Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems

Definitions

• JAK Janus kinase
• pharmaceutical compositions comprising such compounds and methods of using such compounds to treat, e.g., inflammatory and fibrotic diseases, including respiratory diseases.
• Asth a is a chronic disease of the airways for which there are no preventions or cures.
• the disease is characterized by inflammation, fibrosis, hyper-responsiveness, and remodeling of the airways, all of which contribute to airflow limitation.
• An estimated 300 million people worldwide suffer from asthma and it is estimated that the number of people with asthma will grow by more than 100 million by 2025.
• asthma afflicts about 6 % to 8 % of the population, making it one of the most common chronic diseases in the country.
• most patients can achieve control of asthma symptoms with the use of inhaled corticosteroids that may be combined with a leukotriene modifier and/or a long acting beta agonist, there remains a subset of patients with severe asthma whose disease is not controlled by conventional therapies.
• Severe persistent asthma is defined as disease that remains uncontrolled on high doses of inhaled corticosteroids. While severe asthmatics are estimated to account for approximately 5 % of all asthma sufferers, they have a high risk of morbidity and mortality and are responsible for a disproportionate share of health care resource utilization among asthmatics. There remains a need for novel therapies to treat these patients.
• Cytokines are intercellular signaling molecules which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor. Cytokines are critical for normal cell growth and immunoregulation but also drive immune-media ted diseases and contribute to the growth of malignant cells. Elevated levels of many cytokines have been implicated in the pathology of asthma inflammation. For example, antibody-based therapies targeted at interleukins (IL)-5, and 13 have been shown to provide clinical benefit in subsets of severe asthma patients.
• IL interleukins
• Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon- ⁇ (IFN ⁇ ) and granulocyte -macrophage colony-stimulating factor (GM- CSF).
• JAK-STAT Signal Transducer and Activator of Transcription
• the JAK family comprises four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Binding of cytokine to a JAK-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation. Phosphorylated JAKs, in turn, bind and phosphorylate various STAT proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease.
• the JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Specific cytokines are associated with specific JAK pairings.
• Each of the four members of the JAK family is implicated in the signaling of at least one of the cytokines associated with asthma inflammation. Consequently, a chemical inhibitor with pan-activity against all members of the JAK family could modulate a broad range of pro-inflammatory pathways that contribute to severe asthma.
• Chronic obstructive pulmonary disease COPD
• cystic fibrosis CF
• pneumonitis interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and sarcoidosis are also respiratory tract diseases in which the pathophysiology is believed to be related to JAK-signaling cytokines.
• Local administration of a JAK inhibitor to the lungs by inhalation offers the potential to be therapeutically efficacious by delivering a potent anti-cytokine agent directly to the site of action, limiting systemic exposure and therefore limiting the potential for adverse systemic immunosuppression.
• the need remains for a potent JAK inhibitor suitable for local administration to the lungs for treatment of respiratory disease.
• JAK-signaling cytokines also play a major role in the activation of T cells, a sub-type of immune cells that is central to many immune processes.
• Pathological T cell activation is critical in the etiology of multiple respiratory diseases.
• Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipient’ s T cells by the transplanted donor lung.
• Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD).
• CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction.
• Chronic lung allograft dysfunction (CLAD) is a major challenge in long-term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr. Transplant. Rep., 2016, 3(3), 185-191).
• CLAD is poorly responsive to treatment and therefore, there remains a need for effective compounds capable of preventing or treating this condition.
• JAK-dependent cytokines such as IFN ⁇ and IL-5 are up-regulated in CLAD and lung transplant rejection (Berastegui et al, Clin. Transplant. 2017, 31, el2898).
• high lung levels of CXCR3 chemokines such as CXCL9 and CXCL10 which are downstream of JAK-dependent IFN signaling, are linked to worse outcomes in lung transplant patients (Shino et al, PLOS One, 2017, 12 (7), eOl 80281).
• JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors have the potential to be effective in treating or preventing lung transplant rejection and CLAD. Similar T cell activation events as described as the basis for lung transplant rejection also are considered the main driver of lung graft-versus-host disease (GVHD) which can occur post hematopoietic stem cell transplants. Similar to CLAD, lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved.
• W is H, -C 1-6 alkyl or halogen
• X is H or F
• Y is H, -CH 3 , or F
• Z is -CH 2 CH 3 , -CF 2 CH 3 , or -CH 2 CF 3 ;
• A is a 4 to 7 membered monocyclic heterocyclic group having a double bond and optionally substituted with 1 to 8 substituents independently selected from the group consisting of -C 1-6 alkyl, - COR 1 , -SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 , aryl, heteroaryl, a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CN, -CO 2 R 2 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -SH, -O-C 1-6 alkyl, -S-C 1-6 alkyl
• each R 1 is independently selected from the group consisting of aryl, a 3 to 7 membered cycloalkyl group, a 4 to 7 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of - NR a R b , -OH, -O-C 1-6 alkyl, -O-C 1-6 alkyl-NR a R b , aryl, heteroaryl, and a 4 to 7 membered heterocyclic group, wherein the aryl, 3 to 7 membered cycloalkyl group, 4 to 7 membered heterocyclic group and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR 14 R 15 , -OH,
• the compound of formula (I) is a compound of formula (II): or a pharmaceutically-acceptable salt thereof, wherein:
• X is H or F
• Y is H or F
• A is a 4 to 7 membered monocyclic heterocyclic group having a double bond and optionally substituted with 1 to 8 substituents independently selected from the group consisting of -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 , a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CN, -CO 2 R 2 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -SH, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -OC(O)NR
• -OCO 2 R 8 -NR 8 C(O)-C 1-6 alkyl, -NR 8 C(O) 2 R 9 , -NR 8 -C(O)NR 9 R 10 , -C 1-6 alkyl-OR 8 , -C 1-6 alkyl-NR 8 R 9 , and -C 1-6 alkyl-CO 2 R 8 , wherein A is optionally fused or bridged with a 3 to 7 membered cycloalkyl group or a 4 to 7 membered heterocyclic group, wherein each 3 to 7 membered cycloalkyl group and each 4 to 7 membered heterocyclic group is optionally substituted with 1 to 5 substituents independently selected from the group consisting of a spiro 3 to 7 membered cycloalkyl group, a spiro 4 to 7 membered heterocyclic group, a 3 to 7 membered cycloalkyl group, a 4 to 7 membered heterocyclic group, -
• each R 1 is independently selected from the group consisting of aryl, a 3 to 7 membered cycloalkyl group, a 4 to 7 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of - NR a R b , -OH, -O-C 1-6 alkyl, aryl, and heteroaryl, wherein the aryl, 3 to 7 membered cycloalkyl group, 4 to 7 membered heterocyclic group and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR 14 R 15 , -OH, -C 1-6 alkyl, -CN, -CO 2 R 14 , -CONR 14 R 15 , -
• compositions comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier.
• a mammal e.g. a human
• the method comprising administering to the mammal (or human) a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof.
• the present disclosure also provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for use in medical therapy, as well as the use of such compound in the manufacture of a formulation or medicament for treating a respiratory disease in a mammal (e.g. a human).
• a mammal e.g. a human
• W is H. In some embodiments, W is -C 1-6 alkyl (including, e.g., methyl, ethyl, n-propyl, and isopropyl). In some embodiments, W is halogen (including, e.g., fluoro, chloro and bromo). In some embodiments, W is H, -CH3 or bromo.
• X is H. In some embodiments, X is F.
• Y is H. In some embodiments, Y is F. In some embodiments, Y is -CH 3 . In some embodiments, Y is Fi or F.
• Z is -CH 2 CH 3 . In some embodiments, Z is -CF 2 CH 3 . In some embodiments, Z is -CH 2 CF 3 .
• the compound of formula (I) is a compound of formula (II): or a pharmaceutically-acceptable salt thereof, wherein:
• X Fi or F
• Y is Fi or F
• A is a 4 to 7 membered monocyclic heterocyclic group having a double bond and optionally substituted with 1 to 8 substituents independently selected from the group consisting of -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 , a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CN, -CO 2 R 2 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -SH, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -OC(O)NR
• each R 1 is independently selected from the group consisting of aryl, a 3 to 7 membered cycloalkyl group, a 4 to 7 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of - NR a R b , -OH, -O-C 1-6 alkyl, aryl, and heteroaryl, wherein the aryl, 3 to 7 membered cycloalkyl group, 4 to 7 membered heterocyclic group and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR 14 R 15 , -OH, -C 1-6 alkyl, -CN, -CO 2 R 14 , -CONR 14 R 15 , -
• X is H or F
• Y is H or F
• A is a piperidine or a pyrrolidine having a double bond and optionally substituted with 1 to 6 substituents independently selected from the group consisting of C 1-6 alkyl, -COR 1 , SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , SO 2 NR 2 R 3 , a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 2 C(O)-C 1-6 alkyl, -NR 2 SO 2 -C 1-6 alkyl,
• A is selected from the group consisting of: each of which is optionally substituted with 1 to 3 R x independently selected from the group consisting of -CC>2R y , -CONR y R z , and -C 1-6 alkyl, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -CN, -OH, -O-C 1-6 alkyl, -CO 2 R y , and -CONR y R z ;
• R is selected from the group consisting of H, -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 ,
• C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CN, -CO 2 R 2 , -CONR 2 R 3 , OH, -SO 2 NR 2 R 3 , SO 2 -C 1-6 alkyl, SH, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -OC(O)NR 2 R 3 , -NR 2 C(O)-C 1-6 alkyl, -NR 2 C(O) 2 R 3 , -NR 2 -C(O)NR 3 R 4 , -OCO 2 R 2 , -NR 2 SO 2 -C 1-6 alkyl, aryl, heteroaryl,
• each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R a , R b , R c , R d , R y , and R z is independently selected from the group consisting of H and C 1-6 alkyl; and wherein in -CONR y R z , R y and R z are optionally joined to form a 4 to 7 membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of NR c R
• A is selected from the group consisting of: each of which is optionally substituted with 1 to 3 R x wherein each R x is independently -C 1-3 alkyl optionally substituted with -OH, -OC 1-3 alkyl, -CN, -CO 2 -C 1-3 alkyl, and -CONR y R z wherein R y and R z are each independently selected from C 1-3 alkyl and wherein R y and R z are optionally joined to form a 4 to 6 membered heterocyclic group optionally substituted with NR c R d , wherein R c and R d are each independently selected from the group consisting of H and C 1-3 alkyl.
• each R x is independently selected from the group consisting of Me,
• R is selected from the group consisting of H, -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 , a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 2 C(O)-C 1-6 alkyl, -NR 2 SO 2 -C 1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered cyclo
• each 3 to 7 membered cycloalkyl group and each 4 to 7 membered heterocyclic group is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, oxo, and -OH; each R 1 is independently selected from the group consisting of aryl, a 4 to 7 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR -NR
• R is selected from the group consisting of H, -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 , a 4 to 6 membered cycloalkyl group, and a 4 to 6 membered heterocyclic group, wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl,
• each R 1 is independently selected from the group consisting of phenyl, a 4 to 6 membered heterocyclic group, and a 4 to 6 membered heterocyclic group, wherein the 4 to 6 membered cycloalkyl group and the 4 to 6 membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, and -OH, wherein the 4 to 6 membered cycloalkyl group and the 4 to 6 membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, oxo, and -OH; each R 1 is independently selected from the group consisting of phenyl, a 4 to 6 membered heterocyclic group, and
• Y is H
• A is selected from the group consisting of: each of which is optionally substituted with 1 to 3 R x wherein each R x is independently -C 1-3 alkyl optionally substituted with -OH, -OC 1-3 alkyl, -CN, -CO 2 -C 1-3 alkyl, and -CONR y R z wherein R y and R z are each independently selected from C 1-3 alkyl and wherein R y and R z are optionally joined to form a 4 to 6 membered heterocyclic group optionally substituted with NR c R d , wherein R c and R d are each independently selected from the group consisting of H and C 1-3 alkyl;
• R is selected from the group consisting of H, -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 ,
• -CONR 2 R 3 -SO 2 NR 2 R 3 , a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group
• the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C 1-6 alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 2 C(O)-C 1-6 alkyl, -NR 2 SO 2 -C 1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered cycloalkyl group, and a 4 to 7 membered heterocyclic group, wherein the 3 to 7 membered cycloalkyl group and the 4 to 7 membered heterocyclic group are
• each R 1 is independently selected from the group consisting of aryl, a 4 to 7 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR a R b , -OH, and aryl; and each R 2 , R 3 , R 8 , R 9 , R 10 , R a , and R b is independently selected from the group consisting of H and C 1-6 alkyl.
• Y is H
• A is selected from the group consisting of: each of which is optionally substituted with 1 to 3 R x independently selected from the group consisting of Me, -CH 2 OH, -CH 2 OMe, -CH 2 CN, -CH 2 CONMe 2 , -CH 2 CO 2 Me,
• R is selected from the group consisting of H, -C 1-6 alkyl, -COR 1 , -SO 2 R 1 , -CO 2 R 2 ,
• -CONR 2 R 3 -SO 2 NR 2 R 3 , a 4 to 6 membered cycloalkyl group, and a 4 to 6 membered heterocyclic group
• the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO 2 NR 2 R 3 , -SO 2 -C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 2 C(O)-C 1-6 alkyl,
• each R 1 is independently selected from the group consisting of phenyl, a 4 to 6 membered heterocyclic group, and -C 1-6 alkyl wherein the -C 1-6 alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of
• X is H. In some embodiments, X is F.
• Y is H. In some embodiments, Y is F.
• Also provided herein is a compound of formula 3: or a pharmaceutically-acceptable salt thereof.
• the compound of formula I is selected from a compound having the chemical structure of any one of Examples 1 to 393, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I is a compound having a chemical structure of any one of compounds in Table 4 of the Examples section, or a pharmaceutically acceptable salt thereof.
• the imidazole portion of the compounds of the present disclosure exists in tautomeric forms. It will be understood that although structures are shown, or named, in a particular form, the invention and present disclosure also include the tautomer thereof.
• the compounds of the present disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like.
• Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated.
• the depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
• the compounds of the present disclosure may also contain several basic groups (e.g., amino groups) and therefore, such compounds can exist as the free base or in various salt forms, such a mono- protonated salt form, a di-protonated salt form, a tri-protonated salt form, etc or mixtures thereof. All such forms are included within the scope of this invention and disclosure, unless otherwise indicated.
• This invention and disclosure also include isotopically-labeled compounds of formula (I) or formula (II), i.e., compounds of formula (I) or formula (II) where one or more atom has been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass that predominates in nature.
• isotopes that may be incorporated into a compound of formula (I) include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, and 18 O.
• alkyl means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl (Me), ethyl (Et), n- propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t- Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2- dimethylpentyl, 2-propylpentyl, and the like.
• C 1-3 alkyl means an alkyl group having from 1 to 3 carbon atoms wherein the carbon atoms are in any chemically-acceptable configuration, including linear or branched configurations.
• aryl means an aromatic hydrocarbon group having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl (i.e., a benzene ring), naphthyl (i.e., a naphthalene ring), and the like. As used herein, the term aryl includes monovalent, divalent or multivalent aryl groups.
• cycloalkyl means a monovalent saturated or partially unsaturated carbocyclic group which may be monocyclic or multicyclic. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl (cPr), cyclobutyl (cBu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
• halo or halogen means fluoro, chloro, bromo or iodo.
• heteroaryl means an aromatic group having a single ring or two fused rings and containing in a ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur (i.e., a heteroaromatic group). Unless otherwise defined, such heteroaryl groups typically contain from 1 to 9 carbon atoms and from 3 to 10 total ring atoms.
• heteroaryl groups include, by way of example, mono-, di- or multivalent species of benzimidazole, benzofuran, benzothiazole, benzothiophene, furan, imidazole, indole, isoquinoline, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiazole, thiophene, triazole, triazine and the like, where the point or points of attachment are at any available carbon or nitrogen ring atom.
• heteroaryl includes monovalent, divalent or multivalent heteroaryl groups.
• heterocyclyl means a monovalent saturated or partially unsaturated cyclic non-aromatic group, having from 3 to 10 total ring atoms, wherein the ring contains from 2 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• Heterocyclic groups may be monocyclic or multicyclic (i.e., fused or bridged).
• heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl, 2-imidazolinyl, tetrahydropyranyl, l,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom.
• such groups may alternatively be referred to as a non- valent species, i.e. pyrrolidine, piperidine, piperazine, imidazole, tetrahydropyran etc.
• pharmaceutically acceptable salt means a salt that is acceptable for administration to a patient or a mammal, such as a human (e.g., salts having acceptable mammalian safety for a given dosage regime).
• Representative pharmaceutically acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene- 1, 5 -disulfonic, naphthalene-2, 6- disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succ
• terapéuticaally effective amount means an amount sufficient to effect treatment when administered to a patient in need of treatment.
• treating means ameliorating or suppressing the medical condition, disease or disorder being treated (e.g., a respiratory disease) in a patient (particularly a human); or alleviating the symptoms of the medical condition, disease or disorder.
• a respiratory disease e.g., a respiratory disease
• salt thereof means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
• the cation can be a protonated form of a compound of formula (I), i.e. a form where one or more amino groups have been protonated by an acid.
• the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
• Compounds 1-17, 1-27, 1-54 can be prepared as shown in the Example section.
• the 7-des-fluoro analog of 1-54 can be prepared using similar chemistry with the appropriate reagents and starting materials.
• the starting material (1-17, 1-27, 1-54, or its 7-des-fluoro analog) (1 equivalent) can be reacted with a boronic acid or ester of A (1-5 equivalents) by dissolving them in a solvent, such as 1,4-dioxane to achieve a concentration of 0.05 to 1 mmol, or about 0.15 ⁇ mol of the starting material.
• a base such as sodium carbonate is dissolved in a solvent such as water (volume equal to between 1/10 and 2 volumes of 1,4-dioxane used or about 1/3 the volume of 1,4-dioxane used), and the resulting solution is added to the above solvent solution, for example 1 ,4-dioxane.
• the reaction flask is then purged with nitrogen, and a palladium catalyst such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T- biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (between 0.01 and 0.2 equivalents, or about 0.05 equivalents) is added, and the reaction mixture is stirred and heated at between 80 and 130 °C, or at about 110 °C until the reaction is complete, or between 2 to 24 hours, or between 8 and 24 hours.
• a palladium catalyst such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T- biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (
• the reaction mixture is then worked up, for example by partitioning between dichloromethane and a saturated sodium bicarbonate solution, and the solvent layer (e.g. dichloromethane) is collected, dried (for example by using sodium sulfate), then concentrated (for example by rotary evaporation).
• the resulting crude product is then purified, for example by silica gel chromatography (0-10% methanol/dichloromethane gradient).
• the product of the Suzuki reaction described above can be dissolved in a sufficient volume of solvent such as methanol to achieve a solution concentration of 0.05-lmmol, or 0.1-0.2 mmol, then concentrated HC1 equal to about 1/2 the volume of solvent used (for example methanol) is added and the reaction mixture is stirred and heated at between 35 and 65 °C, or about 50 °C until complete, or between 1 and 24 hours, or between 4 and 24 hours.
• solvent such as methanol
• the reaction mixtures are then partially concentrated to remove the bulk of the solvent (for example methanol) and the resulting solutions are diluted with a solvent/water mixture, for example acetonitrile/water mixtures and purified, for example by reverse phase chromatography (for example with 5-70% acetonitrile/water gradient with 0.05% TFA).
• a solvent/water mixture for example acetonitrile/water mixtures
• purified for example by reverse phase chromatography (for example with 5-70% acetonitrile/water gradient with 0.05% TFA).
• aqueous ammonia for example in concentrated ammonia solution diluted 1:5 in water
• the resulting solid is then purified by reverse phase chromatography (5-70% acetonitrile/water gradient with 0.05% TFA).
• the product of the Suzuki reaction can be dissolved in a mixture of 4 M HC1 in 1 ,4-dioxane (30- 40 equivalents) and water (about 5-50 % or 20% of the volume of the HCl/dioxane solution), then the reaction mixture is stirred and heated at 40-80 °C or 60 °C until complete or for 1-48 hours or for 8-48 hours). The reaction mixture is then frozen and lyophilized, and the resulting solid purified, for example by reverse phase chromatography (for example with 0-70% acetonitrile/water gradient with 0.05% TFA).
• Method C Method C
• the product of the Suzuki reaction is dissolved in TFA (30-50 equivalents) and the reaction mixture is stirred at room temperature until complete, or for 1-24 hours.
• the reaction mixture is then concentrated by rotary evaporation and the crude product purified, for example by preparative HPLC (for example with 5-70% acetontrile/water gradient with 0.05% TFA).
• Ring A may be further substituted using conventional chemistry as illustrated in the Examples section.
• compositions typically used in the form of a pharmaceutical composition or formulation.
• Such pharmaceutical compositions may advantageously be administered to a patient by inhalation.
• pharmaceutical compositions may be administered by any acceptable route of administration including, but not limited to, oral, rectal, nasal, topical (including transdermal) and parenteral modes of administration.
• the invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or excipient and a compound of formula (I) or formula (II) where, as defined above, “compound of formula (I)” means a compound of formula (I) or a pharmaceutically-acceptable salt thereof; and “compound of formula (II)” means a compound of formula (II) or a pharmaceutically-acceptable salt thereof.
• such pharmaceutical compositions may contain other therapeutic and/or formulating agents if desired.
• such pharmaceutical compositions further comprise one or more other therapeutic agents.
• the one or more other therapeutic agents are useful for treating a respiratory disease in a mammal (e.g. a human).
• the “compound of the invention” or “compound of the present disclosure” may also be referred to herein as the “active agent”.
• the term “compound of the invention” or “compound of the present disclosure” is intended to include all compounds encompassed by formula (I) or formula (II) as well as the species embodied in formula (I) or formula (II), and pharmaceutically-acceptable salts thereof.
• compositions of the present disclosure typically contain a therapeutically effective amount of a compound of the present disclosure.
• a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.
• compositions will contain from about 0.01 to about 95% by weight of the active agent; including, for example, from about 0.05 to about 30% by weight; and from about 0.1 % to about 10% by weight of the active agent.
• pharmaceutical compositions contain from 0.1 mg to 100 mg of the active agent; including, for example, from 1 mg to 20 mg of the active agent including, for example, from 1 mg to 10 mg of the active agent.
• any conventional carrier or excipient may be used in the pharmaceutical compositions of the present disclosure.
• the choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of the present disclosure are commercially-available.
• conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen
• compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically-acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills and the like using conventional procedures and equipment.
• the pharmaceutical composition is suitable for inhaled administration.
• Pharmaceutical compositions for inhaled administration are typically in the form of an aerosol or a powder.
• Such compositions are generally administered using inhaler delivery devices, such as a dry powder inhaler (DPI), a metered-dose inhaler (MDI), a nebulizer inhaler, or a similar delivery device.
• DPI dry powder inhaler
• MDI metered-dose inhaler
• nebulizer inhaler or a similar delivery device.
• the pharmaceutical composition is administered by inhalation using a dry powder inhaler.
• dry powder inhalers typically administer the pharmaceutical composition as a free-flowing powder that is dispersed in a patient's air-stream during inspiration.
• the therapeutic agent is typically formulated with a suitable excipient such as lactose, starch, mannitol, dextrose, polylactic acid (PLA), polylactide-co-glycolide (PLGA) or combinations thereof.
• the therapeutic agent is micronized and combined with a suitable carrier to form a composition suitable for inhalation.
• a representative pharmaceutical composition for use in a dry powder inhaler comprises lactose and a compound of the present disclosure in micronized form.
• a dry powder composition can be made, for example, by combining dry milled lactose with the therapeutic agent and then dry blending the components. The composition is then typically loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
• Dry powder inhaler delivery devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
• representative dry powder inhaler delivery devices or products include Aeolizer (Novartis); Airmax (IV AX); ClickHaler (Innovata Biomed); Diskhaler (GlaxoSmithKline); Diskus/Accuhaler (GlaxoSmithKline); Ellipta (GlaxoSmithKline); Easyhaler (Orion Pharma); Eclipse (Aventis); FlowCaps (Hovione); Handihaler (Boehringer Ingelheim); Pulvinal (Chiesi); Rotahaler (GlaxoSmithKline); SkyeHaler/Certihaler (SkyePharma); Twisthaler (Schering-Plough); Turbuhaler (AstraZeneca); Ultrahaler (Aventis); and the like.
• the pharmaceutical composition is administered by inhalation using a metered-dose inhaler.
• metered-dose inhalers typically discharge a measured amount of a therapeutic agent using a compressed propellant gas.
• pharmaceutical compositions administered using a metered-dose inhaler typically comprise a solution or suspension of the therapeutic agent in a liquefied propellant.
• Any suitable liquefied propellant may be employed including hydrofluoroalkanes (HFAs), such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro- n-propane, (HFA 227); and chlorofluorocarbons, such as CCl 3 F.
• the propellant is hydrofluoroalkanes.
• the hydrofluoroalkane formulation contains a co-solvent, such as ethanol or pentane, and/or a surfactant, such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
• a representative pharmaceutical composition for use in a metered-dose inhaler comprises from about 0.01% to about 5% by weight of a compound of the present disclosure; from about 0% to about 20% by weight ethanol; and from about 0% to about 5% by weight surfactant; with the remainder being an HFA propellant.
• Such compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the therapeutic agent, ethanol (if present) and the surfactant (if present). To prepare a suspension, the therapeutic agent is micronized and then combined with the propellant. The composition is then loaded into an aerosol canister, which typically forms a portion of a metered-dose inhaler device.
• Metered-dose inhaler devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
• representative metered-dose inhaler devices or products include AeroBid Inhaler System (Forest Pharmaceuticals); Atrovent Inhalation Aerosol (Boehringer Ingelheim); Flo vent (GlaxoSmithKline); Maxair Inhaler (3M); Proventil Inhaler (Schering); Serevent Inhalation Aerosol (GlaxoSmithKline); and the like.
• the pharmaceutical composition is administered by inhalation using a nebulizer inhaler.
• nebulizer devices typically produce a stream of high velocity air that causes the pharmaceutical composition to spray as a mist that is carried into the patient's respiratory tract.
• the therapeutic agent when formulated for use in a nebulizer inhaler, can be dissolved in a suitable carrier to form a solution.
• the therapeutic agent can be micronized or nanomilled and combined with a suitable carrier to form a suspension.
• a representative pharmaceutical composition for use in a nebulizer inhaler comprises a solution or suspension comprising from about 0.05 mg/mL to about 20 mg/mL of a compound of the present disclosure and excipients compatible with nebulized formulations.
• the solution has a pH of about 3 to about 8.
• Nebulizer devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
• representative nebulizer devices or products include the Respimat Softmist Inhalaler (Boehringer Ingelheim); the AERx Pulmonary Delivery System (Aradigm Corp.); the PARI LC Plus Reusable Nebulizer (Pari GmbH); and the like.
• compositions of the present disclosure may alternatively be prepared in a dosage form intended for oral administration.
• suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
• the pharmaceutical compositions of the present disclosure will typically comprise the active agent and one or more pharmaceutically- acceptable carriers, such as sodium citrate or dicalcium phosphate.
• such solid dosage forms may also comprise: fillers or extenders, binders, humectants, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, and buffering agents. Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the pharmaceutical compositions of the present disclosure.
• Alternative formulations may also include controlled release formulations, liquid dosage forms for oral administration, transdermal patches, and parenteral formulations. Conventional excipients and methods of preparation of such alternative formulations are described, for example, in the reference by Remington, supra.
• a micronized compound of formula (I) or formula (II) (1 g) is blended with milled lactose (25 g). This blended mixture is then loaded into individual blisters of a peelable blister pack in an amount sufficient to provide between about 0.1 mg to about 4 mg of the compound of formula (I) or formula (II) per dose. The contents of the blisters are administered using a dry powder inhaler.
• a micronized compound of formula (I) or formula (II) (1 g) is blended with milled lactose (20 g) to form a bulk composition having a weight ratio of compound to milled lactose of 1 :20.
• the blended composition is packed into a dry powder inhalation device capable of delivering between about 0.1 mg to about 4 mg of the compound of formula (I) or formula (II) per dose.
• a micronized compound of formula (I) or formula (II) (10 g) is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL).
• the resulting suspension is spray dried and then micronized to form a micronized composition comprising particles having a mean diameter less than about 1.5 pm.
• the micronized composition is then loaded into metered-dose inhaler cartridges containing pressurized 1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 0.1 mg to about 4 mg of the compound of formula (I) or formula (II) per dose when administered by the metered dose inhaler.
• a compound of formula (I) or formula (II) (25 mg) is dissolved in a solution containing 1.5-2.5 equivalents of hydrochloric acid, followed by addition of sodium hydroxide to adjust the pH to 3.5 to 5.5 and 3% by weight of glycerol. The solution is stirred well until all the components are dissolved. The solution is administered using a nebulizer device that provides about 0.1 mg to about 4 mg of the compound of formula (I) or formula (II) per dose.
• the compounds of the present dislcosure are Janus kinase (JAK) inhibitors.
• the JAK inhibitors of the present disclosure have been designed for the treatment of inflammatory and fibrotic diseases, including inflammatory and fibrotic diseases of the respiratory tract.
• the compounds have been designed to enable delivery of a potent anti-cytokine agent directly to the site of action of respiratory disease in the lung while limiting systemic exposure.
• Compounds 1-3 have been shown to inhibit an effect of the pro-inflammatory cytokine IL-13 in mouse lung tissue. Specifically, the compounds have demonstrated inhibition of IL-13 -induced phosphorylation of STAT6 in lung tissue which provides evidence of local lung JAK target engagement in vivo. This effect has been observed when the pro-inflammatory cytokine IL-13 is administered 8 hours after administration of the test compound, providing further evidence of significant retention in the lung.
• JAK inhibitors The anti-inflammatory activity of JAK inhibitors has been robustly demonstrated in preclinical models of asthma (Malaviya et al., Int. Immunopharmacol, 2010, 10, 829,-836; Matsunaga et al., Biochem. and Biophys. Res. Commun., 2011, 404, 261-267; Kudlacz et al., Eur. J. Pharmacol, 2008, 582, 154-161).
• Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon- ⁇ (IFN ⁇ ) and granulocyte -macrophage colony-stimulating factor (GM- CSF). Accordingly, the compounds of the present disclosure are expected to be useful for the treatment of inflammatory respiratory disorders, in particular, asthma.
• TSLP thymic stromal lymphopoietin
• IFN ⁇ interferon- ⁇
• GM- CSF granulocyte -macrophage colony-stimulating factor
• Inflammation and fibrosis of the lung is characteristic of other respiratory diseases in addition to asthma such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
• COPD chronic obstructive pulmonary disease
• CF cystic fibrosis
• pneumonitis interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
• the present compounds are also expected to be useful for the treatment of chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
• Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low (Kuruvilla et al, Clin Rev Allergy Immunol, 2019, 56(2), 219-233). Based on their mechanism of action, the compounds of the disclosure have the potential to treat both endotypes, T2-high and T2-low.
• the compounds of the present disclosure possess biological activity involved in the inhibition of cytokines associated with inflammation. Therefore, the compounds of the present disclosure are expected to be useful for the treatment of certain specific respiratory diseases, as detailed below.
• Eosinophilic airway inflammation is a characteristic feature of diseases collectively termed eosinophilic lung diseases (Cottin et al., Clin. Chest. Med., 2016, 37(3), 535-56). Eosinophilic diseases have been associated with IL-4, IL-13 and IL-5 signaling. Eosinophilic lung diseases include infections (especially helminthic infections), drug-induced pneumonitis (induced for example by therapeutic drugs such as antibiotics, phenytoin, or 1-tryptophan), fungal-induced pneumonitis (e.g.
• Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumoni, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, and Ldffler syndrome.
• a polymorphism in the IL-6 gene has been associated with elevated IL-6 levels and an increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177).
• PAH pulmonary arterial hypertension
• Cytokines such as IENg, IL-12 and IL-6 have been implicated in a range of non-allergic lung diseases such as sarcoidosis, and lymphangioleiomyomatosis (El-Hashemite et al., Am. J. Respir. Cell. Mol. Biol., 2005, 33, 227-230, and El-Hashemite et al., Cancer Res., 2004, 64, 3436-3443).
• Bronchiectasis and infiltrative pulmonary diseases are diseases associated with chronic neutrophilic inflammation.
• Pathological T cell activation is critical in the etiology of multiple respiratory diseases.
• Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipients T cells by the transplanted donor lung.
• Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD).
• PGD Primary Graft Dysfunction
• OP organizing pneumonia
• AR acute rejection
• LB lymphocytic bronchiolitis
• CLAD chronic lung allograft dysfunction
• rCLAD or RAS restrictive CLAD
• neutrophilic allograft dysfunction chronic lung allograft dysfunction
• CLAD chronic lung allograft dysfunction
• IFN ⁇ and IL-5 JAK-dependent cytokines
• GVHD lung graft-versus-host disease
• CLAD lung graft-versus-host disease
• ruxolitinib is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved.
• the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction.
• the lung transplant rejection is acute lung transplant rejection.
• the lung transplant rejection is chronic lung allograft dysfunction.
• the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction.
• immune-checkpoint inhibitor induced pneumonitis another T cell mediated lung disease emerged with the increased use of immune-checkpoint inhibitors. In cancer patients treated with these T cell stimulating agents, fatal pneumonitis can develop.
• the compounds of the disclosure possess biological activity allowing inhibition of IHNg secretion.
• the present disclosure provides a method of treating a respiratory disease in a mammal (e.g., a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonitis, cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, or sarcoidosis.
• the respiratory disease is asthma or chronic obstructive pulmonary disease.
• the Asthma is T2- high Asthma. In some embodiments, the Asthma is T2-low Asthma.
• the respiratory disease is a lung infection, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Ldffler syndrome, bronchiolitis obliterans organizing pneumonia, acute and chronic lung transplant rejections (including PGD, OP, LB, AR and CLAD, BO, restrictive CLAD and neutrophilic allograft dysfunction), lung graft-versus-host disease, or immune-checkpoint-inhibitor induced pneumonitis.
• lung infection an eosinophilic disease
• the present disclosure further provides a method of treating asthma in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• a mammal e.g. a human
• the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• the compounds of the present disclosure When used to treat asthma, the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used.
• the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• the present disclosure further provides a method of treating a respiratory disease (including but not limited to the disease described herein) in a mammal (e.g. a human), the method comprising administering to the mammal (or human), a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• a respiratory disease including but not limited to the disease described herein
• a mammal e.g. a human
• the method comprising administering to the mammal (or human), a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• the compounds of the present disclosure When used to treat a respiratory disease (including but not limited to the disease described herein), the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used.
• the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• Human coronavirus is a common respiratory pathogen and typically induces mild upper respiratory disease.
• the two highly pathogenic viruses Severe Acute Respiratory Syndrome associated- Coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome-associated Coronavirus (MERS- CoV), caused severe respiratory syndromes resulting in more than 10% and 35% mortality, respectively (Assiri et al., N Engl J Med., 2013, 369, 407-1).
• SARS-CoV-1 Severe Acute Respiratory Syndrome associated- Coronavirus
• MERS- CoV Middle East Respiratory Syndrome-associated Coronavirus
• a subset of patients can develop a severe respiratory illness manifested by acute lung injury (ALI) leading to ICU admission (about 5%), respiratory failure (about 6.1%) and death (Wang et al., JAMA, 2020, 323, 11, 1061-1069; Guan et al., N Engl J Med., 2020, 382, 1708-1720; Huang et al., The Lancet, 2020. 395 (10223), 497-506; Chen et al., The Lancet, 2020, 395(10223), 507-13).
• a subgroup of patients with COVID-19 appears to have a hyperinflammatory “cytokine storm” resulting in acute lung injury and acute respiratory distress syndrome (ARDS).
• This cytokine storm may also spill over into the systemic circulation and produce sepsis and ultimately, multi- organ dysfunction syndrome.
• the dysregulated cytokine signaling that appears in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs), and chemokines, resulting in ALI and associated mortality.
• IFNs interferons
• ILs interleukins
• chemokines resulting in ALI and associated mortality.
• This hyperinflammatory response can potentially be modulated and treated by a lung-selective pan-Janus Kinase (JAK) inhibitor.
• Monoclonal antibodies directed against IL- 6 (tocilizumab) appear to be effective in treating patients with ALI from COVID-19 (Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al.
• JAK inhibitors have also been shown to be beneficial in mouse models of lipopolysaccharide-or ganciclovir-induced ALI (Severgnini et al., Am J Respir Crit Care Med., 2005, 171(8), 858-67; Jin et al., Am J Physiol-Lung Cell Mol Physiol., 2018, 314(5), L882-92).
• baricitinib a JAK inhibitor
• EUA emergency use authorization
• compounds of formula (I) or formula (II), which are lung-selective inhaled pan-JAK inhibitors could be uniquely suited to dampen the cytokine storm associated with COVID-19.
• an inhaled medication may be a way to avoid systemic immunosuppression that would pre-dispose patients to these risks.
• the present disclosure provides a method of treating a mammal (or patient) infected with a coronavirus such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, or the symptoms thereof, the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• a coronavirus such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV
• the present disclosure also provides a method of treating ALI and/or ARDS in a mammal (or a patient) caused by a coronavirus infection (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• a coronavirus infection such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV
• JAK inhibitors The mechanism of action of JAK inhibitors has been linked to the treatment of nasal inflammatory diseases (Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice, Joo et al., The Laryngoscope, 2020, https://doi.org/10.1002/lary.29129). Further, Dupilumab, which acts by blocking the IL-4 and IL-13 signaling pathways, has been approved for the treatment of chronic rhinosinusitis with nasal polyps.
• nasal inflammatory diseases in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• the nasal inflammatory disease is selected from the group consisting of chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, and rhinitis (non-allergic, allergic, perenial, and vasomotor rhinitis).
• the compounds of the present disclosure may also be useful for a variety of other diseases.
• the compounds of the present disclosure may be useful for a variety of gastrointestinal inflammatory indications that include, but are not limited to, inflammatory bowel disease, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn’s disease, collagenous colitis, lymphocytic colitis, Behcet’s disease, celiac disease, immune checkpoint inhibitor induced colitis, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis. Ulcerative colitis (Reimund et al., J. Clin.
• PD-1- or PD-L1 -inhibitor-induced colitis are characterized by elevation of certain pro-inflammatory cytokine levels.
• pro-inflammatory cytokines signal via JAK activation
• compounds described in this application may be able to alleviate the inflammation and provide symptom relief.
• the compounds of the present disclosure may be useful for the induction and maintenance of remission of ulcerative colitis, and for the treatment of Crohn's disease, immune checkpoint inhibitor induced colitis, and the gastrointestinal adverse effects in graft versus host disease.
• the present disclosure provides a method of treating a gastrointestinal inflammatory disease in a mammal (e.g., a human), the method comprising administering to the mammal a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• a mammal e.g., a human
• the method comprising administering to the mammal a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
• Atopic dermatitis and other inflammatory skin diseases have been associated with elevation of proinflammatory cytokines that rely on the JAK-STAT pathway. Therefore, the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be beneficial in a number of dermal inflammatory or pruritic conditions that include, but are not limited to atopic dermatitis, alopecia areata, vitiligo, psoriasis, dermatomyositis, cutaneous T cell lymphoma (Netchiporouk et al., Cell Cycle 2014;
• atopic dermatitis (Bao et al., JAK-STAT, 2013, 2, e24137), alopecia areata (Xing et al., Nat. Med. 2014, 20, 1043-1049), vitiligo (Craiglow et al, JAMA Dermatol. 2015, 151, 1110-1112), prurigo nodularis (Sonkoly et al., J. Allergy Clin. Immunol. 2006, 117, 411-417), lichen planus (Welz-Kubiak et al., J. Immunol. Res. 2015, ID:854747), primary localized cutaneous amyloidosis (Tanaka et al., Br. J.
• the present disclosure provides a method of treating an inflammatory skin disease in a mammal (e.g., a human), the method comprising applying a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier to the skin of the mammal.
• a mammal e.g., a human
• the inflammatory skin disease is atopic dermatitis.
• ocular diseases have been shown to be associated with elevations of proinflammatory cytokines that rely on the JAK-STAT pathway.
• the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may be useful for the treatment of a number of ocular diseases that include, but are not limited to, uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, and atopic keratoconjunctivitis.
• uveitis Horai and Caspi, J. Interferon Cytokine Res., 2011, 31, 733-744
• diabetic retinopathy Abcouwer, J. Clin. Cell.
• the present disclosure provides a method of treating an ocular disease in a mammal (e.g. a human), the method comprising administering a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically-acceptable salt thereof and a pharmaceutical carrier to the eye of the mammal (or human).
• a mammal e.g. a human
• the ocular disease is uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, or atopic keratoconjunctivitis.
• the method comprises administering the compound of the present disclosure, or a pharmaceutically acceptable salt thereof by intravitreal injection.
• Compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may also be used in combination with one or more compound useful to ocular diseases.
• the compounds of the present disclosure may also be useful to treat other diseases such as other inflammatory diseases, autoimmune diseases or cancers.
• the compounds of the present disclosure may be useful to treat one or more of cytokine release syndrome (CRS), arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, transplant rejection, xerophthalmia, psoriatic arthritis, diabetes, insulin dependent diabetes, motor neurone disease, myelodysplastic syndrome, pain, sarcopenia, cachexia, septic shock, systemic lupus erythematosus, leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, ankylosing spondylitis, myelofibrosis, B-cell lymphoma, hepatocellular carcinoma, Hodgkins disease, breast cancer, Multiple myeloma, melanoma, non-Hodgkin lymphoma, non-small-cell lung cancer, ovarian clear cell carcinoma, ova
• CRS cytokine release
• Compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used in combination with one or more agents which act by the same mechanism or by different mechanisms to treat a disease.
• the different agents may be administered sequentially or simultaneously, in separate compositions or in the same composition.
• Useful classes of agents for combination therapy include, but are not limited to, a beta 2 adrenoceptor agonist, a muscarinic receptor antagonist, a glucocorticoid agonist, a G-protein coupled receptor-44 antagonist, a leukotriene D4 antagonist, a muscarinic M3 receptor antagonist, a histamine HI receptor antagonist, an immunoglobulin E antagonist, a PDE 4 inhibitor, an IL-4 antagonist, a muscarinic Ml receptor antagonist, a histamine receptor antagonist, an IL- 13 antagonist, an IL-5 antagonist, a 5 -Lipoxygenase inhibitor, a beta adrenoceptor agonist, a CCR3 chemokine
• JAK inhibitor compounds include, but are not limited to rosiptor acetate, umeclidinium bromide, secukinumab, metenkefalin acetate, tridecactide acetate, fluticasone propionate, alpha-cyclodextrin-stabilized sulforaphane, tezepelumab, mometasone furoate, BI-1467335, dupilumab, aclidinium, formoterol, AZD-1419, HI- 1640V, rivipansel, CMP-001, mannitol, ANB-020, omalizumab, tregalizumab, Mitizax, benralizumab, golimumab, roflumilast, imatinib, REGN-3500, masitinib, apremilast, RPL-554, Actimmune, ada
• a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
• the therapeutic agent may be selected from the class of agents specified above and from the list of specific agents described above.
• the pharmaceutical composition is suitable for delivery to the lungs.
• the pharmaceutical composition is suitable for inhaled or nebulized administration.
• the pharmaceutical composition is a dry powder or a liquid composition.
• the present disclosure provides a method of treating a disease or disorder in a mammal (e.g. a human) comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
• a mammal e.g. a human
• administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
• the agents When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. Such compositions can be packaged separately or may be packaged together as a kit. The two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration.
• DIPEA N,N -diisopropyl ethyl amine
• PdCl 2 (dppf) [1,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)
• HATU N, N, N', N'-tetramethyl-O-(7-azabenzotriazol- 1 -yl)uronium hexafluorophosphate
• HBTU N, N, N', N'-Tetramethyl-O-( 1 H-benzotriazol- 1 -yl)uronium hexafluorophosphate
• NaHMDS sodium bis(trimethylsilyl)amide
• NBS N-Bromosuccinimide
• Pd(PPh3)4 tetrakis(friphenylphosphine)palladium(0)
• TBAF tetra-N-butylammonium fluoride
• TBDPSC1 tert-Butyl(chloro)diphenylsilane
• reaction mixtures were worked up as described specifically in each reaction; commonly they were purified by extraction and other purification methods such as temperature-, and solvent- dependent crystallization, and precipitation.
• reaction mixtures were routinely purified by column chromatography or by preparative HPLC, typically using Cl 8 or BDS column packings and conventional eluents. Typical preparative HPLC conditions are described below.
• Injection volume (100-1500 ⁇ L)
• the reaction mixture was then filtered through celite and the pad was washed with DCM.
• the resulting organic filtrate was then washed with aqueous sodium carbonate solution and extracted with DCM (3 x 100 ml).
• the combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure.
• the crude product was then purified by silica gel chromatography, eluting in 20-25% EtOAc/heptane to the product (1-31) as a white solid (5.0 g, 84% yield).
• reaction mixture was purged with nitrogen for 10 min, then [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (612 mg, 0.1 eq., 837 ⁇ mol) was added and the reaction mixture was stirred at 110 °C for 5 h.
• the reaction mixture was then filtered through a pad of celite, the pad was washed with EtOAc (60 ml), and the resulting filtrate was concentrated under reduced pressure.
• the crude product was then purified by silica gel chromatography, eluting with 5% EtOAc/heptane to provide the product (1-33) as a pale yellow liquid (1.95 g, 40% yield).
• reaction mixture was then purged with argon for 10 minutes followed by the addition of 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (1.31 g, 1.61 mmol).
• the reaction mixture was then stirred at 110 °C until judged complete by TEC and LCMS (4 h).
• the reaction mixture was then filtered through a pad of celite, which was then rinsed with EtOAc.
• the filtrate was then concentrated under reduced pressure and the resulting crude product was purified by silica gel chromatography, eluting at 5% EtOAc/heptane to provide the product (1-42) (1.9 g, 34% yield).
• reaction mixture was carefully quenched with saturated NH4CI solution (800 mL), and further diluted with water (300 mL).
• the mixture was extracted with ethyl acetate (3 x 500 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to afford the desired product as a colorless liquid (80 g, 83% yield).
• the reaction was used directly in the subsequent step without further purification.
• the reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate solution, and the dichloromethane layer was collected, dried over sodium sulfate, then concentrated by rotary evaporation.
• the resulting crude product was then purified by silica gel chromatography (0-10% methanol/dichloromethane gradient) .
• the product of the Suzuki reaction was dissolved in a sufficient volume of methanol to achieve a solution concentration of 0.1 -0.2 mmol, then concentrated HC1 equal to 1/2 the volume of methanol used was added and the reaction mixture was stirred and heated at 50 °C until judged complete by LCMS (4- 24 hours).
• solution volume ⁇ 5 mL the reaction mixtures were then partially concentrated to remove the bulk of the methanol, and the resulting solutions were diluted with acetonitrile/water mixtures and purified by reverse phase chromatography (5-70% acetonitrile/water gradient with 0.05% TFA).
• reaction mixture was dripped into a solution of aqueous ammonia (concentrated ammonia solution diluted 1:5 in water) to precipitate out the product, which was then collected by filtration.
• aqueous ammonia concentrated ammonia solution diluted 1:5 in water
• the resulting solid was then purified by reverse phase chromatography (5-70% acetonitrile/water gradient with 0.05% TFA).
• the product of the Suzuki reaction was dissolved in a mixture of of 4 M F1C1 in 1 ,4-dioxane (30- 40 eq) and water (20% of the volume of the FICl/dioxane solution), then the reaction mixture was stirred and heated at 60 °C until judged complete by LCMS (8-48 hours). The reaction mixture was then frozen and lyophilized, and the resulting solid was purified by reverse phase chromatography (0-70% acetonitrile/water gradient with 0.05% TFA).
• Example 7 4-(3-(4-(3-oxa-9-azabicyclo[3.3.1]non-6-en-7-yl)-lH-imidazol-2-yl)-lH-indazol- 6-yl)-3-ethylphenol (7)
• HATU (19 mg, 0.050 mmol) was then added and the reaction mixture was stirred at room temperature until judged complete by LCMS (24 hours). Hydrazine (5 ⁇ l, 0.166 mmol) was then added to cleave undesired byproducts and the reaction mixture was concentrated. The residue was then dissolved in TFA (1 mL) and stirred at room temperature until LCMS showed complete removal of the Boc protecting group (30 minutes).
• the reaction vial was purged with nitrogen, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.10 mg, 0.020 mmol) was added and the reaction mixture was stirred at 110 °C until judged complete by LCMS (16 h). The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate solution, after which the dichloromethane layer was dried over sodium sulfate and concentrated.
• a panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were carried in a common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , and 1 mM EGTA).
• Recombinant GST-tagged JAK enzymes and a GFP-tagged STAT1 peptide substrate were obtained from Life Technologies.
• Serially diluted compounds were pre-incubated with each of the four JAK enzymes and the substrate in white 384-well microplates (Corning) at ambient temperature for lh. ATP was subsequently added to initiate the kinase reactions in 10 mE total volume, with 1% DMSO.
• the final enzyme concentrations for JAK1, 2, 3 and Tyk2 are 4.2 nM, 0.1 nM, 1 nM, and 0.25 nM respectively; the corresponding Km ATP concentrations used are 25 mM, 3 mM, 1.6 mM, and 10 mM; while the substrate concentration is 200 nM for all four assays.
• Kinase reactions were allowed to proceed for 1 hour at ambient temperature before a 10 ⁇ L preparation of EDTA (lOmM final concentration) and Tb-anti- pSTATl (pTyr701) antibody (Life Technologies, 2 nM final concentration) in TR-FRET dilution buffer (Life Technologies) was added. The plates were allowed to incubate at ambient temperature for lh before being read on the EnVision reader (Perkin Elmer). Emission ratio signals (520nm/495nm) were recorded and utilized to calculate the percent inhibition values based on DMSO and background controls.
• the JAKI cellular potency assay was carried out by measuring inhibition of interleukin- 13 (IL- 13, R&D Systems) induced STAT6 phosphorylation in BEAS-2B human lung epithelial cells (ATCC).
• BEAS-2B cells were grown at 37°C in a 5% CO 2 humidified incubator in 50% DMEM/50% F-12 medium (Life Technologies) supplemented with 10% FBS (Hyclone), 100 U/mL penicillin, 100 ⁇ g/mL streptomycin (Life Technologies), and 2 mM GlutaMAX (Life Technologies).
• Cells were incubated with test compounds at 37°C for 1 h and followed by the addition of 12 pi of pre-warmed IL-13 (80 ng/mL in assay buffer) for stimulation. After incubating at 37°C for 30 min, the assay buffer (containing compound and IL-13) was removed, and 10 ⁇ L of cell lysis buffer (25 mM HEPES, 0.1 % SDS, 1 % NP-40, 5 mM MgCl 2 , 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra mini protease inhibitors and PhosSTOP from Roche Diagnostics).
• cell lysis buffer 25 mM HEPES, 0.1 % SDS, 1 % NP-40, 5 mM MgCl 2 , 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra mini protease inhibitors and PhosSTOP from Roche Diagnostics.
• the plates were shaken at ambient temperature for 30min before the addition of detection reagents.
• pSTAT6 levels of pSTAT6 were measured using the AlphaLISA SureFire Ultra pSTAT6 (Tyr641) assay kit from PerkinElmer. For dose -response analysis, percent inhibition data were plotted vs. compound concentrations, and IC 50 values were determined from a 4-parameter robust fit model with the Graphpad Prism software. Results are expressed as the negative logarithm of the IC 50 value, pICso-
• Test compounds having a lower IC 50 value or higher pICso value in this assay show greater inhibition of IL-13 induced STAT6 phosphorylation.
• the compounds were tested in the BEAS-2B cellular potency assay and at least two of the four JAK enzyme assays; JAKI, JAK2, JAK3, and TYK2 described above.
• A represents a pKi value > 10 (Ki ⁇ 0.1 nM)
• B represents a pKi value between 9 (included) and 10 (Ki between 1 nM and 0.1 nM)
• C represents a pKi value between 8 (included) and 9 (Ki between 10 nM and 1 nM)
• D represents a pKi value between 7 (included) and 8 (Ki between 100 nM and 10 nM)
• E represents a pKi value of 7 or below (Ki of 100 nM or above).
• A represents a pICso value between 8 (included) and 8.5
• B represents a pICso value between 7.5 (included) and 8
• C represents a pICso value between 7 (included) and 7.5
• D represents a pICso value between 6.5 (included) and 7
• E represents a pICso value between 6.0 and 6.5.
• a blank in Table 1 means not tested.
• Assay 3 Murine (Mouse) model of IL-13 induced pSTAT6 induction in lung tissue
• IL-13 binds to cell surface receptors activating members of the Janus family of kinases (JAK) which then phosphorylate STAT6 and subsequently activate further transcription pathways.
• JK Janus family of kinases
• a dose of IL-13 was delivered locally into the lungs of mice to induce the phosphorylation of STAT6 (pSTAT6) which is then measured as the endpoint.
• Selected compounds of the present disclosure were tested in the assay. Activity in the model is evidenced by a decrease in the level of pSTAT6 present in the lungs of treated animals at 9 hours compared to the vehicle treated, IL-13 challenged control animals. The difference between the control animals which were vehicle- treated, IL-13 challenged and the control animals which were vehicle- treated, vehicle challenged dictated the 0% and 100% inhibitory effect, respectively, in any given experiment. Exemplary compounds were tested in the assay and exhibited inhibition of STAT6 phosphorylation at 9 hours after IL-13 challenge as documented below.
• A represents between 80 % and 100 % inhibition
• B represents between 60 % and 80 % inhibition
• C represents between 40 % and 60 % inhibition.
• Plasma and lung concentrations of test compounds were quantified and pharmacokinetic parameters were calculated in the following manner.
• Male CD1 mice from Charles River Laboratories were used in the pharmacokinetic studies.
• Test compounds were individually formulated in 20% propylene glycol in pH 4 citrate buffer at a concentration of 0.2 mg/mL.
• Test compounds were administered in two, 25 ⁇ L increments introduced into the trachea of each mouse by oral aspiration using a calibrated pipette once the animal was anesthetized using isoflurane. Blood samples were collected as terminal collections via cardiac puncture at 0.167, 1, 4, 8, and 24 hr post-dosing.
• Plasma and lung concentrations of test compounds were determined by LC-MS/MS analysis against analytical standards constructed into a standard curve in the test matrix.
• the pharmacokinetic parameters of test compounds were determined by non-compartmental analysis. For concentrations below the limit of quantification, zero was used for mean calculations. Mean values were not reported if more than 50% of the samples were below the limit of quantification at a timepoint, or if more than 50% of a calculated pharmacokinetic parameter was not reportable.
• AUC (0-inf) AUC (0 -t) + C last / k
• AUC (0 -t) the area under the concentration-time curve from the time of dosing to the last measurable concentration calculated by the linear trapezoidal rule
• C last is the last measurable concentration
• k the first order rate constant associated with the terminal elimination phase, estimated by linear regression of time versus log concentration.
• the lung-to-plasma AUC ratio was determined as the ratio of the lung AUC (0-inf) in ⁇ g*hr/g to the plasma AUC (0-inf) in ⁇ g*hr/mL.
• A denotes a value below 0.5
• B denotes a value between 0.5 and 1
• C denotes a value between 1 and 1.5.
• A denotes a value between 100 and 200
• B denotes a value between 50 and 100
• C denotes a value between 9 and 50.
• A denotes a ratio 300-410
• B denotes a ratio between 200 and 300
• C denotes a ratio between 100 and 200
• D denotes a ratio between 50 and 100
• E denotes a ratio between 30 and 50.

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