SUBSTITUTED BENZOAZEPINES AS TOLL-TYPE RECEPTOR MODULATORS

专利摘要:
substituted benzoazepines as toll-like receptor modulators. Compositions and methods useful for modulating signaling through the toll-like tlr7 and/or tlr8 receptors are provided. the compositions and methods have use in treating or preventing disease, including cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease.
公开号:BR112012003703A2
申请号:R112012003703-0
申请日:2010-08-18
公开日:2020-12-08
发明作者:James Jeffrey Howbert；Gregory Dietsch；Robert Hershberg；Laurence E. Burgess；George A. Doherty；C. Todd Eray；Robert D. Groneberg；Zachary Jones
申请人:Ventrix Phramaceuticals, INC.；Array Biopharma Inc.；
IPC主号:

专利说明:

, Invention Patent Descriptive Report for "BENZOAZE-
REPLACED PINS AS TOLL-TYPE RECEIVER MODULATORS". This application claims priority to U.S. Provisional Patent Application No. 61/234,971, filed August 18, 2009. The contents of the aforementioned application are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION Field of the Invention This invention relates to methods and compositions for modulating immune function. More specifically, this invention relates to compositions and methods for modulating signaling mediated by TLR7' and/or TLRE. í Description of the state of the art Immune system stimulation, which includes stimulation of one or the other, or both, natural immunity and adaptive immunity, is a complex phenomenon that can result in protective or adverse physiological outcomes for the host . In recent years, there has been increased interest in the mechanisms that underlie natural immunity, which are believed to initiate and support adaptive immunity. This interest has been stimulated, in part, by the recent discovery of a family of highly conserved pattern recognition receptor proteins known as toll-like receptors (TLRs), believed to be involved in natural immunity as receptors for molecular patterns. associated with pathogens (PAMPs). Compositions and methods useful for modulating natural immunity are, therefore, of great interest, as they may affect therapeutic approaches for conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft disease, and graft disease. sus host (GvHD), infection, cancer, and immunodeficiency. Toll-like receptors (TLRs) are transmembrane proteins of the | that allow organisms (including mammals) to detect microbes and initiate a natural immune response (Beutler, B., Nature
B 2004, 430:257-263). They contain homologous cytoplasmic domains and leucine-rich extracellular domains and typically form homodimers that sense extracellular (or internalized) and subsequent signals. mentally initiate a signal transduction cascade through molecules. 5 adapters, such as MyD88 (myeloid differentiation factor 88). There is such high homology in the cytoplasmic domains of TLRs that it was initially suggested that similar signaling pathways exist for all TLRs (Re, F., Strominger, J.
L., Immunobiology 2004, 209:191-198). In fact, all TLRs can activate NF-kB and MAP kinases; however, the cytokine/chemokine release profiles derived from TLR activation appear unique to each TLR.
Additionally, the signaling pathway that TL-Rs stimulate is very similar to the pathway that the cytokine receptor IL-1R induces. ' This may be due to the homology that these receptors share, i.e., the . TIR domains (Toll/IL-1R homology). Once the TIR domain is activated in TLRs and MyD88 is recruited, activation of the IRAK family of serine/threonine kinases results, which consequently promotes Ik-B degradation and NF-kB activation (Means T.
K., et al.
Life Sci. 2000, 68:241-258). Although it appears that this cascade is designed to allow extracellular stimuli to promote intracellular events, there is evidence that some TLRs migrate to endosomes, where signaling can also be initiated.
This process may allow intimate contact with the ingrained microbes and is consistent with the role these receptors play in the natural immune response (Underhill, D.
M., et al., Nature 1999, 401:811-815). This process could also allow host nucleic acids, released by damaged tissues (eg, in inflammatory disease) or by apoptosis to trigger a response through endosomal presentation.
Among mammals, there are 11 TLRs that coordinate this rapid response.
Now a hypothesis formulated years ago has been proven (Janeway, C.
A., Jr., Cold Spring Harb.
Syrup.
amount
Biol. 1989,54:1-13) that the natural immune response initiates the adaptive immune response through the pattern of TLR activation caused by microbes.
In this way, pathogen-associated molecular patterns (PAMPs) present
mediated by a diverse group of infectious organisms result in a natural immune response involving certain cytokines, chemokines and growth factors, followed by an exact adaptive immune response adapted to the . infectious pathogen through antigen presentation, resulting in " 5 — antibody production and the generation of cytotoxic T cells.
Gram-negative bacterial lipopolysaccharide (LPS) has long been recognized as an immune adjuvant and stimulant and as a pharmacological tool to induce an inflammatory reaction in mammals, similar to septic shock. Using a genetic approach, TLRA4 was identified as the receptor for LPS. The discovery that LPS is an agonist of TLRA4 illustrates the utility of TLR modulation for vaccine and human disease therapy (Aderem, A.; Ulevitch, R.J., Nature 2000, at 406:782-787). It is now recognized that various TLR agonists can activate B cells, neutrophils, mast cells, eosinophils, endothelial cells, and various types of epithelia, in addition to regulating proliferation and apoptosis of certain cell types.
To date, TLR7 and TLR8, which are relatively similar, have been characterized as receptors for single-stranded RNA found in endosomal compartments and thus believed to be important for the immune response to viral challenge. Imiquimod, an approved topical antiviral/anticancer drug, was recently described as a TLR7 agonist that has demonstrated clinical efficacy in certain skin disorders (Miller RL, et al., /nt. J. Inmunopharm. 1999, 21:1 -14). This small molecule drug has been described as a structural mimetic of —ssRNA. TLR8 was first described in 2000 (Du, X,, et al., European Cytokine Network 2000 (Sep.), 11(3):362-371) and was quickly credited with being involved in the natural immune response to infection. (Miettinen, M., et al., Genes and Immunity 2001 (Oct.), 2(6):349-355).
Recently, certain imidazo-quinoline compounds having antiviral activity have been reported to bind TLR7 and TLR8 (Hemmi H., et al. (2002) Nat. Immunol. 3:196-200; Jurk M., et al. (2002) Nat. Immunol. 3:499). Imidazoquinolines are potent synthetic activators of the
immune squids, with antiviral and antitumor properties. Using macrophages from wild-type and MyD88-deficient mice, Hemmi et al. recently described that two imidazoquinolines, imiquimod and resiquimod (R848), induce tumor necrosis factor (TNF) and interleukin- . 5 12(I1-12) and activate NF-icB only in wild-type cells, consistent with activation via a TLR (Hemmi H., et al. (2002) Nat. Immunol. 3:196 -200). Macrophages from TLR7-deficient mice, but not other TLRs, did not produce any detectable cytokine in response to these imidazoquinolines. In addition, imidazoquinolines induced dose-dependent proliferation of splenic B cells and activation of intracellular signaling cascades in cells from wild-type but not TLR7-/- mice. Luciferase analysis established that expression of human TLR7, but not TLR2 or TLRA4, in cells. las of human embryonic kidneys results in the activation of NF-KB in response to resiquimod. The findings of Hemmi et al, therefore, suggest that these imidazoquinoline compounds are unnatural ligands of TLR7 that can induce signaling through TLR7. Recently, R848 has been reported to be also a binder for human TLR8 ( Jurk M., et al. (2002) Nat. Immunol. 3:499 ).
In view of the great therapeutic potential for compounds that modulate toll-like receptors, and despite the work that has already been done, there is a substantial ongoing need to expand their use and therapeutic benefits.
SUMMARY OF THE INVENTION The compositions described herein are useful for modulating immune responses in vitro and in vivo. Such compositions will find use in a variety of clinical applications, such as in methods of treating or preventing conditions involving unwanted immune activity, including inflammatory and autoimmune disorders.
Specifically, the invention relates to a compound having the formula |:
the - R NH q) Is either a tautomer, enantiomer or salt thereof, where: "Y is substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with one or more groups independently selected from CN, OH, - C(=O)Rº, halogen, and -CH=CHC(=O)Rº; Rº is selected from alkyl, OR*”, and NRºR''; R** is selected from H, alkyl, and -CH2O(alkyl), R'º and R'' are each independently alkyl, where said -10 alkyl is optionally substituted with -OH or R"º and R"', together with the atom of nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -OH; R is selected from OR and NRºR”; Rº and R7 are each independently , selected from H, alkyl, cycloalkyl, heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl is optionally substituted with one or more groups independently selected tioned from -F, -ORº, -NR/ SOR”, -CEEOINRR" , or Rº and R”, together with the nitrogen atom to which they are attached, form a heterocyclic ring, additionally where said ring heterocyclyl is optionally substituted with one or more -OH; Rº is selected from hydrogen and alkyl, and R , Rº and R!* are each independently selected from H and alkyl, where said alkyl is optionally substituted with -
OH since o o a) when Y is aryl substituted with <r or ão, then R not be -OCH2CH; (-OEt), or b) when Y is aryl substituted with -C(=O)Rº, and Rº = NRººR", É and R'º and R'!, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring, then R' is not -OEt or - -Ni(propyl). tautomer, enantiomer, or salt thereof, where W is H or -OH; Z is H or -OH; en is 1 or 2, and R' is as defined in the formula |; Tt provided that when W and Z are both H and n is 1, then R' is not -OEt or -N(propyl). The invention also relates to a compound having formula (II-): o R'O -.wW" Ts(a) or a tautomer, enantiomer or salt thereof, where T is CH, CZ, or N; U is CH, CZ, or N; V is CH, CZ, or N; X is CH, CZ, or N; W is CH, CZ, or N; Z is selected from halogen, -CN, -CONR'ºR”, -COOR" , -CH=CHCOOR" , and -OR"*; R'º, R7, R'º, and R'º are , each independently selected from H, alkyl, and -CH2O(alkyl), and R' is as defined in the formula.
The invention also relates to a compound having formula IV: . o « " NE . N (IV) or a tautomer, enantiomer or salt thereof, where R is as defined in the formula |. The invention also relates to a compound having the formula V: o ” (3 O Laughter. Ú > NH, ' or VV : or a tautomer, enantiomer or salt thereof, where U is N or CZ, and Z is halogen; and R' is as defined in formula I. The invention also relates to a compound having the formula VI: o Nn=”Ip”NH>vn or a tautomer, enantiomer or salt thereof, where J is independently selected from halogen, -C(=O0)Rº and -CH=CHC(=O)R* ; p is selected from 1,2, and 3; and R is as defined in the formula; o are” ; no since when p is 1 and J is joined at the 4 position of the aryl ring, Soo R no be -OEt, and additionally provided that when p
For 1 and J is joined at position 4 of the aryl ring, then R not be -OEt or -N(propyl),. The invention also relates to a compound having the formula
VIE there is the = NR6R NH (VII) Á or a tautomer, enantiomer or salt thereof, wherein: Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from -C(=O)Rº , halogen, and -CH=CHC(=O)R°; Rº is selected from alkyl, OR", and NRYºR"!; R'* is selected from H, alkyl, and -CH>O(alkyl); R'º and R' are each independently alkyl, where said -10 —alkyl is optionally substituted with -OH, or R** and R*, together with the nitrogen atom to which they are attached. , form a heterocyclic ring, where said heterocyclic ring is optionally substituted with one or more -OH; and R$ and R' are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more groups independently selected from -F or -OH; provided that when Y is aryl substituted with -C(=O)Rº, and Rº = NR'ºR*, and Rºº and R'!, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring , then Rº and Rº are not both propyl.
Compounds of the invention can be used in combination with other known therapeutic agents. Accordingly, this invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention or a salt thereof, in combination with a second therapeutic agent.
This invention further provides methods of modulating signaling mediated by TLR7 and/or TLR8, comprising contacting a cell expressing TLR7 and/or TLR8 with an effective amount of a compound of the invention, or a salt thereof. In one aspect, the method inhibits TLR7 and/or TLR8-mediated immunostimulatory signaling.
This invention further provides methods of modulating - TLR7 and/or TLR8-mediated immunostimulation in a patient, comprising administering to a patient who has, or is at risk of developing, TLR7 and/or TLR8-mediated immunostimulation. a compound of the invention, or a salt thereof, in an amount effective to inhibit TLR7 and/or TLR8-mediated immunostimulation in the patient. This invention further provides methods of modulating TLR7 and/or TLR8-mediated immunostimulation in a patient, comprising administering to a patient who has, or is at risk of developing, TLR7 and/or TLR8-mediated immunostimulation a compound of the - "vention, or a salt thereof, in an amount effective to promote TLR7 and/or TLR8-mediated immunostimulation in the patient.
This invention further provides methods of treating or preventing a disease or condition by modulating the cellular activities mediated by TLR7 and/or TLR8, comprising administering to a warm-blooded animal, such as a mammal, for example a human, that has or runs the risk of developing said disease or condition, a compound, invention, or a salt thereof.
This invention further provides methods of modulating a mammal's immune system, comprising administering to a mammal a compound of the invention, or a salt thereof, in an amount effective to modulate said immune system.
Further provided is a compound of the invention, or a salt thereof, for use as a medicament in the treatment of the diseases or conditions described herein (e.g., cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection). , and graft versus host disease) in a mammal, e.g., a human, suffering from such a disease or condition. Also provided is the use of a compound of the invention, a salt thereof, in the preparation of a medicament for the treatment of the diseases and conditions described herein (e.g.,
cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease) in a mammal, e.g., a human, suffering from such a disease or condition. - Further provided is a compound of the invention, or a salt thereof, for use as a medicament in preventing the diseases or conditions described herein (e.g., cancer, autoimmune disease, infectious disease, inflammatory disorder, rejection of graft, and graft versus host disease) in a mammal, for example, a human, exposed to or predisposed to the disease or condition, but the mammal does not yet experience or show symptoms of such disease or condition. Also provided is the use of a compound of the invention, a salt thereof, in the preparation of a medicament for the treatment of the diseases and conditions described herein (e.g., cancer, autoimmune disease, infectious disease, inflammatory disorder). , graft rejection, and graft versus host disease) in a mammal, e.g., a human, suffering from such a disease or condition.
The disease or condition is selected from, for example, cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease.
This invention further provides kits comprising one or more compounds of the invention, or a salt thereof. The kit may additionally comprise a second compound or formulation comprising a second pharmaceutical agent.
Another aspect provides intermediates for preparing the compounds of formula |. Certain compounds of formula | can be used as intermediates for other compounds of formula I.
Additional advantages and novel features of this invention will be set forth, in part, in the description which follows, and, in part, will become apparent to those skilled in the art upon examination of the specification which follows, or may be learned by practicing the invention. The advantages of the invention can be achieved and obtained by means of the instruments, combinations, compositions, and methods particularly observed in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION In certain aspects, the invention provides compositions and methods useful for modulating TLR7 and/or TLR8-mediated signaling. More specifically, one aspect of this invention provides a compound having the formula I: the R NH A) or a tautomer, enantiomer or salt thereof, where: Y is substituted aryl, heteroaryl, or substituted heteroaryl, where - 10 adds substituted aryl or substituted heteroaryl is substituted with one or more groups independently selected from CN, OH, - C(=O)Rº, halogen, and -CH=CHC(=O)Rº; Rº is selected from alkyl, OR”, and NRºR'!; R** is selected from H, alkyl, and -CH2O(alkyl), R'º and R'' are each independently alkyl, wherein said alkyl is optionally substituted with -OH or R'º and R'!, together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -OH; R is selected from OR'* and NRºR”; R6 and R7 are each independently selected from H, alkyl, cycloalkyl, heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl is optionally substituted with one or more groups independently selected from -F, - ORô, -NR SOR" , -CEONR”R"* or Rº and Rº, together with the nitrogen atom to which they are attached, form a heterocyclic ring, additionally wherein said heterocyclic ring is optionally substituted with one or more -OH; Rº is selected from hydrogen and alkyl, and R' , Rº and R'º are each independently selected from H and alkyl, wherein said alkyl is optionally substituted with -1 OH; provided that ooa) when Y is aryl substituted with x or <<, then ' 5 —R is not -OCH;CH;3 (-OEt), or b) when Y is aryl substituted with -C(=O)Rº, and Rº = NR/ºR"', and R'º and R'!, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring, then R is not -OEt or -N(propyl For example, a compound of the invention is a compound of formula I, where Y is aryl substituted with a or o and R' is not -OEt. - In another embodiment, a compound of the invention is a compound of formula I. , where Y is aryl substituted with -C(=O)Rº, Rº is NR RL, and R' and Rº, together with the nitrogen atom to which they are attached, form a pyrrolidine ring, and R is not -OEt or -N(propyl),.
In another embodiment, a compound of the invention is a compound of formula I, where Y is substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with one or more groups independently selected from -C (=O)R° and -CH=CHC(=O)R . In another embodiment, a compound of the invention is a compound of formula I, where Y is substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with -C(=O)R6. In another embodiment, a compound of the invention is a compound of formula I, where Y is substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with -CH=CHC(=O)R6.
One aspect of the invention pertains to a compound having the formula |1:
the V n2 " if ' Z in (1) or a tautomer, enantiomer, or salt thereof, where W is H or -OH; Z is H or -OH; n is 1 or 2 and R' is as described for the formula | In one embodiment, the invention relates to a compound or salt thereof, having the formula 1l, provided that when WeZ are both H, n is 1, then Rº is not -OEt or -Ní(propyl) In one embodiment, the invention relates to a compound having the formula lla: o - * w if Zz is (lla) or a tautomer, enantiomer, or salt thereof, where W is H or -OH; and R' is as described for formula I. In one embodiment, the invention relates to a compound or salt thereof, having formula IIa, provided that when W and Z are both H, then R' is not - OEt or -N(propyl),.
In one embodiment, the invention relates to a compound having formulaIIb: the R2 * UU Zz =
N QOLTI is a (llb) or a tautomer, enantiomer, or salt thereof, where W is H or -OH; Zé H or - OH and R is as described for the formula |. In one embodiment, the invention relates to a compound or salt thereof, having formula II or IIa, where W is HeZ is H. In one embodiment, the invention relates to a compound or salt thereof, where one of Wou Zé Heo Is the other is -OH. In one embodiment, the invention relates to a compound or salt thereof, where W is H and Z is -OH. In one embodiment, the invention pertains to - a compound or salt thereof, where W is -OH and Z is H. In one embodiment, a. The invention relates to a compound or salt thereof, where W is -OH and Z is -OH.
In one embodiment, the invention relates to a compound or salt thereof, having the formula I or IIa, where the stereochemistry of the stereogenic center adjacent to Z is the R configuration. In one embodiment, the invention relates to if to a compound or salt thereof, where the stereochemistry of the stereogenic center adjacent to Z is the S configuration. In one embodiment, the invention relates to a compound or salt thereof, where the stereochemistry of the stereogenic center adjacent to W is the R configuration. In one embodiment, the invention pertains to a compound or salt thereof, where the stereochemistry of the stereogenic center adjacent to W is the S configuration. In one embodiment, the invention pertains to to a compound or salt thereof, where the stereochemistry of the stereogenic center adjacent to Z is the R configuration and the stereocenter adjacent to W is the S configuration. In one embodiment, the invention relates to a compound or salt thereof, wherein the stereochemistry of the stereogenic center adjacent to Z is the configuration R and the stereocenter adj In one embodiment, the invention relates to a compound or salt thereof, wherein the stereochemistry of the stereogenic center adjacent to Z is the S configuration and the stereocenter adjacent to W is the R configuration. , the invention relates to a compound or salt thereof, where the stereochemistry of the stereogenic center adjacent to Z is the S configuration and the westreocenter adjacent to W is the S configuration.
One aspect of the invention pertains to a compound having formula III: the R
NE wi" ; NH2 TV a or a tautomer, enantiomer or salt thereof, where T is CH, CZ, or N, U is CH, CZ, or N, . V is CH, CZ, or N, . 5 X is CH, CZ, or N, W is CH, CZ, or N, Z is selected from halogen, -CN, -CONR'SR””, -COOR"%, -CH=CHCOOR'" , and -OR"* ; R'º, R', R'3, and R1º are each independently selected from H, alkyl, and -CH>O(alkyl); and R is as described for the formula |.
In one embodiment, the invention relates to a compound having: the formula IIIa: o - R2 ; oC Ss ) Tx (la) or a tautomer, enantiomer, or salt thereof, where T is CH, CZ, or N; Z is selected from halogen, -CN, -CONR'ºR”, -CooR"*, -CH=CHCOOR'8, and -OR"*; R'8, R7, R'º, and R'º are each independently selected from H, alkyl, and -CH2O(alkyl); and R is as described for the formula |.
In one embodiment, the invention relates to a compound, having the formula IIIb: o n2 Nn= SA, 2 « ) U (lb) or a tautomer, enantiomer, or salt thereof, where U is CH, CZ, or N; Z is selected from halogen, -
CN, -CONR'ºR'!, -COOR' , -CH=CHCOOR" , and -OR"*; R'º, RU, R$, and Rº À are each independently selected from H, alkyl, and - CHoO(alkyl); and R is as described for the formula |. . In one embodiment, the invention relates to a compound having formulalyl E 5 : the R 2 ga
E ss V (Ito) or a tautomer, enantiomer, or salt thereof, where V is CH, CZ, or N; Z is selected from halogen, -CN, -CONR'ºR””, -COOR'%, -CH=CHCOOR" , and -OR"*; R'º, R7, Rº, and R'* are, & 10 each independently selected from H, alkyl, and - CH>O(alkyl); and R is as described for the formula |. In one embodiment, the invention relates to a compound having the formula lild: the R |
E Po” (1d) or a|tautomer, enantiomer, or salt thereof, where T, U, and V are each independently selected from CH, CZ, or N; Z is selected from halogen, -CN, -CONR*ºR””, -COOR**, -CH=CHCOOR'" , and -OR"*; R*º, RU”, R' , and R** are each independently selected from H, alkyl, and -CHrO(alkyl); and R is as described for the formula |. In one embodiment, the invention relates to a compound or salt thereof, having formula III, IIIa, IIIb, IIIc, IIId, or salt thereof, where Z is CN. In one embodiment, the invention relates to a compound or salt thereof, having formula III, IIIa, IIIb, IIIc, IIId or a salt thereof, where Z is CONR'ºR”!.
In one embodiment, the invention relates to a compound or salt thereof, where R'° and R'7 are both alkyl. In one embodiment, the invention relates to a compound or salt thereof, wherein the alkyl is selected from methyl and . ethyl. In one embodiment, the invention relates to a compound or salt thereof, where the alkyl is methyl. In one embodiment, the invention relates to a compound or salt thereof, wherein the alkyl is ethyl.
In one embodiment, the invention relates to a compound or salt thereof, having formula III, IIIa, IIIb, IIIc, INd or a salt thereof, where Z is COOR'*. In one embodiment, the invention pertains to a compound or salt thereof, where R* is H. In one embodiment, the invention pertains to a compound or salt thereof, where R'° is alkyl. In one embodiment, the invention relates to a compound or salt thereof, wherein the alkyl is selected from methyl and ethyl.
In one embodiment, the invention relates to a compound or salt thereof, having formula III, IIIa, IIIb, IIIc, IIId or salt thereof, where Z is OR"*. In one embodiment, the invention relates to a compound or salt thereof, where R6 is H.
In one embodiment, the invention relates to a compound or salt thereof, having the formula III, IIIa, IIIb, IIIc, IIId or a salt thereof, where Z is -CH 2 O(alkyl). In one embodiment, the invention relates to a compound or salt, wherein the alkyl is ethyl.
In one embodiment, the invention relates to a compound or salt thereof, having formula III, IIIa, IIIb, IIIc, IIId or a salt thereof, where Z is halogen.
In one embodiment, the invention pertains to a compound or salt thereof, having the formula III, IIIla, IIIb, Hlc, IIId or a salt thereof, wherein Z is -CH=CHCOOR"*. One aspect of the invention pertains to a compound having formula IV: the R'N(1) or a tautomer, enantiomer, or salt thereof, where R' is as described for formula I. An aspect of the invention pertains to a compound having the formula V: o - R Ro sees NH p V) or a|tautomer, enantiomer, or salt thereof, where U is N or CZ; Z is halogen; R*$ is selected from H, alkyl, and -CH>O(alkyl); and R' is as described for formula I. In one embodiment, the invention relates to a compound or salt thereof, where R'** is ethyl or methyl. Aspect of the invention relates to a compound having the formula Vl: - the R2 SS = or a tautomer, enantiomer, or salt thereof, where
J is independently selected from halogen, -C(=O)R' and -CH=CHC(=O)R';
p is selected from 1,2,e 3;
R is selected from OR'* and NRºR”;
R$ and R' are each independently selected from H, alkyl, cycloalkyl, heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl is optionally substituted with one or more groups independently selected from -F , -OR , -NRSOR” , -C(=O)NR' R**, or Rº and R”, together with the nitrogen atom to which they are attached, form a heterocyclic ring, additionally where said heterocyclic ring is optionally substituted with one or more -OH;
Rº is selected from hydrogen and alkyl;
Rº is selected from alkyte, OR'*, and NRºR";
R'*º and R'* are each independently alkyl, where said IS alkyl is optionally substituted with -OH or R*º and R"', together with the nitrogen atom to which they are attached. , form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more: 5 -OH R' , R6 and R** are each independently selected from H and alkyl; and R' * is selected from H, alkyl, and -CH>O(alkyl) In one embodiment, the invention relates to a compound or a salt thereof, having : do : in formula VI, provided that when p is 1 and J is joined at the 4 position of the aryl ring, then R is not -OEt, and additionally since when p - > O, . is 1 and J is joined at the 4 position of the aryl ring, then Rº is not -OEt or - N(propyl), In one embodiment, the invention relates to a compound or salt thereof, having formula VI, where J is attached at the 4-position of the aryl ring.
In one embodiment, the invention relates to a compound or salt thereof, where J is attached at the 3-position of the aryl ring.
In one embodiment, the invention relates to a compound or salt thereof, where J is attached at the 2-position of the aryl ring.
In one embodiment, the invention relates to a compound or salt thereof, where Jé-CH=CHC(=O)Rº.
In one embodiment, the invention relates to a compound or salt thereof, having formula VI, where J is -C(=O)Rº.
In one embodiment, the invention relates to a compound or salt thereof, where p is 2, one J is -C(=O)R , and the other J is halogen.
In one embodiment, the invention relates to a compound or salt thereof, where Rº is OR”. In one embodiment, the invention relates to a compound or salt thereof, where R'* is alkyl.
In one embodiment, the invention relates to a compound or salt thereof, wherein R'* is selected from ethyl and methyl.
In one embodiment, the invention relates to a compound or salt thereof, where one J is -C(=O)Rº and the other J is F.
In one embodiment, the invention relates to a compound or salt thereof, where Rº is OR.
In one embodiment, the invention relates to a compound or salt thereof, where R** Ki is -CH2 O(alkyte). One aspect of the invention pertains to a compound having the form. mule VII: o - = NRºR NH(VI) or a tautomer, enantiomer or salt thereof, wherein: Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from -C(=O)Rº , halogen, and -CH=CHC(=O)R°; . 10 Rº is selected from alkyl, OR*, and NR!ºR; R'* is selected from H, alkyl, and -CH2O(alkyl); ' R*º and R* are each independently alkyl, where said alkyl is optionally substituted with -OH, or R'º and R'!, together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -OH; and Rº and R are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenite is optionally substituted with one or more groups independently selected from -Fou-OH; provided that when Y is substituted aryl with -C(=O)Rº , and Rº = NR'ºR", and R'º and R'1, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring, then Rº and R are not both propyl.
In another embodiment, the invention relates to a compound having formula VII, where: Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from - C(=O)Rº, halogen, and -CH=CHC(=O)Rº;
Rº is OR; f R** is selected from H, alkyl, and -CH2O(alkyl); and Rº and R are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenyl is optionally: 5 — substituted with one or more groups independently selected from -F or -OH. In another embodiment, the invention relates to a compound having formula VII, where: Y is substituted aryl, wherein said aryl is substituted with -C(=O)R6; Rº is selected from alkyl, OR", and NR!ºR!!; R** is selected from H, alkyl, and -CH2O(alkyl); - R'*º and R'!, together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -OH; and R6 and R' are each independently selected from H , alkyl or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more groups independently selected from -F or -OH; provided that when Rº = NR'ºR"!, and R'º and R* !, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring, then R° and R are not both propyl.
In another embodiment, the invention relates to a compound having formula VII, where R° and R' are each independently alkyl, where the saidalkyl is substituted with one or more groups independently selected from -F and - oh. In another embodiment, the invention relates to a compound having formula VII, where R° and R' are each independently alkyl, wherein said alkyl is unsubstituted. In another embodiment, the invention relates to a compound having formula VII, where Y is substituted aryl. In another embodiment, the invention relates to a compound having formula VII, where Y is substituted phenyl. In another embodiment, the invention relates to a compound having formula VII, where Y is substituted heteroaryl. In another embodiment, the invention relates to a compound having the formula VIIa: o, NR$R” es Co, (Vila) or a|tautomer, enantiomer or salt thereof, where: v O, 1.0u2; R$ is selected from H, allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more -OH; R" is selected from allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more -OH; provided that when v is 0, then Rº and R' are not both propyl.
In another embodiment, the invention relates to a compound having formula VIIa, where R° and R° are each independently propyl, wherein said propyl is optionally substituted with one or more -OH.
In another embodiment, the invention relates to a compound having formula VIIa, where R$ and R' are each independently propyl, where one of R$ or R" is substituted with one or more -OH and the another is unsubstituted.
In another embodiment, the invention relates to a compound having formula VIIa, where R° and R' are each unsubstituted propyl.
In another embodiment, the invention relates to a compound having the formula Villa, where v is 0. In another embodiment, the invention relates to a compound having the formula Villa, where v is 1 or 2. of the invention refers to a compound or salt thereof, having the formula I, HI, Ia, lb, III, Wa, Hb, IIIc, Hd, IV, V, or VI, where R is -OR"*. In one embodiment, the invention relates to a compound or a salt thereof, where R** is alkyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is ethyl.
One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, Hla, lib, 111, Hlla, Ilib, Wc, ad, IV, V, or VI, where R° is -. NRR”. In one embodiment, the invention relates to a compound or a :5 susal, wherein one of R₂ or R₂ is H and the other is alkyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein both R° and R' are each independently alkyl.
In one embodiment, the invention pertains to a compound or a salt thereof, wherein each alkyl is independently selected from isopropyl, propyl, isobutyl, and secbutyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is optionally substituted with one or more -OH.
In one embodiment, the invention relates to a compound or a salt thereof, where the alkyl is substituted with an -OH.
In one embodiment, the invention relates to a compound or a salt thereof, where the stereocenter adjacent to the -OH group is the S configuration.
In one embodiment, the invention relates to a compound or a salt thereof, where the stereocenter adjacent to the OH group is the R configuration.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is substituted with two -OH.
In one embodiment, the invention pertains to a compound or a salt thereof, wherein the alkyl is optionally substituted with one or more -O(alkyl). In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is substituted with an -O(alkyl). In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is substituted with two -O(alkyl). One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, IIIa, IIb, III, IIa, Wlb, Wc, IIId, IV, V, or VI, where R is - NRºR”. In one embodiment, the invention relates to a compound or a salt thereof, wherein one of R° or R' is alkyl, and the other is benzyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the benzyl is substituted with -OH.
One aspect of the invention pertains to a compound or salt thereof, having the formula I, II, IIIa, Ib, III, Hila, IIIb, Hc, Hd, IV, V, or VI, where R° is -
No. R”. In one embodiment, the invention relates to a compound or a salt thereof, wherein at least one of R$ or R$ is alkyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein an alkyl is substituted with -NR'SOR' . In one embodiment, the invention relates to a compound or a salt thereof, where R' is H.
In one embodiment, the invention relates to a compound or a salt thereof, where R** is methyl.
One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, Ita, IIb, III, Ha, IIIb, Hc, Hd, IV, V, or VI, where R° is -NR°R". In one embodiment, the invention relates to a compound or a salt thereof, wherein at least one of R$ or R' is alkyl.
In one embodiment, the invention pertains to a compound or a salt thereof, wherein an alkyl is substituted with -C(=ONR*ºR" . In one embodiment, the invention pertains to a compound or a its salt, where R' and R' are both H.
One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, IIIa, IIb, III, IIIa, IIb, Mec, Id, IV, V, or VI, where R° is -NR°R ”. In one embodiment, the invention relates to a compound or a salt thereof, wherein at least one of R° or R it's alkyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the alkyl is substituted with halogen.
One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, Ia, IIb, III, IHla, Hb, Wllc, Wd, IV, V, or VI, where R is -NR°R". In one embodiment, the invention relates to a compound or a salt thereof, where R° and R are both propyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein one is R° or R° cycloalkyl and the other is heterocycloalkyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the cycloalkyl is cyclopropyl.
In one embodiment, the invention relates to a compound or a salt thereof, wherein the heterocycloalkyl is piperidine.
One aspect of the invention pertains to a compound or a salt thereof, having the formula I, II, IIIa, IIb, III, Na, IIIb, Hllc, Nid, IV, V, or VI, where RA is -NR°R". In one embodiment, the invention relates to a compound or a salt thereof, where R° and R", together with the nitrogen atom to which they are attached.
25/135 : joined, they form a heterocyclic ring. In one embodiment, the invention relates to a compound, wherein the heterocyclic ring is selected from pyrrolidine and piperidine.
. One aspect of the invention pertains to a compound or an R 5 salt thereof selected from a compound in Table 1 (formula 1). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 156, 101, 102, 103, 104, 105, 106, 107, 109, 110, 112, 117, 119, 120, 174, 176, 178, 127, 128, 129, 130, 182, 115, 121, 122, 126, and 202 (formula II). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 101, 102, 103, 104, 105, 106, 107, 109, 110, 112, 117, 119, 120, 174, 176, 178, 127, 128, 129, 130, 182, 115, 121, 122, and 202 (formula IIa). In one embodiment, the invention pertains to a compound or a salt thereof selected from Compound 126 and 156 (formula IIb). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 143, 146, 154, 155, 124, 125, 134, 137, 139, 188, 190, 195, 202, 206, 207, 208, 209, and 220 (formula IIIa). In one embodiment, the invention pertains to a compound or a salt thereof selected from Compound 142, 145, 147, 133, 136, 138, 186, 187, and 194 (formula IIIb). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 141, 203, and 204 (formula IIIc). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 144 and 135 (formula IV). In one embodiment, the invention pertains to a compound or a salt thereof selected from Compound 210, 211, and 212 (formula V) In one embodiment, the invention pertains to a compound or a salt thereof selected from Compound 139, 220, 211, 187, 190, 203, 204, 206, 207, 208, 212, and 210 (formula VI). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 101, 102, 103, 104, 105, 106, 107, 109, 110, 117, 124, 125, 126, I 236, 237, 238, and 239 (formula VII). In one embodiment, the invention relates to a compound or a salt thereof selected from Compound 101, 104, 105, 106, 109, f 110, 127, 128, 129, 130, 182, 227, 228, 229 , 230, 231, 232, 233, 234, 235, 236, 237, 238, and 239 (formula Vila). . One aspect of the invention pertains to a salt of a compound of the invention, wherein the salt is a pharmaceutically acceptable salt.
One aspect of the invention pertains to a kit for treating a condition mediated by TLR7 and/or TLR8, comprising: a) a first pharmaceutical composition comprising a compound of the invention or a salt thereof; and b) optionally, instructions for use. In one embodiment, the invention relates to the kit further comprising (c) a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a second compound for treating a condition mediated by TLR7 and/or TLR8. In one embodiment, the invention relates to the kit, further comprising instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.
One aspect of the invention pertains to a pharmaceutical composition which comprises a compound of the invention or a salt thereof, together with a pharmaceutically acceptable diluent or carrier.
One aspect of the invention pertains to a compound of the invention for use as a medicament to treat a condition measured by TLR7 and/or TLR8 in a human or animal. In one embodiment, the invention relates to a compound of the invention, or a salt thereof, in the manufacture of a medicament for treating an abnormal cell growth condition in a human or animal.
One aspect of the invention pertains to a method of treating a condition mediated by TLR7 and/or TLR8, comprising administering to a patient in need thereof an effective amount of a compound of the invention or a salt thereof.
One aspect of the invention pertains to a method of modulating a patient's immune system, comprising administering to a patient in need thereof an effective amount of a compound of the invention or a salt thereof. The invention includes a compound selected from the compounds listed in Table 1. Table 1. | [in] EsmaQumea — [in] — Estuwaduímica — | o o A as NA = N 101 O nN= m 102 Cl O O e Ox O o o 9 o
SPO NT 103 O and E | 104 O = - A O NH, O O NH7 o o A A $ ia fi = ON ôe = N or 105 O ” - 106 Qi nN= q O O NH a O NH is o À CO ) NOd..om
A SR 107 e O QE e 112 O. O O e, o o o 3 nO TOR b a OM ia eba oH | EL 4 or
NH 3.5 So fo CX 2 1117 G E SS AQE "
| [the haphazard [mm] Euusdine | ' For 9 AD FE N = sa and a [o] E . - o — O = O 121 O n= 122 O = [e O NHo Ox O "ooo ” NA ” va 132 Ns 124 O nº mh (x MN, D. O Na: o - ” NO S NE 125 O = nm 126 O | ( O NO NH O Nino Cs Or É 9 a == ON ss ON 127 O o 128 “a DR oo CD Fo
N N RO > 129 and GO x, 130 e. O x, o Ô o” ne 3 nl 133 E s 134 . S o NH, $ >» NO NH o o = NE q A 135 à M 136 Ss 7 NO NH, No O Nx,
[ at the. |] Chemical Structure | at the. | Chemical Structure . the o o
QL SI 137 O O ” SN 1388] CX - s NH “ NANA . N 2 " O : a q N OEt «AX = 139 2 154 O = (DZ NÔ NH V GO N NH, ” . Eto- o o o o OEt / TOEt 141 142 . (À NO NH, ( NO NH
No. o o = TOEt = “OEt 143 144 = NO == NO ú A NH, 7 NH> b 3 OEt OEt Fe 145 146 NC Nn= (OD NH: NHo 2
Ç NC o LN Ron OEt = ON Es WS 17) O 220 ” | ST IH. Eto. 7 (O a PP o o O = OEt O and OEt 155 156 N= N= DALI [QL o o
[ETR RE OF ERON | o N NR o = AA - p 174 Sd, 176 Ie " | AO ASS oo NH. Q À : Co : NV = 186 O AN | 178 Sº NE NHa o NODE NH DO & ' OH S nTMNoH Q PA NX s 211 E 182 () P - Eto. in NÔ NH, the F GQ (OD o - UC
N o SJ E Ss 187 SS | 188 (CD) 2 nd ” NÔ NH, O NONHR Eto (CD Ho. THE
DS x IS IS RR = N NH;
NODE NH O HO. (CD Eto. (o)
[the | Emas love — [rm] Emusdme — | QER jet f 195 (À E fo 202 (D NÔ NH, NÉ NH q (OD (> Y Ho g Q LM nO M>oH 203 | EO o O 204 | eo o = W/ ON NH, GO NNE Rg NO o ps. . = ty N CD E o : 206 NH 207 ” ns, À Meo. C EO o O -" eooo nO OF NO «XxX, = 208 pf 209 O ” NNHo Eto. HO. ooog ADO OS <t 212 Da 210 (CS) An, MO AZ Eto. O * O EF
OH o pt on HC e 227 Of 228 | Ho COS HO Nº NH, G NA GG (D N O NH > a o o
[ at the. | Chemical Structure | at the. | Chemical Structure o 1 o = C = o . 229 O ” 230 & O ” | GSI Ars 1 LO, o o == o
FC LC 231 O or 232 DP. CG ” ” G O rx NH> no N. O NH2 o o o o oH — CE E O 233 s K. 234 | CO SS me SO hr ro O Auto o ' o o oH TL es 235 | - 236 — ro O Ss NH GG OG "NH oooo St” ST” 237 238 = NE AI Au GALO wo ooo E fo 239 CG ” GL vo o In one aspect, the invention includes a compound, or salt thereof, having a value of MCso < 25,000 nM for TLR8. In another aspect, the invention includes a compound or its salt, with a value of MCso < 10,000 nM for TLR 8. In another aspect, the invention includes a compound or its salt, with a -MCso value< 1000 nM for TLR8 In another aspect, the invention includes a compound or its salt, with a value of MCs50 < 100 nM for TLR8. In another aspect, the invention includes a compound or its salt, with a value of MCso
<25 nM for TLR8. In one aspect, the invention includes a compound or salt thereof, having an MCso value < 25,000 nM for TLR7. In another aspect, the invention. includes a compound or its salt, with an MCso value of <10,000 nM for is 5 TLR7. In another aspect, the invention includes a compound or its salt, with an MCso value of <1,000 nM for TLR7. In another aspect, the invention includes a compound or salt thereof, having an MCso value <100 nM for TLR7. In another aspect, the invention includes a compound or salt thereof, having an MCso value <25 nM for TLR7.
In one aspect, the invention does not include a compound or salt thereof, with an MCs, >25,000 for TLR7. In one aspect, the invention does not include a compound or salt thereof, with an MCs, >25,000 for TLR8. In one respect, the invention does not include a compound or its salt, with MCs50 values >25,000 for TLR7 and for TLR8.
Another aspect of the invention relates to soft drugs (also known as "anti-drugs"). "Soft drugs" can be defined as biologically active chemical compounds (drugs) that are metabolically deactivated after they achieve their therapeutic role at their designed site of action. Using soft drugs, rather than their non-deactivatable analogues, can prevent unwanted side effects. In one respect, the metabolic distribution of soft drugs occurs at a controllable rate in a predictable manner. One embodiment of the invention pertains to compounds that are soft drugs. Specifically, the invention relates to compounds that are designed to cleave in vivo, after reaching their therapeutic effect, with a less active moiety. The invention relates to compounds which are designed to cleave in vivo, after reaching their therapeutic effect, with a non-toxic moiety. Soft drugs of the invention include compounds such as Compound 139, 220, 211, 187, 190, 203, 204, 206, 207, 208, 212, and 210.
The term "compound of the invention" refers to exemplified compounds and compounds covered under the formulas described herein.
The term "substituted", as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated group, provided that a va- . normal lence of the designated atom is not exceeded, and that the substitution is 5 to result in a stable compound. When a substituent is keto (i.e., =O), then 2 hydrogens on the atom are substituted. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).
A chemical structure showing a dotted-line representation for a chemical bond indicates that the bond is optionally present. For example, a dotted line drawn next to a solid single bond indicates that the bond can be a single bond or a double bond. When a bond to a substituent is shown to cross a bond that joins two atoms in a ring, then that substituent can be bonded to any atom on the ring.
The term "alkyl" as used herein refers to a straight or branched-chain saturated monovalent hydrocarbon radical having one to twelve, including one to ten carbon atoms (C1-C10), one to six carbon atoms. carbon atoms (C1-Cs) and one to four carbon atoms (C1-Ca), where the alkyl radical may be optionally substituted, independently, with one or more substituents described below. Examples of alkyl radicals include the hydrocarbon moieties such as, but not limited to: methyl (Me, -CH;3), ethyl (Et, -CHCH;3), 1-propyl (n-Pr, n-propyl , -CHxCH2CHs), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CHCH2CH2COH3), 2-methyl-1-propyl (i -Bu, i-butyl, -CHxCH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH;3), 2-methyl-2-propyl (t-Bu, t -butyl, -C(CH3 )s), 1-pentyl -(n-pentyl — -CHCHxCHxCH2COH3), 2-pentyl (-CH(CH3)CHXCHCH3), 3-pentyl (CCH(CHxCH3)»), 2-methyl -2-butyl (- -C(CH2)xCHCH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CHCH2CH(CH3)2) , 2-methyl-1-butyl (-CHCH(CH3)CH2CH3), 1-hexyl (-CHICH;CH;CHCHCH3), 2-hexyl (-CH(CH3)CH2CH2CH2COHs3), 3-hexyl (-
: CH(CHCH3)(CHCH2CH3)), 2-methyl-2-pentyl (-C(CH3)»CH2CH2CH3), 3-methyl-2-pentyl (-CH(CHa)CH(CH3)CH2CH;3), 4 -methyl-2-pentyl CCH(CH3 )CHxCH(CH3 )2 ), 3-methyl-3-pentyl (-C(CH3 )(CH2 CH3 )2 ), 2-methyl-3-. pentyl (-CH(CHCH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ).CH(CH 3 )>2), : 5 3,3-dimethyl-2-butyl - CCH(CH3)C(CH3)3, 1-heptyl, and 1-octyl.
The term "alkenyl" refers to a monovalent, linear or branched-chain hydrocarbon radical having two to ten carbon atoms (C2-C19), including two to six carbon atoms (C2>-Cs) and two to four carbon atoms (C2>-C4), and at least one double bond, and includes, but is not limited to, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex -5-enyl and the like, where the alkenyl radical may be optionally substituted, independently, with one or more substituents described herein, and includes radicals having the "cis" and "trans" orientations, or alternatively, the "cis" and "trans" orientations. E" and "Z". The term "alkenyl" includes allyl.
The term "alkynyl" refers to a monovalent straight or branched hydrocarbon radical of two to twelve carbon atoms (C2-C+12), including two to 10 carbon atoms (C2>-C19), two to six carbon atoms (C2-Cs) and two to four carbon atoms (C2-C4), containing at least one triple bond.
Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyn-2-yl and the like, where the alkynyl radical may be optionally substituted, independently, with one or more substituents described herein.
The terms "carbocycle", "carbocyclyl" or "cycloalkyl" are used interchangeably herein and refer to the cyclic hydrocarbon radical, saturated or partially unsaturated, having from three to twelve carbon atoms (C3-C12 ), including three to ten carbon atoms (C3-C109) and three to six carbon atoms (C3-Cs). The term "cycloalkyl" includes both monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, where the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated or an aryl or heteroaryl ring.
Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloethyl, and the like.
Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as a [4.5], [5.5], [5.6] or [6.6] bicycle system, or 9 or 10 : ring atoms arranged as a [5,6] or [6,6] bicyclo system, or as joined systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[2.2.1]heptane. [3.2.2]nonane.
The cycloalkyl may be optionally substituted, independently, at one or more substitutable positions, with one or more substituents described herein.
Such cycloalkyl groups may be optionally substituted with, for example, one or more groups independently selected from C1 -Cs alkyl, C1 -Cs alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C, Cs )alkylamino, di(C 1 -Cs )alkylamino, C 2 -C 6 alkenyl, C 3x -Cs alkynyl, C 1 -C s haloalkyl, C 1 -C 6s haloalkoxy, amiso(C 1 -Cs )alkyl, "mono(C s ) ;-Cs)alkylamino(C1-Cs)alkyl and di(C,Cs)alkylamino(C1-Cs)alkyl.
The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon radical having three to ten carbon atoms (C3-C10), including three to six carbon atoms (C3-Cs) and having at least one double bond within the carbocycle.
The term "heteroalkyl" refers to the hydrocarbon radical —monovalent, saturated, straight or branched chain, of one to twelve carbon atoms (C1-C12), including one to six carbon atoms (C;-Cs) and from one to four carbon atoms (C 1 -C 4 ), where at least one of the carbon atoms is substituted with a heteroatom selected from N, O, or S, and where the radical can be a carbon radical or heteroatom radical (ie, the heteroatom may appear in the middle or at the end of the radical). The heteroalkyl radical may be optionally substituted, independently, with one or more substituents described herein.
The term "heteroalkyl" includes both alkoxy and heteroalkoxy radicals.
The terms "heterocycloalkyl", "heterocycle" and "heterocyclyl" are used interchangeably herein and refer to a saturated or partially unsaturated carbocyclic radical of 3 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from
tir of nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted, independently, with one or more substituents described below.
The radi- cal may be a carbon radical or heteroatom radical.
The term "heterocycloalkoxy" includes heterocycloalkoxy.
The term further includes fused ring systems which include a heterocycle fused to an aromatic group.
"Heterocycloalkyl" also includes radicals where heterocyclic radicals are fused to aromatic or heteroaromatic rings.
Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranite, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl , oxepanil, tiepanil, oxazepinyl, diazepinyl, thiazepinite, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl , pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas.
Spiro moieties are also included in the scope of this definition.
The preceding groups, as derived from the groups listed above, may be C-linked or N-linked where possible.
For example, a group derived from pyrrole can be pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached). Furthermore, an imidazole-derived group can be imidazol-1-yl (attached to the N) or imidazol-3-yl (attached to the OC). An example of a heterocyclic group where 2 carbon atoms are substituted with oxo (=O) moieties is 1,1-dioxo-thiomorpholinyl.
The heterocycle groups contained herein are unsubstituted or, as specified, substituted at one or more positions substitutable with various groups.
For example, such heterocycle groups may be optionally substituted with, for example, one or more groups independently selected from C 1 -C s alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 ) -Cs)alkylamino, di(C1-Cs)alkylamino, C2-Cs alkenyl, C2-C; alkynyl, C1-Cs haloalkyl, C1-C6 haloalkoxy, amino
(C1-Ce)alkyl, mono-(Cr-Cs)alkylamino(C1-Cs)alkyl" or —di(Cr ]Cs)alkylamino(C+1-Ce)alkyl.
The term "aryl" refers to an aromatic carbocyclic radical. monovalent, having a single ring (eg, phenyl), multiple rings (eg, biphenyl), or multiple condensed rings, at least one of which is aromatic' (eg, 1,2 ,3,4-tetrahydronaphthyl, naphthyl, etc.), which is optionally substituted with one or more substituents independently selected from, for example, halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxy.
In one embodiment, the aril is a 6-element aril.
For example, aryl is phenyl.
The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings and includes fused ring systems. (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, and sulfur.
Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, 1(3H) -one, and furopyridinil.
Spiro moieties are also included in the scope of this definition.
Heteroaryl groups are optionally substituted with one or more substituents independently selected from, for example, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
The term "halogen" represents fluorine, bromine, chlorine, and iodine.
The term "oxo" represents =O.
In general, the various moieties or functional groups of the compounds of the invention may be optionally substituted by one or more substituents.
Examples of suitable substituents for the purposes
: of this invention include, but are not limited to, oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SOR', -SONR'R", -C(O)R'-C (O)JOR', -OC(OJR, -NR"C(O)JOR', -NR"C(OJ)R', -.C(OINR'R",-NRC(O)NR",-NRC (NCNJ)NR'R", -OR"', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where, R', R' and R" are independently H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl.
An "(alkyl)aryl" group, as used herein, is an aryl substituent that is bonded to a compound by a straight-chain or branched alkyl group having one to twelve carbon atoms. In one aspect, the aryl substituent is attached to a compound by a straight-chain or branched alkyl group having 1-6 carbon atoms. The alkyl moiety R of the (alkyl)aryl group is optionally substituted. In one embodiment, the aryl is a 6-element aryl. For example, aryl is phenyl.
An "(alkyl)heterocycloalkyl" group, as used herein, is a heterocycle substituent that is bonded to a compound by a straight-chain or branched alkyl group having one to twelve carbon atoms. In one aspect, the heterocycle substituent is bonded to a compound by a straight-chain or branched alkyl group having 1-6 carbon atoms. The alkyl portion of the (alkyl)heterocycle group is optionally substituted.
An "(alkyl)cycloalkyl" group, as used herein, is a cycloalkyl substituent that is bonded to a compound by a straight-chain or branched alkyl group having one to twelve carbon atoms. In one aspect, the cycloalkyl substituent is bonded to a compound by a straight chain or branched alkyl group having 1-6 carbon atoms. The alkyl portion of the (alkyl)cycloalkyl group is optionally substituted.
An "(alkyl)cycloalkenyl" group, as used herein, is a cycloalkenyl substituent that is bonded to a compound by a straight-chain or branched alkyl group having one to twelve carbon atoms. In one aspect, the cycloalkenyl substituent is bonded to a compound by a straight-chain or branched alkyl group having 1-6 E carbon atoms. The alkyl portion of the (alkyl)cycloalkenyl group is optionally substituted. . The compounds of this invention may have one or more asymmetric centers: 5; such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or nomenclature of a particular compound in the specification and claims is intended to include both the individual enantiomers, the racemic and non-racemic mixtures of diastereomers thereof. Accordingly, this invention also includes all such isomers, including diastereoisomeric mixtures, pure diastereoisomers and pure enantiomers of compounds of the formulas described herein.
Diastereoisomeric mixtures can be separated into their individual diastereoisomers according to their physicochemical differences by methods known to those skilled in the art, for example, through chromatography or fractional crystallization. Enantiomers can be separated by converting the mixture of enantiomers to a diastereoisomeric mixture by reaction with an appropriate optically active compound (eg, the alcohol), separating the diastereoisomers, and converting (eg, hydrolysation) of the individual diastereoisomers into the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J.March, John Wiley and Sons, New York, 1992).
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then this stereoisomer is therefore specified and defined.
. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer, can be obtained by resolving the racemic mixture using a method, such as diastereoisomer formation, using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemically of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the invention may be separated and isolated by any suitable method, including: (1) formation of diastereoisomeric, ionic salts with the chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereoisomeric compounds with chiral derivatization reagents, separation of diastereoisomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers under chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
According to method (1), diastereoisomeric salts can be formed by reaction of enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, α-methyl-13-phenylethylamine (amphetamine), and similar, with asymmetric compounds containing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereoisomeric salts can be induced to separate by fractional crystallization or ion chromatography. For the separation of optical isomers from amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in the formation of diastereoisomeric salts.
Alternatively, by method (2), the substrate to be resolved is reacted with an enantiomer of a chiral compound to form a diastereoisomeric pair (E. and Wilen, S."Stereochemistry of Organic Compounds", John Wiley & Sons, Inc. , 1994, page 322). Diastereoisomeric compounds can be formed by reaction of asymmetric compounds with enantiomerically pure, chiral derivatization reagents, such as menthyl derivatives, followed by separation of the diastereoisomers and hydrolysis to produce
deduce the pure or enriched enantiomer. One method of determining optical purity involves preparing chiral esters, for example a menthyl ester, such as (-) menthyl chloroformate, in the presence of base, or Mo- ester. sher, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob Ill, (1982) J. Org. Chem .47:4165), from the racemic mixture, and analyze the NMR spectrum for the presence of the two enantiomers or atropisomeric diastereoisomers. Stable diastereoisomers of atropisomeric compounds can be separated and isolated by normal and reversed phase chromatography following the methods for the separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) WJ Lough, Ed., Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or purified enantiomers can be distinguished by the methods used. 15 methods to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. A "tautomer" refers to a compound whose structures differ markedly in the arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that compounds of the invention may be represented as different tautomers. It is also to be understood that where the compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the nomenclature of the compounds does not exclude any tautomer forms. The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-
14. In addition to the compounds of the invention, the invention also includes pharmaceutically acceptable salts of such compounds. A "pharmaceutically acceptable salt", unless otherwise indicated.
. on the contrary, includes those salts which retain the biological effectiveness of the free acids and bases of the specified compound and which are not biologically or otherwise undesirable. Compound of the invention may have a sufficient group. strongly acidic, one sufficiently basic, or both functional groups and, . 5, consequently, reacting with any of a variety of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates. caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. Since a single compound of the present invention may include more than one acidic or basic moiety, the compounds of the present invention may include the mono-, di- or tri-salts in a single compound.
If the inventive compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyruvic acid
nosidyl such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base. Examples of suitable inorganic salts include those formed with alkali and alkaline earth metals, such as lithium, sodium, potassium, barium and calcium. Examples of suitable organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and similar salts. . Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. The present invention also provides salts of the compounds of the invention which are not necessarily pharmaceutically acceptable salts, but which may be useful as intermediates for the preparation and/or purification of the compounds of the invention and/or for the separation of enantiomers. of the compounds of the invention. The inventive compounds can be prepared using the reaction routes and synthetic schemes as described in Scheme I, employing practices available in the art, using starting materials that are readily available.
ê Scheme 1 EIA, o04E R R
NO AO : LA > Y NO > 2 NO, Y NO, 1 n R o " as a Y NO, CN " nÊ2 m wW rt In Scheme I, compounds of Formula II can be prepared from an alkyl arene of Formula I, by treatment with dimethylformamide dimethyl acetal, with or without the use of pyrolidine (J. Org. Chem., (1986), 51(26), 5106-5110), in DMF, the 70-90°C. The crude intermediate (not shown) can be cleaved to the aldehyde of Formula II with NalO, in THF/phosphate buffer pH 7.2, at or around room temperature. The aldehyde of Formula II can be olefinized with phosphonium ylide in toluene at temperatures ranging from 70 to 110°C (1 - 16 hours) to give compounds of Formula III. Compounds of Formula IV can be prepared from a compound of Formula III, using iron powder in acetic acid. The reaction can be carried out at temperatures of about 90°C for about 3 - 14 hours.
It is noted that some of the preparations of compounds of the invention described in this document may require protection of distant functionalities. The need for such protection will vary depending on the nature of the functionality and the conditions used in the preparation methods and can be readily determined by those skilled in the art.
Such protection/deprotection methods are well known to those skilled in the art.
Compounds of the invention find use in a variety of applications. For example, in certain aspects, the invention provides methods
used to modulate TLR7 and/or TLR8-mediated signaling. Methods A of the invention are useful, for example, when it is desirable to alter TLR7 and/or TLR8-mediated signaling in response to a TLR7 and/or TLR7 binder. suitable TLR8 or an agonist of TLR7 and/or TLR8 signaling. As used herein, the terms "ligand for TLR7 and/or TLR8", "ligand for TLR7 and/or TLR8" and "agonist of TLR7 and/or TLR8 signaling" refer to a molecule other than a compound of the invention, which directly or indirectly interacts with TLR7 and/or TLR8 and induces TLR7 and/or TLR8-mediated signaling. In certain embodiments, a TLR7 and/or TLR8 binder is a naturally occurring binder, i.e., a TLR7 and/or TLR8 binder that is found in nature. In certain embodiments, a TLR7 and/or TLR8 binder refers to a molecule other than a naturally occurring TLR7 and/or TLR8 binder, e.g., a molecule prepared by human activity.
The term "modulate", as used herein in relation to the TLR7 and/or TLR8 receptors, means the mediation of a pharmacodynamic response in a patient (i) by inhibiting or activating the receptor, or (ii) directly or indirectly by affecting the normal regulation of receptor activity. Compounds that modulate receptor activity include agonists, antagonists, mixed agonists/antagonists, and compounds that directly or indirectly affect the regulation of receptor activity.
The term "agonist" refers to a compound that, in combination with a receptor (eg, a TLR), can produce a cellular response.
An agonist can be a ligand that directly binds to the receptor. Alternatively, an agonist may combine with a receptor indirectly, for example, (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise resulting in the modification of another compound. , so that the other compound directly binds to the receptor. An agonist may be referred to as an agonist of a particular TLR (eg, a TLR7 and/or TLR8 agonist). The term "partial agonist" refers to a compound that produces a partial but not a total cellular response. Assays related to TLR7 and TLR8 are known in the
. technique (e.g., Gorden et al., Journal of Immunology 177, pp. 8164-8170 (2006) and Zhu et al., Molecular Immunology, vol. 45 (11), pp. 3238-3242 (2008)) . . The term "antagonist" as used herein refers to a compound that competes with an agonist or partial agonist for binding to a receptor, thereby blocking the action of an agonist or partial agonist on the receptor. More specifically, an antagonist is a compound that inhibits the activity of TLR7 or TLR8 at the TLR7 or TLRS8 receptor, respectively. "Inhibit" refers to any measurable reduction in biological activity. Thus, as used in this document, "inhibit" or "inhibit" may be referred to as a percentage of a normal activity level.
f In one aspect of this invention, a method of treating or preventing a condition or disorder treatable by modulating TLR7 and/or TLR8-mediated cellular activities in a patient comprises administering to said patient a composition comprising a compound of the invention, in a effective amount to treat or prevent the condition or disorder. The term "TLR7 and/or TLR8-mediated" refers to a biological or biochemical activity that results from the function of TLR7 and/or TLR8.
Conditions and disorders that can be treated by the methods of this invention include, but are not limited to, cancer, diseases associated with the immune complex, autoimmune diseases or disorders, inflammatory disorders, immunodeficiency, graft rejection, disease versus host, allergies, cardiovascular disease, fibrotic disease, asthma, infection, and sepsis.
More specifically, methods useful in the treatment of conditions involving cancer (therapeutic or cancer vaccine), allergic disease (eg, atopic dermatitis, allergic rhinitis, asthma), infectious disease (vaccine prophylaxis and antiviral), and immunodeficiency will employ compounds of the invention that inhibit TLR7 and/or TLR8-mediated signaling.
Alternatively, methods useful in treating conditions involving autoimmune disease, CF, sepsis, graft rejection, and GVHD will generally employ compounds of the invention that enhance TLR7 and/or TLR8-mediated signaling. In some situations, the compositions can be used to inhibit or promote TLR7 and/or TLR8-mediated signaling in response to a ligand or agonist of TLR7 and/or TLR8 signaling. In other situations, the compositions can be used to inhibit or promote TLR7 and/or TLR8-mediated immunostimulation in a patient.
The term "treat", as used herein, unless otherwise indicated, means at least the alleviation of a disease or condition and includes, but is not limited to modulating and/or inhibiting an existing disease or condition, and/ or alleviate the disease or condition to which such term applies, or one or more symptoms of such disease or condition.
The term "treatment" as used herein, unless otherwise indicated, refers to the act of treating, as "treating" is defined immediately above. ' 15 Therapeutic treatment refers to treatment initiated after the observation of symptoms and/or a presumed exposure to a causative agent of the disease or condition.
Generally, therapeutic treatment can reduce the severity and/or duration of symptoms associated with the disease or condition.
As used herein, "prevent" means causing the clinical symptoms of a disease or condition not to develop, ie, inhibiting the onset of a disease or condition in a patient who may be exposed to or predisposed to the disease or condition, but not still feels or shows symptoms of the disease or condition.
Prophylactic treatment means that a compound of the invention is administered to a patient prior to observation of symptoms and/or presumed exposure to a causative agent of the condition (e.g., a pathogen or carcinogen). Generally, prophylactic treatment can reduce (a) the likelihood that a patient receiving treatment will develop the condition and/or (b) the duration and/or severity of symptoms if the patient does develop the condition.
As used herein, the terms "autoimmune disease", "autoimmune disorder" and "autoimmunity" refer to immunologically mediated acute or chronic injury to a tissue or organ derived from the host. Terms include both cellular and antibody-mediated autoimmune phenomena, as well as organ-specific and non-organ-specific autoimmunity. Autoimmune diseases include E 5 insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus. , multiple sclerosis, atherosclerosis, and inflammatory bowel disease. Autoimmune diseases also include, without limitation, ankylosing spondylitis, autoimmune hemolytic anemia, Bechet syndrome, Goodpasture syndrome, Graves, Guillain Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia, myasthenia gravis, pernicious anemia, polyarterte nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, psoriasis, sarcoidosis, af cholangitis sclerosing disease, Sjogren's syndrome, systemic sclerosis (scleroderma and CREST syndrome), Takayasu's arteritis, temporal arteritis, : 15 and Wegener's granulomatosis. Autoimmune disorders also include certain diseases associated with the immune complex.
As used herein, the term "fibrotic disease" refers to diseases or disorders involving excessive and persistent formation of scar tissue associated with organ failure, in a variety of chronic diseases that affect the lungs. , kidneys, eyes, heart, liver, and skin. Although tissue remodeling and healing is part of the normal wound healing process, repeated injury or aggression can result in persistent and excessive scarring and, ultimately, organ failure.
Fibrotic conditions include diffuse fibrotic lung disease, chronic kidney disease, including diabetic kidney disease; liver fibrosis (eg, chronic liver disease (CLD) caused by continuous and repeated damage to the liver from causes such as viral hepatitis B and C, alcoholic cirrhosis, or non-alcoholic fatty liver disease ( NA- —FLD), or primary sclerosing cholangitis (PSC), a rare disease characterized by fibrosing inflammatory destruction of the bile ducts inside and outside the liver, resulting in bile stasis, liver fibrosis, and, ultimately, cirrhosis, and end-stage liver disease); lung fibrosis (eg, idiopathic pulmonary fibrosis (IPF); and systemic sclerosis (a degenerative disorder in which excessive fibrosis occurs in multiple organ systems, including the skin, blood vessels, heart, the lungs, and the kidneys).
Other examples include cystic fibrosis of the pancreas and lungs; injection fibrosis, which can occur as a complication of intramuscular injections, especially in children; endomyocardial fibrosis; mediastinal fibrosis, myelofibrosis; retroperitoneal fibrosis; progressive generalized fibrosis, a complication of coal workers' pneumoconiosis; nephrogenic systemic fibrosis; and the complication of certain types of surgical implants (eg, the occurrence in efforts to create an artificial pancreas for the treatment of diabetes mellitus).
- As used herein, the term "cardiovascular disease" refers to diseases or disorders of the cardiovascular system involving an inflammatory component, and/or the accumulation of plaque, including without limitation coronary artery disease, cerebrovascular disease, peripheral arterial disease, atherosclerosis and arteriosclerosis. As used herein, the terms "cancer" and "tumor" refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a patient. Cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; chori-ocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (eg, small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas. Cancers can be primary or metastatic.
As used herein, the terms "inflammatory disease" and "inflammatory disorder" refer to a condition characterized by inflammation, e.g., a localized protective tissue reaction to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function. Inflammatory diseases or disorders include, for example, allergy, asthma, and allergic rash.
As used herein, the term "immune complex-associated disease" refers to any disease characterized by the production and/or tissue deposition of immune complexes (ie, any conjugate, including an antibody and a specifically bound antigen). by the antibody), including but not limited to systemic lupus erythematosus (SLE) and related connective tissue diseases, rheumatoid arthritis, hepatitis C and hepatitis B-related immune complex disease (eg, cryoglobulinemia) , Bechet syndrome, autoimmune glomerulonephritis, and vasculopathy associated with the presence of LDL/anti-LDL immune complexes. As used herein, "immunodeficiency" refers to a disease or disorder in which the patient's immune system is not functioning at its normal capacity or in which it would be useful to enhance a patient's immune response, for example, to eliminate a tumor or cancer (eg, tumors of the brain, lung (eg, small cell and non-small cell), ovary, breast, prostate, colon, as well as other carcinomas and sarcomas) or an infection in a patient . Immunodeficiency can be acquired or it can be congenital.
As used herein, "graft rejection" refers to hyperacute, acute, or chronic, immunologically mediated injury to a tissue or organ derived from a source other than the host. The term thus includes both cellular and antibody-mediated rejection, as well as rejection of both allografts and xenografts. "Graft versus host disease" (GvHD) is a reaction of donated bone marrow against a patient's own tissue. GVHD is seen most often in cases where the bone marrow donor is unrelated to the patient or when the donor is related to the patient but is not a perfect matched donor. There are two forms of GVHD: an early form, called acute GVHD, which occurs shortly after
. transplantation, when white blood cells are high, and a late form, called chronic GVHD.
Atopic diseases mediated by Tr2 include, but are not limited to, atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome.
As used herein, "allergy" refers to acquired hypersensitivity to a substance (allergen). Allergic conditions include eczema, allergic rhinitis or runny nose, hay fever, asthma, hives and food allergies, and other atopic conditions.
As used herein, "asthma" refers to a disorder of the respiratory system characterized by inflammation, narrowing of the airways, and increased reactivity of the airways to inhaled agents. Asthma is often, though not exclusively, associated with atopic or allergic symptoms. For example, asthma can be precipitated by exposure to an allergen, exposure to cold air, respiratory infection, and exertion.
As used herein, the terms "infection" and, equivalently, "infectious disease" refer to a condition in which an infectious organism or agent is present in a detectable amount in blood or normally sterile tissue or tissue. normally sterile compartment of a patient. Infectious organisms and agents include viruses, bacteria, fungi, and parasites. Terms include both acute and chronic infections as well as sepsis.
As used herein, the term "sepsis" refers to the presence of bacteria (bacteremia) or other infectious organisms or their toxins in the blood (septicemia) or other body tissue.
A compound of the invention, or a salt thereof, is further provided for use as a medicament in the treatment of the diseases or conditions described above, in a mammal, for example a human, suffering from such a disease or condition. Also provided is the use of a compound of the invention, or a salt thereof, in the preparation of a medicament for the treatment of the diseases or conditions described above, in a
: mammal, e.g. a human, suffering from such a disorder. This invention also includes pharmaceutical compositions containing a compound of the invention and methods of treating or preventing the conditions and disorders by modulating cellular activities mediated by TLR7 and/or TLR8, by administering a pharmaceutical composition with - delivering a compound of the invention, or a salt thereof, to a patient in need thereof.
To use a compound of the invention or a salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, it is normally formulated, in accordance with standard pharmaceutical practice, as a pharmaceutical composition. . In accordance with this aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention, or a salt thereof, as defined above, in association with a pharmaceutically acceptable diluent or carrier.
"To prepare pharmaceutical compositions in accordance with this invention, a therapeutically or prophylactically effective amount of a compound of the invention, or a salt thereof (alone or together with an additional therapeutic agent, as disclosed herein), is intimately mixed, for example, with a pharmaceutically acceptable carrier, in accordance with conventional pharmaceutical compounding techniques, to produce a dose.. A carrier can take a wide variety of forms, depending on the form of preparation desired for administration, e.g. Examples of suitable carriers include any solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, stabilizers (to promote long-term storage). duration), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, anti-aging agents antibacterials and antifungals, isotonic and absorption delaying agents, flavoring agents, and miscellaneous materials such as tampons and absorbents that may be necessary to prepare a therapeutic composition
: particular. The use of such media and agents with the pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with a compound. of the invention, its use in therapeutic compositions and preparations is contemplated. Supplementary active ingredients may also be incorporated into the compositions and preparations as described herein. The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) for use. topical (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g. as a finely divided powder or a liquid aerosol), for administration by insufflation (e.g. , as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing, or as a suppository for rectal dosing). For example, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated, to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in any case, using coating agents and conventional procedures well known in the art.
h Compositions for oral use may be in the form of hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate F or kaolin, or as soft gelatine capsules, in which the ingredient . 5 active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form, together with one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth. and acacia gum; dispersing or wetting agents, such as lecithin or the condensation products of an alkylene oxide with fatty acids (eg, polyoxyethylene stearate), or the condensation products of . ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or the condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or the condensation products - tion of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, eg polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharin or aspartame).
Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). . Oil suspensions may also contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those demonstrated above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present. Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as, for example, liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soy, lecithin, osesters or partial esters derived from fatty acids and hexitol anhydrides (eg sorbitan monooleate) and the condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening, flavoring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension which may be formulated in accordance with known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents which have been mentioned above. For parenteral formulations, the carrier will normally comprise sterile water, aqueous sodium chloride solution, 1,3-butanediol, or any other suitable non-toxic parenterally acceptable diluent or solvent. Other ingredients may be included, including those that aid dispersion. Obviously where the water
. sterile is to be used and maintained as sterile, the compositions and vehicles must also be sterile. Injectable suspensions may also be prepared, in which case suitable liquid vehicles, suspending agents and the like may be used.
y 5 Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions can generally be obtained by formulating an active ingredient with a conventional topically acceptable carrier or diluent using conventional procedures well known in the art. technique.
Compositions for administration by insufflation may be in the form of a finely divided powder which contains particles of average diameter of, for example, 30 microns or much less, the powder itself comprising the active ingredient alone or diluted with one or more more physiologically acceptable carriers, such as lactose. The powder for insufflation is then conveniently held in a capsule containing, for example, 1 to 50 mg of active ingredient, for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol designed to deliver the active ingredient as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants, such as volatile fluorinated hydrocarbons or hydrocarbons, may be used, and the aerosol device is conveniently designed to deliver a metered amount of the active ingredient.
Compositions for transdermal administration may be in the form of transdermal skin patches which are well known to those of ordinary skill in the art. Other delivery systems may include time-release, delayed-release, or continuous-release delivery systems. Such systems can avoid repeated administrations of the compounds, increasing convenience for the patient and physician. Many types of delivery delivery system are available and are known to those of ordinary skill in the art. They include polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid), and polyanhydrides. Microcapsules of the foregoing polymers containing the drugs are described, for example, in U.S. Patent No. 5,075,109. Delivery systems also include non-polymer systems, which are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-, di- and triglycerides; hydrogel delivery systems; silastic systems; peptide-based systems; coatings | 15 wax; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) etching systems, in which an agent of the invention is contained in a form within a matrix, such as those described in U.S. Patent Nos. 4,452,775, 4,675,189, and
5,736,152, and (b) diffusion systems, in which an active component permeates at a controlled rate from a polymer, such as described in U.S. Patent Nos. 3,854,480, 5,133,974 and 5,407,686. In addition, pump-based hardware distribution systems can be used, some of which are adapted for deployment.
The compositions can be administered in the form of a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic with nasal secretions and of approximately the same pH, varying, e.g. from about pH 4.0 to about pH 7.4 or from pH 6.0 to pH 7.0. Buffers must be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a de-
Representative nasal congestion is described as being buffered to a pH of about 6.2 (Remington's Pharmaceutical Sciences, Ed. By Arthur Osol, p. 1445 (1980)). Of course, the skilled artisan can readily determine a saline content and pH suitable for an innocuous aqueous vehicle for nasal administration.
Other non-limiting examples of intranasal dosage forms containing the composition include nasal gels, creams, pastes or ointments having a viscosity of, e.g., about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, which may provide more continuous contact with the nasal mucosal surfaces. Such viscous vehicle formulations may be based on, simply by way of example, polymeric vehicles, such as alkylcelluloses, and/or other high-viscosity biocompatible vehicles well known in the art (see, e.g. , Remington's, cited above). The vehicle containing the composition may also be embedded in a tissue material, such as gauze, which may be applied to the nasal mucosal surfaces to allow the active substances in the isolated fraction to penetrate the mucosa.
Other ingredients may also be included, such as preservatives, colorings, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts, such as aromatic oils, and humectants and water enhancers. viscosity, such as, e.g., glycerol, known in the art, to provide additional viscosity, moisture retention, and a pleasant texture and odor to the formulation.
Furthermore, for the nasal administration of the solutions or suspensions of the composition, various devices are available in the art for the generation of drops, droplets and sprays. For example, solutions comprising the isolated fraction can be administered to the nasal passages by —by means of a simple dropper (or pipette) that includes a glass, plastic or metal dispensing tube, from which the contents are expelled, drop by drop, by means of air pressure supplied by a manual pump-
. driven, eg a flexible rubber bulb, joined to one end. The fine droplets and sprays may be provided by a manually or electrically driven intranasal pump dispenser or squeeze bottle, as is well known in the art, e.g., which is designed. 5 to blow a mixture of air and fine droplets into the nasal passages.
The amount of a compound of this invention, which is combined with one or more excipients to produce a single dosage form, will necessarily vary depending on the patient treated, the severity of the disorder or condition, the rate of administration, the arrangement of the compound, and the criterion of the prescribing doctor. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, for example, about 0.05 to about 35 mg/kg/day, in individual doses. or divided. For example, a dosage is about 0.0005 to about 2.5 g/day. For example, a dosage is about 0.0005 to about 1 g/day in single or divided dosages. In some situations, dosage levels below the lower limit of the aforementioned range may be more than adequate, although in other cases even higher doses can be used without causing any harmful side effects, provided such larger doses are first divided into several small doses for administration throughout the day.
For additional information on routes of administration and dosing regimens, see Chapter 25.3 in Volume 5 of the Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated in this document by reference.
The magnitude of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, in accordance with the principles of well-known medicine. It will be understood that the specific dosage level and frequency of dosing for any particular patient may be varied and will depend on a variety of factors, including the activity of the drug.
. specific compound of the invention, the species, age, body weight, general health, sex and diet of the patient, the mode and time of administration, the rate of excretion, the drug combination, and the severity of the particular condition, but can nevertheless be routinely determined. 5 by someone versed in the technique.
A compound of the invention or its salt is, in some aspects, administered to a patient in combination (e.g., in the same formulation or in separate formulations) with another therapeutic agent ("combination therapy"). The compound of the invention is administered in admixture with another therapeutic agent or is administered in a separate formulation. When administered in separate formulations, one compound of the invention and the other therapeutic agent are administered substantially simultaneously or sequentially. In one aspect, a compound of the invention is administered to a patient in combination with another therapeutic agent, to treat a condition or disease. In one aspect, a compound of the invention is administered to a patient in combination with another therapeutic agent, to prevent a condition or disease. In one aspect, a compound of the invention is administered to a patient in combination with a vaccine to prevent a condition or disease. In one aspect, a compound of the invention is administered to a patient in combination with an infectious disease vaccine. In one aspect, a compound of the invention is administered to a patient in combination with a cancer vaccine.
A compound of the invention may be useful as a vaccine adjuvant for use in conjunction with any material that promotes a humoral and/or cell-mediated immune response, such as, for example, viral, bacterial, or parasitic immunogens. alive; viral, tumor-derived, protozoan, organism-derived, fungal, or bacterial, inactivated, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cell vaccines; DNA vaccines; re-combinant proteins; glycoproteins; peptides; and the like, for use in connection with, for example, BCG, anti-cholera, plague, anti-typhus, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza,
anti-polio, anti-rabies, anti-measles, anti-mumps, against rubella, against yellow fever, anti-tetanus, anti-diphtheria, hemophilus influenza b, against tuberculosis, meningococcal and pneumococcal, against adenovirus, HIV, anticapox, .: against cytomegalovirus, against dengue, feline leukemia, avian influenza, HSV-1 and HSV, swine anticholera, against Japanese encephalitis, respiratory syncytial virus, against rotavirus, papilloma virus, yellow fever, and Alzheimer's disease.
Compound of the invention may also be useful in individuals having compromised immune function. For example, a compound of the invention can be used to treat or prevent opportunistic infections and tumors that occur after suppression of cell-mediated immunity in, for example, transplant patients, cancer patients, and patients. with HIV. Such a combination treatment may involve, in addition to a compound of the invention, surgery or conventional radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents: (i) antiproliferative/antineoplastic drugs and combinations thereof; (ii) cytostatic agents; (iii) agents that inhibit cancer cell invasion; (iv) inhibitors of growth factor function; (v) antiangiogenic agents; (vi) vascular damaging agents; (vii) antisense therapies; (viii) gene therapy approaches; (ix) interferon; and (x) immunotherapy approaches. Therapeutic agents for treating or preventing respiratory diseases which can be administered in combination with a compound of the invention in a foregoing method include, but are not limited to, beta adrenergics, which include bronchodilators, including albuterol, isoproterenol sulfate, metaproterenol sulfate, terbutaline sulfate, pirbuterol acetate and formotorol sahneterol; steroids, which include beclomethasone dipropionate, flunisolide, fluticasone, bu-desonide and triamcinolone acetonide. Anti-inflammatory drugs used in connection with the treatment or prevention of respiratory diseases include steroids such as beclomethasone dipropionate,
nolone acetonide, flunisolide and fluticasone. Other anti-inflammatory drugs include cromolyn, such as cromolyn sodium. Other respiratory drugs that would qualify as bronchodilators include anticholinergics, including ipratropium bromide. Antihistamines include, but are not limited to, diphenhydramine, carbinoxamine, clemastine, dimenhydrinate, priylamine, tripelenamine, chlorpheniramine, bromopheniramine, hydroxyzine, cyclizine, meclizine, chlorcyclizine, promethazine, doxylamine, loratadine, and terfenadine. Particular antihistamines include rhinolast (Astelin®), claratin (Claritin®), claritin D (Claritin D ), telfast (Allegra ), Zyrtec®, and beconase.
In some embodiments, a compound of the invention is administered as a combination therapy with interferon-gamma (IFN-gamma), - a corticosteroid, such as prednisone, prednisolone, methyl prednisolone, hydrocortisone, cortisone, dexamethasone, betamethasone, etc.,] 15 or a combination thereof, for the treatment or prevention of interstitial lung disease, eg, idiopathic pulmonary fibrosis.
In some embodiments, a compound of the invention is administered in combination therapy with a known therapeutic agent used in the treatment of cystic fibrosis ("CF"). Therapeutic agents used in the treatment of CF include, but are not limited to, antibiotics; anti-inflammatory agents; DNAse (eg, recombinant human DNAse; pulmozyme; dornase alfa); mucolytic agents (e.g., N-acetylcysteine; Mucomyst®; Mucosyl®); decongestants; bronchodilators (eg, theophylline; ipratropium bromide); and the like.
In some embodiments, a compound of the invention is administered prophylactically for the prevention of cardiovascular disease, e.g., atherosclerosis.
In another embodiment of the invention, an article of manufacture, or "kit", is provided containing materials useful for treating or preventing the diseases described above.
In one embodiment, the kit comprises a container comprising a composition of the invention, or its pharmaceutically active salt.
. acceptable. In one embodiment, the invention provides a kit for treating or preventing a disorder mediated by TLR7 and/or TLR8. In another embodiment, the invention provides a Kit for a condition or disorder treatable by selectively modulating the immune system in a patient. The kit may additionally comprise a label or package insert on, or associated with, the container. Suitable containers include, for example, vials, vials, syringes, blister packs, etc. The container can be formed from a variety of materials, such as glass or plastic. The container contains a compound of the invention, or a pharmaceutical formulation thereof, in an amount effective to treat or prevent the condition, and may have a sterile access compartment (e.g., the container may be a bag of intravenous solution or vial having AND a cap pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used to treat or prevent the condition of choice. In one embodiment, the label or package insert indicates that the composition - comprising a compound of the invention can be used, for example, to treat or prevent a disorder treatable by modulating TLR7 and/or TLR8-mediated cellular activities. The label or package insert may also indicate that the composition can be used to treat or prevent other disorders. Alternatively, or in addition, the kit may also comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may additionally include other materials desirable from a commercial or user point of view, including other buffers, diluents, filters, needles, and syringes.
The Kkit may additionally comprise instructions for administering the compound of the invention and, if present, the second pharmaceutical formulation. For example, if the Kit comprises a first composition comprising a compound of the invention and a second pharmaceutical formulation, the kit may additionally comprise instructions for the simultaneous, sequential or separate administration of the first and second.
: pharmaceutical compositions to a patient in need thereof.
In another embodiment, the kits are suitable for the administration of solid oral forms of a compound of the invention, such as tablets or capsules. Such a kit includes, for example, different dosages: 5 units. Such kits may include a card with dosages listed in the order of their intended use. An example of such a kit is a "card". Cartons are well known in the packaging industry and are widely used to package dosage forms for pharmaceutical units. If desired, a memory aid may be provided, for example, in the form of numbers, letters, or other markings or with a record insert designating the days in the treatment program on which dosages may be administered.
According to one embodiment, the kit may comprise (a) a & first container with a compound of the invention contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound which may be effective in treating or preventing a condition or disorder by selectively modulating the cellular activities mediated by TLR7 and/or TLR8. Alternatively, or in addition, the kit may also comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may additionally include other materials desirable from a commercial or user point of view, including other buffers, diluents, filters, needles, and syringes.
In certain other embodiments where the kit comprises a pharmaceutical formulation of a compound of the invention and a second formulation comprising a second therapeutic agent, the kit may comprise a container to hold the separate formulations, such as a divided vial or a split laminated package; however, separate compositions may also be contained within a single undivided container. Typically, the kit comprises instructions for the administration of
D traction of separate components. The kit form is particularly advantageous when the separate components are administered in different dosage forms (e.g., oral and parenteral), are administered at different dose intervals, or when titration of the individual components is used. . 5 visuals of the combination is desired by the prescribing physician. The activity of the compounds can be evaluated according to procedures described, e.g., in Gorden et al., Journal of Immunology 177, p. 8164-8170 (2006) and Zhu et al., Molecular Immunology, vol. 45 (11), pgs. 3238-3242 (2008). The MCs,o values for TLR8 activity are, for example, as shown below: TIRS (Cs) : o = TOEt : 143 45 nM CC " NH Í o = OE 154 O ” 116 nM — GO NH o o HUH
XX 106 Ne 10 nM
O O NH Oo *arbitrary stereochemistry o OS 127" and O” n 4 nM
Ooo o
TRE (MCs) or
FT NO 124 O “ 104 nM | LI-N, the OH O, Z
NR 190 (Xe NÓ NH, Eto. | o - MCrs5.5 values for TLR7 activity are, for example, as shown below: : TLR7 (MCso) o NH
O 178 (> NO NH7 767 nM
GS or
Q nl 135 or S 744 NM “7 N NH,
EXAMPLES To illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only intended to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare various other compounds of the invention, and alternative methods of preparing the compounds of this invention are also considered to be within the scope of this invention. For example, the synthesis of the unexemplified compounds of a-
in accordance with the invention can be successfully effected by modifications apparent to those skilled in the art, e.g. by appropriately protecting the interfering groups, using other suitable reagents known in the art, except those described, and/or by making routine modifications to the reaction conditions.
Alternatively, the other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the other compounds of the invention.
In the examples described below, unless otherwise indicated, all temperatures are given in degrees Celsius.
Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, Acros, TCI, Alfa Aesar or Maybridge, and were used without further purification unless otherwise noted. : In the examples described below, the term "Example fHHt" refers to "Compound tHfHt". For example, Example 101 is directed to Compound 15 101 and/or synthetic procedures relating to Compound 113. The reactions shown below were generally performed under positive pressure of nitrogen or argon or with a drying tube (unless otherwise noted ) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via the syringe.
The glassware was oven-dried and/or heat-dried.
Microwave reactions were performed on a Biotage Initiator system.
Column chromatography was performed on a Biotage system or Isolute Flash Si SPE column (manufacturer: Biotage AB) having a silica gel column or on a SepPak silica cartridge (Waters). The *H and “*F NMR spectra were recorded on a Varian instrument operating at 400 MHz and 376 MHz, respectively.
1H-NMR spectra were obtained as solutions of CDCI;3 or ds-DMSO (described in ppm), using chloroform (7.26 ppm) or tetramethylsilane (0 ppm) as the reference standards. .
When peak multiplicities are described, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), br (es-
. tended), dd (doublet of triplets), dt (doublet of triplets), m (multiplet). Example 1 Synthetic Procedures Scheme II. General Synthetic Route NOz NOz NOs from io GO, HO, LIST HEI, EloH LO N Br Br Br toluene, reflux SM 15 coDEt coOEt
LA 16 1 178 ' COOEt COOEt cOooEt Boc20 LO RB(OH)z Br N DCM, ta Br R - Hs NHBoc HBoc f 7 18 20 is COODEt 2: O DCM, t ta R N Hz 2
1. Synthesis of Compound 15 NOz NO NO, LS Cro, H,SOs LT HC, EtoH O” Br Br Br SM 15 In a three-neck flask, equipped with a mechanical stirrer, dropping funnel, and thermometer, surrounded by an ice-salt bath, 400 ml of acetic anhydride and 50 g (0.23 mol) of 4-bromo-1-methyl-2-nitrobenzene are added. 54 ml of concentrated sulfuric acid are slowly added to this solution with stirring. When the mixture has cooled to 0°C, a solution of 64 g of chromium trioxide in 360 ml of acetic anhydride is added slowly, with stirring, at such a rate that the temperature does not exceed 10, and stirring is continued. continued for 2 hours at 5-10°C in an ice-water bath after the addition is complete. The contents of the vial are poured into the ice-water mixture. The solid was filtered and washed with water until the washes were colorless. The product is suspended in 300 ml of 2% aqueous sodium carbonate solution and stirred. ted. After thorough mixing, the solid was filtered and washed with water and dried. A suspension of the diacetate, in a mixture of 272 mL of concentrated hydrochloric acid, 250 mL of water, and 80 mL of ethanol, was stirred and refluxed. for 45 minutes. The mixture was then cooled to RT and the solid was filtered and washed with water. The crude product is purified by column (229, 42%).
2. Synthesis of Compound 16 Ro. OE eN LOOP mr Z NO toluene, reflux Bran NOz CN “ A mixture of the aldehyde (0.73 g, 3.17 mmol) and the ylide (1.429, 3.65 mmol) in toluene (8 mL) was gently refluxed for 2.5 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material, which was used directly without further purification.
3. Synthesis of Compounds 17 and 17B ÀE peca ane re A . fo to Br Nut CN AcOH BU NE Wo Br N% 16 17 17B To a solution of the crude nitrile in ACOH (25 ml) was added iron (1.15 g, 20.61 mmol) at room temperature. The resulting mixture was heated at 85 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl3; (8 ml). The resulting mixture was filtered, the solids washed with CH2Cl>. The filtrate was concentrated under reduced pressure to give a viscous oil. To the crude material was added CH2Cl> (8 mL). The Na2CO; aq., followed by water, was slowly added
. with stirring until its pH = 9-10. The mixture was filtered and washed with CH2Cl2. The organic layer was separated. The aqueous layer was extracted with CH2Cb. The organic layer was separated. The aqueous layer was extracted with ECH2Cb. The combined organic layers were washed with brine, dried over Na2 -SO4 , the mixture was concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography over silica gel to provide 0.329 g ( 33% for both steps) of the desired product, obtained on the basis of 1 H-NMR.
4. Synthesis of Compound 18 cOooEt cooE AQ =. To the benzazepine (2.34 g, 7.57 mmol) in DCM (25 mL) was added Boc 2 O (2.06 g, 9.46 mmol) in the at room temperature. The reaction mixture was stirred for 20 h. The resulting mixture was washed consecutively with NaHCO, saturated aq., and brine. The organic layer was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography over silica gel (10% EtOAc in hexanes) to provide 1.64 g (52.9%) of the desired product. Synthesis of Species Example 101 3 NH
MOO CG O " NH' o (1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide Step A: Preparation of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine: A solution of 4-bromo-2-nitrotoluene (100 g, 463 mmol), pyrrolidine (46.2 mL, 565 mmol), and N ,N-dimethylformamide dimethylacetal (75.6 mL, 565
. mmoles) was refluxed for 4 hours at 110°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine, which was used directly without further purification.
- 5 Step B: Preparation of 4-bromo-2-nitrobenzaldehyde: A solution of sodium periodate (298 g, 1.40 mol) in THF-HzO (4 L, 1:1) at 0°C was (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine (138 g, 464 mmol) is added. The mixture was stirred for 15 h and then filtered to remove solid precipitates. The aqueous layer from the filtrate was separated and extracted with EtOAc (4x200 mL). The combined organic layers were washed with H₂O (2 x 200 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (5 % EtOAc in hexanes) to provide 91 g (86%) of 4-bromo-2-nitrobenzaldehyde. Step C: Preparation of 3-nitro-4"-(pyrrolidine-1-carbonyl)biphenyl-4-"carbaldehyde: To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol) , 4-(pyrrolidine-1-carbonyl)phenylboronic acid (21.2 g, 96.7 mmol), and Pd(PPh3) to (508 mg, 0.440 mmol), in toluene (200 mL), was added the EtOH ( 40 mL), followed by Na>CO 3 (70.0 mL, 140 mmol, 2M aq solution) at room temperature. The resulting mixture was heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (500 mL), dried over MgSO4 , filtered, and concentrated under reduced pressure to the raw material, which was combined with another batch of the raw material obtained from an additional run on the same reaction scale. . The combined crude material was purified by silica gel flash column chromatography (CH2Cl2 to 1% MeOH in CH22Cb) to provide 519g (90%) of the 3-nitro-4'-(pyrrolidine-1-carbonyl)biphenyl -4-carbaldehyde. Step D: Preparation of (E)-ethyl 2-(cyanomethyl)-3-(3-nitro-4'-(pyrrolidine-1-carbonyl)biphenyl-4-i)acrylate: A mixture of 3-nitro-4 '-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde — (20.0 g, 617 mmol) and the cyanomethylcarboethoxyethylidene triphenylphosphorane (26.3 g, 67.8 mmol), in tobluene (200 mL), was gently refluxed for 2.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, & to give 2-(cyanomethyl)-3-(3-nitro-4'-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylate de(E)-ethylcrude, which was used directly without further purification.
1 Step E: Preparation — of (1E,4E)-ethyl —2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate: - elution of crude (E)-ethyl 2-(cyanomethyl)-3-(3-nitro-4'-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylate in AcOH (650 mL) was added iron (29.1 g, 521 mmol) at room temperature. The resulting mixture was heated at 85 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with CH2Ckl (250 mL). The solids were filtered and washed with 'CH 2 Cl (200 mL). The filtrate was concentrated under reduced pressure to give the crude material, which was diluted with CH2Cl> (250 mL) again. To this mixture was slowly added NaCO; here sat. (-330 mL), with vigorous stirring, until it becomes basic (pH —-9-10). The resulting mixture was filtered i and washed with CH 2 Cl 2 (-250 mL). The aqueous layer was separated and extracted with CH 2 Cl 2 (2 x 150 mL). The combined organic layers were washed with brine, dried over MgSO₄, and filtered to give the crude material, which was diluted with EtOAc (70 mL). The mixture was kept for 16 h at room temperature. The suspension was filtered. The filtered solids were washed with EtOAc (100 mL) to give the crude product, which was washed with a small amount of CH2Cl; to provide 20 g (62% based on 95% purity); of (1E,4E)-ethyl 2-amino-8-(4(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]lazepine-4-carboxylate.
Step F: Preparation of (1E6E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate: At a (1E,4E)-ethyl 2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzol[b]lazepine-4-carboxylate mixture (9.60 g, 23.8 mmol ) in -CHCl; (100 mL) Boc 2 O (5.97 mg, 27.4 mmol) was added at room temperature. The reaction mixture was stirred for 3 days. The resulting mixture was washed with NaHCO; here sat. and brine. The organic layer was
. separated and dried over MgSO4 , filtered, and concentrated under reduced pressure to give 12.7 g of 2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[ crude (1E,4E)-ethyl b]azepine-4-carboxylate, which Y was used directly without further purification. MS APCI(+) m/z 504 (M+1) V 5 detected.
Step G: Preparation of (16,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid: To a solution (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate (12.0 9.23 .8mmol) in THF-EtOH (60 mL/60 mL) was added aq. at 4N (23.8 mL, 95.3 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 21 h. An additional 6 mL of 4N aq LIOH was added twice after 21 h and 24 h. After stirring for an additional 6 h, the resulting mixture was concentrated under reduced pressure to give the crude material, which was diluted with water (50 mL) and acidified to a pH of - —-3.5 with aq. at 1N (-450 mL). -250 mL of CH2Cl was added during acidification to extract the crude product from the viscous suspension. Solids formed during acidification were filtered off. using a Celite-compacted glass filter. The aqueous layer was separated and extracted with CH2Cl (3 x 100 mL). The combined organic layers were dried over MgSO4 , filtered, and concentrated under reduced pressure to give 102 g (90%) of (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine)-acid. 1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid, which was used directly without further purification. MS APCI(+) m/z 476 (M+1) detected.
Step H: Preparation of tert-butyl (1E/4E)A4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate: A mixture of (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid (200 mg, 0.42 mmol) , HOBt (114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol), in DMF (5 mL), was stirred for 1 h at room temperature. To this mixture were added triethylamine (0.12 mL, 0.84 mmol) and propan-1-amine (0.043 mL, 0.53
-mmol) at room temperature. The resulting solution was stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with sat. NH Cl aq. The aqueous layer was separated and extracted with EtOAc (3 x 5' mL). The combined organic layers were washed with brine (5.5 mL), NaHCO; here sat. (5 mL), and brine (5 mL). The organic layer was dried over MgSO2 , filtered, and concentrated under reduced pressure to give (1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H - crude tert-butyl benzol[b]azepin-2-ylcarbamate, which was used directly without further purification.
Step | Preparation of (11E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide: To a solution of ( 1E4E)4(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-tert-butyl benzo[b]azepin-2-ylcarbamate (450 mg, 0.87 mmol) in CH 2 Cl . (5 mL) 2,2,2-trifluoroacetic acid (1.36 mL, 17.4 mmol) was added at , 150°C. The reaction mixture was warmed to room temperature and stirred - for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude material, which was diluted with CH2Cl2 (10 mL) and NaHCO; here sat. (15 mL) again. The resulting mixture was stirred for 30 min at room temperature. The aqueous layer was separated and extracted with CH2Cl2 (1 x 10 mL). The combined organic layers were washed with NaHCO; here sat. (2x 10 mL) and brine (1 x 10 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude material again, which was purified by flash column chromatography over silica gel (1 to 5% Me-OH in CH2Cb, gradient) to yield 27 mg (7%) of (1E,4E)-2-amino-N--propyl-B-(4-(pyrrolidine-1-carbonyl)phenyl)- 3H-benzo[b]azepine-4-carboxamide. MS APCI(+) m/z 417 (M+1) detected; 1 H-NMR (400 MHz, ds-DMSO) is 8.27 (t, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 7.50 (d, 2H), 7 .41 (d, 2H), 3.43-3.51 (m, 4H), 3.18 (q, 2H), 2.99 (s, 2H), 1.81-1.90 (m, 4H ), 1.48-1.58 (m, 2H), 0.90 (t, 3H).
Examples 102 and 103 below were prepared by the procedures as described in Example 101 (Steps H and I), using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine) acid. 1-carbonyl)phenyl)-3H-
benzo[b]azepine-4-carboxylic acid and N-propylbutan-2-amine or diisobutylamine. Example 102 Q=F=—4: and CO ON NH₂ (1E,4E)-2-amino-N-sec-butyl-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)- 3H-benzo[b]azepine-4-carboxamide MS APCI(+) m/z 473 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl 3 ) 8 7.67 (d, 2H), 7.60 (d, 2H), 7.52 (s, 1H), 7.36 (d, 1H), 7 .32 (dd, 1H), 6.80 (s, 1H), 4.21-4.26 (m, 1H), 3.67 (t, 2H), 3.50 (t, 2H), 3, 37-3.44 (m, 1H), , 10 2.95-3.10 (m, 1H), 2.92 (d, 1H), 2.79 (d, 1H), 1.88-2, 00 (m, 4H), 1.50-1.77. (m, 4H), 1.29 (d, 3H), 0.94 (t, 3H), 0.86 (br s, 3H). Example 103 o A a. 2 o (1E,4E)-2-amino-N N-diisobutyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[blazepine-4-carboxamide MS APCI(+) m/z 487 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl 3 ) 5 7.68 (d, 2H), 7.60 (d, 2H), 7.51 (s, 1H), 7.39 (d, 1H), 7 .31 (dd, 1H), 6.82 (s, 1H), 3.67 (t, 2H), 3.51 (t, 2H), 3.22-3.52 (br s, 4H), 2 .81 (s, 2H), 1.88-2.14 (m, 6H), 0.90 (br s, 12H). Example 104 o = e.
CG O frog NH, (1E,4E)-2-amino-N-(2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-
carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide Step A Preparation of 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine: To a solution of 1-(propylamino)propan-2- ol (8.00 g, - 68.3 mmol), tert-butylchlorodimethylsilane (10.9 g, 72.4 mmol), and a catalytic amount of DMAP in CH>Cl, (68 mL) at 0 °C was TEA (9.61 ml, 68.3 mmol) is added dropwise. The reaction mixture was warmed to room temperature and stirred for 20 h. Additional 1 mL of TEA was added and stirred for an additional 20 h. Water (60 ml) was added. The layers were separated. The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude material, which was filtered again to provide 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1 -amine quantitatively, which was used directly without further purification.
Step B: Preparation of (16,4E)-2-amino-N-(2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]Jazepine- 4-carboxamide: The title compound was prepared by the procedures as described in Example 101 (Steps H and 1) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine) acid. 1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylium and 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS AP-CI(+) m/z 475 (M+1) detected; 1 H-NMR (400 MHz, CDCI;) 8 7.67 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.34 (m, 2H ), 6.87 (s, 1H), 4.11 (br s, 1H), 3.48-3.71 (m, 7H), 3.29 (dd, 1H), 2.93 (d, 1H ), 2.80 (d, 1H), 1.86-2.01 (m, 4H), 1.61-1.74 (m, 2H), 1.22 (d, 3H), 0.91 ( t 3H).
Examples 105 and 106 below were prepared by chiral separation of example 104 (column: Chiral Tech IA semi-prep column (10 mm x 250 mm); flow rate: 4.8 mL/min; UV: 220 nm, solvents : EtoH-isooctane (50:50)). Its absolute configuration was determined arbitrarily. Example 105
FA = OH OO 5 . C O N NH o'(1E,4E)-2-amino-N-((S)-2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]Jazepine -4-carboxamide Retention time 10.08 min. Example106
O o ALI Su' o ; (1E,4E)-2-amino-N-((R)-2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-fr-1-carbonyl)phenyl)-3H-benzo[b]azepine- 4-carboxamide. Retention time 9.09 min. Example 107 "Nba OO 5 ALT "Ss o (1E,4E)-2-amino-N-(2-hydroxyethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[ b]Jazepine-4-carboxamide The title compound was prepared by the procedures as described in Example 104, using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl) acid phenyl)-3H-benzo[b]azepine-4-carboxylic acid and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-1-amine, which was prepared by the procedure as described in Example 104 (Step A) , using 2-(propylamino)ethanol. MS APCI (+) m/z 461 (M+1) detected; 1H-NMR (400 MHz, CDCI;) δ 7.68 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.35 (m, 2H) , 6.88 (s, 1H), 3.84 (s, 2H), 3.67 (t, 4H), 3.50 (t, 4H), 2.84 (s, 2H), 1.88-
2.00 (m, 4H), 1.66-1.72 (m, 2H), 0.93 (t, 3H). À Example 109 o : O == or . CG GO SN NH (1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonylphenyl)-3H-benzo[b]azepine-4-carboxamide Step A Preparation of 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine: The title compound was prepared by the procedure as described in Example 104 (Step A), using 3-(propylamino)propan-1-ol.
Step B: Preparation of (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-: 3H tert-butyl benzo[b]azepin-2-ylcarbamate: The title compound was prepared by the procedure as described in Example 101 (Step H), using (1E,4E)-2-(tert- butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine.
MS APCI(+) m/z 689 detected.
Step C: Preparation of (11E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carboniN)phenyl)-3H-benzo[b]lazepine- 4-carboxamide: To a mixture of (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H- tert-butyl benzo[b]lazepin-2-ylcarbamate (459 mg, 0.37 mmol) in CH 2 Cl (4 mL) at 0 °C was added TFA (1.00 mL). The resulting mixture was warmed to room temperature and stirred for 1 h.
The reaction mixture was concentrated under reduced pressure to give the crude material, which was azeotroped with toluene-EtOH (3 mL/1 mL) twice.
The crude material was dried under reduced pressure for 30 min.
The crude material was dissolved in CH2Cl> (-3 mL) again and treated with NH3 in MeOH (0.30 mL, 2.1 mmol, 7N solution in MeOH) at room temperature.
The mis-
resulting mixture was stirred for 1 h.
The resulting mixture was concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography over silica gel (3 to 7% MeOH in CH2Ch, gradient) to provide 105 mg (59% ) from (1E,4E)-2-amino-N-(3--hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-'4 -carboxamide.
MS APCI (+) m/z 475 detected; 1 H-NMR (400 MHz, CDC) δ 7.67 (d, 2H), 7.60 (d, 2H), 7.51 (br s, 1H), 7.30-7.37 (m, 2H ), 6.88 (s, 1H), 3.60-3.69 (m, 6H), 3.48-3.52 (m, 4H), 2.83 (s, 2H), 1.82- 2.00 (m, 6H), 1.68-1.74 (m, 2H), 0.93 (t, 3H). Example 110 o oH O = Cos' GG G NH' o (1E,4E)-2-amino-N-(2,3-dihydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-:carbonyl)phenyl )-3H-benzo[b]azepine-4-carboxamide Step A: Preparation of 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde: A solution of anhydrous DMSO (3.41 mL, 48 mmol) in CH2Cl > (5 mL) was added dropwise to a stirred solution of oxalyl chloride (1.92 mL, 22 mmol) in CHHzChk (50 mL) at -60°C.
To this mixture was added a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (2.48 mL, 20 mmol) in CH2Chl (10 mL). The resulting mixture was stirred for 15 min at -60°C.
To the TEA(13.0mL, 100mmol) was added dropwise.
The reaction mixture was then warmed to room temperature.
Water (50 mL) and CH2Cl, (50 mL) were added.
The organic layer was separated and washed with water (25 mL). The aqueous layer was extracted with CH2Cl7 (3 x 50 mL). The organic layers were dried over MgSO4 , filtered, and concentrated under reduced pressure to provide the crude 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, which was used directly without further purification.
Step B: Preparation of N-((22-dimethyl-1,3-dioxolan-4-iNmethyl)propan-1-amine: To a solution of propylamine (0.72 mL, 7.7 mmo-
:les) and 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (1.0 g, 7.7 mmol) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (2.28 9, 10.8 mmol). The mixture was stirred for 1.5 h at room temperature. The reaction mixture was then quenched with NaHCO; here sat. and extracted with: 5 EtOAc. The organic layer was dried over MgSO4 , filtered, and concentrated under reduced pressure to give the crude material, which was purified by silica gel column chromatography (CH2Cl > to 10% MeOH in CH2Cb, gradient) to provide 1.26 g (73%) of N-((2,2-dimethyl-1,3-dioxolan-4-iDmethyl)propan-1-amine.
Step C: Preparation of (1E,4E)-2-amino-N-(2,3-dihydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b] azepine-4-carboxamide: The title compound was prepared by the procedures as * described in Example 101 (Steps H and |), using (1E,4E)-2-(tert-E-butoxycarbonylamino)-8-(4- (pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-A 15 carboxylic acid and N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1 -the mine. : Example 112 > NO" Ca — "om CC ON NH [o] (4-((1E,4E)-2-amino-4-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl) - 3H-benzo[b]azepin-8-yl)phenyl)(pyrrolidin-1-iN)methanone Step A: Preparation of (3R4R)-1-benzyl-34-bis(tert-butyldimethylsilyloxy)pyrrolidine: To a solution of (3R,4R)-1-benzylpyrrolidine-3,4-diol (7.00 g, 36.2 mmol) and 1H-imidazole (10.9 g, 159 mmol) in DMF (35 mL) at 0°C was tert-butylchlorodimethylsilane (12.0 g, 79.7 mmol) was added. After stirring for 10 min, the mixture was heated to 60 °C for 4 hours. After cooling to room temperature, the reaction was diluted with HO (25 ml) and extracted with pet ether (3 x 20 ml) The combined organic layers were washed with H22O (2 x 20 ml) and sat. aq NaHCO; ;,, filtered and concentrated under reduced pressure to give the crude, which was filtered through a pad of silica (1% MeOH in i CH2Clz) to provide 13.4 g (88%) of (3R,4R)-1 -benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrroli dina. and Step B: Preparation of (3R,4R)-3 4-bis(tert-butyldimethylsilyloxy)pyrrolidine: A mixture of (3R,4R)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine (13 .49, 31.8 mmol) and Pd(OH) 7 /C (2.23 g, 3.18 mmol, 20%) in MeOH (134 mL) was stirred for 20 h under an atmosphere of H2 (balloon ). The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to provide 10.5 g (91%) of crude (SRAR)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine, which was used directly. mind without further purification. Step C: Preparation of (4-((11,4E)-2-amino-4-((SR4R)-3,4-3-dihydroxypyrrolidine-1-carbonyl)-3H-benzo[b]azepin-8-iN) phenyl)(pyrrolidin-1-i)methanone: The title compound was prepared by the procedures as E. 15 described in Example 101 (Steps H and I) with conc. instead of TFA, using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-Ecarbonyl)phenyl)-3H-benzo[b]azepine-4- carboxylic acid and (SRAR)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine. Examples 115 and 117 below were prepared by the procedures as described in Example 101 (Steps H and I), using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine) acid. 1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and the appropriate amines (2-methyl-1-(propylamino)propane-2-ol was prepared by the procedure described in J. Am. Chem. Soc., 1939, 61, 3562) or hydroxylamine. Example 115
NH 8 O OO dh ao (1E,4E)-2-amino-N-cyclopropyl-N-(piperidin-4-yl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b ]azepine-4-carboxamide
. m/z (APCI-pos) M+1 = 481.2. Example 117 | & » Co . Q : (1E,4E)-2-amino-N-(2-hydroxy-2-methylpropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)Yphenyl)-3H-benzo[b] azepine-4-carboxamide m/z (APCI-pos) M+1 = 489.2. Examples 119, 120, 121, and 122 below were prepared by the procedures as described in Example 101 (Steps H and I), using (1E,4E)-2-(tert-butoxycarbonylamino)-8-acid. (4-(pyrrolidine-1-carbonylphenyl)-3H-benzo[blazepine-4-carboxylic acid] and the appropriate amines.
Example 119 » s NL OO 5 CC O la NHz o (1E,4E)-2-amino-N-(2-methoxyethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl) -3H-benzo[b]azepine-4-carboxamide MS APCI (+) m/z 475 (M+1) detected; 1H-NMR (400 MHz, CD-Cla) 8 7.67 (d, 2H), 7.60 (d, 2H), 7.52 (s, 1H), 7.37 (d, 1H), 7. 31-7.33 (m, 1H), 6.91 (s, 1H), 3.68 (t, 4H), 3.58 (br s, 2H), 3.50 (t, 4H), 3. 37 (s, 3H), 2.85 (s, 2H), 1.88-2.01 (m, 4H), 1.62-1.70 (m, 2H), 0.93 (t, 3H) . Example 120 o oo GMT Tu | (1E,4E)-2-amino-N N-bis(2-methoxyethyl)-8-(4-(pyrrolidine-1-
. carbonyl)phenyl)-3H-benzo[b]Jazepine-4-carboxamide MS APCI (+) m/z 491 (M+1) detected; 1H-NMR (400 MHz, CD-Cla) 5 7.67 (d, 2H), 7.60 (d, 2H), 7.50 (s, 1H), 7.38 (d, 1H), 7. 30 (dd, 1H), 6.99 (s, 1H), 3.76 (br s, 4H), 3.67 (t, 2H), 3.60 (br s, 4H), 3.50 (t , 2H), 3.37 (s, ' 5 6H) 2.83(s, 2H), 1.88-2.00 (m, 4H). Example 121 THE THE
E a A o (4-((1E 4E)-2-amino-4-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepin-:8-iNphenyl)(pyrrolidin-1-yl))methanone MS APCI (+) m/z 429 (M+1) detected; 1H-NMR (400 MHz, CD-E Cl 3 ) 8 7.68 (d, 2H), 7.60 (d, 2H), 7.51 (s, 1H), 7.38 (d, 1H), 7 .30 (d, 1H), 7.06 (s, 1H), 3.74 (br s, 2H), 3.67 (br s, 2H), 3.60 (br s, 2H), 3.50 (br s, 2H), 2.88 (s, 2H), 1.90-1.97 (m, 8H). Example 122 the THE
E GALI TSw o (4-((1E,4E)-2-amino-4-(piperidine-1-carbonyl)-3H-benzo[b]azepin-8-iDphenyl)(pyrrolidin-1-i)mnethanone MS APCI (+) m/z 443 (M+1) detected; 1H-NMR (400 MHz, CD-Cl) 5 7.68 (d, 1H), 7.62-7.67 (m, 4H), 7. 56 (dd, 1H), 7.45 (d, 1H), 6.93 (s, 1H), 3.66-3.70 (m, 6H), 3.49 (t, 2H), 3.23 (s, 2H), 1.90-2.01 (m, 4H), 1.74 (m, 2H), 1.67 (m, 4H) Example 124
; SA IO 5 : ALT Ae o . (1E,4E)-2-amino-8-(4-(dimethylcarbamoyl)phenyl)-N N-dipropyl-3H-benzo[b]azepine-4-carboxamide Step A: Preparation of 3-(4-bromo-2 -nitrophenyl)-2-((E)-ethyl cyanomethylacrylate: A mixture of 4-bromo-2-nitrobenzaldehyde (30.0 g, 130.4 mmol) and α-cyanomethylcarboethoxyethylidene triphenylphosphorane (54.4 g, 140 mmol) , in toluene (480 mL), was heated for 3 h at 110 °C. The reaction mixture was cooled to room temperature. The solids were filtered and washed with toluene (50 mL). The filtrate was reconcentrated. under reduced pressure to give the crude material, which was triturated in heptane (100 ml).The precipitates were filtered and washed with heptane (20 ml).After drying under reduced pressure, the crude product was taken up in ' MeOH (250 mL), at room temperature, and spun several times for 30 min. The mixture was kept in the freezer for 16 h, filtered, and rinsed with pre-cooled MeOH (2 x 20 mL) to provide 36, 6 g (83%) of 3-(4-bromo-2-nitrophenyl)-2- (E)-ethyl (cyanomethyl)acrylate.
Step B: Preparation of (11E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate: A mixture of 3-(4-bromo-2-nitrophenyl)-2- (E)-ethyl (cyanomethyl)acrylate (20.0 g, 59.0 mmol) in AcCOH (380 ml) was heated to 80°C. To this mixture was added iron (19.8 g, 354 mmol) in portions over 1 h, keeping the internal temperature below 100 °C. After completion of the iron addition, the reaction mixture was heated for an additional 2.5 h at 80-85 °C until the starting material disappeared on HPLC. The reaction mixture was cooled to room temperature and filtered through a GF/F filter packed with Celite, rinsing with AcOH. The filtrate was concentrated under reduced pressure to give the crude material, which was diluted with water (150 mL). The aqueous mixture was treated with NaHCO; sat. (200 mL), until it becomes basic (pH >8). to suspension
& additional EtOAc (350 mL) was added. The entire mixture was filtered through a filter packed with Celite.
The filtered solids were diluted with EtOAc (300 mL), stirred for 15 min, and filtered again.
This process with the filtered solids was repeated once more.
All organic E:5 layers were combined and washed with NaHCO; ag sat. (300 mL), followed by brine (300 mL), dried over MgSO4 , filtered while rinsing with EtOAc, and concentrated under reduced pressure to give the crude material, which was triturated with ether (100 mL) to provide 16.5 g (91%) of (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate
Step C: Preparation of (1E,4E)-ethyl 8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]lazepine-4-carboxylate: To a suspension of 2-amino-8-bromo- (1E,4E)-ethyl 3H-benzo[b]azepine-4-carboxylate (16.59, 53.4 mmol) in CH2Cl; (165 mL) at 0 °C was added to TEA (11.2 mL, % 80.2 mmol). The resulting mixture was stirred for 10 min at 0 °C.
To this | To the mixture was added Boc 2 O (17.5 g, 80.2 mmol) in CH 2 Ckb (10 mL) at 0°C.
The reaction mixture was warmed to room temperature and stirred for 24 h. An additional 1.16 g (5.32 mmol) of Boc 2 O and 0.75 mL (5.35 mmol) of TEA were added.
The resulting mixture was stirred for an additional 24 h.
The reaction mixture was quenched with water (65 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl> (65 mL). The combined organic layers were washed with NaHCO; here sat. (2 x 100 mL), followed by brine (100 mL). The organic layer was dried over MgSO₄, filtered, rinsed with CH₂Cl₂, and concentrated under reduced pressure to give the crude material, which was treated with heptane (100 mL). The suspension of the crude material in heptane was stirred for 1.5 h at room temperature, filtered, and rinsed with heptane to provide 19.0 g (87%) of 8-bromo-2-(tert-butoxycarbonylamino)- (1E,4E)-ethyl 3H-benzo[b]azepine-4-carboxylate.
MS APCI(+) m/z 409, 411 (M+1, Br standard) de-
ceiling.
Step D: Preparation of (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]lazepine-4-carboxylic acid: To a solution of 8-
(1E,4E)-ethyl bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate (15.0 g, 36.7 mmol) in THF (195 mL), at -15°C, 1N aq NaOH (55.0 mL, 55.0 mmol) was slowly added over 10 min.
The reaction mixture was warmed to room temperature and stirred for 18 and 5 h. The reaction mixture was poured into ice water (500 mL). The pH of the mixture was carefully adjusted to 5-6 with 0.5N aq HCl (-260 mL). The resulting mixture was extracted with EtOAc.
The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine, dried over MgSO4 , filtered while rinsing with EtOAc, and concentrated under reduced pressure to give the crude material, which was triturated with MeCN (20 mL). The solids were filtered and dried under reduced pressure to provide 7.56 g (54%) of the desired product.
The filtrate was concentrated under reduced pressure again to give the second crude material, which was triturated with MeCN again to provide an additional 1.33 g (9.5%) of product. 8.89 total (64%) of (1E,4E)-8-bromo-2- is (tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid were obtained.
MS APCI(+) m/z 381, 383 (M+1, Br pattern) detected.
Step E: Preparation of tert-butyl (11E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzol[b]azepin-2-ylcarbamate: To a solution of dipropylamine (2.16 ml, 15.7 mmol) in CH2Clz (50 mL) at -10°C, EDCI (3.02 g, 15.7 mmol) was added, followed by diisopropylethylamine (2.97 mL, 17.1 mmol) over 5 min. .
The resulting mixture was stirred for 40 min at -15°C.
To the reaction mixture was added (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid (5.00 g, 13.1 mmol) , followed by HOBt (2.13 g, 15.7 mmol), for 5 min, keeping the reaction temperature between -15 to -12°C.
The resulting mixture was warmed to room temperature and stirred for 19 h.
The reaction mixture was poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl (50 mL). The combined organic layers were washed with sat. aq. (75 ml). The organic layer was separated.
The sat. aq NH,CI solution. was extracted with CH2Cl> (50 mL) again.
The combined organic layers were washed with NaHCO; here sat. (2 x 75
. mL), followed by brine (2 x 100 mL). The organic layer was dried over MgSO4 , filtered, and concentrated under reduced pressure to give the crude material, which was taken up in ether (50 mL) and kept in the freezer for 16 h. The precipitates were filtered and the filtrate was concentrated under reduced pressure. 5 to provide 4.64 g (76%) of tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. MS APCI(+) m/z 464.466 (M+1, Br pattern) detected.
Step F: Preparation of tert-butyl (1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate: Ao NaCO; (129 mg, 1.214 mmol), in a 50 mL round bottom flask, was added to water (3.7 mL) and bubbled with N for 10 min. To this mixture was added tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-'benzol[b]Jazepin-2-ylcarbamate (200mg, 0.40mmol) in EtoH : (4.9 mL), at room temperature. The resulting mixture was bubbled with 15.N> for 10 min. Pd(OAc); (9.3mg, 0.040mmol) and 4.4"(phenylphosphinene)bisbenzenesulfonic acid dipotassium hydrate (45mg, 0.081mmol) were added. The resulting mixture was heated to 65°C with N2 bubbling. To this mixture was added a solution of 4-(dimethylcarbamoyl)phenylboronic acid (97 mg, 0.49 mmol) in EtoOH (0.6 mL) The resulting mixture was stirred at 65 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material, which was diluted with water (5 mL) and EtOAc (10 mL). The mixture was filtered through GF/F filter. The aqueous layer was separated and extracted with EtOAc (10 mL) The combined organic layers were washed with brine (10 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography over silica gel (CH 2 Cl > until 2% MeOH in CH 2 Cl) to provide 178 mg (83%) of (11E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(di tert-butyl propylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. MS AP-CI(+)m/z533(M+1) detected. Step G: Preparation of (1E,4E)-2-amino-8-(4-(dimethylcarbamoyl)phenyl)-N,N-dipropyl-38H-benzo[b]azepine-4-carboxamide: O
: Title compound was prepared by the procedure as described in Example 101 (Step 1). MS APCI(+) m/z 433 (M+1) detected; 1H-NMR (400 MHz, CDCl3 ) d 7.68 (d, 2H), 7.49-7.51 (m, 3H), 7.36 (d, 1H), 7.30 (dd, 1H), 6.83 (s, f 1H), 3.47 (br s, 4H), 3.13 (br s, 3H), 3.05 (br s, 3H), 2.81 (s, 2H), 1 .62-1.72 δ 5 (m, 4H) 0.93(t,6H).
Examples 125 and 126 below were prepared by the procedures as described in Example 124 (Steps F and G), using (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]jazepin -2-ylcarbamate = from -tert-butyl and the appropriate boronic acids.
Example 125 ds AT THE
A o So O. NHz o (1E,4E)-2-amino-8-(4-(diethylcarbamoyl)phenyl)-N,N-dipropyl-3H-:benzo[b]azepine-4-carboxamide MS APCI (+) m/z 461 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl2) 67.68 (d, 2H), 7.50 (d, 1H), 7.45 (d, 2H), 7.36 (d, 1H), 7 .30 (dd, 1H), 6.83 (s, 1H), 3.56 (br s, 2H), 3.47 (br s, 4H), 3.33 (br s, 2H), 2.81 (s, 2H), 1.62-1.72 (m, 4H), 1.25 (br s, 3H), 1.17 (br s, 3H), 0.93 (t, 6H). Example 126 PAN
A OS, (1E,4E)-2-amino-8-(4-(piperidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[blazepine-4-carboxamide MS APCI (+) m /z 473 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 8 7.68 (d, 2H), 7.46-7.50 (m, 3H), 7.36 (d, 1H), 7.29 (dd, 1H), 1H), 6.83 (s, 1H), 3.73 (br s, 2H), 3.47 (br s, 6H), 2.81 (s, 2H), 1.62-1.70 (m , 10H), 0.93 (t, 6H).
- Example 127
DO y HO OE and ON NH>zione (1E,4E)-2-amino-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N N-dipropyl-3H-benzo[b ]azepine-4-carboxamide Step A: Preparation of (R)-1-benzyl-3-(tert-butyldimethylsilyloxy)pyrrolidine: The title compound was prepared by the procedure as described in Example 112 (Step A), using the (R)-1-benzylpyrrolidin-3-ol. .: Step B: Preparation of (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine: The title compound was prepared by the procedure as described in E-"Example 112 (Step B), using (R)-1-benzyl -3-(tert-butyldimethylsilyloxy)pyrrolidine Step C: Preparation of (R)-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-iN)(4-(4,4,5,5-tetramethyl-1,3) ,2-dioxaborolan-2-yl)phenyl)methanone: The title compound was prepared by the procedure as described in Example 101 (Step H), using 4-(4,4,5,5-tetramethyl-1,3 acid ,2-dioxaborolan-2-yl)benzoic acid and (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine Step D: Preparation of (1E,4E)-8-(4-((R)-3-(tert) - tert-butyl butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzolbjlazepin-2-ylcarbamate: The title compound was prepared by the procedure as described in Example 124 (Step F), using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate — and (R)(3-(tert-butyldimethylsilyloxy)pyrrolidin-1 -i1 )(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanone. MS APCI (+) m/z 689 (M+1) detected. Step E: Preparation of (1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate from tert-butyl: To a solution of (1E,4E)-8-(4-((R)-3-(tert-
. tert-butyl butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzolb]azepin-2-ylcarbamate (225 mg, 0.327 mmol) in THF (4 mL) at 0 °C was added a solution of TBAF (0.34 mL, 0.34 mmol, 1 M solution in THF). The resulting mixture was warmed to room temperature: 5 °C and stirred for 1.5 h. The reaction mixture was diluted with EtOAc and washed with brine (2x). The organic layer was dried over MgSO4 , filtered, and concentrated under reduced pressure to give (16E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1 Crude tert-butyl -carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate, which was used directly without further purification. MS APCI (+) m/z 575 (M+1) detected. Step F: Preparation of (1E6E,4E)2-amino-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N N-dipropyl-8H-benzo[b]azepine-4- - carboxamide: The title compound was prepared by the procedure as described in Example 101 (Step 1), using (1E,4E)-4-(dipropylcarbamoyl)-8-(4((R)-3-hydroxypyrrolidine- 1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate. of tert-butyl. MS APCI (+) m/z 475 (M+1) detected; 1 H-NMR (400 MHz, CDCl3 ) d 7.53-7.65 (m, 5H), 7.33-7.38 (m, 2H), 6.84 (s, 1H), 4.60 ( br s, 0.5H), 4.47 (br s, 0.5H), 3.45-3.83 (m, 8H), 2.92 (s, 2H), 1.99-2.12 ( m, 2H), 1.62-1.71 (m, 4H), 0.93 (t, 6H). Example 128 "
NO o OO 5 ado o (1E,4E)-2-amino-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N N-dipropyl-3H-benzo[b]azepine- 4-carboxamide The title compound was prepared by the procedures as described in Example 127, using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]lazepin-2-ylcarbamate and (S)-1-benzylpyrrolidin-3-ol. MS APCI (+) m/z 475 (M+1) detected; 1 H-NMR (400 MHz, CDCl3 ) d 7.53-7.66 (m, 5H), 7.32-7.38 (m, 2H), 6.84 (s, 1H), 4.60 ( br s, 0.5H), 4.47 (br s,
0.5H), 3.46-3.84 (m, 8H), 2.88 (s, 2H), 1.99-2.11 (m, 2H), 1.62-1.71 (m, 4H), δ 0.93 (t, 6H). Examples 129 and 130 below were prepared by the procedures as described in Example 124 (Step F) and Example 101 (Step ) using (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H - tert-butyl β-benzol[bJazepin-2-ylcarbamate and α((38,4S)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3- diioxolan-2-yl)phenyl)methanone or ((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-diloxolan-2- yl)phenyl)]methanone. Example 129 the
NO HO O E | (ON NH2 ooh (1E,4E)-2-amino-8-(4-((3S,4S)-3,4-dihydroxypyrrolidine-1-E carbonyl)phenyl)-N N-dipropyl-3H-benzo[ b]azepine-4-carboxamide Step A: Preparation of (3S,4S)-pyrrolidine-3,4-diol: The title compound was prepared by the procedure as described in Example 112 (StepB), using the (3S,4S) )-1-benzylpyrrolidine-3,4-diol.
Step B: Preparation of ((3S,4S)-3,4-dihydroxypyrrolidin-1-i)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-i)phenyl) methanone: The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-it)benzoic acid and (3S,4S)-pyrrolidine-3,4-diol.
Etahaa C: Preparation of tert-butyl (1IE4E)8(4((38848)34-dihydroxypyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate: The compound of the title was prepared by the procedure as described in Example 124 (Step F), using tert. -butyl and ((38S,4S)-3,4-dihydroxypyrrolidin-1-i)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iNpheni)methanone. APCI (+) m/z 591 (M+1) detected Step D: Preparation of (1E,4E)-2-amino-8-(4-((38,48)-3,4-
dihydroxypyrrolidine-1-carbonyl)phenyl)-N N-dipropyl-3H-benzo[b]azepine-4-Is carboxamide: The title compound was prepared by the procedure as described in Example 109 (Step C), using (16, 4E)-8-(4-((3S8,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate tert-butyl : MS APCI (+) m/z 491 (M+1) detected; 1 H-NMR E (400 MHz, CDC) d 7.65 (d, 2H), 7.57 (d, 2H), 7.47 (s, 1H), 7.34 (d, 1H), 7. 27-7.29 (m, 1H), 6.82 (s, 1H), 4.28 (s, 1H), 4.18 (s, 1H), 3.97-4.00 (m, 1H) , 3.85-3.87 (m, 1H), 3.66 (d, 1H), 3.46 (br s, 5H), 2.81 (s, 2H), 1.62-1.71 ( m, 4H), 0.93 (t, 6H). Example 130
SD Ho O É no O oeo A (1E,4E)-2-amino-8-(4-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-N N-dipropyl-8H -benzo[b]azepine-4-carboxamide The title compound was prepared by the procedures as described in Example 129, using (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzol[b]azepin- 2-ylcabamate — from tert-butyl and (3R4AR)1-benzylpyrrolidine-3,4-diol. MS APCI (+) m/z 491 (M+1) detected; 1 H-NMR (400 MHz, CDC) d 7.62 (d, 2H), 7.54 (d, 2H), 7.45 (s, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.80 (s, 1H), 4.25 (s, 1H), 4.14 (s, 1H), 3.94-3.96 (m, 1H), 3.81- 3.83(m, 1H), 3.63 (d, 1H), 3.44 (br s, 5H), 2.79 (s, 2H), 1.62-1.68 (m, 4H), 0.92 (t, 6H). Example 133 Q “ | Sn | The. no NH>
N (1E,4E)-2-amino-N N-dipropyl-8-(pyridin-3-yl)-SH-benzo[b]azepine-4-carboxamide
: MS APCI (+) m/z 363 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 5 8.91 (d, 1H), 8.59 (dd, 1H), 7.94 (dt, 1H), 7.49 (d, 1H), 7 .35-7.40 (m, 2H), 7.29 (dd, 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.81 (s, 2H), 1 .63-1.72 (m, -4H), 0.94 (m, -6H). “ 5 Example134
SA Ds TS Se (1E,4E)-2-amino-N N-dipropyl-8-(pyridin-4-yl)-3H-benzo[b]azepine-4-carboxamide MS APCI (-) m/z 361 ( M-1) detected; 1 H-NMR (400 MHz, CD-E 10 Cl) 38.66 (d, 2H), 7.55-7.57 (m, 3H), 7.39 (d, 1H), 7.33 (dd , 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.81 (s, 2H), 1.63-1.72 (m, 4H), 0.94 (m , 6H). D Example 135 | NH, (1E,4E)-2-amino-N N-dipropyl-8-(pyrimidin-5-yl)-3H-benzo[blazepine-4-carboxamide] Step A: Preparation of (11E,4E )-2-amino-8-bromo-N N-dipropyl-3H-benzo[b]azepine-4-carboxamide: The title compound was prepared by the procedures as described in Example 101 (Step |), using the ( 1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate - tert-butyl. MS APCI (+) m/z 364.366 (M+1, Br standard) detected Step B: Preparation of (1E,4E)-2-amino-N N-dipropyl-8-(pyrimidin-5-yl)- 3H-benzo[b]azepine-4-carboxamide: The title compound was prepared by the procedure as described in Example 124 (Step F), using (16,4E)-2-amino-8-bromo-N, N-dipropyl-3H-benzo[b]azepine-4-carboxamide, pyrimidin-S-ylboronic acid, and sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate in H2O-MeCN. MS APCI (+) m/z 364
: (M+1) detected; 1H-NMR (400 MHz, CDCIs) d 9.21 (s, 1H), 9.01 (s, 2H), 7.50 (s, 1H), 7.43 (d, 1H), 7.27- 7.29 (m, 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.84 (s, 2H), 1.63-1.72 (m, 4H), 0.94 (t, 6H). S Example 136 o : NO of NC. OO# NH2 (1E,4E)-2-amino-8-(3-cyanophenyl)-N N-dipropyl-3H-benzol[b]azepine-4-carboxamide The title compound was prepared by the procedure as described in Example 124 (Step F), using (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]lazepine-4-carboxamide and 3-cyanophenylboronic acid. It is MS APCI (+) m/z 387 (M+1) detected; 1H-NMR (400 MHz, CDCl3 ) d 7.91 Å (m, 1H), 7.87-7.89 (m, 1H), 7.63-7.65 (m, 1H), 7.55 ( t, 1H), 7.51 (br s, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 6.85 (s, 1H), 3.46 (br s, 4H ), 2.90 (s, 2H), 1.62, 1.72 (m, 4H), 0.94 (t, 6H). Examples 137 and 138 below were prepared by the procedures as described in Example 136, using (1E,4E)-2-amino-8-bromo-N N-dipropyl-3H-benzo[b]azepine-4- carboxamide and 4-cyanophenylboronic acid or 3-(dimethylcarbamoyl)phenylboronic acid. Example 137 what ca
NC (1E,4E)-2-amino-8-(4-cyanophenyl)-N N-dipropyl-3H-benzo[b]azepine-4-carboxamide MS APCI (+) m/z 387 (M+1) detected ; 1H-NMR (400 MHz, CD-Cla) 8 7.71-7.76 (m, 4H), 7.52 (s, 1H), 7.39 (d, 1H), 7.31 (d, 1H ), 6.84 (s, 1H), 3.46(brs,4H), 2.86(s,2H), 1.62-1.72 (m, 4H), 0.93 (t, 6H) . Example 138
It is SA or OO Ex. h = tt (1E,4E)-2-amino-8-(3-(dimethylcarbamoyl)phenyl)-N,N-dipropyl-3H-1-benzol[b]Jazepine-4-carboxamide MS APCI (+) m/z 433 (M+1) detected; 1H-NMR (400 MHz, CD-Cl2) δ 7.68-7.69 (m, 2H), 7.54 (br s, 1H), 7.46-7.50 (m, 1H), 7. 40-7.42 (m, 1H), 7.37 (s, 2H), 6.85 (s, 1H), 3.46 (br s, 4H), 3.14 (br s, 3H), 3 .03 (br s, 3H), 2.92 (s, 2H), 1.62-1.71 (m, 4H), 0.93 (t, 6H). Example 139 O. o am GS Cl : Eto.
NH H o : 10 Ethyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-iN)benzoate The title compound was prepared by the procedures as described in Example 124 (Step F) and Example 101 (Step I), using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate - and 4-(ethoxycarbonyl)phenylboronic acid.
MS APCI (+) m/z 434 (M+1) detected; 1H-NMR (400 MHz, CDCl3 ) 8.11 (d, 2H), 7.72 (d, 2H), 7.54 (d, 1H), 7.38 (d, 1H), 7.34 ( dd, 1H), 6.84 (s, 1H), 4.40 (q, 2H), 3.47 (br s, 4H), 2.83 (s, 2H), 1.62-1.72 ( m, 4H), 1.42 (t, 3H), 0.94 (t, 6H). Example 141 "OEt E and 2N NH2 2-amino-8-(pyridin-2-yl)-3H-benzo[b]Jazepine-4-carboxylate (1E 4E)-ethyl Step A: Preparation of 2-nitro-4 -(4,4,5,5-tetramethyl-1,3,2-
. dioxaborolan-2-yl)benzaldehyde: The title compound was prepared by the procedure as described in Example 124 (Step F), using 4-bromo-2-nitrobenzaldehyde, bis(pinacolato)diboron, o'tris(dibenzylidineacetone) )dipalladium(O0), the PCy3, and the KOAc in dioxane (reflux.
Step B: Preparation of 2-nitro-4-(pyridin-2-i)benzaldehyde: The title compound was prepared by the procedure as described in Example 101 (Step C), using 2-nitro-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 2-bromopyridine in dioxane (reflux).
Step C: Preparation of (E)-Ethyl 2-(cyanomethyl)-3-(2-nitro-4-(pyridin-2-iNphenynacrylate): The title compound was prepared by the procedure as described in Example 101 (Step D), using 2-nitro-4-(pyridin-"2-i)benzaldehyde and α-cyanomethylcarboethoxyethylidene triphenylphosphorane.
. Step D: Preparation of (11E,4E)-ethyl 2-amino-8-(pyridin-2-yl)-3H-3H-benzolblazepine-4-carboxylate: The title compound was prepared by the procedure as described in Example 101 (Step E), using (E)-ethyl 2-(cyanomethyl)-3-(2-nitro-4-(pyridin-2-yl)phenyl)acrylate. MS APCI (+) m/z 308 (M+1) detected; 1 H-NMR (400 MHz, CDCl3 ) δ 8.70 (d, 1H), 7.85 (s, 1H), 7.73-7.81 (m, 4H), 7.50 (d, 1H) , 7.23-7.26 (m, 1H), 4.32 (q, 2H), 2.98 (s, 2H) 1.38(t 3H) Examples 142 and 143 below were prepared by the following procedures. ingredients as described in Example 101 (Steps C, D, and E), using 4-bromo-2-nitrobenzaldehyde and pyridine-3-ylboronic acid or pyridine-4-ylboronic acid.
Example142 : = OEt | is NH2 Node
N 2-amino-8-(pyridin-3-yl)-3H-benzo[bJazepine-4-carboxylate MS APCI (+) m/z 308 (M+1) detected; 1 H NMR (400 MHz, de-
"DMSO) 5 8.92 (s, 1H), 8.58 (d, 1H), 8.11 (d, 1H), 7.80 (2, 1H), 7.58 (d, 1H), 7 .49 (dd, 1H), 7.36-7.38 (m, 2H), 4.26 (q, 2H), 2.98 (s, 2H), 1.32 (t, 3H) Example 143 and (1E 4E)-ethyl MS APCI 3H-benzo[b]azepine-4-carboxylate (>NAN NH, 2-amino-8-(pyridin-4-yl)-3H-benzo[b]azepine-4-carboxylate (+) m/z 308 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 8.66-8.68 (m, 2H), 7.84 (s, 1H), 7.49-7.57 ( m, 4H), 7.36 (dd, 1H), 4.33 (q, 2H), 2.99 (s, 2H), 1.39 (t, 3H)."i 10 Example 144
The E OEt
NOS F f [> to NH
N 2-amino-8-(pyrimidin-5-yl)-8H-benzo[b]Jazepine4-carboxylate — from (1E 4E)-ethyl The title compound was prepared by the procedure as described in Example 124 (Step F), using (1E,4E)-ethyl 2-amino-8-bromo-3H-benzol[b]azepine-4-carboxylate and pyrimidin-5-ylboronic acid. MS APCI (+) m/z 309 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl3 ) 8 9.22 (s, 1H), 9.02 (s, 2H), 7.84 (s, 1H), 7.54 (d, 1H), 7 .47 (d, 1H), 7.30 (dd, 1H), 4.34 (q, 2H), 2.99(s, 2H), 1.40 (t, 3H). Example 145
what age No
ACE (1E,4E)-ethyl 2-amino-8-(3-cyanophenyl)-3H-benzo[b]Jazepine-4-carboxylate
, Step A: Preparation of (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate: A mixture of 8-bromo-2 (1E,4E)-ethyl -(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate, 3-cyanophenylboronic acid (1.47 g, 10 mmol), CsF (2.28.5 g 15mmol), and PAd(PPh3)a (0.345 g, 0.3 mmol), in anhydrous THF (100 mL), was refluxed for 12 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography over silica gel to provide 1.12 g (52%) (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate. f Step B: Preparation of 2-amino-8-(3-cyanophenyl)-3H-. (1E,4E)-ethyl benzol[b]lazepine-4-carboxylate: The title compound was prepared by the procedure as described in Example 101 (Step I), using 2-(tert-butoxycarbonylamino) (1E,4E)-ethyl -8-(3-cyanophenyl)-3H-benzo[b]lazepine-4-carboxylate. MS APCI (+) m/z 332 (M+1) detected; 1 H-NMR (400 MHz, ds-DMSO) 8.17 (s, 1H), 8.04-8.06 (m, 1H), 7.82-7.84 (m, 1H), 7. 78 (s, 1H), 7.67 (t, 1H), 7.54 (d, 1H), 7.33-7.37 (m, 2H), 6.93 (s, 2H), 4.25 (q 2H) 2.92 (s,2H),1.31(t 3H) Examples 146 and 147 below were prepared by the procedures as described in Example 145. In the case of example 146, Cs2CO; it was used as a base for the Suzuki docking. Example 146 Erica to
NC 2-amino-8-(4-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate — from (1E 4E)-ethyl MS APCI (+) m/z 332 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 8 7.83 (s, 1H), 7.72-7.77 (m, 4H), 7.49 (d, 1H), 7.47 (d, 1H), 1H), 7.30 (dd,
. 1H), 4.33 (q, 2H), 2.98 (s, 2H), 1.39 (t, 3H). Example 147 (11,4E)-ethyl 2-amino-8-(3-(dimethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate MS APCI (+) m /z 378 (M+1) detected; 1 H-NMR (400 MHz, CD-Cla) 5 7.83 (s, 1H), 7.69-7.71 (m, 2H), 7.45-7.50 (m, 3H), 7. 40-7.42 (m, 1H), 7.32 (dd, 1H), 4.32 (q, 2H), 3.14 (br s, 3H), 3.02 (br s, 3H), 2 .98 (s, 2H), 1.39 (t, 3H). Examples 154, 155, and 156 below were prepared by the procedures as described in Example 101 (Steps C, D, and E), using 4-bromo-2-nitrobenzaldehyde and the appropriate boronic acids. Example 154 » OEt ! (OO No. NH. N 2 o (11,4E)-ethyl 2-amino-8-(4-(dimethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate MS APCI (+) m/z 378 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 8 7.84 (s, 1H), 7.69 (d, 2H), 7.46-7.51 (m, 4H ), 7.32 (dd, 1H), 4.32 (q, 2H), 3.14 (br s, 3H), 3.05 (br s, 3H), 2.98 (s, 2H), 1 .39 (t, 3H). Example 155 "OEt
IF ON NH 2-amino-8-(4-(diethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-
. (1E,4E)-ethyl carboxylate MS APCI (+) m/z 406 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 5 7.84 (s, 1H), 7.68 (d, 2H), 7.44-7.49 (m, 4H), 7.32 (dd, 1H), 4.33 (q, at 2H), 3.57 (br s, 2H), 3.33 (br s, 2H), 2.98 (s, 2H), 1.39 (t, 3H) , 1.25 (brs, 3H), : 5 1/17 (brs, 3H). Example 156 Q SD OEt O GO " NH o 2-amino-8-(4-(piperidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-;(1E,4E)-ethyl carboxylate MS APCI (+) m/z 418 (M+1) detected; 1 H-NMR (400 MHz, CD-E Cla) 8 7.84 (s, 1H), 7.68 (d, 2H), 7.46 -7.48 (m, 4H), 7.32 (dd, 1H), 4.33 (α, 2H), 3.73 (br s, 2H), 3.42 (br s, 2H), 2, 98 (s, 2H), 1.62-1.70 (m, 6H), 1.39 (t, IS 3H) Example 174 o IO
no salt
OC GG O Hei N°He (1E,4E)-2-amino-N-(2-hydroxybenzyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b] hydrochloride ]azepine-4-carboxamide Step A: Preparation of methyl 2-hydroxybenzoate: To a solution of 2-hydroxybenzoic acid (110 g, 796 mmol) in MeOH (400 mL) was bubbled HC! (gas), for 1 h. The resulting mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude methyl 2-hydroxybenzoate, which was used directly without further purification. Step B: Preparation of 2-hydroxy-N-propylbenzamide: O 2-
- crude methyl hydroxybenzoate was dissolved in n-propylamine (400 ml). The reaction mixture in a sealed reactor was stirred at 80°C overnight. The reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography on silica gel to provide 120 g (84%) of the 2-hydroxy-N-propylbenzamide. LCMS ESI (+) m/z 180 (M+1) detected. Step C: Preparation of tert-butyl 2-hydroxybenzyl(propyl)carbamate: To a solution of LiAlH, (35 g, 0.92 mol) in THF (500 mL) at 0°C was added 2-hydroxy-N -propylbenzamide (66 g, 0.37 mol) in THF 10 . (200 ml) dropwise. The reaction mixture was heated at 80°C overnight. The reaction mixture was quenched by addition of HO (300 mL) at 0 °C. Then, the Boc 2 O (96.5 g, 0.44 mol) in THF (200 mL) was added dropwise. After stirring 5 h, the NaHCO; here sat. (200 mL) was added. the layer. aqueous solution was separated and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over MgSO4 , filtered, and concentrated - under reduced pressure, to give the crude material, which was purified by flash column chromatography over silica gel to provide 89 g (91%) of tert-butyl 2-hydroxybenzyl(propyl)carbamate.
Step D: Preparation of 2-((propylamino)methyl)phenol hydrochloride: A solution of tert-butyl 2-hydroxybenzyl(propyl)carbamate (899, 0.34 mol) in MeOH (400 mL) was bubbled with gas. HCI. After stirring for 5 h at room temperature, the reaction mixture was concentrated under reduced pressure to provide 61 g (90%) of the 2-((propylamino)methyl)phenol as the HCl salt.
Step E: Preparation of (1E,4E)-4-((2-hydroxybenzyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carboniN)phenyl)-3H-benzolb]azepin-2-ylcarbamate from tert-butyl: The title compound was prepared by the procedure as described in Example 101 (Step H), using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1) acid -carbonyl)phenyl)-3H-benzo[blazepine-4-carboxylic acid and 2-((propylamino)methyl)phenol hydrochloride.
Step F: Preparation of (11E,4E)-2-amino-N-(2-
: hydroxybenzyl)-N-propyl-8-(4-(pyrrolidine-1-carboniD)phenyl)-3H-benzo[b]azepine-4-carboxamide: A solution of (1E,4E)-4-((2- Crude tert-butyl hydroxybenzyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate in anhydrous CH 2 Cl 7 (15 mL) R 5 was bubbled through with HCI (gas) for 4 h at 0 °C. The resulting mixture was warmed to room temperature and stirred until the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by silica gel flash column chromatography (EtOAc) to give (11,4E)-2-amino-N-(2-hydroxybenzyl) - —N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide with hydrochloride salt. MS APCI (+) m/z 523 (M+1) detected; 1H-NMR (400 MHz, ds-DMSO) 3 9.68 (br s, 1H), 7.76 (d, 2H), 7.64 (d, 2H), 7.59 (br s, 3H), . 7.10-7.14 (m, 2H), 7.03 (br s, 1H), 6.80-6.87 (m, 2H), 4.62 (br s, 2H), 3.44- . 3.49 (m, 6H), 3.19 (br s, 2H), 1.83-1.89 (m, 4H), 1.56-1.57 (m, 2H), 0.77-0 .83: 15. (m,3H).
and The following example, 176, was prepared by the procedures as described in Example 101 (Step H) and Example 178 (Step C) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-( 4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and N-(2-(propylamino)ethyl)methanesulfonamide or 3-(propylamino)propane-1-sulfonamide. Example 176 "Ne and
The Cl is (1E,4E)-2-amino-N-(2-(methylsulfonamido)ethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H- benzo[b]azepine-4-carboxamide MS APCI (+) m/z 538 (M+1) detected; 1 H-NMR (400 MHz, CD-Cl) 8 7.67 (d, 2H), 7.60 (d, 2H), 7.47 (s, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 6.86 (s, 1H), 3.66-3.69 ( m, 4H), 3.51 (t, 2H), 3.42 (t, 4H), 2.90 (s, 5H), 1.89-
It is 2.00 (m, 4H), 1.60-1.68 (m, 2H), 0.87 (t, 3H). Example 178 oo: O — Qi 2 GG O t NH 2 o (1E,4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine- 1-carbonylphenyl)-3H-benzo[blazepine-4-carboxamide Step A: Preparation of 2-(propylamino)acetamide hydrochloride: To a solution of propan-1-amine (236 g, 3.99 mmol) in acetonitrile (100 mL) at 0 °C, a solution of 2-chloroacetamide (93.6 g, 1.00 mmol) in acetonitrile (1500 mL) was added over 3 h. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by recrystallization (MeOH and CH2Ch2) to give 80 gf (69%) of the 2-(propylamino)acetamide as HCl salt LCMS ES1 (+) m/z 117 (M+1) detected.
Step B: Preparation of (1E,4E)-4-((2-amino-2-oxoethyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzolb]azepin- tert-Butyl 2-ylcarbamate: The title compound was prepared by the procedures as described in Example 101 (Step H), using (1E,4E)2-(tert-butoxycarbonylamino)-8-(4 -(pyrrolidine-1-carbonyl)phenyl)-38H-benzo[blazepine-4-carboxylic acid and 2-(propylamino)acetamide hydrochloride.
Step C: Preparation of (11,4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[ b]azepine-4-carboxamide: A solution of (1E,4E)-4-((2-amino-2- -oxoethyl(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)- Crude tert-butyl 3H-benzolb]azepin-2-ylcarbamate in anhydrous CH2Cl7 (15 mL) was bubbled through with HCl (gas) for 4 h at 0° C. The resulting mixture was warmed to room temperature and stirred until the reaction was complete.
full.
To this mixture was added NaHCO; saturated at 0°C.
The aqueous layer was separated and extracted with CH2Clz.
The combined organic layers were dried over Na>SO4, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography over silica gel (MEOH:CH2Cl, = 1:50 ), to provide 225 mg (45%) of (1E 4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl) -3H-benzo[b]azepine-4-carboxamide.
MS APCI (+) m/z 474 (M+1) detected; 1H-NMR (400 MHz, CDCl3 ) d 7.67 (d, 2H), 7.60 (d, 2H), 7.50 (br s, 1H), 7.30-7.36 (m, 2H) , 6.93 (s, 1H), 4.11 (s, 2H), 3.67 (t 2H) 3.58 (brs, 2H), 3.50 (t, 2H), 2.87 (s, 2H), 1.89-2.00 (m, 4H), 1.69-1.74 (m, 2H), 0.93 (t, 3H). Example 182 R = Xeon - ro Os CC O N NH (1E,4E)-2-amino-N-(3-hydroxypropyl)-8-(4-((S)-3-hydroxypyrrolidine--1-carboniphenyl)-N-propyl-3H-benzo[bJazepine-4] -carboxamide Step A Preparation of tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate : The title compound was prepared by the procedure as described in Example 101 (Step H), using (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]lazepine4-carboxylic acid —and 3-(terrobutyldimethylsilyloxy)-N-propylpropan-1-amine.
MS APCI (+) m/z 594, 596 (M+1, Br pattern) detected.
Step B: Preparation of (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-((S)-3-hydroxypyrrolidine-1--(carbonylYphenyl)) tert-Butyl -3H-benzo[blazepin-2-ylcarbamate: The title compound was prepared by the procedure as described in Example 124 (Step PF), using (1E,4E)-8-bromo-4-((3 tert-butyl -(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (S)-(S-hydroxypyrrolidin-1-yl)(4-(4) ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, which was prepared by the procedure as described in Example 101 (Step H), using 4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (S)-pyrrolidin-3-01. MS APCI (+) m/z 705 (M+1) detected. Step C: Preparation of (116,4E)-2-amino-N-(3-hydroxypropyl)-8-4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N-propyl-38H-benzo [b]azepine-4-carboxamide: The title compound was prepared by the procedure as described in Example 109 (Step C), using (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl )carbamoyl)-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-8H-benzo[b]azepin-2-ylcarbamate tert-butyl. MS APCI (+) m/z 491 (M+1) detected; 1 H-NMR (400 MHz, CDC) d 7.59-7.66 (m, 4H), 7.50 (s, 1H), 7.386 (d, 1H), 7.31 (d, 1H), 6 .88 (s, 1H), 4.61 (br s, 0.5H), 4.48 (br s, 0.5H), 3.75-3.84 (m, 2H), 3.62-3 .70 (m, 6H), 3.46-3.50 (m, 2H), 2.84 (s,
15. 2H), 1.96-2.15(m, 4H), 1.82-1.87 (m, 2H), 1.65-1.72 (m, 2H), 0.93 (t, 3H). Example 186 q
N OH CG -s | STEEL, NH, 3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzol[b]azepin-8-yl)benzoic acid Step AO 3((1E4E)-2-amino4-( Benzyl dipropylcarbamoyl)-3H-benzol[b]azepin-8-yl)benzoate (52%) was prepared according to Example 206, Step B, substituting 3-(benzyloxycarbonyl) for 4-(methoxycarbonyl)phenylboronic acid. phenylboronic. m/z (APCI-pos) M+1 = 496.2. Step B: 3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzolblazepin-8-i)benzoic acid (61%) was prepared according to Example 188, Step B, substituting Benzyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzol[b]azepin-8-yl)benzoate by S3-((1E,4E)-2-amino-4 - benzyl (dipropylcarbamoyl)-8H-benzo[b]azepin-8-yl)benzoate. 1 H NMR (400 MHz, DMSO-ds) δ 8.37-8.42 (m, 1H), 8.00-8.06 (m, 1H), 7.81-7.87 (m, 1H),
b 1H), 7.68-7.73 (m, 1H), 7.51-7.63 (m, 3H), 6.96 (s, 1H), 3.51 (s, 2H), 3, 15-3.41 (m, 4H, partially hidden by water peak), 1.53-1.68 (m, 4H), 0.75-0.94 (m, 6H); m/z (APCI-pos) M+1 = 406.2. i Example 187 THE QA
3-((1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-ibenzoate Ethyl 3-((1E,4E)-2-Amino-4-(dipropylcarbamoyl) Ethyl -3H-benzol[b]azepin-8-yl)benzoate (45%) was prepared according to Example 206, Step B, substituting 3-(methoxycarbonyl) for 4-(methoxycarbonyl)phenylboronic acid W. )phenylboronic acid *H NMR (400 MHz, CDCl3 ) 5 8.34 E -8.37 (m, 1H), 8.02 — 8.05 (m, 1H), 7.82 — 7.86 (m, 1H), 1H), 7.49 — 7.55 (m, 2H), - 7.33 — 7.39 (m, 2H), 6.84 (s, 1H), 5.17 (br s, 1H), 4 .37 - 4.45 (m, 2H), 3.36 - 3.55 (m, 4H), 2.84 (s, 2H), 1.62 - 1.72 (m, 4H), 1.38 — 1.45 (m, 3H), 0.89 — 0.98 (m, 6H); m/z (APCI-pos) M+1 = 434.3 Example 188 q Sn Ness 4-(( 1E ,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoic Etaphaa AO 4((1E4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzol[ b]Benzyl jazepin-8-yl)benzoate (31%) was prepared according to Example 206, Step B, substituting 4-(benzyloxycarbonyl) for 4-(methoxycarbonyl)phenylboronic acid. )phenylboronic acid. m/z (APCI-pos) M+1 = 496.2. Step B Benzyl 4((1E4E)-2-amino-4-(dipropylcarbamoyl)-3H- —benzolblazepin-8-yl)benzoate (0.025 g, 0.0504 mmol) was suspended
. in 1 ml of methanol, and 25 mg of 10% Pd/C (Degussa type) were added and the mixture was hydrogenated under a balloon of hydrogen for one hour.
This mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to 16 mg of 4-((11E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzolblazepin-acid. 8&yl)benzoic acid (78%). 1 H NMR (400 MHz, DMSO-ds) δ 7.98-8.03 (m, 2H), 7.76-7.82 (m, 2H), 7.38-7.43 (m, 1H ), 7.33-7.37 (m, 1H), 7.27-7.31 (m, 1H), 6.92 (br s, 1H), 6.76 (s, 1H), 3.28 -3.36 (m, 4H, partially hidden by water peak), 2.74 (s, 2H), 1.51-1.62 (m, 4H), 0.71-0.97 (m , 6H); m/z (APCI-pos) M+1 = 406.2. Example 190 Z/ToH = * In NH, : : 4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8 -yl) ethyl benzoate Step A: 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[ Ethyl b]azepin-8-yl)benzoate (44%) was prepared according to Example 206, Step B, replacing (1E,4E)-2-amino-8-bromo-N,N-dipropyl -3SH-benzo[b]azepine-4-carboxamide by (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin- tert-butyl 2-ylcarbamate and 4-(methoxycarbonyl)phenylboronic acid for 4-(ethoxycarbonyl)phenylboronic acid. m/z (APCI-pos) M+1 = 664.0 Step B: 4-((11E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)( Ethyl propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture stirred vigorously for 15 minutes.
This mixture was then diluted with
. water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2 x 0.5 mm plates, 10% MeOH/DCM/0.5% .NH 2 OH) provided 0.012 g (35%) of the 4((1E,4E)-2 ethyl -amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. ' H NMR (400 MHz, CDCl3 ) δ 8.08-8.14 (m, 2H), 7.69-7.74 (m, 2H), 7.52-7.55 (m, 1H), 7.32-7.40 (m, 2H), 6.89 (s, 1H), 4.35-4.44 (m, 2H), 3.58-3.71 (m, 5H), 3. 45-3.53 (m, 2H), 2.85 (s, 2H), 1.81-1.88 (m, 2H), 1.64-1.77 (m, 2H), 1.36- 1.44 (m, 3H), 0.90-0.97 (m, 3H); m/z (APCI-pos) M+1 = 450.2. Example 194 q
At the. the NH>2 | (1E,4E)-2-amino-8-(3-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]Jazepine-4-carboxamide Step A: (1E,4E)-2-amino- 8-(3-hydroxyphenyl)-N,N-dipropyl-38H-benzolblazepine-4-carboxamide (39%) was prepared according to Example 206, Step B, substituting 4-(methoxycarbonyl)phenylboronic acid for 3-hydroxyphenylboronic acid. *H NMR (400 MHz, CDCI; 3) 5 7.59-7.64 (m, 1H), 7.24-7.38 (m, 4H), 7.08-7.14 (m, 1H) , 6.81-6.86 (m, 2H), 5.10 (br s, 2H), 3.35-3.35 (m, 4H), 2.86 (s, 2H), 1.58- 1.71 (m, 4H), 0.80-0.98 (m, 6H); m/z (APCI-pos) M+1=378.2. Example 195 q Ãs e. Ho (1E,4E)-2-amino-8-(4-hydroxyphenyl)-N N-dipropyl-3H-benzo[b]azepine-4-carboxamide Step A: (1E,4E)-8-bromo-4 tert-Butyl -(dipropylcarbamoyl)-3H-benzo[b]jazepin-2-ylcarbamate (0.095 g, 0.205 mmol), 4-
' hydroxyphenylboronic acid (0.040 g, 0.286 mmol), Pd(OAc)> (0.0045 g, 0.020 mmol), 4,4'-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate (0.022 g, 0.041 mmol), the solution of 2M sodium carbonate (0.307 ml, i 0.614 mmol) were combined in 2 mil of ethanol and this mixture was purged -5 with Argon for 5 minutes and then heated to 65°C under argon for 1.5 hours. The mixture was then diluted with citric acid, extracted with EtOAc (2X), the extracts washed with saturated sodium carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. Flash 40 Biotage (408 cartridge, 30% EtoAc/Hexane) provided 0.040 g of tert. butyl (41%). m/z (APCI-pos) M+1 = 478.0. Step B: Tert-butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-'benzolb]azepin-2-ylcarbamate (0.040 g, 0.084 mmol) was dissolved. in 1 ml of dichloromethane. 0.5 ml of TFA was then added and the mixture was stirred at room temperature for one hour. The reaction was then terminated by the addition of saturated sodium bicarbonate solution and stirred for 15 minutes, then extracted twice with dichloromethane, the extracts dried over sodium sulfate and concentrated. Preparative thin layer chromatography (0.5 mm plate, 7% MeOH/DCM) provided 6 mg (19%) of (1E,4E)-2-amino-8-(4-hydroxyphenyl)-N N- dipropyl-3H-benzo[b]azepine-4-carboxamide as a yellow solid. H NMR (400 MHz, CDCl3 ) 5 7.47-7.53 (m, 2H), 7.41-7.44 (m, 1H), 7.30-7.33 (m, 1H), 6, 88-6.93 (m, 2H), 6.83 (s, 2H), 3.42-3.54 (m, 4H), 2.81 (s, 2H), 1.61-1.72 ( m, 4H), 0.89-0.97 (m, 6H); m/z (APCI-pos) M+1 = 378.2. Example 202 FAN No
AQ GQ O" NH, iso (1E,4E)-2-Amino-N-(3-fluoropropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b ]azepine-4-carboxamide f Step A: O (1E,4E)4-((3-fluoropropyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b tert-Butyl]azepin-2-ylcarbamate (19%) was prepared according to Example 208, Step D, substituting (1E,4E)-8-Bromo-2-(tert-butoxycarbonylamino)-3H-acid benzo[b]azepine-4-carboxylic acid by (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]lazepine- 4-carboxylic m/z (APCI-pos) M+1 = 577.0 Step BA (1E4E)-2-amino-N-(3-fluoropropyl)-N-propyl-8-(4-(pyrrolidine- 1-carbonyl)phenyl)-3H-benzo[b]azepine4-carboxamide (45%) was prepared according to Example 208, Step F, substituting 4-((1E,4E)-2-(tert-butoxycarbonylamino) Ethyl -4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate for (1E,4E)-4-((3-.fluoropropyl)(propyl)carbamoyl )-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-"benzol tert-butyl [b]azepin-2-ylcarbamate. 1H NMR (400 MHz, DMSO-ds) 5 . 15. 7.70-7.76 (m, 2H), 7.57-7.64 (m, 2H), 7.36-7.42 (m, 1H), 7.24-7.34 (m , 2H), - 6.78-6.84 (m, 3H), 4.40-4.61 (m, 2H), 3.43-3.52 (m, 6H), 2.75 (s, 2H), 1.79-1.96 (m, 6H), 1.53-1.63 (m, 2H), 0.79-0.90 (m, 3H); m/z (APCI-pos) M+1 = 477.8. Example 203 q A
AS O N NH Ethyl 2-((1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-iNbenzoate Step AO 2((1E4E)-2-amino-4-(dipropylcarbamoyl)- Ethyl 3H-benzol[b]azepin-8-yl)benzoate (24%) was prepared according to Example 206, Step B, substituting 2-(methoxycarbonyl)phenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid. *H (400 MHz, CDCl3 ) at 7.83-7.86 (m, 1H), 7.49-7.55 (m, 1H), 7.38-7.45 (m, 2H), 7, 23-7.29 (m, 2H), 6.98-7.01 (m, 1H), 6.83 (s, 1H), 5.28 (br s, 1H), 4.08-4.16 (m, 2H), 3.41-3.51 (m, 4H), 2.82 (s, 2H), 1.61-1.72 (m, 4H), 1.00-1.05 (m, 2H). , 3H), 0.90-0.97 (m,
. 6H); m/z (APCI-pos) M+1 = 434.2. Example 204 — the //ToH . OF THE GC AND
E Ethyl 2-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzol[bjlazepin-8-yl)benzoate Step A: Oo 2(1E,4E Ethyl )-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (30%) was prepared according to Example 190, Steps A and B, replacing 4-(ethoxycarbonyl)phenylboronic acid with 2-*10(ethoxycarbonyl)phenylboronic acid. *H NMR (400 MHz, DMSO-ds) 5 7.57-7.76 (m, 2H), 7.43-7.56 (m, 2H), 7.28-7.39 (m, 1H ), 6.74-7.01 (m, 5H), 4.43-4.55 (m, : 1H), 3.98-4.14 (m, 2H), 3.26-3.55 ( m, 6H, partially hidden by peak of is: water), 2.74 (s, 2H), 1.67-1.82 (m, 2H), 1.49-1.66 (m, 2H), 0 .71-1.02 (m, 6H); m/z (APCI-pos) M+1 = 450.2. —Example 206 methyl 4-((1E 4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-iN)benzoate Step A: A round bottom flask 50 ml, equipped with a stir bar and nitrogen inlet, was charged with 15 ml of dry toluene and dipropylamine (0.44 ml, 3.24 mmol). This was cooled to 0°C and AlMe;z (4.04 ml, 8.09 mmol, 2M in toluene) was then added. Once the addition was complete, the mixture was allowed to warm to room temperature (-20-380 minutes) 2-amino-8-bromo-3H- —benzo[bjlazepine-4-carboxylate (1E,4E) -ethyl (0.5 g, 1.62 mmol) was then
M added, in portions, resulting in a dark solution. This mixture was heated to 100°C for about 16 hours, and then allowed to cool to room temperature. This mixture was then poured into 50 ml of an aq. to 30% Rochelle's salt and stirred vigorously for 20 minutes, then extracted with EtOAc (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Flash 40 Biotage (40M cartridge, 5% MeOH/DCM) provided 201 mg (32%) of (11E,4E)-2-amino-8-bromo-N,N-dipropyl-38H-benzo[b]azepine -4-carboxamide. m/z (APCI-pos) M+H1 = 364.2, 366.2.
Step B: A (1E,4E)-2-amino-8-bromo-N N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4-(methoxycarbonyl) acid phenylboronic acid — (55.6 mg, 0.309 mmol), tetra 7-kis(triphenitphosphine)palladium(0) (23.8 mg, 0.021 mmol), potassium carbonate. 2M aqueous solution (0.309 ml, 0.618 mmol) were combined in 2 ml of acetonitrile in a small microwave reaction flask. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2 x 0.5 mm plates, 7% MeOH/DCM) provided 20 mg (23%) of 44((1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H -benzo[b]azepin-8-i)methyl benzoate. *H NMR (400 MHz, CDC) 5 8.08-8.13 (m, 2H), 7.68-7.74 (m, 2H), 7.52-7.56 (m, 1H), 7 .33-7.39 (m, 2H), 6.84 (s, 1H), 3.94 (s, 3H), 3.60-3.68 (m, 2H), 3.37-3.51 (m, 4H), 2.86 (s, 2H), 1.60-1.72 (m, 4H), 0.88-0.98 (m, 6H); m/z (APCI-pos) M+1 = 420.2.
Example 207 or DRY
EO O O ANTA o Ethoxymethyl 4-((1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-iNbenzoate
1 Step A: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-iN-benzoic acid (0.50 g, 2.02 mmol) was dissolved in 20 ml of dry acetonitrile. To this solution was added powdered potassium carbonate (0.429, 3.02 mmol), followed by chloromethyl ethyl ether (0.24 ml, 2.42 mmol). 65°C for 2 hours, then allowed to cool to room temperature, filtered and the filtrate concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ethoxymethyl as a solid (84%).This material was used in the next step without further purification.Step BO 4((11E4E)2-amino4-(dipropylcarbamoyl)-3H-benzolb]azepin-8-yl)benzoate ethoxymethyl (17%) was prepared according to Example 206, Step B, replacing 4f(methoxycarbonyl)phenylboronic acid with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- y ethoxymethyl iNbenzoate.* H NMR (400 MHz, CDCI;) δ 8.12-8.17 (m, 2H), δ 15. 7.72-7.76 (m, 2H), 7.54-7 .56 (m, 1H), 7.33-7.40 (m, 2H) , 6.84 (s, 1H), 5.57 - (s, 2H), 3.78-3.85 (m, 2H), 3.61-3.70 (m, 2H), 3.36- 3.53 (m, 4H), 2.84 (s, 2H), 1.58-1.74 (m, 4H), 1.26-1.31 (m, 3H), 0.89-0, 99 (m, 6H); m/z (APCI-pos) M+1 = 464.2. Example 208 the TF No
COS in NH OE, ethyl 4-((1E,4E)-2-Amino-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate Step A: 3-Fluoropropan-1-amine hydrochloride (1.00 g, 8.81 mmol) was dissolved in 90 ml! of dry dichloromethane. To this were added di-t-butyl dicarbonate (2.11 g, 9.689 mmol) and triethylamine (2.70 ml, 19.37 mmol). This mixture was stirred at room temperature for 16 hours, then washed with aq. a IN (1X), saturated sodium bicarbonate solution (1X), dried over sodium sulfate and concentrated under pressure
: reduced, to give 1.6 g (100%) of tert-butyl 3-fluoropropylcarbamate as a clear, colorless oil.
Step B: Tert-butyl 3-fluoropropylcarbamate (1.6 g, 9.03 µmoles) was dissolved in 90 ml of dry DMF.
To this solution was added sodium 5 ohydride (1.44 g, 36.12 mmol, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 20 minutes.
Iodopropane (3.17 ml, 27.09 mmol) was then added and the mixture was heated to 65°C for 10 hours, then quenched with saturated ammonium chloride solution.
This was extracted with EtOAc (2X), the extracts washed twice with brine, dried over sodium sulfate and concentrated to 29 (100%) tert-butyl 3-fluoropropylpropyl)carbamate as a clear oil.
Step C: Tert-butyl 3-fluoropropyl(propyl)carbamate (2.00 9: 9.12 mmol) was dissolved in 90 ml of ether.
This mixture was cooled to 0°C and HCl gas was bubbled into the reaction mixture for 15 minutes, the reaction vessel capped and the mixture allowed to warm to room temperature and stirred for 6 hours.
The mixture was then concentrated to a viscous solid, yielding 1.6 g (99%) of 3-fluoro-N-propylpropan-1-amine hydrochloride.
Step D: (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[blazepine-4-carboxylic acid (0.275 g, 0.721 mmol) was dissolved in 7 ml of dry DMF.
To this solution were added HOBT (0.107 g, 0.794 mmol) and EDCI (0.152 mmol, 0.794 mmol), and this mixture was stirred at room temperature for 20 minutes.
3-Fluoro-N-propylpropan-1-amine hydrochloride (0.124 mmol, 0.794 mmol), followed by triethylamine (0.211 mL, 1.515 mmol), was then added and the reaction mixture stirred at room temperature for 16 hours. .
The mixture was then diluted with EtOAc, washed several times with brine, dried over sodium sulfate and concentrated under reduced pressure.
Flash 40 Biotage (40S cartridge, 25% EtO-Ac/Hexane) provided 0.089 g (26%) of (1E,4E)-8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H tert-butyl -benzo[b]azepin-2-ylcarbamate. m/z(APCI-pos)M+1=481.8and 483.8. Step E Ethyl 4-((114E)-2-(tert-butoxycarbonylamino)-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-ibenzoate was
: prepared according to Example 206, Step B, substituting (11,4E)-2-amino-8-bromo-N-N-dipropyl-3H-benzo[b]Jazepine-4-carboxamide for (1E,4E) tert-Butyl -8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and 4-(methoxycarbonyl)phenylboronic acid for 4J(ethoxycarbonyl) acid )phenylboronic acid. m/z (APCI-pos) M+1 = 551.9.
Step F: The crude product from Step E was then taken up in 2 ml of dichloromethane and 1 ml of TFA, and stirred at room temperature for one hour. The mixture was concentrated under reduced pressure and the resulting crude product was taken up in DCM (10 ml) and concentrated ammonium hydroxide (5 ml) and stirred at room temperature for 15 minutes, then extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography. va (2 x 0.5 mm plates, 7% MeOH/DCM/0.5% NH.OH) provided 17 mg (36%) of 4-((1E,4E)-2-amino- 4-((3-fluoropropyl)(propyl)carbamoyl)-Lp 15 Ethyl 3H-benzo[bjazepin-8-yl)benzoate. *H NMR (400 MHz, CDCl3 ) 5 8.09-8.14 (m, 2H), 7.70-7.74 (m, 2H), 7.52-7.55 (m, 1H), 7 .32-7.41 (m, 2H), 6.87 E (m, 1H), 5.11 (br s, 1H), 4.57-4.63 (m, 1H), 4.46-4 .52 (m, 1H), 4.37-4.45 (m, 2H), 3.57-3.73 (m, 2H), 3.42-3.55 (m, 2H), 2.82 (s, 2H), 1.99-2.15 (m, 2H), 1.62-1.76 (m, 2H), 1.38-1.45 (m, 3H), 0.89-0 .98 (m, 3H); m/z (APCI-pos) M+1=452.2. Example 209 o Je ToH Ea SS o — 4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoic acid Step A: Benzyl 4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (8%) was prepared according to Example 190, Steps A and B, substituting 4-(ethoxycarbonyl)phenylboronic acid for 4-(ethoxycarbonyl)phenylboronic acid.
M (benzyloxycarbonyl)phenylboronic. Step B: 4-((11E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-i)benzoic acid (63%) was prepared according to Example 188, Step B, substituting benzyl 4--5((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate for the Benzyl 4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. m/z (APCI-pos) M+1 = 422.3. Example 210 Q
SE CC NO O “NE - Oo F ethyl 4-((1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-.iN)-2-fluorobenzoate : Etahaa AO Ethyl 4((1E4E)-2-amino4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoate (32%) was prepared according to Example 206, Step B, substituting the 4(methoxycarbonyl)phenylboronic acid for 3-fluoro-4-(methoxycarbonyl)phenylboronic acid. *H NMR (400 MHz, CDCl3 ) 5 7.97-8.02 (m, 1H), 7.47-7.53 (m, 2H), 7.29-7.43 (m, 3H), 6 .89 (s, 1H), 4.36-4.46 (m, 2H), 3.56-3.68 (m, 2H), 3.38-3.50 (m, 4H), 2.84 (s, 2H), 1.60-1.71 (m, 4H), 1.38-1.44 (m, 3H), 0.90-0.97 (m, 6H); m/z (APCI-pos) M+1 = 452.2. Example211 or /ToH
FF NR in NH>
OF Ethyl 4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzol[b]azepin-8-yl)-2-fluorobenzoate Step A: O 4-((1E,4E)-2-amino-4-((3- —hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoate — from
Ethyl (19%) was prepared according to Example 190, Steps A and B, substituting 4-(ethoxycarbonyl)-3-fluorophenylboronic acid for 4-(ethoxycarbonyl)phenylboronic acid.
*H NMR (400 MHz, CDCl3 ) 5 7.97-8.04 (m, 1H), 7.47-7.52 (m, 2H), 7.36-7.45 (m, 2H), 7 .29-7.33 (m, 1H), 6.88 (s, 1H), 5.19 (br s, 1H), 4.38-4.47 (m, 2H), 3.59-3, 72 (m, 5H), 3.45-3.52 (m, 2H), 2.84 (s, 2H), 1.79-1.90 (m, 2H), 1.67-1.76 ( m, 2H), 1.40-1.42 (m, 3H), 0.89-0.97 (m, 3H); m/z (APCI-pos) M+1 = 468.2. Example 212 q DS No. - Methyl 5(1E,4E)-2-Amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-2N)picolinate: Step AO BS5-((1E4E) Methyl -2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)picolinate (17%) was prepared according to Example 206, Step B, substituting 4-(methoxycarbonyl) acid phenylboronic acid with methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate.
1H NMR (400 MHz, DMSO-ds) 5 9.89 (s, 1H), 8.98-9.10 (s, 1H), 8.32-8.36 (m, 1H), 8.18- 8.22 (m, 1H), 7.71-7.89 (m, 3H), 7.06 (s, 1H), 3.93 (s, 3H), 3.23-3.40 (m, 4H), 1.53-1.63 (m, 4H), 0.75-0.97 (m, 6H); m/z (APCI-pos) M+1 = 421.2. Example 220 OoH ov PEA: Ss 6 PO NO, NH 2 o 3-(4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin (E)-ethyl -8-yl)phenyl)acrylate Step A: Oo 3-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H- (E)-ethyl benzo[b]azepin-8-i)Yphenyl)acrylate (40%) was prepared according to Example 190, Steps A and B,
' replacing 4-(ethoxycarbonyl)phenylboronic acid with (E)-4-(3-ethoxy-3-oxoprop-1-enyl)phenylboronic acid.
*H NMR (400 MHz, CDCl3 ) 5 7.67-7.75 (m, 3H), 7.58-7.62 (m, 2H), 7.51-7.53 (m, 1H), 7 .30-7.39 (m, 2H), 6.88 (s, 1H), 6.48 i (d, 1H), 5.11 (br s, 1H), 4.24-4.32 (m 2H), 3.58-3.70 (m, 4H), 2.82 (s, 2H), -5 1.78-1.89 (m, 2H), 1.66-1.78 (m, 2H), 1.30-1.40 (m, 3H), 0.89-0.99 (m, 3H); m/z (APCI-pos) M+1 = 476.2. Example 2 HEKTLR Assays The activity of the compounds of this invention can be determined by the following assays.
The hTLR transfectant HEK-293 assay employs HEK293 cells stably transfected with various hTLRs and transiently cotransfected with a plasmid containing a reporter gene. secreted embryonic alkaline phosphatase (SEAP) driven by NF-<B.
Stimulation of TLRs activates their downstream signaling pathways and induces nuclear translocation of the NF-xB transcription factor.
Reporter gene activity is then measured using a spectrophotometric assay.
To measure agonist activity, human embryonic kidney (HEK) cells that stably express several TLR genes, including TLR7 and TLR8, and an NFκB-luciferase reporter gene (eg, 293XL-hTLR8 cells) available from InvivoGen, San Diego, CA) are prepared according to the manufacturer's instructions and incubated with various concentrations of test compound overnight.
The amount of induced luciferase is measured by reading the absorbance at 650 mu.
The agonist compounds of the invention have an MCs, of 25 µM or less, where MCs, is defined as the concentration at which 50% maximal induction is seen.
Example 3 PBMC Assays for TLR7 and TLR8 Peripheral blood mononuclear cells (PBMCs) from human blood were isolated using the BD Vacutainer Cell Preparation Tubes with sodium citrate.
Cells were incubated with the compound overnight.
TLR8 activity was tested by measuring the amount
TNFα in the ELISA supernatants. TLR7 activity was tested by measuring the amount of IFNa in the supernatants by ELISA (R&D Systems). The compounds of this invention had an MCs5.o of 100 or less, where MCs, is the concentration at which 50% maximum induction is seen - 5 ma. The results of this test are shown below, in Tables 2 and 3. The numbers of MCs, are represented as factors of ten, for example, + indicates a value of MCs,5 of X 10º, or a value in the tens of thousands of nanomolar (nM range); ++ indicates a value of MCs9 of X 10th, or a value in thousands; +++ indicates a value of MCs9 of X 10th, or a —value in the hundreds; and ++++ indicates a value of MCso of X 10º or 10º, or a value in tens or units. Table 2. TLR8. o É e TOEt 141 +++ (Cd A xH o / TOEt 142 ++++ IQ “e
N o = OEt 143 ++++ Fm NO ú >» NH o = TOEt 144 ++++ NX N NH2 o my TOEt 145 OC ++++ NC. (OD N NHo o : Ot O — +++ Mr
NC o = OEt 147 o O in D: NH No:
FA or GQ a / TOEt 154 -. +++ : ALI In o 7 o O — OEt S 155 ” +++ DIO, o o = OEt 156 es in
QL or
CON 101 pl Wo
N A O “ o o os 102 — nm ALI Ém Oo o
QN Í 103 O was ++ Cx O E not ; The
A 104 Q O O nN= ms ++++ NH; à o E, bu OH NOS | It's the . *stereoquin. arbitrary E the o. 106 Q O NS NH ++++ o * stereokin. arbitrary o OH ss N 107 O and q ++++
Mr Rg Nro 109 NX x ++++ Pes x o ate OQ OC res No = o o = tros ao É o o
N Fo 1117 O à. DD +++ [e O Noz o o OO . u -. ; 7 o : ns ' 120 a to. ++ "HO, 9 O
N 174 o”. you stay
GQ Di o, HE 176 (CD NODE NH ++ AS o o NH> 178 A E NODE NH +++ Go THE
LA — N po : Y —
N o o E — N
DA SAS - E o a to N fp 130 in XX +++ | ÇA - o FT oO 182 to SS nn, ++++ Cd o o OS
N 115 OA + Hm a o o 7 S — N 121 O ne + O O NH The
Ooo
TO O ' 122 = ++
N ' OQ O Da o o qe 124 — +++
N 2 O “ Oo [o] the 125 — +++ No
COP | CS Fr o a r 126 —, +++ No
O O NH o o
NA 133 s ++++ Fm NO tz NH
At the
NA 134 s++ = NE"NH; o No. 135 D ++++ F= NE NX NH, o No. 136 O Ss ++++ NC. (THE NO
* AI 137 o ++++ Nº o FE in 138 9 S +n++ dense and a 139 Se +++ z Eto- > o : >”
N e 186 -- os + o (DZ NÔ NH,
PO q
No. 187 +++ Q (SD NODE NH Eto CD q — 188 O ft HO. (7 o
TLR8
oh oh
NR f 190 0 ++
NODE ONH Eto- o o, = = 194 — +++ . HO. : So - and 195 +++ Ho O,
NE 202 ” NODE NH +++
GS Oo or 203 Eto. TJ . To the
Q Non Á 204 A(O a . O NO NH o NWA
A 206 e = +++ meo LD
o o o
SA ace (END Arara e: 207 CW” No. SS ++ i EO o O é : o E $ Ne
A 208 (D Ny ++ o A o o
NO OH mi 209 ee . Y 2 so SO o o AT THE
AA 210 (7 Nx, +++ and The EF
TLR8 Comp. at the. MCso structure | $ EO i ã O Bece Eidos ART 211 A, ++ : Eto. THE
OF or 212 IDEs, ++. Meo. (knot or NRO
PA 220 ” NL +++ iz BO A (O o , Table 3. | level o and TOEt 142 + A NH,
No aaa OE 144++
NO NO NH re o = OE! 147 o O ++ o NON N h
O o o 103 js++
N OO numbers o bo à 104 LC) = m ++ Cx O N NH * o
NE O = | ++
OA TO o - — Aaass Nx OH 106 o n2 ++ O O NHz Ff o - g NEON 109 a O ++ f o o = NO sound 112 AEE *
O NH Or o Io 07 O - = + Cx CG o o o as
E N for No o H
32. 0O - N 174 O " and + : hz
ASI [ ) o << 178 ” N NH +++
ASI o Fi k OS ' 127 És) Auto ++ o e o OS 128 no O les +" in o - oH o o
Up until Ho (DZ NODE NH, fi
WATCH WHAT
QN 124 O ” nm +" AI Om o o o e | o -
CS or
SOR 126 "+"
N O O no o o nl . 133 R s ++ (3 "mm . N Í o nl - 134 S ++ S > NO NHA o nl 135 B S +++ 7 NH o
NA 136 O ã y — NC O No, nl 137 XX Y TS
NC or nl 138 3 IQ y +”
PSA |
TLR7 q. = = Eto-” o
OH o e a 190 (O se + EtO- 7 o . à É : 194 pet media ++ q
N << 195 E +++
HO o 203 FO ZO A ++ o
NT TOH 204 and AS . du ++ DO Eee
CC no. TLR7 ;op. at the. MCso o 206 (CD nº ++ NHo : neo AA o o = ++ 207 (DJ WS e as A o o 210 ” Õ ++ í NH : Eto. O O Fr fo nO Mo
PLA ” A " h Eto. O
OF 8 NS Bisa GEda MAP cd 212 nº ++ *y No Meo. h Node o o
IN PA A: 220 ” NO + >
NO [o The foregoing description is considered to be illustrative only of the principles of the invention. Furthermore, since various modifications and alterations will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown,
as described above.
Accordingly, all suitable modifications and equivalents may be invoked to fall within the scope of the invention, as defined by the claims that follow. : The words "comprises", "comprising", . 5 "includes", "including", and "includes", when used in this specification and the claims that follow, specify the presence of stated characteristics, integers, components, or steps, but they do not exclude the presence or the addition of one or more other features, integers, components, steps, or groups thereof.
Unless otherwise noted, all references listed in this document are specifically incorporated by reference.

权利要求:
Claims (19)
[1]
1. Compound having the formula |: . YN NH, ó” or a tautomer, enantiomer or salt thereof, wherein: Y is substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with one or more groups independently selected from CN, OH , -C(=O)Rº, halogen, and -CH=CHC(=O)Rº; Rº is selected from alkyte, OR”, and NRººR"; : 10 R'* is selected from H, alkyl, and -CH2O(alkyl), R'*º and R are each independently alkyl , where said alkyl is optionally substituted with -OH or R'* and R'!, together with the nitrogen atom to which they are attached, form a heterocyclic ring, f where said heterocyclic ring is optionally substituted with one or more -OH; R is selected from OR** and NRºR"; R$ and R are each independently selected from H, alkyl, cycloalkyl, heterocycle or benzyl, where said alkyl , cycloalkyl, or benzyl is optionally substituted with one or more groups independently selected from -F, -ORº, -NRSOR”, -C(=O)NR* R** or Rº and R” , together with the nitrogen atom to which they are attached, form a heterocyclic ring, additionally where said heterocyclic ring is optionally substituted with one or more -OH; Rº is selected from hydrogen and alkyl, and R" , R° and R** are each independently selected from H and alkyl, wherein said alkyl is optionally substituted with -OH; provided that o o a) when Y is aryl substituted with v or <, then
R is not -OEt, or b) when Y is aryl substituted with -C(=O)Rº, and Rº = NR'ºR", É and R'"º and R!), together with the nitrogen atom to which they are joined, : 5 form an unsubstituted pyrrolidine ring, then R not be -OEt or -Ní(propyl),.
[2]
A compound according to claim 1, having the formula ": o n2 O = o. GO N = NH
Z : in a) is 10 or a |tautomer, enantiomer or salt thereof, where W is H or -OH; Zé Hou-, OH; and n is 1 or 2, since when W and Z are both H and n are 1, then R A is not -OEt or -N(propyl),.
[3]
A compound according to claim 1, the formula (UU) having R O = NE NH. San E. E TV(1) or a tautomer, enantiomer or salt thereof, where T is CH, CZ, or N; U is CH, CZ, or N; See CH, CZ, or N; X is CH, CZ, or N; W is CH, CZ, or N; Z is selected from halogen, -CN, -CONRºR”, -COOR" , -CH=CHCOOR" , and -OR"*; and
R'º, R7, Rº, and R'º are each independently selected from H, alkyl, and -CH>O(alkyl).
[4]
A compound according to claim 1, having the formula Iv: o + R2 NOS = d — NH N (Iv) or a tautomer, enantiomer or salt thereof.
[5]
A compound according to claim 1, having the formula Vv: the R2 [at No. x 18, > NH; River. U 2 : the V) or a tautomer, enantiomer or salt thereof, where U is N or CZ, and Z is halogen.
[6]
A compound according to claim 1, having the formula
SEE the
SO Ps NO Up NH, Ê(VI) or a tautomer, enantiomer, or salt thereof, where J is independently selected from halogen, - C(=O)R and -CH=CHC(=0)Rº; p is selected from 1,2,e 3; the do” since when p is 1 and J is joined at position 4 of the aryl ring, then R not be -OEt, and additionally since when p o õ O is 1 and J is joined at position 4 of the aryl ring, then R other than : -OEt or -N(propyl),.
[7]
A compound according to claim 1, having the formula e VII: oe NR$R” NH (VI) or a tautomer, enantiomer or salt thereof, wherein: Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from -C(=O)Rº, halogen, and -CH=CHC(=O)Rº; 2 Ao Rº is selected from alkyl, OR”, and NRººR"; ' R'* is selected from H, alkyl, and -CH>O(alkyl); is R'º and R* are each independently alkyl, where said alkyl is optionally substituted with -OH, or R*º and R', together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -oH; and R° and R' are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more groups independently selected from - Fou-OH; provided that when Y is aryl substituted with -C(=O)Rº, and Rº = NR"ºR!, and Rºº and R"!, together with the nitrogen atom to which they are attached, form a ring of unsubstituted pyrrolidine, then R6 and R' are not both propyl.
[8]
A compound according to claim 7, wherein: Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from -C(=O)R , halogen , and -CH=CHC(=O)R°;
Rº is OR"; R** is selected from H, alkyl, and -CH;O(alkyl); and Rº and R are each independently selected from " H, alkyl, or alkenyl, where said alkyl or alkenyl is optionally substituted with one or more groups independently selected from -F or -OH.
[9]
A compound according to claim 7, wherein: Y is substituted aryl, wherein said aryl is substituted with -C(=O)Rº; Rº is selected from alkyl, OR”*, and NRºR"'; R'* is selected from H, alkyl, and -CH>O(alkyl); R'º and R'', together with the atom of nitrogen to which they are joined, form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more -OH; and É 15 Rô and R are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more groups independently selected from -F or -OH; provided that when Rº = NR"ºR*!, and R"º and R' !, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidine ring, then R° and R are not both propyl.
[10]
10. A compound according to claim 7, having the formula Vila: o Sã NR6R No.
N Cro, (Vila) or a|tautomer, enantiomer or salt thereof, where: veoO, 1, or 2; R$ is selected from H, allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more -OH; R" is selected from allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more -OH; provided that when v is O, then Rº and R are not both pro- . 5 dick
[11]
A compound according to claim 1, selected from the group consisting of: Q o es NA and O 101 OO ” 102 OQ) NE E Cx NH, q NH, ooooxo A = N = N or : 103 E e ST | 104 Ea Ê O O NH & (The NON is S : nr ga = N ôõu = N on 105 O = 106 O = OO o [e O a ”. o ” NE ” E 107 CL) = Ee 112 O = bu [8 O o O » Nao oo la e ais o 109 O - E 110 O ” o
O O NO NH OQ O OW € o
NH 3 5th Sa eto: — N E 115 CAIA 117 -
N NH O Y io NH O Ç o O O 119 K. o — Phase Ha o O Q O ie = 3 | 121 2 o ã a a, 122 2. O OQ O nt NH2 - o 132 tea E NA . > 124 — : VN o À > . * and | Ss o t 125 E & : (If 126 E.
SS d NI : CS ado OM - the he OS << the LOTA, 128 | on E.
XY Ç O > o Ni - Oo 129 | E and FC ba YEAR, 130 | THE.
N T moh OQ e e o 133 a | O je] oa 2 NO . | : CS NO NH . o 136 à o o nl IgA 137 NK Ss 188] à EX. Ss NH or NH; O A a: is NC o f . C eeé OE do 9 139 rs [984] CP,” o Eto- Oo o j 5 OE ss OE! = t 141 A. 142 - . ho NM 7 NH) Is the Q . 7 Hi honey OE : 143 144 . = VR No. fi N N NH IH: . NZ E “NV o b OEt ã o — OEt Ci FE 145 146 ” ne NS, () NHo O . Ss Zone OEt = A
N “NH, DA O : ! o o = TOEt es TOR 155 O 156 O pç EA or ENA an [o] o
| E a À << O at 176 > NA 174 x - | Aa & - the NH | P CC
ONOE ” A 178 NÔ NH, 186 L () Ab q O HO (O 3d = ooo SS Edir e a : n O De no 182], (DS a : 2 : ”- Pyí O Co o : : 7 aea 188 (CS nto É o (DZ NÔ NH, O Eto (O Ho.
S OH - a Id 2 A. - 190 (> KNOT NH O ” NÔ NH, O Ho. O ãS o
Q 7 R and N = 195 () RS 202 ” NÓ NHA Õ NÓ NH O (DJ : ” Y
HO o = f g NO SON Eto. “1 CAKE = AS 203 S in, 204 . QRO Ly : mo 206 O ” No 207 E > Meo, E Ko o o : Fo $. Co =X, E 208 or NANA 209 * Ne NH Et. (O Ho. GO o o o o ANE se a oo 212 EN 210 Nx eo. In Eto. O Or oH O É oH x e GC C 227 | in NNE, 228 | 4º B A (O | O O "Ses o
/ 3 a e 3 o 229 1 e “23018 O e - : CG o NHo G O NH o o o : & SD e S : = 231 and 232 ne = f) o FERA o = or Nou N 233 in A. efe 234 in MPa, A in ATOS, o o o : o A o — or 235 | (OA 236 O AA > ro O ii NH eo O in NHo oo | O ” e ” 1 mo 237 = 238 × <A (O ” NH E O bi NH oo OE 3 fe 239 . <AO Ne oe the tautomers , the enantiomers and its salts.
[12]
A compound according to claim 11, selected from the group consisting of: o, -o - Ro. E Me 139 O ev 220 O If Eto-SO IS O S o
Q = = à Cro 186 and "NV 211 ” Nu, r o NÔ NH eo. O HO and o F - 3 o Na = NX 187 "” 188 CC 2 o tv à GS NÔ NH, EtO (O Ho. Oo
S OH o =
The 190” N NH Eto.
O o o E LO =— Y NON 203 A 2 204 | FOO — "|" a o NE o o e a NO ce 206 O NH 207 ” NH, Meo. O O O OO
$ E b NT OH PA A X / : 208 ão E 209 á. E o o o o o o NO ON o 212 E 210 G ” Ns, Vea Eto. í o F [o] o ia TN: No by 101 O = 104 E | GOOD a OA - o o .- o o = No e ar - 105 NK los O W OQ O NH AE () NH o o o as ie
PR SNPA S o o o a Q NE aa FE 127 o o 128 > Rs o o o o o NT a WE AAA > 2 129 o GS Sd à. 130 of the x, San. oh oh
oh
oh and the
N ass ta A - 182 P 227 , q e E A o NHA Node . To GS the o and the tautomers, the enantiomers and the salts thereof.
[13]
A compound according to claim 11 selected from the group consisting of: o. the o o
NON — ÇA 139 PA 220 DA, : O e Eto- o o O E $ Won - = e 187 O 211 (7 Nu > À o Nº “NH; Eto. O EO > or
OH o E = O x R N 208 Of not 190 (OD — Eto. O No. “NH, : (D Eto. o o o Eto o ii. aaa:
AAA 203 ” ” 204 | I (SJ to
O NH O NNH
Lo fe a ão NO o o, PA 206 m IN NH, 207 (7 NO in SS o [) 1 o g OS San NEN XX and WS 212 & o 210 NA, Me An Eto. (To the
The F and the tautomers, the enantiomers and its salts.
[14]
A compound according to claim 11, selected from the group consisting of: o. - . Q N - N party) k - 186 O " N 188 > Nú NA o Nà NH, O * po (O Ho.
o o o
SOUND
AAA 209" ne
NH to A o o o = NH NS 101 O - O md Sus Da e o o o o Sor 3 A = N ou = N oo 105 O e Mm 1106 Ed O Írla O NH Ox Ox tó O o
IS O OS lr OCS do Om EAD É o o o [o] + NO NO É 127 | O à” mm la2B/l O No A O As DO A, o o o o no WO 129] 4 o à e 130 no. O Ns - o HO Sm o RA E o Oo e O % - o . == — A : 182 | to” ninth, 227 and . &Q CO Ho NNH, : TO OSS ff. the o and the tautomers, the enantiomers and the salts thereof.
[15]
A compound according to claim 1, wherein the salt is a pharmaceutically acceptable salt.
[16]
A kit for treating a condition mediated by TLR7 and/or TLR8, comprising: a) a pharmaceutical composition comprising a compound as defined in claim 1 or a tautomer, enantiomer or salt thereof; b) optionally, instructions for use.
[17]
A pharmaceutical composition which comprises a compound as defined in claim 1 or a tautomer, enantiomer or salt thereof, together with a pharmaceutically acceptable diluent or carrier.
[18]
A method of treating a condition mediated by TLR7 and/or TLR8, comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 1 or a tautomer, enantiomer or salt thereof.
[19]
19. A method of modulating a patient's immune system, comprising administering to a patient in need thereof an amount; of a compound as defined in claim 1 or a tautomer, and enantiomer or a salt thereof.

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AU2017200936A1|2017-03-02|

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IL243710A|2017-10-31|

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EP2467380B1|2016-11-30|

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PT2467380T|2017-03-07|

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PL2467380T3|2017-09-29|

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DK2467380T3|2017-03-13|

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EP3159337A2|2017-04-26|

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CA2771484A1|2011-02-24|

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HUE031797T2|2017-08-28|

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ES2617676T3|2017-06-19|

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JP5756805B2|2015-07-29|

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RU2016108987A|2018-11-26|

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HRP20170268T1|2017-05-19|

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JP2013502431A|2013-01-24|

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CN102781933A|2012-11-14|

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RU2580320C2|2016-04-10|

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US8524702B2|2013-09-03|

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CN102781933B|2016-01-20|

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法律状态:
2020-12-22| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-12-29| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-01-05| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-01-12| B07B| Technical examination (opinion): publication cancelled [chapter 7.2 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 7.4 NA RPI NO 2609 DE 05/01/2021 POR TER SIDO INDEVIDA. |

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2021-03-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-04-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-06-22| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 11A ANUIDADE. |

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2021-08-10| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

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2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US23497109P| true| 2009-08-18|2009-08-18|

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US61/234,971|2009-08-18|

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