then, X-Phos (0.05g,0.10mmol) and Pd were added₂(dba)₃(0.02g,0.02mmol), the vessel was sealed and heated to 120 ℃ for 25 minutes by microwave irradiation. After cooling to room temperature, the organic layer was separated and concentrated in vacuo. Flash chromatography (SiO)₂0-100% EtOAc-hexanes, gradient elution) afforded the desired product contaminated with the starting chloropyrimidine 11 (280mg total weight). The material was not further processedPurification is carried out, namely, the step of deprotection is carried out: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.84 min, (M + H) 673.55.

To the crude product (280mg) in CH at room temperature₂Cl₂Et (5mL) solution added₃SiH (2.0mL,12.5mmol) and TFA (2.0mL,26.0 mmol). After 1 hour, the solution was diluted with EtOAc and concentrated in vacuo. Carefully perform flash chromatography (SiO)₂，0-20%MeOH-CH₂Cl₂Gradient elution) to yield 77mg of the desired product:¹h NMR (300MHz, MeOD) δ 8.98(d, J =2.3Hz,1H),8.53(d, J =2.3Hz,1H),8.12(d, J =3.8Hz,1H),4.99(d, J =6.8Hz,1H),3.67(s,3H),2.85(d, J =7.1Hz,1H),2.08(s,1H),1.93-1.42(m,8H),1.20(d, J =4.7Hz, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.52 min, (M + H) 431.69.

(+/-) trans- (2S,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidine-4- Yl) amino) bicyclo [2.2.2]Formation of octane-2-carboxylic acid

To (+/-) -trans- (2,3) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2]A solution of octane-2-carboxylic acid methyl ester 34(0.06g,0.13mmol) in THF (0.75mL) and MeOH (0.25mL) was added NaOH (0.25mL, 2M, 0.50 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was eluted with MeOH (2mL), neutralized with 2N HCl (0.251mL) and concentrated in vacuo. The white solid formed during acidification was repeatedly triturated with a very small amount of water to give 52mg of the desired product (racemic mixture) as an amorphous white solid:¹HNMR (300MHz, MeOD) δ 8.96(d, J =2.4Hz,1H),8.58(d, J =2.4Hz,1H),8.19(d, J =4.4Hz,1H),5.06(d, J =6.9Hz,1H),2.85(d, J =7.0Hz,1H),2.20-2.12(m,1H),2.09-1.97(m,2H),1.91-1.47(m, 8H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.23 min, (M + H) 417.28.

Chiral SFC (30% MeOH, 70% CO) on Chiralpak IC₂(DEA modifier)) to give the individual enantiomers I-9 and I-10.

(2R,3R) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b) ]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) -amino) Bicyclo [2.2.2]Octane-2-carboxylic acid (I-10)

Rapidly eluting enantiomer: chiralpak IC (4.6X 250) on 30% MeOH,70% CO₂(5 mL/min, DEA modifier), Retention time R_t=3.93 minutes.

¹H NMR (300MHz, MeOD) δ 8.96(s,1H),8.57(d, J =2.0Hz,1H),8.18(d, J =3.8Hz,1H),5.04(d, J =6.9Hz,1H),2.85(d, J =6.9Hz,1H),2.15(s,1H),2.04(s,2H),1.96-1.45(m, 7H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.24 min (M + H) 417.08.

(2S,3S) -3- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) -amino) bis Ring [2.2.2]Octane-2-carboxylic acid (I-9)

Slow eluting enantiomer: chiralpak IC (4.6X 250) with 30% MeOH70% CO₂(5 mL/min, DEA modifier), retention time =4.53 minutes.

¹H NMR (300MHz, MeOD) δ 8.96(s,1H),8.57(d, J =2.0Hz,1H),8.18(d, J =3.8Hz,1H),5.04(d, J =6.9Hz,1H),2.85(d, J =6.9Hz,1H),2.15(s,1H),2.04(s,2H),1.96-1.45(m, 7H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.24 min (M + H) 417.33.

Synthetic scheme 9: preparation of Compounds I-32, I-34 and I-35

(a)Pd(PPh₃)₄、K₃PO₄、THF-H₂O，90℃；(b)Et₃SiH、TFA、DCM，0℃；(c)NaOH，THF-MeOH-H₂O; (d) chiral SFC separation.

(+/-) -trans- (2,3) -3- ((5-chloro-2- (5-fluoro-1-trityl-1H-pyrazolo- [3, 4-b) ]Pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Formation of methyl octane-2-carboxylate (38)

(+/-) -trans- (2,3) -3- ((2, 5-dichloropyrimidin-4-yl) amino) -bicyclo- [2.2.2 ] was reacted with a nitrogen stream]Octane-2-carboxylic acid methyl ester, 37, (0.50g,1.51mmol) and K₃PO₄A solution of (0.96g,4.54mmol) in water (2.5mL) and THF (10.00mL) was degassed for 15 minutes. Then, 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b ] was added]Pyridine 6(0.84g,1.67mmol) and the mixture degassed for a further 15 minutes. Then, Pd (PPh)₃)₄(0.09g,0.08mmol) was added to the mixture. The vessel was sealed and heated to 90 ℃. After 2.5 hours, an additional 0.1 equivalent of borate 6 was added and the mixture was heated for an additional 30 minutes. The cooled solution was diluted with EtOAc, washed with water and Na₂SO₄Dried, filtered and concentrated in vacuo. Performing flash chromatography (SiO)₂0-35% EtOAc in DCM) gave the desired product (0.85 g, 83% yield) pure enough for the next reaction: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.85 min, (M + H) 673.27.

(+/-) -trans- (2,3) -3- ((5-chloro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2]Formation of methyl octane-2-carboxylate (I-32)

To (+/-) -trans- (2,3) -3- ((5-chloro-2- (5-fluoro-1-trityl-1H-pyrazolo [3, 4-b) at room temperature]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester 38(0.85g,1.26mmol) in CH₂Cl₂Et (42.5mL) solution was added₃SiH (1.00mL,6.32mmol) and then trifluoroacetic acid (0.97mL,12.60mmol) was added. The reaction was stirred at room temperature. After the reaction was complete as judged by LC-MS, the solution was concentrated in vacuo. Carefully perform flash chromatography (SiO)₂，0-7%MeOH-CH₂Cl₂Gradient elution) to give the desired product (373 mg, 66% yield) L¹H NMR (400MHz, MeOD) δ 8.66(dd, J =8.3,2.5Hz,1H),8.53(s,1H),8.28(s,1H),5.05(d, J =6.5Hz,1H),3.69(s,3H),2.95(d, J =6.8Hz,1H),2.09(s,1H),1.98(s,1H),1.96-1.79(m,3H),1.77-1.61(m,3H),1.61-1.45(m, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.55 min, (M + H) 431.14.

(+/-) -trans- (2,3) -3- ((5-chloro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2]Formation of octane-2-carboxylic acid

Racemic-trans- (2,3) -3- ((5-chloro-2- (5-fluoro-1H-pyrazolo [3, 4-b) is reacted at room temperature]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2 ]A solution of octane-2-carboxylic acid methyl ester I-32(0.31g,0.72mmol) in THF (5.4mL) and MeOH (1.8mL) was treated with NaOH (1.80mL, 2M, 3.60mmol) for 16 h. The reaction was diluted with 5-7mL of water, concentrated to remove organic solvent and extracted with MBTE (2 ×) to remove neutral organics. The mixture was acidified to pH6 with 6N HCl and extracted several times with EtOAc. Subjecting the milky white organic layer to acetonitrile and CH₂Cl₂Diluted and then concentrated in vacuo. The resulting solid was suspended in acetonitrile and concentrated twice in vacuo to afford the desired product (280 mg, 90% yield) as an off-white amorphous solid:¹h NMR (400MHz, MeOD) δ 8.67(dd, J =8.4,2.5Hz,1H),8.53(s,1H),8.27(s,1H),5.05(d, J =6.7Hz,1H),2.92(d, J =6.6Hz,1H),2.15(s,1H),2.03-1.79(m,4H),1.79-1.62(m,3H),1.62-1.45(m, 2H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.28 min, (M + H) 417.09.

Chiral SFC chromatographic resolution (20% MeOH, 80% CO) on Chiralpak IC (10X 250)₂(10 mL/min)) to give the individual enantiomers.

(2S,3S) -3- ((5-chloro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) bis Ring [2.2.2]Octane-2-carboxylic acid (I-34)

Quick elution The enantiomer of (a): chiralpak IC (10X 250) on 20% MeOH, 80% CO₂(10mL/min), retention time =8.18 minutes.

¹H NMR (300MHz, MeOD) δ 8.67(d, J =6.6Hz,1H),8.53(s,1H),8.27(s,1H),5.13-4.98(m,1H),2.98-2.87(m,1H),2.11 (broad singlet, 1H),2.05-1.82(m, J =36.5Hz,3H),1.82-1.44(m, 4H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.27 min (M + H) 417.09.

(2R,3R) -3- ((5-chloro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) bis Ring [2.2.2]Octane-2-carboxylic acid (I-35)

Slow eluting enantiomer: chiralpak IC (10X 250) on 20% MeOH, 80% CO₂(10mL/min), retention time =9.56 minutes.

¹H NMR (300MHz, MeOD). delta.8.69 (s,1H),8.52(s,1H),8.27(s,1H),5.18-4.99(m,1H),3.00-2.86(m,1H),2.15(s,1H),2.07-1.82(m,3H),1.81-1.45(m, 4H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.27 min (M + H) 417.09.

Synthesis scheme 10

(a) Hydrazine hydrate, ethanol, 80 ℃; (b) NBS, DMF; (c) trityl-Cl, NaH, DMF, 0 ℃; (d) bis (pinacolborane), Pd (dppf)₂Cl₂、KOAc、DMF

1H-pyrazolo [3,4-b]Formation of pyridine (42)

Hydrazine hydrate (64%, 0.29L, 5.99mol hydrazine, 3 eq.) was added dropwise over 1 hour to a solution of 2-fluoropyridine-3-carbaldehyde (0.25kg,1.99mol) in EtOH (600 mL). During the addition, a thick suspension is formed, which is suspended towards the end of the addition The liquid turned into a clear red solution. The reaction mixture was heated to 80 ℃ overnight. The reaction mixture was cooled to room temperature and washed with H₂O/NaHCO₃Saturated aqueous solution (1/1 mixture, 600 mL) was quenched and extracted with EtOAc (2X 800mL, 1X 500 mL). The combined organic layers were washed with brine (400mL) and Na₂SO₄Dried and concentrated in vacuo. The resulting solid was washed with heptane (3X 800mL), dried under reduced pressure and stripped twice with heptane. The product (214 g, 90% yield) was obtained as a pale yellow solid:¹H NMR(CDCl₃、300MHz)δ8.65-8.64(m,1H)；8.14-8.10(m,2H)；7.17-7.12(m,1H)ppm。

3-bromo-1H-pyrazolo [3,4-b]Formation of pyridine (43)

1H-pyrazolo [3,4-b ] in 1 hour]NBS (0.34 kg, 1.07 equiv.) was added in portions to a solution of pyridine 42(0.21kg,1.79mol) in DMF (2L). During the addition, the temperature reached 44 ℃. The reaction mixture was stirred for 40 minutes. Ice water (total volume 3L) was added and the resulting precipitate was collected by filtration. The product is treated with H₂O (3X 2L) was washed and left on the filter for 3 days. The product was washed with heptane (1 ×) and dissolved in EtOAc (4L). The aqueous phase was separated and the remaining organic layer was washed with brine and concentrated to dryness to give the product (229 g, 65% yield) as a pale yellow solid:¹H NMR(CDCl₃、300MHz)δ8.71-8.64(m,1H)；8.08-8.02(m,1H)；7.30-7.24m,1H)ppm。

3-bromo-1-trityl-1H-pyrazolo [3,4-b]Formation of pyridine (44)

To 3-bromo-1H-pyrazolo [3, 4-b)]Triphenylmethyl chloride (0.34 kg, 1.21mol, 1.05 eq) was added to a solution of pyridine 43(0.23kg,1.16mmol) in DMF (2.2L). The reaction mixture was cooled to with an ice-salt bath<60% NaH (0.05 kg of 60% suspension, 1.35mol, 1.17 eq.) was added in portions over 1 hour at 0 ℃. During the addition, the temperature did not exceed 5 ℃. After complete addition, the reaction mixture was allowed to reach room temperature overnight. Addition of Ice (2L) and H₂O (1L), the reaction mixture was stirred vigorously for 30 minutes. Filtering and collecting the precipitated productCombined use of H₂O (3X 1.5L) and heptane (2X). Dissolving the product in CH₂Cl₂(2.5L) and diluted with heptane (1.5L). The solution was filtered through silica gel (1.5kg) and washed with 50% CH₂Cl₂Heptane elution. The product containing fractions were pooled and concentrated in vacuo to a small volume. The suspension was cooled and the product was collected by filtration, washed with heptane (3x) and TBME (1 x). After drying under reduced pressure, the product was isolated as a yellow solid (369 g, 72% yield):¹H NMR(CDCl₃、300MHz)δ8.30-8.26(m,1H)；7.91-7.88(m,1H)；7.34-7.18(m,15H)；7.10-7.04(m,1H)ppm。

3-bromo-1-trityl-1H-pyrazolo [3,4-b]Formation of pyridine (45)

Reacting 3-bromo-5-fluoro-1-trityl-pyrazolo [3,4-b]A solution of pyridine 44(16.86g,36.79mmol), KOAc (10.83g,110.4mmol) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (14.01g,55.18mmol) in DMF (250mL) was degassed under a stream of nitrogen for 40 minutes. Adding Pd (dppf) to the mixture ₂Cl₂(3.00g,3.68 mmol). The reaction mixture was heated at 100 ℃ for 90 minutes. The reaction mixture was filtered through a pad of Florisil (florisil) and Celite (celite). The filtrate was diluted with ether and brine. The organic phase was washed with MgSO₄Dried, filtered and concentrated in vacuo. The product was dried on a high vacuum pump for 3 days. To this product was added 200mL Et₂O, stirring and filtering the mixture. The filtrate was concentrated in vacuo. The crude residue was diluted with 150mL of hexane and the suspension was stirred for 3 hours, filtered and concentrated in vacuo to give 12.6g of the desired product.

Synthetic scheme 11: preparation of Compound I-13

(a) Benzyl alcohol, toluene, 4 angstrom sieve, refluxing (b) NaH, MeI, DMF (c) benzylamine, TiCl₄、CH₂Cl₂Then NaCNBH₃、MeOH，0℃(d)H₂、Pd-C、MeOH(i)Pd₂(dba)₃、X-Phos、K₃PO₄、MeTHF-H₂O，125℃；(ii)mCPBA、CH₂Cl₂，0℃；(iii)49、Na₂CO₃、CH₃CN-THF，135℃；(iv)Et₃SiH、TFA、CH₂Cl₂，0℃。

A general procedure for the synthesis of trans-2-amino-1-alkyl-cyclohexanecarboxylic acid is shown in the above scheme.

Compound 46 was prepared according to the procedure described in the following literature: matsuo, J.et al, tetrahedron: Asymmetry2007,18, 1906-.

Formation of benzyl 1-methyl-2-oxocyclohexanecarboxylate (47)

This compound was prepared according to the procedure described in the following literature: (a) hayashi, y.; Shoji, m.; Kishida, s.tetrahedron lett.2005,46,681 @ (Winfield, c.j.; Al-Mahrizy, z.; Gravestock, m.; Bugg, t.d.h.j.chem.soc., Perkin trans.1,2000, 3277).

Formation of (+/-) -trans-2- (benzylamino) -1-methylcyclohexanecarboxylic acid benzyl ester (48)

To a solution of benzyl 1-methyl-2-oxo-cyclohexanecarboxylate 47(0.50g,2.03mmol) and benzylamine (0.63mL,5.75mmol) in dichloromethane (10.0mL) was added dropwise TiCl at room temperature₄(1.93 mL, 1M solution, 1.93 mmol). The mixture was stirred for 2 hours. The mixture was cooled to 0 ℃ and NaBH was added dropwise over a period of 3 minutes₃CN (0.21g,3.34mmol) in MeOH. After 15 minutes, the solution was allowed to warm to room temperature and stirred for an additional 45 minutes. The mixture was then diluted with EtOAc and quenched with 10mL of 1M NaOHAnd (6) extinguishing. The mixture was washed with Et₂O partition and Et₂The aqueous layer was extracted several times with O (2X) and EtOAc (1X). The combined organic phases were washed with MgSO₄Dried, filtered and concentrated in vacuo. Performing flash chromatography (SiO)₂0-50% EtOAc-hexanes gradient) and the major components were separated to give the desired product (320mg) as a single racemic trans isomer:¹h NMR (300MHz, MeOD) δ 7.34-7.16(m,10H),5.07(dd, J =12.4,31.2Hz,2H),3.78(d, J =13.0Hz,1H),3.57(d, J =13.0Hz,1H),2.96(m,1H),1.86(m,1H),1.74-1.57(m,3H),1.52-1.25(m,4H) and 1.20(s,3H) ppm.

Formation of (+/-) -trans-2-amino-1-methylcyclohexanecarboxylic acid (49)

To a solution of racemic benzyl trans- (1S,2S) -2- (benzylamino) -1-ethyl-cyclohexanecarboxylate 48(0.32g,0.91mmol) in MeOH (12.8mL) was added Pd (5% palladium on carbon, 0.07 g). The solution was degassed and placed in 50PSI H₂Overnight under atmosphere (Parr shaker). The mixture was filtered through celite and the filtrate was washed with MeOH. The mother liquor was concentrated then azeotroped with acetonitrile (2 ×) to remove residual MeOH to give the desired product (162 mg):¹h NMR (300MHz, MeOD). delta.3.22 (m,1H),1.93(m,1H),1.77(m,2H),1.57-1.23(m,5H) and 1.17(s,3H) ppm.

5-chloro-3- (5-fluoro-4- (methylthio) pyrimidin-2-yl) -1-trityl-1H-pyrazolo [3,4-b]Pyridine compound (50) Formation of

2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (0.26g,1.44mmol) and 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b]Pyridine 33(0.75g,1.44mmol) and K₃PO₄A mixture of (0.96g,4.53mmol) in water (1.5mL) and 2-Me-THF (7.5mL) was degassed by bubbling nitrogen through it for 15 minutes. Then, X-Phos (0.07g,0.14mmol) and Pd were added₂(dba)₃(0.03g,0.04mmol), the vessel was sealed and heated to 125 ℃ for 30 minutes by microwave irradiation. After cooling to room temperature, water was added and extracted with ether and 2-Me-THF. The combined organic phases were washed with Na ₂SO₄Dried, filtered and concentrated in vacuo.Performing flash chromatography (SiO)₂0-100% EtOAc-hexanes, gradient elution) yielded 230mg of the desired product, which was used without further purification: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.46 min (M + H) 538.01.

5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-trityl-1H-pyrazolo [3,4-b] Formation of pyridine (51)

To 5-chloro-3- (5-fluoro-4- (methylthio) pyrimidin-2-yl) -1-trityl-1H-pyrazolo [3,4-b ] at 0 DEG C]Pyridine 50(0.078g,0.150mmol) in CH₂Cl₂To the stirred solution of (1), mCPBA (0.036g,0.160mmol) was added. The mixture was kept at 0 ℃ for 2 hours. Then, the mixture is treated with CH₂Cl₂Diluting with K₂CO₃(2X) washing with Na₂SO₄Dried, filtered and concentrated in vacuo to give 78mg of the desired crude which was used without further purification in the next step: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =1.62 min (M + H) 554.47.

(+/-) -2- ((2- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) -1-methyl Formation of Cyclohexanecarboxylic acid (I-13)

Crude 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-trityl-1H-pyrazolo [3, 4-b) ]Pyridine 51(0.078g,0.140mmol) and (1S,2S) -2-amino-1-methyl-cyclohexanecarboxylic acid 49(0.044g,0.280mmol) with Na₂CO₃(0.059g,0.560mmol) in dry CH₃The mixture in CN and THF was heated at 135 ℃ (30 minutes, microwave irradiation) in a sealed vial. The reaction mixture was neutralized with a slight excess of 2N HCl and water, and CH₂Cl₂(3x) extracting the mixture. The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated in vacuo to afford 68mg trityl protected product: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT =3.43 min (M + H) 647.67.

Dissolving the above crude product in CH at 0 deg.C₂Cl₂(3mL) and treated with triethylsilane (0.75mL,4.70mmol) followed by 2,2, 2-trifluoroacetic acid (0.75mL,9.70mmol) for 30 minutes. The solution was concentrated in vacuo. Preparative HPLC was performed to give 16mg of the desired product:¹h NMR (300MHz, d 6-DMSO). delta.8.96 (s,1H),8.64(s,1H),8.36(br,1H),7.58(br s,1H),5.08-4.88(m,1H),2.04-1.85(m,1H),1.85-1.61(m,4H),1.61-1.32(m,3H),1.21(s,3H) ppm; LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.17 min (M + H) 405.01.

Synthetic scheme 12: preparation of Compounds I-36 and I-37

(a) Maleic anhydride, benzene, 150 ℃; (b) sodium methoxide, MeOH; (c) ethyl chloroformate, Et ₃N, THF0 deg.C, 1 hour, then sodium azide, H₂O, 0 ℃,2 hours, then benzyl alcohol, Et₃N、CH₂Cl₂(ii) a (d) Hydrogen, Pd/C, EtOAc; (e) refluxing 2, 4-dichloro-5-fluoropyrimidine, THF and MeOH; (f) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyrrolo [2,3-b ]]Pyridine (6), Pd₂(dba)₃XPhos, water/2-methyl-THF, 120 ℃; (g) triethylsilane, TFA, CH₂Cl₂；(h)LiOH、H₂O/THF，85℃。

(di-exo) -4,5,6,7,8,8 a-hexahydro-1H-4, 8-methanocyclohepta [ c)]Furan-1, 3(3aH) -diones (53) Formation of

Solid maleic anhydride (4.73g,48.23mmol) was added to a stirred solution of cyclohepta-1, 3-diene (5.00g,53.10mmol) in benzene (10mL) in a sealed tube (Q-tube). The suspension was heated at 150 ℃ for 18 hours to give a clear yellow solution. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 9.3g of the desired productOff-white solid of material:¹H NMR(400MHz,d6-DMSO)δ6.16(dt,J=9.1,4.5Hz,2H),3.50(s,2H),2.82(s,2H),1.77–1.55(m,4H),1.52–1.38(m,2H)。

(+/-) - (Exo) -trans-7- (methoxycarbonyl) bicyclo [3.2.2]Formation of non-8-ene-6-carboxylic acid (54)

Sodium methoxide (40.5 mL of a 25% W/W solution in methanol, 176.9 mmol) was added to the pulverized (di-exo) -4,5,6,7,8,8 a-hexahydro-1H-4, 8-methanone cyclohepta [ c)]Furan-1, 3(3aH) -dione 53(8.5g,44.2mmol), and the suspension was diluted with methanol (10 mL). The resulting suspension was stirred vigorously at room temperature for 24 hours to give a thick white suspension. The suspension was cooled to 0 ℃. The cold suspension was added dropwise to a cold solution (0 ℃) of concentrated HCl (22.0mL,265.3mmol) in water (22mL) while cooling on ice. The dropping funnel was washed with methanol (25mL) and the solution was added dropwise to the HCl solution. The suspension was diluted with water (500mL) and the aqueous phase was extracted with EtOAc (3X 100 mL). The organic layer was washed with Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAC/hexane) to give 7.5g of the desired product as a white solid:¹H NMR(400MHz,CDCl₃)δ6.23(t,J=8.2Hz,1H),6.15–6.03(m,1H),3.76(s,3H),3.52(d,J=6.9Hz,1H),3.20(dd,J=6.7,4.7Hz,1H),3.06–2.85(m,2H),1.79–1.37(m,6H)。

(+/-) - (Exo) -trans-9- (((benzyloxy) carbonyl) amino) bicyclo [3.2.2]-non-6-ene-8-carboxylic acid methyl ester (55) Formation of

Ethyl chloroformate (3.36mL,35.11mmol) was added dropwise to rac- (rac) -trans-7- (methoxycarbonyl) bicyclo [3.2.2 ] at 0 ℃ with vigorous stirring]Non-8-ene-6-carboxylic acid 54(7.50g,33.44mmol) and Et₃A stirred solution of N (6.39mL,45.81mmol) in THF (100 mL). A white precipitate formed and THF (50mL) was added. The suspension was stirred at 0 ℃ for 1 hour. A solution of sodium azide (7.39g,113.70mmol) in water (30mL) was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and water (200) was addedmL). The aqueous phase was extracted with EtOAc (3X 100 mL). The combined organic phases were dried (MgSO)₄) Filtered and concentrated in vacuo to give 7.7g of azide as a clear oil. The crude azide was dissolved in benzene (80mL) and refluxed for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to give a thick oil of intermediate isocyanate. The oil was dissolved in dichloromethane (25mL) and benzyl alcohol (3.90mL,37.69mmol) and Et were added ₃Solution of N (18.65mL,133.80 mmol). The clear solution was stirred at room temperature for 18 hours and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give 10.8g of the desired product as a clear oil.¹H NMR(400MHz,CDCl₃) δ 7.24(m,5H),6.16(t, J =8.1Hz,1H),5.98(t, J =7.8Hz,1H),5.00(s,2H),4.58(m,1H),3.67(s,3H),2.75(brs,1H),2.36-2.44(m,2H), 1.66-1.29 (m, 6H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.4 min (M + H) 330.17.

(+/-) - (Exo) -7-aminobicyclo [3.2.2]Formation of methyl nonane-6-carboxylate (56)

Pd/C (1.65 g, 1.55mmol, 10% Desmoset, Wet) was added to a nitrogen-purged rac- (rac) -9- (((benzyloxy) carbonyl) amino) bicyclo [3.2.2]-solution of methyl non-6-ene-8-carboxylate 55(10.0g) in EtOAc (50 mL). The solution was kept under a hydrogen atmosphere (1 atm) at room temperature for 18 hours. The resulting solid suspension was diluted with dichloromethane (100mL) and stirred at room temperature for 1 hour. The solution was filtered through a pad of celite and the pad was washed thoroughly with dichloromethane (3 × 50 mL). The filtrate was concentrated in vacuo to give 5.7g of the desired product:¹H NMR(400MHz,CDCl3)δ3.77–3.59(m,3H),3.47(d,J=7.4Hz,1H),2.27(m,1H),2.09(dd,J=7.4,3.3Hz,1H),1.85–1.33(m,11H)。

(+/-) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) bicyclo- [3.2.2 ]Form of nonane-6-carboxylic acid methyl ester (57) Become into

Reacting racemic-trans-7-aminobicyclo [3.2.2]Nonane-6-carboxylic acid methyl ester 56(1.00g,5.07mmol), 2, 4-dichloro-5-fluoro-pyrimidine (0.85g,5.07mmol) and NA solution of N-diisopropylethylamine (1.94mL,11.15mmol) in THF (20mL) and MeOH (5mL) was heated at 85 deg.C for 2 h. The solvent was evaporated. The crude product was purified by silica gel chromatography (gradient 0% to 30% EtOAc/hexanes) to give 1.2g of the desired product as an oil which solidified upon standing.¹H NMR(400MHz,CDCl₃) δ 7.78(d, J =2.8Hz,1H),5.16(m,1H),4.63(m,1H),3.67(s,3H),2.34(m,2H),1.97(m,1H),1.88(m,1H), 1.77-1.38 (m, 8H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.43 min (M + H) 328.43.

(+/-) -trans-7- (5-fluoro-2- (5-fluoro-1-trityl-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidines -4-ylamino) bicyclo [3.2.2]Formation of methyl nonane-6-carboxylate (58)

Racemic 7- (2-chloro-5-fluoropyrimidin-4-ylamino) bicyclo [3.2.2]Nonane-6-carboxylic acid methyl ester 57(0.20g,0.61mmol), 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b]Pyridine 6(0.370g,0.732mmol) and K₃PO₄(0.39g mg,1.83mmol) in 2-MeTHF (4.0mL) and H₂The solution in O (0.40mL) was purged with nitrogen for 30 minutes. X-phos (0.035g,0.073mmol) and Pd were added ₂(dba)₃(0.014g,0.015 mmol). The reaction mixture was heated in a sealed tube at 135 ℃ for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% EtOAc/hexanes gradient) to give 365mg of the desired product as a white foamy solid:¹H NMR(400MHz,CDCl₃) δ 8.57(dd, J =8.3,2.8Hz,1H),8.14(s,1H),8.11(s,1H), 7.41-7.02 (m,15H),5.10(m,1H),3.66(s,3H),2.52(m,2H),2.17(d, J =25.1Hz,1H),1.95-1.50(m, 10H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.09 min (M + H) 671.19.

(+/-) -7- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclic rings [3.2.2]Formation of methyl nonane-6-carboxylate (I-36)

Triethylsilane (0.434mL,2.721mmol)To racemic 7- (5-fluoro-2- (5-fluoro-1-trityl-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclo [3.2.2]A stirred solution of methyl nonane-6-carboxylate 58(0.365g,0.544mmol) and trifluoroacetic acid (0.419mL,5.440mmol) in dichloromethane (20 mL). The resulting yellow solution was stirred at room temperature for 2 hours and concentrated in vacuo. Water (10mL) and NaHCO were added₃Saturated aqueous (5mL) and extracted the aqueous layer with EtOAc (3X 10 mL). The combined organic phases were dried (MgSO) ₄) Filtered and the solvent removed under reduced pressure. Chromatography on silica gel (10-90% MeOH/CH)₂Cl₂Gradient) to yield 178mg of the desired product as a white foamy solid:¹H NMR(400MHz,CDCl₃) δ 8.63(s,1H),8.55(s,1H),8.31(s,1H),5.20(s,1H),3.71(s,3H),2.62(m,1H),2.53(m,1H),2.24(m,1H),2.06(m,1H), 1.98-1.58 (m, 9H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.74 min (M + H) 329.86.

(+/-) -7- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclic rings [3.2.2]Formation of nonane-6-carboxylic acid (I-37)

A solution of lithium hydroxide (2.10 mL, 2N solution, 4.15 mmol) was added to racemic 7- (5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-ylamino) bicyclo [3.2.2]A stirred solution of methyl nonane-6-carboxylate I-36(0.18g,0.42mmol) in THF (7 mL). The solution was heated at 85 ℃ for 6 hours and cooled to room temperature. The solution was concentrated in vacuo and water (5mL) was added. The solution was slowly neutralized with 1N HCl to produce a white precipitate. The precipitate was filtered and washed with water (10 mL). The wet solid was lyophilized for 2 days to a white powder of 112mg of the desired product:¹H NMR(400MHz,CD₃OD) δ 8.77(s,1H),8.52(s,1H),8.10(s,1H),5.29(m,1H),2.82(m,1H),2.53(m,1H),2.11-1.54(brm,10H),1.29(m, 1H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.33 min (M + H) 415.44.

Synthesis scheme 13: preparation of Compound I-38 (I-39 and I-40)

(a)KO^tBu、^tBuOH, benzene, 120 ℃; (b) NaH, dimethyl carbonate, THF, 80 ℃; (c) NH (NH)₄OAc、NaCNBH₃MeOH; (d)2, 4-dichloro-5-fluoropyrimidine,ⁱPr₂NEt, THF, 80 ℃; (e) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyrrolo [2,3-b ]]Pyridine (6), K₃PO₄、Pd₂(dba)₃XPhos, water/2-methyl-THF, 100 ℃; (f) et (Et)₃SiH、TFA、CH₂Cl₂(ii) a (g) HCl, THF, 80 ℃; (h) chiral SFC separation.

Spiro [4.5 ]]Formation of decan-6-one (59)

To a flask containing t-BuOH (200mL) and potassium tert-butoxide (45.7g,407.6mmol) in benzene (150mL) were added cyclohexanone (20.0g,203.8mmol) and 1, 4-dibromobutane (44.0g,203.8 mmol). The solution was heated at 120 ℃ for 6 hours. The mixture was cooled to room temperature and neutralized with HCl (1N). The solution was extracted with diethyl ether and Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (1% EtOAc/hexanes) to give the title compound: GCMS ES + = 153.1.

6-oxo-spiro [4.5 ]]Formation of methyl decane-7-carboxylate (60)

To a flask containing NaH (4.73g,118.20mmol) in THF (30mL) was added dimethyl carbonate (8.30mL,98.52 mmol). The mixture was heated at 80 ℃. To this mixture was added dropwise a spiro [4.5 ] ring ]Solution of decan-10-one 59(6.00g,39.41mmol) in THF (25 mL). The reaction was heated at 80 ℃ for 6 hours. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated, the crude residue diluted with water and extracted with EtOAc. The organic layer was washed with NaHCO₃Washed with saturated aqueous solution and brine, and then with Na₂SO₄Dried, filtered and concentrated in vacuo.

The resulting crude material was purified by silica gel chromatography (0-15% diethyl ether/hexanes) to give a racemic mixture of the title compound: GCMS ES + = 211.1.

6-Aminospiro [4.5 ]]Formation of methyl decane-7-carboxylate (61)

6-Oxaspiro [4.5 ] in MeOH (35mL)]In a flask of decane-7-carboxylic acid methyl ester 60(4.10g,19.50mmol) were added ammonium acetate (10.52g,136.50mmol) and NaCNBH₃(1.47g,23.40 mmol). The mixture was stirred at room temperature for 24 hours. GCMS showed conversion to product SM (retention time =12.3 min, E + = 211), product (retention time =12.6 min, ES + =212[ predominantly]And retention time =12.45 minutes, ES + =212[ secondary]). The solvent was evaporated, HCl (1N) was added, and the aqueous phase was extracted with EtOAc. The organic phase was neutralized with NaOH (6N) to pH 10. The aqueous phase was extracted three times with EtOAc and two times with dichloromethane, Na ₂SO₄Drying gave 1.6g of product.

6- ((2-chloro-5-fluoropyrimidin-4-yl) amino) spiro [4.5]Formation of decane-7-carboxylic acid methyl ester (62)

6-Aminospiro [4.5 ] in THF (18.44mL)]To a flask of decane-7-carboxylic acid methyl ester 61(3.60g,10.22mmol) was added N, N-diisopropylethylamine (4.10mL,23.51 mmol). To the mixture was added a solution of 2, 4-dichloro-5-fluoro-pyrimidine (2.39g,14.31mmol) in THF. The mixture was stirred at 80 ℃ for 12 hours. The reaction was diluted into EtOAc and washed with water and then brine. The organic phase is treated with Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to give 2.0g of a yellow oil which solidified on standing: LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.6 min (M + H) 343.2.

63 formation

Adding 5-fluoro-3- (4,4,5, 5-tetramethyl-1,3, 2-Dioxopentaborane-2-yl) -1-trityl-pyrazolo [3,4-b]Pyridine 6(0.886g,1.756mmol) and 6- ((2-chloro-5-fluoropyrimidin-4-yl) amino) spiro [4.5]A solution of decane-7-carboxylic acid methyl ester 62(0.500g,1.463mmol) in 2-MeTHF (17mL) was then K₃PO₄(0.777g,3.658mmol) and H₂O (2.83 mL). The mixture was degassed under a stream of nitrogen for 5 minutes. Then Pd is added ₂(dba)₃(0.094g,0.102mmol) and X-Phos (0.105g,0.220mmol), and the solution was degassed again under a stream of nitrogen. The reaction mixture was sealed and heated to 100 ℃ for 3 hours. The solution was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc, washed with brine, and Na₂SO₄Dried, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give the title compound.

6- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) spiro [4.5]Decane Formation of methyl-7-carboxylate (64)

To a solution of 63(0.100g,0.146mmol) in dichloromethane was added triethylsilane (0.233mL,1.460mmol) followed by trifluoroacetic acid (0.337mL,4.380 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the product was purified by silica gel chromatography (50-100% EtOAc/hexanes gradient): LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =3.16 min (M + H) 443.4.

(6R,7R) -6- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -pyrimidin-4-yl) amino) spiro [4.5]Decane-7-carboxylic acid (I-40) and (6S,7S) -6- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) Pyrimidin-4-yl) amino) spiro [4.5 ]Formation of decane-7-carboxylic acid (I-39)

To a solution of methyl 6- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3,4-b ] pyridin-3-yl) pyrimidin-4-yl) amino) spiro [4.5] decane-7-carboxylate 64(0.500g,1.130mmol) in THF was added HCl (18.83 mL, 6N solution, 113.0 mmol). The reaction mixture was stirred at 80 ℃ for 1 hour. The solvent was removed under reduced pressure and the product was purified by preparative HPLC followed by SFC chiral separation to give a racemic mixture of cis-isomers.

Profile data for I-40:¹h NMR (MeOH-d4) Δ 8.6(m,2H),8.3(d,1H),5.2(s,1H),3.0(m,1H),1.3-2.0(m, 14H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.79 min (M + H) 429.4.

Map data for I-39: same profile data as for I-40:¹h NMR (MeOH-d4) Δ 8.6(m,2H),8.3(d,1H),5.2(s,1H),3.0(m,1H),1.3-2.0(m, 14H); LC/MS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.75 min (M + H) 429.3.

Preparation of Compounds I-41, I-47, I-42 and I-43

N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) Cyclohexyl) thiophene-3-carboxamide (I-41) formation

This compound was prepared in a similar manner as described for compound I-24.

LCMS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.07 min, (M + H) 457.0.

5-chloro-N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) Amino) cyclohexyl) thiophene-3-carboxamide (I-47) formation

This compound was prepared in a similar manner as described for compound I-24.

LCMS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.46 min, (M + H) 490.3.

(+/-) -trans-3- ((2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclic rings [2.2.2]Formation of methyl octane-2-carboxylate (I-42)

This compound was prepared in a similar manner as described for compound I-32.

¹H NMR (300MHz, MeOD) δ 8.71(s,1H),8.62-8.45(m,1H),8.11(s,1H),6.44(d, J =6.1Hz,1H),3.65(s,3H),2.61(s,1H),2.03(s,1H),2.01-1.39(m, 8H); LCMS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.33, (M + H) 397.06.

(+/-) -trans-3- ((2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclic rings [2.2.2]Formation of octane-2-carboxylic acid (I-43)

This compound was prepared in a similar manner as described for compound I-31.

¹H NMR (300MHz, d6-DMSO) δ 14.19(s,1H),12.43(s,1H),9.08-8.49(m,2H),8.49-8.08(m,1H),7.74(s,1H),6.50(d, J =5.4Hz,1H),4.71(s,1H),2.21-1.90(m,1H),1.67(d, J =50.0Hz, 6H); LCMS gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, retention time =2.13, (M + H) 383.05.

Synthesis scheme 14: preparation of Compounds I-48 and I-49

(a)1N LiOH and THF, and refluxing; (b) BH₃-DMS, THF; (c) dess-martin periodinane; (d) MeOCH (MeOCH)₂P⁺Ph₃、LiHMDS、THF，0℃；(e)1N HCl、THF；(f)NaClO₂、H₂O、CH₂Cl₂(ii) a (g) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyrrolo [2,3-b ]]Pyridine (6), K₃PO₄、Pd₂(dba)₃XPhos, water/2-methyl-THF, 100 ℃; (h) chiral SFC separation.

(+/-) -trans-3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2]-octane-2-yl) methanol (65) Formation of

To a solution of racemic methyl 3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] bicyclo [2.2.2] octane-2-carboxylate 11(3.00g,9.56mmol) in THF (50mL) was added LiOH (10 mL, 1N solution, 10.00 mmol). The reaction mixture was heated to reflux and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in THF (50 mL). To this mixture was added borane-DMS (3 mL of a 10mmol solution). The reaction mixture was stirred at room temperature for 2 hours. The mixture was carefully quenched with methanol. The mixture was concentrated in vacuo and redissolved in methanol. Citric acid (2.0g) was added to the mixture and the mixture was allowed to stir at room temperature overnight. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (EtOAc) to give 1.5g of the desired product.

(+/-) -trans 3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2]Of octane-2-carbaldehyde (66) Form a

To a solution of racemic trans-3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-yl) methanol 65(0.200g,0.700mmol) in THF (10mL) was added busulfan (0.300g,0.700 mmol). The reaction mixture was stirred under vacuum at room temperature overnight. The mixture was concentrated and the resulting residue was purified by silica gel chromatography (50% EtOAc/CH2Cl2) to give 120mg of the desired product.

(+/-) -trans 2-chloro-5-fluoro-N-3- ((E) -2-methoxyvinyl) bicyclo [2.2.2]-octane-2-yl) pyrimidine Formation of the Pyridin-4-amine (67)

To a cold (0 ℃) suspension of methoxymethyl (triphenyl) phosphonium chloride (1.657g,4.833mmol) in THF (20mL) was added [ bis (trimethylsilyl) amino ] lithium (3.947 mL, 1M solution, 3.947 mmol). After stirring the mixture for 10 min, rac-trans-3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] bicyclo [2.2.2] octane-2-carbaldehyde 66(0.700g,2.467mmol) was added and the reaction mixture was stirred for another 30 min. After concentration in vacuo, the resulting residue was purified by silica gel chromatography (100% EtOAc) to give 365mg of the desired product.

(+/-) -trans-3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo- [2.2.2 ]Octane-2-yl) acetic acid (68) Formation of

To rac-trans 2-chloro-5-fluoro-N-3- ((E) -2-methoxyvinyl) -bicyclo [2.2.2]To a solution of (E) -octan-2-yl) pyrimidin-4-amine 67(0.37g,1.17mmol) in THF (5mL) was added aqueous HCl (1.00mL, 1N solution, 1.00 mmol). The reaction mixture was stirred at room temperature overnight. After the mixture was concentrated in vacuo, it was again dissolved in 10mL of methylene chloride, 2 methylbutane (0.10mL) was added, followed by NaClO₂(0.10g) solution in water (1.00 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (EtOAc) to give the desired product.

2- ((2S,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2]Octane-2-yl) acetic acid (I-48) and 2- ((2R,3R) -3- ((5-fluoro-2- (5-fluoro-1H-pyrazolo) [3,4-b]Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Formation of Octane-2-yl) acetic acid (I-49)

Racemic-trans-3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo- [2.2.2]Octane-2-yl) acetic acid 68(0.300g,0.956mmol), 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-pyrazolo [3,4-b ]6(0.720g,1.430mmol), Pd (dppf) (0.080g,0.096mmol) and NaHCO₃(0.080g,0.956mmol) in THF (10mL) and water (1 mL). The reaction mixture was stirred at 135 ℃ for 15 minutes under microwave irradiation. The mixture was concentrated in vacuo and chromatographed on silica gel (EtOAc/CH)₂Cl₂Gradient) the resulting residue was purified to give the Suzuki product. The intermediate was treated with 1N LiOH and heated to 65 ℃ for 3 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the resulting residue was purified by SFC chiral separation to give the individual enantiomers I48 and I-49. Compound I-48: h NMR (300.0MHz, DMSO) d8.62(dd, J =1.6,2.8Hz, H),8.50(s, H),8.43(dd, J =2.8,8.8Hz, H),8.25(d, J =3.8Hz, H),7.79(d, J =6.3Hz, H),3.57(d, J =7.0Hz, H),3.44(q, J =7.0Hz, H),3.36-3.24(m, H),2.93(s, H),2.73(d, J =2.0Hz, H),2.60-2.49(m, H),2.33-2.18(m, H),1.85(d, J =12.7Hz, H),1.65(d, J =7.9, H), 1.48-1.35.39 (m, H), 1.35-1.08 (m, H), and 1.08 ppm. LC/MS: 2.28 min (M201)/415.37(M + H). Compound I-49: LC/MS: 2.28 min (M201)/414.37(M + H).

Anti-influenza virus assay

Antiviral assays were performed using two cell-based methods:

a modified form of 384-well microtiter plate was developed for standard cytopathic effect (CPE) assays, similar to that of Noah et al (Antiviral Res. ("Antiviral research") 73:50-60,2006). Briefly, MDCK cells were incubated with test compound and influenza a virus (a/PR/8/34) at low multiplicity of infection (approximately MOI ═ 0.005) at 37 ℃ for 72 hours and cell viability was measured using ATP assay (CellTiter Glo, Promega Inc. Control wells containing cells and virus showed cell death, Whereas wells containing cells, virus and active antiviral compound showed cell survival (cytoprotection). Different concentrations of test compound were evaluated in quadruplicate, e.g., in the range of about 20 μ M to 1 nM. Dose-response curves were generated using standard 4-parameter curve fitting methods and the concentration of test compound that resulted in 50% cell protection or in cell survival equivalent to 50% uninfected wells was reported as IC₅₀。

A second cell-based antiviral assay was developed, which is based on the proliferation of virus-specific RNA molecules in infected cells, in which RNA levels were measured directly using the branched-chain DNA (bDNA) hybridization method (Wagaman et al, J.Virol Meth (J.Virol. methods), 105:105-114, 2002). In this assay, cells are initially infected in wells of a 96-well microtiter plate, the virus is allowed to replicate in the infected cells and spread to several additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped earlier than the CPE assay, usually after 18-36 hours, while all target cells are still viable. Viral RNA was quantified as follows: the well lysates were hybridized to specific oligonucleotide probes immobilized to the wells of the assay plate, according to the kit manufacturer's instructions (quantigene1.0, Panomics, Inc.) and the signals were amplified by hybridization to additional probes attached to reporter enzymes. Negative strand viral RNA was measured using probes designed against the common type a hemagglutination gene. Control wells containing cells and virus were used to define 100% virus replication levels and dose-response curves of antiviral test compounds were analyzed using a 4-parameter curve fitting method. The concentration of test compound that results in a viral RNA level equal to 50% of the viral RNA level of the control well is reported as EC ₅₀。

Virus and cell culture methods: madin-darby canine kidney cells (CCL-34 American type culture Collection) were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 2mM L-glutamine, 1,000U/ml penicillin, 1,000. mu.g/ml streptomycin, 10mM HEPES, and 10% fetal bovine medium. For the CPE assay, the day before the assay, cells were suspended by trypsin treatment and 10,000 cells were dispensed in 50. mu.lCells/well were assigned to each well of a 384 well plate. On the day of assay, adherent cells were washed by three changes of DMEM containing 1 μ g/ml TPCK-treated trypsin, fetal bovine serum free. Adding 30TCID to the medium containing 1. mu.g/ml TPCK-treated trypsin₅₀Starting the assay with virus and test compound, the final volume is 50 μ l. Conditioned 5% CO at 37 ℃₂Plates were incubated for 72 hours in an atmosphere. Alternatively, cells were grown in DMEM + fetal calf serum as above, but on the day of the assay the cells were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK Cell culture medium (SAFC Biosciences, Lenexa, KS) and plated into wells at 20,000 cells/well. These wells were then used for the assay without washing after 5 hours of incubation.

Influenza strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC (VR-1469). Low passage virus stocks were prepared in MDCK cells using standard methods (WHO Manual on Animal Influenza Diagnosis and monitoring Manual, 2002) and TCID was performed by testing serial dilutions on MDCK cells in 384-well CPE assay format as above and calculating the results using the Karber method₅₀And (6) measuring.

Average IC of certain specific compounds₅₀The values (all mean values) are summarized in tables 1 and 2:

A：IC₅₀<3.3μM；

B：IC₅₀≥3.3μM。

average EC of certain specific Compounds₅₀The values (all averages) are also summarized in tables 1 and 2:

A：EC₅₀<3.3μM；

B：EC₅₀≥3.3μM。

for example, IC of Compound I-14₅₀And EC₅₀The values were all 0.001. mu.M.

Table 1: IC of the Compounds of the invention ₅₀ 、EC ₅₀ NMR and LCMS data.

Table 2: IC of the Compounds of the invention ₅₀ 、EC ₅₀ NMR and LCMS data.

In vivo assay

For efficacy studies, a total volume of 50 μ l was used by intranasal instillation (25 μ l/nostril) under general anesthesia (ketamine/xylazine)³TCID₅₀Balb/c mice (4-5 weeks old) were challenged. Uninfected controls were challenged with tissue culture medium (DMEM, total volume 50. mu.l). At 48 hours post-infection, mice were initially treated with compound I-14 at 30mg/kg twice daily for 10 days. Body weight and survival were scored daily for 21 days. In addition, Whole Body Plethysmography (WBP) was performed approximately every three days after challenge and reported as enhanced pause in expiration (Penh). Total survival, percent weight loss were recorded at day 8 post challenge and Penh was recorded at day 6/7 of the study.

TABLE 3 influenza treatment mouse model (administered at 30mg/kg at 48 hours post-infection, two days Second, 10 days)

Compound (I)	Percentage of survival	Percent weight loss (day 8)¹	WBP (Penh, day 6)²
				I-14	100	23.4	1.59

¹The average body weight loss of untreated controls was 30-32% on day 8.

²The average Penh score for untreated controls was 2.2-2.5 on study day 6 or 7, and-0.35-0.45 for uninfected mice.

All references provided herein are incorporated by reference in their entirety. All abbreviations, symbols and conventions used herein are consistent with those used in the contemporary scientific literature. See, for example, JanetS.Dodd, editor, The ACS Style Guide, A Manual for Authors and Editors (American Chemical Society for culture Manual: Manual of The Authors and Editors), 2 nd edition, Columbia, Washington, D.C., American Chemical Society, 1997.

It should be understood that while the invention has been described in conjunction with the "detailed description" above, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, represented by structural formula (I):

wherein:

x is optionally substituted by one or more J¹substituted-H, -Cl, -Br, -F, -CN or C₁-C₆An aliphatic group;

Y¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-B(O)₂-or-CO₂SO₂-；

Optionally, -Q¹-R¹Together with ring T, form optionally substituted one or more J⁴A substituted 4-10 membered non-aromatic spirocyclic ring; and

R³is-H, -F, -Cl, -CN, -NO₂、–OR、–CO₂R, -CONRR' or optionally substituted by one or more J¹Substituted C₁-C₆An aliphatic group;

J^A、J^Band J^TEach independently oxo or J ^C；

J^CEach and independently selected from halogen, cyano, M, R^aOr R^a-M；

Optionally, two J^TTwo J^ATwo J^BAnd two J^CIndependently form, optionally substituted by one or more J, taken together with the atoms to which they are attached⁴A substituted 4-10 membered ring; and

R^aindependently are:

iii) a 5-10 membered heteroaryl or 6-10 membered aryl, each of which is optionally and independently substituted with one or more J³Substitution; and

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTogether with the nitrogen atom to which they are attached, each independently form an optionally substituted J or J ²A substituted 4-8 membered heterocyclic group;

each J²Independently selected from halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

J³and J⁴Each of which is independently selected from halogen, cyano, hydroxy, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

p is 1, 2, 3 or 4; and

k is 1, 2, 3 or 4.

2. The compound of claim 1, wherein X is-Cl, -Br, -F, -CN, or optionally substituted C ₁-C₆An alkyl group.

3. The compound of claim 1 or 2, wherein R²is-H, -O (C)₁-C₄Alkyl), -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group.

4. The compound of any one of claims 1-3, wherein R³is-H, -F, -Cl, -CN, -NO₂、-O(C₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) N (C)₁-C₄Alkyl radical)₂Or optionally substituted C₁-C₄An alkyl group.

5. The compound of any one of claims 1-4, wherein:

p and k are each and independently 1 or 2; and

R^tand R^sEach independently is-H, halogen or C₁-C₄An alkyl group.

6. The compound of any one of claims 1-5, wherein X is-Cl, -Br, -F, -CN, C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

7. The compound of any one of claims 1-6, wherein R²is-H, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

8. The compound of any one of claims 1-7, wherein R³is-H, -F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

9. The compound of any one of claims 1-8, wherein ring T is optionally substituted C₅-C₁₀A carbocyclic group or an optionally substituted 5-10 membered heterocarbocyclic group.

10. The compound of any one of claims 1-9, wherein R³is-F, -Cl, -CN, -O (C)₁-C₄Alkyl group), C₁-C₄Alkyl or C₁-C₄A haloalkyl group.

11. The compound of any one of claims 1-10, which is represented by structural formula (II):

or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-11, wherein X is-Cl, -F, -Br, -CN, -CH₃or-CF₃。

13. The compound of any one of claims 1-12, wherein R³is-F, -Cl, -CN or C₁-C₄A haloalkyl group.

14. The compound of any one of claims 1-13, wherein:

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、–C(O)N(R’)-O–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂–、-OC(O)NR’–、-OSO₂NR'-、-S(O)-、–SO₂–、-SO₂NR’–、–NRSO₂–、-NRSO₂NR’-、-B(O)₂-or- (CR)^tR^s)_p–Y¹-; and

15. The compound of any one of claims 1-14, wherein:

Q¹is-CO₂–、-O(CR^tR^s)_k–C(O)O-、-P(O)(OR)O-、-OP(O)(OR^a)O-、-P(O)₂O-、-CO₂SO₂-or- (CR)^tR^s)_p–Y¹-; and

16. The compound of any one of claims 1-15, wherein:

R¹independently i) -H;ii) optionally substituted by one or more J^ASubstituted C₁-C₆-an aliphatic group; iii) C₃–C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more J^BSubstitution; iv) phenyl or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more J ^CSubstitution; or

J^A、J^Band J^TEach independently is oxo or J^C(ii) a And

Optionally, two J^ATwo J^BTwo J^CAnd two J^TEach of the atoms to which they are attached taken together independently form an optionally substituted 4-10 membered non-aromatic ring.

17. The compound of any one of claims 1-16, wherein:

R^band R ^cEach independently is R^aor-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form an optionally substituted 4-8 membered heterocyclic group; and

18. The compound of any one of claims 1-17, which is represented by structural formula (IIIA) or (IIIB):

(IIIA) or

(IIIB) or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-18, wherein X is-Cl, -F, -CN, or-CF₃。

20. The compound of any one of claims 1-19, wherein X is-Cl or-F.

21. The compound of any one of claims 1-20, wherein ring T is an optionally substituted bridging C₅-C₁₀A carbocyclic group.

22. The compound of any one of claims 1-20, wherein ring T is an optionally substituted monocyclic C₅-C₈A carbocyclic group.

23. The compound of any one of claims 1-20, wherein ring T is:

And wherein:

R¹²、R¹³and R¹⁴Each independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

x is 0, 1 or 2.

24. The compound of any one of claims 1-23, wherein:

J^A、J^B、J^Cand J^TEach independently selected from halogen, cyano, R ^a、–OR^b、–NHR^c、–C(O)R^b、–C(O)OR^b、–OC(O)R^b、–NHC(O)R^b、–C(O)NHR^c、–NHC(O)NHR^c、–NHC(O)OR^b、–OCONHR^c、–N(CH₃)R^c、–N(CH₃)C(O)R^b、–C(O)N(CH₃)R^c、–N(CH₃)C(O)NHR^c、–N(CH₃)C(O)OR^b、-NHSO₂R^b、-SO₂NHR^b、-SO₂N(CH₃)R^band-N (CH)₃)SO₂R^b(ii) a Or

25. The compound of any one of claims 1-24, wherein:

R^aindependently are: i) c optionally substituted by one or more substituents selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl), -O (C)₁-C₄Alkyl group), C₃-C₈Carbocycle, 4-8 membered heterocycle, 5-6 membered heteroaryl and phenyl; ii) C₃-C₈A carbocyclic group or a 4-8 membered heterocyclic group, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or iii)5-6 membered heteroaryl or phenyl, each of which is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); and

R^band R^cEach independently is R^aor-H; or optionally, R^bAnd R^cTaken together with the nitrogen atom to which they are attached, each independently form a 4-8 membered heterocyclyl group optionally substituted with one or more substituents selected fromAnd (3) clustering: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

26. The compound of any one of claims 1-25, wherein:

Q¹is-C (O) -, -CO₂–、–OC(O)–、-O(CR^tR^s)_k–C(O)O-、–C(O)NR’–、-C(O)NRC(O)O–、–NRC(O)–、–NRC(O)NR’–、–NRCO₂-, -OC (O) NR' -, or- (CR)^tR^s)_p–Y¹-; and

27. The compound of any one of claims 23-26, wherein:

R¹²、R¹³and R¹⁴Each independently of the others is-H, halogen, cyano, hydroxy, -O (C)₁-C₆Alkyl) or optionally substituted C₁-C₆An alkyl group;

R¹⁵is-H or optionally substituted C₁-C₆An alkyl group; and

28. The compound of any one of claims 23-27, wherein:

R¹²and R¹³Each independently is-H, halogen, hydroxy, C ₁-C₆Alkyl radical, C₁-C₆Haloalkyl or-O (C)₁-C₆Alkyl groups);

R¹⁴and R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and

R^tand R^sEach independently is-H or C₁-C₆An alkyl group.

29. The compound of any one of claims 1-28, wherein:

with R¹Of and forWith R¹Is represented by C₁-C₆Said carbocyclic group, phenyl, heterocyclic and heteroaryl group being substituents of aliphatic groups, and R¹Said heterocyclic group formed with R', each of which is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

30. The compound of any one of claims 23-29, wherein ring a is a carbocyclic group or a heterocyclic group, each of which is optionally and independently further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups); or rings A and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently and optionally forming a bridged carbocyclic group or a bridged heterocyclic group, each of which is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical、C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

31. The compound of any one of claims 23-30, wherein ring a and R¹⁵Ring A and R¹⁴Or rings A and R¹³Independently forming an optionally substituted 4-10 membered bridged ring.

32. The compound of claim 31, wherein ring T is:

wherein:

each of rings a1-a5 is independently a 5-10 membered bridged carbocyclic ring optionally further substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

each R¹⁴Independently is-H, halogen, cyanoHydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

R²¹、R²²、R²³、R²⁴and R²⁵Each independently is-H, halogen, -OH, C ₁-C₆Alkoxy or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

z is-O-, -S-or-NR^g-；

R^gis-H or C optionally substituted with one or more substituents independently selected from₁-C₆Alkyl groups: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups);

q is 0, 1 or 2; and

r is 1 or 2.

33. The compound of claim 32, wherein:

R¹⁴and each R¹⁵Each independently is-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group; and

R²¹、R²²、R²³、R²⁴and R²⁵Each independently is-H, halogen, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

34. The compound of claim 32 or 33, wherein:

z is-O-or-NR^g-; and

R^gis-H, C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

35. The compound of any one of claims 32-34, wherein:

Q¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)₁,₂–Y¹-; and

Y¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

36. The compound of claim 35, wherein Q¹independently-C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

37. The compound of any one of claims 1-36, wherein R and R' are each and independently-H or-CH₃。

38. The compound of any one of claims 32-37, wherein ring T is:

39. The compound of any one of claims 32-38, wherein:

R¹⁴and each R¹⁵Each independently is-H or C_1-6An alkyl group; and

40. The compound of any one of claims 32-39, wherein:

41. The compound of any one of claims 32-40, wherein q is 1.

42. The compound of any one of claims 23-30, wherein ring T is selected from:

wherein:

each of ring A8-a11 is independently and optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups);

each R¹⁴Independently is-H, halogen, cyano, hydroxy, C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-OCO(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -CO₂H or-CO₂(C₁-C₆Alkyl) in which each of said C₁-C₆Alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl) and-O (C)₁-C₄Alkyl groups); and

42. The compound of claim 41, wherein:

Q¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, -NRC (O) NR' -or- (CH)₂)₁,₂-Y-; and

Y¹independently-C (O) -, -C (O) O-, -NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

43. The compound of claim 41 or 42, wherein:

R¹⁴and each R ¹⁵Each independently is-H or C_1-6An alkyl group; and

each of ring A8-a11 is independently and optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

44. The compound of any one of claims 41-43, wherein R and R' are each and independently-H or-CH₃。

45. The compound of any one of claims 41-43, wherein Q¹independently-NRC (O) -, -C (O) NR-, or-NRC (O) NR' -.

46. The compound of claim 45, wherein:

r and R' are each and independently-H or-CH₃(ii) a And

Optionally, R¹And R' taken together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl, each of which is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH ₂、-NH(C₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OCO(C₁-C₄Alkyl), -CO (C)₁-C₄Alkyl), -CO₂H、-CO₂(C₁-C₄Alkyl group), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl and-O (C)₁-C₄Alkyl groups).

47. The compound of any one of claims 1-46, wherein p is 1 or 2, and k is 1 or 2.

48. A compound selected from any one of the structures depicted below, or a pharmaceutically acceptable salt thereof:

49. a compound selected from any one of the structures depicted below, or a pharmaceutically acceptable salt thereof:

50. a pharmaceutical composition comprising a compound according to any one of claims 1-49 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

51. A method of inhibiting influenza virus replication in a biological sample or patient, the method comprising the step of administering to the biological sample or patient an effective amount of a compound of any one of claims 1-49.

52. The method of claim 51, further comprising co-administering an additional therapeutic agent.

53. The method of claim 52, wherein the additional therapeutic agent is selected from an antiviral agent or an influenza vaccine.

54. A method of reducing the amount of influenza virus in a biological sample or in a patient, the method comprising administering to the biological sample or patient an effective amount of a compound of any one of claims 1-49.

55. A method of treating influenza in a patient, the method comprising administering to the patient an effective amount of a compound of any one of claims 1-49.

56. A method of preparing a compound represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, comprising the steps of:

i) reacting a compound A:with compound B:

reacting to form a compound represented by structural formula (XX):

(XX); and

ii) deprotecting the G group of the compound of formula (XX) under suitable conditions to form a compound of formula (I), wherein:

each variable of structural formulae (I) and (XX) and compounds (a) and (B) is independently as defined in any one of claims 1 to 49; and is

L²Is halogen; and

g is trityl.

57. The method of claim 56, wherein L²Br or Cl.

58. A method of preparing a compound represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, comprising the steps of:

i) reacting a compound K or L:with compound D:reacting to form a compound represented by structural formula (XX):

(XX); and

Each variable of structural formulae (I) and (XX) and compounds (L), (K) and (D) is independently and independently as defined in any one of claims 1 to 49; and

g is trityl.

59. A method of preparing a compound represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, comprising the steps of:

i) reacting compound (G) with compound (D):

reacting under suitable conditions to form a compound represented by structural formula (XX):

(XX); and

each variable of structural formulae (I) and (XX) and compounds (G) and (D) is independently and independently as defined in any one of claims 1 to 49;

L¹is halogen; and

g is trityl.

60. The method of claim 59, wherein L¹Br or Cl.

61. A compound represented by structural formula (XX):

wherein each variable of structural formula (XX) is individually and independently as defined in any one of claims 1 to 49; and

g is trityl.

62. The compound of claim 61, represented by any one of the following structural formulae and pharmaceutically acceptable salts thereof:

Wherein Tr is trityl.

63. The compound of claim 61, represented by any one of the following structural formulae and pharmaceutically acceptable salts thereof:

wherein Tr is trityl.