HK40009913A - Non-selective kinase inhibitors - Google Patents

Description

Non-selective kinase inhibitors

This application is a divisional application of chinese patent application No. 201480010529.X (international application No. PCT/US2014/010778), entitled "non-selective kinase inhibitor", filed on 09.01/2014.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority from U.S. provisional application No. 61/751217 filed on 10.1.2013, and U.S. provisional application No. 61/889887, which are incorporated herein by reference in their entirety.

Statement of government sponsored research

The invention was made with U.S. government support grant numbers 1R43HL102946-01 and 2R44HL102946-02 awarded by the national institutes of health. The united states government has certain rights in this invention.

Technical Field

The present disclosure relates generally to the treatment and prevention of diseases associated with protein kinase activity. In particular, the technology relates to therapeutic indications of protein kinase inhibitors and methods for treating or preventing conditions, cancers, and other disorders of the lung and blood vessels.

Background

The following discussion of the background is merely provided to assist the reader in understanding the present invention and does not necessarily describe or constitute prior art.

Receptor Tyrosine Kinases (RTKs) are transmembrane polypeptides that regulate cell and tissue regeneration, remodeling, development and differentiation. See, for example, Mustonen et al, J.cell Biology 129, 895-. Van der Geer, and the like. Ann Rev.cell biol.10, 251-337 (1994). In addition to activating RTKs, growth factors and cytokines of the polypeptide ligand are capable of inducing conformational changes in the outer domains of RTKs, which results in receptor dimerization. Lymboussaki, thesis, university of Helsinki, Moore/Cancer biology laboratory and Pathology department, Haartman institute (Disservation, Univ. of Helsinki, mol./Cancer Bio Lab and depth. of Pathology, Haartman institute) (1999). Ullrich et al, Cell 61, 203-. Furthermore, homologous RTK receptor-ligand binding confers receptor transphosphorylation and subsequent activation of the kinase catalytic domain at specific tyrosine residues, thereby phosphorylating and activating a signaling cascade associated with substrate phosphorylation. As above.

However, aberrant RTK activity, associated with a variety of disease conditions, and systemic delivery of certain RTK inhibitors have shown efficacy for specific disease conditions. This in vivo assay, including the murine Monocrotaline (MCT) model system, has been used to determine whether putative RTK inhibitors act as therapeutic agents. However, MCT models are criticized for efficacy of preclinical drug candidates because such systems do not confirm certain human disease phenotypes, e.g., the development of neointimal and/or plexiform lesions that are symptomatic comorbidities of such diseases. Thus, this model is an imperfect system that may confound the etiology and pathological indications of human disease. Therefore, new or complementary model systems are necessary for accurate and efficient drug development.

See, e.g., Shah et al, Science, 305, 395-402 (2004.) for example, in certain kinase inhibitors, e.g., imatinib refractory patients, it has been shown that the hydrophobic pocket "watch residue" often has mutations see Pao et al, PLos Med.2 (3): e73 (2005.) such mutations have been identified relative to ABL, i.e., at the T315 residue, and at similar positions in KIT, PDGFR α and other kinases, supra.

Disclosure of Invention

In one aspect, the present disclosure provides a method for the inhibition of a non-selective kinase receptor for treating a pulmonary disease in a subject, comprising: administering to the subject a therapeutically effective amount of a compound of structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer or stereoisomer of the compound, or any mixture thereof, wherein structure 1 has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃-a-C-N-C-group, -a-C-N-C (═ O) -group, -C (═ O) R⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical (I)Substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂a-C ≡ N, -C ═ N-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstitutedA substituted dialkylamino group, a substituted and unsubstituted diarylamino group, a substituted and unsubstituted (alkyl) (aryl) amino group, -C (═ O) H, -C (═ O) -alkyl group, -C (═ O) -aryl group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) NH-alkyl group₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; - (alkyl) (aryl) aminoalkyl groups, -C (═ O) -heterocyclyl groups, -C (═ O) -O-heterocyclyl groups, -C (═ O) NH (heterocyclyl) groups, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted hydroxyalkyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted aryloxyalkyl group, and substituted and unsubstituted heterocyclyloxyalkyl group, -NH (alkyl) group, -NH (aryl) group, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N- (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and-N- (aryl) O-aryl group;

R⁸is selected from R¹，R²，R³，R⁴，R⁵，R⁶，R⁷H, absent, -C ═ C, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups (R)⁹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹) Radical, substituted and unsubstituted aryl (R)¹⁰) Radical, substituted and unsubstituted aryl (R)¹¹) Radicals, substituted and unsubstituted aryl radicals(R⁹)(R¹⁰) Radical, substituted and unsubstituted aryl (R)⁹)(R¹¹) Radical, substituted and unsubstituted aryl (R)¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹)(R¹⁰)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰)(R¹¹) A group, and substituted/unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰)(R¹¹)；

R⁹，R¹⁰And R¹¹May be the same or different and is independently selected from the group consisting of absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²a-C ≡ N, -C-N-C-group, -C-N (═ O) -group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N-group, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groupsSubstituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -C (═ O) -aryl groups, -C (═ O) O-alkyl groups, -C (═ O) O-aryl groups, -C (═ O) NH-aryl groups₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted cyano group, substituted and unsubstituted pyrimidinyl group, substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) group, and substituted and unsubstituted cyano-pyrimidinyl group;

R¹²selected from absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²A group, -C ≡ N, -C-N-C-, -C-N-C (═ O) -group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, -C (═ O) -C-group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-a C ≡ C-group, -S (═ O)₂-C＝C-CH₃Alkoxy groups, aryloxy groups, substituted and unsubstituted amidino groups, substituted and unsubstituted guanidino groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted guanidino groups, and substituted or unsubstituted guanidino groupsSubstituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

Q¹selected from direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-, -C ≡ N, -C-N-C-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, -C (═ O) -C-group, -C (═ O) -C ═ C, -CF ═ C-group₃-a C ≡ N, -a C-N-C-group, -a C-N-C (═ O) -C-F, -a C-N-C (═ O) -C ═ C, -OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted heterocyclyl group, an alkoxy group, an aryloxy group, a methoxy group, a dimethoxy group, methoxyphenol, a methoxyphenol group, dimethoxyphenol, a dimethoxyphenol group, a dimethoxybenzene, a dimethoxyphenyl group, a methoxymethylbenzyl group, a substituted and unsubstituted aralkyl group, -NH-N-C-group, -a C-N-C (═ O) -group, -a substituted and unsubstituted aryl group, a substituted and unsubstituted heterocyclyl group, an alkoxy group, an aryloxy group, a methoxy₂Substituted and unsubstituted heterocyclylalkyl groups, substituted/unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, and substituted and unsubstituted alkylaminoalkyl groupsUnsubstituted pyrimidinyl, substituted and unsubstituted cyano (aryl), substituted and unsubstituted cyano (heterocyclyl), and substituted and unsubstituted cyano-pyrimidinyl;

Q²selected from absent, H, Q¹，Q¹(Q³) -OH, alkoxy groups, aryloxy groups; and

Q³selected from absent, direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-a group, -C ≡ N, -C-N-C, -a group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N-a group, -C (═ O) -C ═ C, -CF ═ C₃a-C ≡ N, -C-N-C-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -OH, an alkoxy group, an aryloxy group, a methoxy group, a dimethoxy group, a methoxyphenol group, a dimethoxyphenol group, a dimethoxybenzene, a dimethoxyphenyl group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, and a substituted and unsubstituted heterocyclyl group. Subject matter of the preceding paragraph (i.e., [0009 ]]) Hereinafter referred to as "QXR".

In the illustrative embodiments, R⁸Has the following formula:

wherein X is independently selected from C, N, O, S and-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²，-C≡N，-C-N-C(＝O)-C-F，-C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidyl group, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstitutedSubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl. The contents of the preceding paragraph (i.e., [0010 ]]) Hereinafter referred to as "QXR 2".

In the illustrative embodiments, R⁸Is selected from group a, as shown below.

Structure of group A

In illustrative embodiments, Q¹Or Q²Is selected from the group B, -CH₃，-OH，-O-CH₃-C-N-C (═ O) -C ═ C and-C-N-C (═ O) -CF.

Group B structure

In some embodiments, the compound of structure 1 is a compound of structure 2, 2a, 3,4 or 5, as shown in group C

C group structure

In illustrative embodiments, the compound of structure 1,2, 2a, 3,4 or 5 is administered orally, intravenously, subcutaneously, transdermally, intraperitoneally, or by inhalation, hi illustrative embodiments, the kinase receptor is a Receptor Tyrosine Kinase (RTK), and wherein the RTK is a platelet-derived growth factor receptor (PDGFR). in illustrative embodiments, the PDGFR is platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β), or both.

In illustrative embodiments, the pulmonary disease is selected from Pulmonary Arterial Hypertension (PAH), PAH associated with plexiform and/or neointimal lesions, PAH associated with pulmonary fibrosis and/or progressive vascular degeneration, abnormal fibroblast and/or myofibroblast proliferation, and pulmonary vascular disease associated with abnormal endothelial cell proliferation.

In exemplary embodiments, the PAH is selected from the group consisting of primary PAH, idiopathic PAH, inherited PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with systemic sclerosis, mixed connective tissue disease, HIV, hepatitis, and/or portal hypertension.

In exemplary embodiments, PAH is secondary to pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension in newborns, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), pulmonary hypertension of left heart disease, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, Chronic Obstructive Pulmonary Disease (COPD), sleep disordered breathing, alveolar hypoventilation disorder, long term exposure to high altitude, dysplasia, chronic embolic pulmonary hypertension (CTEPH), pulmonary hypertension with an unclear multi-factorial mechanism, hematologic disorders, myeloproliferative diseases, splenectomy, systemic diseases, sarcoidosis, pulmonary langerhans cell histiocytosis, lymphatic smooth vessel, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage disease, gaucher's disease, thyroid disease, tumor obstruction, fibrous mediastinitis, and/or dialysis chronic renal failure (chronic renal failure).

In illustrative embodiments, the lung disease is associated with an abnormality: right Ventricular Systolic Pressure (RVSP); pulmonary pressure; cardiac output; right Ventricular (RV) hypertrophy; and/or Pulmonary Artery (PA) hypertrophy. In illustrative embodiments, the compound of structure 1 has an IC for kinase receptor of less than 300nM₅₀In illustrative embodiments, the kinase receptor is platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both, wherein the lung disease is pulmonary hypertension.

In one aspect, the invention provides a method of treating Pulmonary Arterial Hypertension (PAH) in a subject, comprising modulating the phosphorylation state of one or more downstream targets of platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both, wherein the downstream target is any phosphorylation substrate as a result of activation of PDGFR- α and/or PDGFR- β, by administering to the subject a compound of structure 1, a tautomer, enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer, or stereoisomer of the compound, or any mixture thereof, wherein the downstream target is selected from AKT, PDGFR, STAT3, ERK1 and ERK2, or PDGFR- α and/or any other downstream target of PDGFR- β, and wherein the compound of structure 1 has the formula:

wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃-a-C-N-C-group, -a-C-N-C (═ O) -group, -C (═ O) R⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical, substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂-a group of formula (i) -C ≡ N, -a group of formula (ii), -C-N-C, -a group of formula (iii), -C-N-C (═ O) -a group of formula (iii) -C-N-CO) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -C (═ O) -aryl groups, -C (═ O) O-alkyl groups, -C (═ O) O-aryl groups, -C (═ O) NH-alkyl groups₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted arylalkyl groupsAn oxyalkyl group, and substituted and unsubstituted heterocycloxyalkyl groups; - (alkyl) (aryl) aminoalkyl groups, -C (═ O) -heterocyclyl groups, -C (═ O) -O-heterocyclyl groups, -C (═ O) NH (heterocyclyl) groups, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted hydroxyalkyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted aryloxyalkyl group, and substituted and unsubstituted heterocyclyloxyalkyl group, -NH (alkyl) group, -NH (aryl) group, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and-N (aryl) O-aryl group;

wherein R is⁸Has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-C ≡ N, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstitutedA heterocyclyl group, -OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted alkylamino group, a substituted and unsubstituted arylamino group, and a substituted and unsubstituted dialkylamino group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, a substituted and unsubstituted cyano (heterocyclyl) group, and substituted and unsubstituted cyano-pyrimidinyl groups;

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidyl group, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

wherein Q is¹Or Q²Is selected from the group consisting of-CH₃，-OH，-O-CH₃，-C-N-C(＝O)-C＝C，-C-N-C(＝O)-C-F，

The entirety of the preceding paragraph (i.e., [0019]) is hereinafter referred to as "QXR 3"

In exemplary embodiments, R⁸In illustrative embodiments, the modulation is a reduction of phosphorylated STAT3 relative to total STAT3, a reduction of diphosphorylated ERK1 relative to total ERK1, a reduction of diphosphorylated ERK2 relative to total ERK2, a reduction of monophosphorylated ERK1 relative to total ERK1, a reduction of phosphorylated PDGFR relative to total PDGFR, or a reduction of phosphorylated AKT relative to total AKT, or any combination thereof, as compared to PSR in the subject prior to administration in illustrative embodiments, the compound of structure 1 interacts with AKT at residues Thr308 and/or Ser, or wherein the compound of structure 1 interacts with one or more of PDGFR- α - β - αα - ββ, and/or PDGFR- αβ amino acids selected from LYS627, VAL607, GLU, MET 644, LYS 836, LYS 658, LYS 826, LYS 658, LYS 826, LYS 658, LYS 826, LYS 658, LYS 844, LYS 658, LYS 844, LYS 654, LYS 844, LYS 658, LYS 654, LYS 844, LYS 654, LYS 658, LYS 844, LYS 836, LYS 658, LYS 844, LYS 654, LYS 658, LYS 654, LYS 844, or any combination thereof in a subject before administration.

In some embodiments, the compound of structure 1 is a compound selected from the aforementioned group C structures, as described in the summary of the invention. In illustrative embodiments, inhibition occurs through non-covalent interactions. In illustrative embodiments, inhibition occurs through covalent interactions. In illustrative embodiments, a compound of structure 1, a tautomer, enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer, or stereoisomer of the compound, or any mixture thereof, is used to treat one or more diseases associated with hyperproliferation, neoplasia, hypoplasia, hyperplasia, dysplasia, metaplasia, dysplasia, fibroplasia (desmoplasia), angiogenesis, inflammation, immune status, metabolism, lung function, and cardiovascular function by non-selectively inhibiting a Receptor Tyrosine Kinase (RTK) selected from AKT, c-Kit, and/or PDGFR, wherein structure 1 is as follows:

wherein X, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷(and R as contained therein⁸，R⁹，R¹⁰，R¹¹And R¹²)，Q¹And Q²(and Q as contained therein)³) Is selected from "XRQ 3" as described above.

In the illustrative embodiments, R⁸Is selected from the group a structure outlined above. In some embodiments, the compound is a structure selected from group C structures mentioned above in the summary of the invention.

In exemplary embodiments, the compound of structure 1 is administered orally, intravenously, subcutaneously, transdermally, intraperitoneally, or by inhalation. In illustrative embodiments, the disease is selected from the group consisting of cancer, metastatic cancer, HIV, hepatitis, PAH, primary PAH, idiopathic PAH, inherited PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with systemic sclerosis, and mixed connective tissue disease, pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, neonatal persistent pulmonary hypertension, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, pulmonary obstructive disease, sleep disordered breathing, alveolar hypoventilation disorder, long term exposure to high altitude, dysplasia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension with an unclear multifactorial mechanism, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, metabolic disorders, glycogen storage disorders, gaucher's disease, thyroid disease, tumor obstruction, fibrositis mediastinitis, and chronic renal failure on dialysis.

In exemplary embodiments, the salt is a chloride, hydrochloride, sulfate, phosphate, mesylate, bismesylate, tosylate, lactate, tartrate, malate, diacetate, citrate, or dihydrochloride salt. In illustrative embodiments, inhibition occurs through non-covalent interactions. In some embodiments, the inhibition occurs by covalent interactions. In some embodiments, the compound of structure 1 has an IC for kinase receptor of less than 300nM₅₀. In illustrative embodiments, the method of treatment results in one or more of the following: improved exercise capacity, improved functional grade, shortness of breath, reduced hospitalization, reduced need for lung transplantation, reduced need for interatrial septal dissection, and increased lifespan or overall survival. In some embodiments, the improved exercise capacity is an increased walking distance of 6 minutes. In suitable embodiments, the functional level of improvement is a level iv to level III, II or I improvement, or a level III to level II or I improvement, or a level II to level I improvement.

Brief description of the drawings

FIG. 1 shows a graph depicting IC of imatinib and PK10453 (Structure 2)₅₀FIG. 1A shows the IC of imatinib on PDGFR α₅₀Is 71nM, while FIG. 1B shows the IC of PK10453 versus PDGFR α₅₀35 nM. furthermore, FIG. 1C shows the IC of imatinib for PDGFR β₅₀Is 607nM, while FIG. 1D shows the IC of PK10453 against PDGFR β₅₀Was 10.1 nM.

FIG. 2 shows graphs and images of In Cell Western (ICW) analysis, which indicates a lower IC of PK10453 (Structure 2) for PDGFBB₅₀Stimulation of phosphorylation of AKT at Ser473 and Thr308, compared to imatinib in human embryonic lung fibroblasts. FIGS. 2A-B show that the IC was comparable between 0.3-0.6. mu.M₅₀PK10453(■) and imatinib (▲) blocked PDGFAA stimulation of pAKT (S473) and pAKT (T308), respectively, at HLFS FIG. 2C shows 0.13 μ M IC compared to 1.8 μ M imatinib (▲)₅₀PK10453(■) blocking PDGFBB stimulation of pAKT (Ser 473.) FIG. 2D shows 0.43 μ M IC compared to 3.25 μ M imatinib (▲)₅₀PK10453(■) blocks PDGFBB stimulation of pAKT (Thr308 FIG. 2E shows that the ICWS examples of PDGFAA and PDGFBB stimulate AKT phosphorylation, PK10453 with imatinib, that the signal at 800nm is color-coded green and represents a phosphoprotein-specific signal, that the signal at 700nm is color-coded red and represents a signal from total AKT, and that the 800 and 700nm signals overlap (§ p<0.01；*p<0.001)。

Fig. 3 depicts fluorescence images of frozen rat lung sections (upper right, middle, and lower lobes) 2 minutes after PK10453 (structure 2) and IR780 tracer inhalation. Image acquisition occurs at 800nm (green), which is λ detected by IR780, while image acquisition at 700nm (red) represents tissue autofluorescence. The digital scale interval (1 cm) is shown.

Fig. 4 shows graphical data for Intravenous (IV) and Inhaled (INH) PK10453 (structure 2). Fig. 4A is a Pharmacokinetic (PK) profile relating to IV administered PK10453 and related concentrations in the lungs and plasma over time. Fig. 4B is a PK profile, which relates to PK10453 and related levels in lung and plasma versus time for INH administration.

Fig. 5 depicts the effect of PK10453 on Right Ventricular (RV) systolic pressure and right ventricular hypertrophy in MCT and MCT + PN model systems (structure 2). Fig. 5A is a graph showing the effect of PK10453 on right ventricular systolic pressure in an MCT model, where C (n ═ 3), V (n ═ 2), D2 (n ═ 6), D4(n ═ 6), and D8(n ═ 5) represent controls, vehicle, 2 minute exposure, 4 minute exposure, and 8 minute exposure times, respectively, for two weeks, three times daily. Asterisks (·) indicate p <0.001 and festoon (§) indicates p < 0.05. Figure 5B is a graph showing the effect of PK10453 on RV hypertrophy in an MCT model wherein inhalation therapy was initiated three weeks after MCT administration. C, D2, D4, and D8 represent controls, 2,4, 8 minute exposures, respectively, for two weeks, three times daily. Asterisks (—) indicate p < 0.001. Figure 5C is a graph showing the effect of PK10453 on RV systolic pressure (RVSP) in the MCT model in rats: comparison of PK10453 with imatinib; # p < 0.01. Figure 5D shows the luminal (Lumen)/media ratio of PK10453, imatinib and vehicle in MCT model: vehicle (V, n ═ 4): 0.55 plus or minus 0.1; PK10453(D8, n ═ 12): 0.94 plus or minus 0.08; imatinib (I8, n ═ 5): 0.99 plus or minus 0.07; p <0.05, # p < 0.01.

Figure 6 shows a graph of a telemetry study in rat MCT + PN model. Fig. 6A is a graph showing pulmonary arterial systolic pressure measured over time in an ambulatory subject using the MCT + PN model system and PK 10453. V (n ═ 5) and D4(n ═ 6) represent three times daily vehicle and 4 min exposure to PK10453 (structure 2), respectively. Asterisks (·) indicate p <0.001 and festoon (§) indicates p < 0.01. Figure 6B is a graph showing the measurement of pulmonary systolic blood pressure over time in an ambulatory subject using the MCT + PN model system with imatinib. V is vehicle; i ═ imatinib (p ═ NS).

Figure 7 shows a graph relating to the hemodynamic and morphological analysis in the rat MCT + PN model. Fig. 7A shows right ventricular systolic pressure: v (n ═ 9) RVS, 75.7 ± 7.1 mm hg, group D4(n ═ 10) RVS40.4 ± 2.7 mm hg, D8(n ═ 8) RVS43 ± 3.0 mm hg (p <0.001V versus D4 and V and D8). FIG. 7B shows that a reduction in right ventricular hypertrophy was treated with PK10453 (Structure 2); (RV + IVS)/LV ratio: v (n ═ 11); d4 (n-13); d8(n ═ 7); p <0.001, § p < 0.05. Figure 7C shows the MCT + PN model in rats with lumen area/media area ratio greater than PK10453D4 (n-6) and vehicle (n-6) in the D8 (n-5) -treated group; p <0.0001D8 and V, D8 and D4. Fig. 7D shows occlusion analysis, which was performed on the same animal samples used for lumen/media ratio analysis. Occlusion analysis showed significant reduction of lesions in the D8 group (# p <0.01) at grade 2 (> 50% occlusion).

Figure 8 microscopic image of pulmonary arteriolar hypertrophy and intracavity cell proliferation 40 fold of PK10453 treated samples by PK10453 illustrates the effect of PK10453 (structure 2) on intimal damage in rat MCT + PN model figure 8A shows a microscopic image of neointimal lesions figure 8B shows an image of PK10453 treated subjects figure 8C shows phosphopdgfr β (pdpdgfr β) staining, vehicle treated animals, and figure 8D shows pdpdgfr β staining of PK10453(D8) treated animals.

Fig. 9 shows lumen area by MCT + PN model: graph of media area, luminal area: the mesomembrane area was increased in the group of D4 (n-6) and D8 (n-5) treatments, compared to vehicle (n-6). Symbol (§ p) 0.032(D4 and V), symbolIs p ═ 0.028(D8 and D4), and the asterisks (×) indicate p ═ 0.00014(D8 and V).

Figure 10 depicts immunohistochemical evaluation of MCT + PN samples. Figure 10A shows pSTAT3 localized to nuclei of vascular endothelial and perivascular cells treated with vehicle. Figure 10B shows lung pSTAT3 nuclear signals from a subject treated with structure 2.

Figure 11 relates to immunohistochemically stained α SMC actin, trichrome and vWF staining of vehicle treated animals (MCT + PN model) at 40X, indicating that in pulmonary arterioles of grade 0, 1, and 2 lesions, lesions of grade 0 comprising a mixed population of neointima and proliferative lesions endothelial cells and myofibroblasts, characterized by early intraluminal endothelial cell proliferation and the presence of vascular smooth muscle cells in the media (figure 11A, α SMC staining; figure 11D, trichrome; figure 11G, vWF.) lesions of grade 1-2 have extensive intraluminal myofibroblast-like cells, some endothelial cells, and local fibrosis of the media layer (figure 11B, α SMC; figure 11E, trichrome; figure 11H, vWF.) the advanced grade 2 lesions are characterized by proliferation of extensive intraluminal myofibroblast-like cells and endothelial cells and by intact fibrotic replacement of the media layer (figure 11C, α; figure 11F, trichrome; figure 11I, vWF.) the long space arrows in the pulmonary arterioles with hyperplastic and proliferative short space pointing to the pulmonary artery layer.

FIG. 12 shows the 40X PDGFR signal in the rat MCT + PN model FIGS. 12A-F show PDGFAA (A), PDGFBB (B), total PDGFR α (C), total PDGFR β (D), PDGFR α phosphate (pPDGFR α; E) and pPDGFR β (F) in the pulmonary arteriole the PDGFBB, PDGFR β, especially pPDGFR β signal intensity is greater compared to PDGFAA, PDGFR α and pPDGFR α.

Figure 13 shows a comparison of pdgfr α and pdgfr β in larger pulmonary arterioles using the rat MCT + PN model system figures 13A and 13B show 20X and 40X immunohistochemistry, respectively, of the pdgfr α signal in the media with arrows pointing to smooth muscle cells positive for pdgfr α figures 13C and D show imaging at 20X and 40X, respectively, in contrast to the above, with little signal from pdgfr β in the media, peripheral cells (top left-figures 13C and D), and endothelial cells where the pdgfr β signal is noted.

FIG. 14 shows a NanoPro immunoassay as shown by the MCT + PN model. Fig. 14A shows pAKT (Thr308) and total AKT treated with vehicle. Fig. 14B shows pAKT (Thr308) and total AKT treated with PK10453, while fig. 14C shows pAKT (Ser473) and total AKT treated with vehicle. Figure 14D shows pAKT (Ser473) and total AKT treated with PK10453, while figure 14E shows that the pAKT (Thr308)/AKT ratio of lung extracts was not significantly different between groups (V ═ vehicle; D4 ═ 4 min exposure 3X/day, 2 weeks, D8 ═ 8 min exposure 3X/day, two weeks, p ═ NS). Figure 14F shows the pAKT (Ser473)/AKT ratio (V, n-5; n-4 in D4; n-5 in D8) p <0.05D8 vs V for vehicle in lung extracts for group D8.

FIG. 15 reveals the results of experiments with pSTAT3 and STAT3 in the MCT + PN model using the NanoPro immunoassay for lumogram. Figure 15A is a diagram of a vehicle treated subject. Fig. 15B is a diagram of PK10453 (structure 2) treated subjects. Figure 15C is a graph showing PK10453 treatment which decreased pSTAT3/STAT3(n ═ 4) in the lungs of subjects using the MCT + PN model, where V denotes vehicle, D4 represents 4 minutes exposure time three times daily, and D8 represents 8 minutes exposure time, two weeks, three times daily; two weeks PK10453 at 3X/day. Asterisk (, p ═ 0.009, and section symbol (§) indicates p ═ 0.024.

FIG. 16 shows the results of experiments with phospho ERK1/2(pERK1/2) and total ERK1/2 in the MCT + PN model using Nanopro immunoassays for lumograms. FIG. 16A shows pERK1/2 in vehicle-treated subjects. FIG. 16B shows pERK1/2 in PK10453 treated subjects. FIG. 16C shows total ERK1/2 and vehicle treated subjects. FIG. 16D shows total ERK1/2 in PK10453 treated patients, where PK10453 reduced ppeRK1/ERK 1. FIG. 16E shows ppeRK1/ERK1 in subjects, as represented therein. FIG. 16F shows pERK2/ERK2, as indicated. FIG. 16G shows ppeRK2/ERK2 as represented in the lung. FIG. 16H shows pERK2/ERK2, as represented in the lung. Each group n is 4 and V denotes vehicle, D4 represents a4 minute exposure time, three times daily, and D8 represents an 8 minute exposure time of PK10453 (structure 2), two weeks, three times daily. Asterisk (#) p is less than or equal to 0.0005; p-value 0.045.

Fig. 17 is a graphical representation showing the efficacy of imatinib, PK10453 (structure 2) and PK10571 (structure 2a) on PDGFAA and PDGFBB stimulated phosphorylation of ERK1 and ERK2 in human fetal lung fibroblasts. See fig. 17A-D.

FIGS. 18A-D are PK compounds: graphical expression of PK10453 (structure 2), PK10467 (structure 3), PK10468 (structure 4), PK10569 (structure 5) and PK10571 (structure 2a) showing that all PK compounds have lower IC inhibiting PDGFBB stimulated AKT phosphorylation in human fetal lung fibroblasts compared to imatinib₅₀And (4) concentration.

Fig. 19 is a subject weight map expression in vehicle administered and PK10453 treated subjects (structure 2), where squares represent vehicle treated group (n ═ 10), triangles represent PK10453D4 group (n ═ 10), and diamonds represent PK10453D8 group (n ═ 6).

Figure 20 is a graph representing PAC40 telemetry transmitter data from a transmitter implanted in the abdominal aorta for monitoring systemic blood pressure in subjects with ambulatory MCT exposure treated with vehicle (n-3) or PK10453 (n-3) for seven days.

Detailed Description

The present disclosure relates, inter alia, to a novel class of compounds that act as kinase inhibitors. As such, methods of using such compounds for the prevention and treatment of disease conditions are disclosed herein. The present disclosure further relates to pharmaceutical formulations of the compounds having prophylactic and/or therapeutic properties for subjects in need of kinase inhibitors, e.g., patients suffering from vascular diseases, proliferative diseases, cancer, and related diseases or disorders, as further detailed below. The following provides definitions of certain terms as used in this specification. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "an amino acid" includes a combination of two or more nucleic acids, and the like. Further, the following abbreviations as used herein have certain meanings, as detailed below.

As used herein, "about" will be understood by those skilled in the art and will vary depending on the context in which it is used. If the use of this term is ambiguous to one of ordinary skill in the art, "about" would mean up to ± 10% of the enumerated value, given the context in which it is used.

As used herein, the following PK compounds and structural designations are used interchangeably throughout the application: PK10453 ═ structure 2; PK10571 ═ structure 2 a; PK10467 ═ structure 3; PK10468 ═ structure 4; and PK10569 ═ structure 5.

As used herein, "administering" a pharmaceutical agent or drug, e.g., one or more kinase inhibitor compounds, to a subject or subjects includes any route of introducing or delivering the compound to the subject to perform its intended function. Administration may be by any suitable route, including oral, intranasal, inhalation, parenteral (intravenous, intramuscular, intraperitoneal, or subcutaneous), rectal, or topical administration. Administration includes self-administration and administration by others. It will also be understood that the various modes of treating or preventing the medical condition are intended to mean "substantially", including total treatment or prevention and also including less than total treatment or prevention, and in which some biologically or medically relevant result is achieved.

As used herein, the term "comparable" or "corresponding" in the context of comparing two or more samples, responses to treatment, or drugs, refers to the same type of sample, response, treatment, and drug, respectively, used in the comparison. For example, the phosphorylation state or level of akt (pakt) in a sample can be compared to the phosphorylation state or level in another sample. In some embodiments, comparable samples may be obtained from the same individual at different times. In other embodiments, comparable samples may be obtained from different individuals, e.g., patients and healthy individuals. In general, comparable samples are normalized (normalized) by common factors for control purposes.

As used herein, the term "composition" refers to a product having the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

As used herein, the terms "drug," "compound," "active agent," "medicament," "active," "pharmaceutical composition," "pharmaceutical formulation," and "pharmacologically active agent" are used interchangeably and refer to any compound, complex or composition, whether charged or uncharged, that is suitable for administration and that has a beneficial biological effect, which has a suitable therapeutic effect in the treatment of a disease or abnormal physiological condition, although the effect may also be prophylactic in nature. The term also includes pharmaceutically acceptable, pharmacologically active derivatives of such active agents specifically mentioned herein, including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the terms "active agent", "pharmacologically active agent", and "API" (active pharmaceutical ingredient) are used, then, or when a particular active agent is specifically identified, it is to be understood that applicant intends to encompass the active agent itself as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs and the like.

As used herein, the term "effective amount" or "pharmaceutically effective amount" or "therapeutically effective amount" of a component (composition) is an amount sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount that results in prevention or reduction of symptoms associated with the disease being treated. The amount of the component (composition) of the present invention administered to a subject will depend on the type and severity of the disease and the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the extent, severity and type of the disease. One skilled in the art will be able to determine the appropriate dosage based on these and other factors. The compositions of the present invention may also be administered in combination with one or more additional therapeutic compounds.

As used herein, reference to a kinase inhibitor is the term "irreversible" or "irreversible" refers to an inhibitor of kinase, tyrosine kinase, and/or RTK activity that is covalently, i.e., permanently bound or associated with such a kinase.

As used herein, "neoplastic disease" refers to any type and origin of cancer and its precursor stages. Thus, the term "neoplastic disease" includes subjects identified by "neoplasia", "neoplasm", "cancer", "pre-cancerous" or "tumor". Neoplastic diseases often manifest themselves as abnormal cell division, which leads to abnormal levels of a particular cell population. Likewise, because monoclonal proliferation of endothelial cells may refer to "neoplasms" of pulmonary arteriole endothelial cells, PAH is also included within the scope of the above term. Moreover, abnormal cell division in neoplastic diseases is usually intrinsic to the cell, not the normal physiological response to infection or inflammation. In some embodiments, neoplastic diseases diagnosed using the methods provided herein include cancer.

As used herein, the term "non-selective," when referring to a kinase inhibitor or receptor kinase inhibitor, refers to an inhibitor of the activity of a kinase, tyrosine kinase, domain and/or RTK that is not completely specific for a single kinase, receptor, tyrosine kinase, RTK or domain, i.e., a cognate target, but, in the case of inhibition of a single kinase, receptor, tyrosine kinase, RTK, domain, etc., e.g., PDGFR, affinity and/or IC for the kinase, receptor, tyrosine kinase, RTK, domain, etc₅₀For example, PK10453 (Structure 2) non-selectively targets PDGFR by inhibiting PDGFR- β and PDGFR- α subtypes, but may still have a lower IC for receptor subtypes, e.g., PDGFR- β₅₀。

As used herein, the term "pharmaceutically acceptable salt" includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. As the salt of an inorganic base, the present invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and salts of ammonia. As the salt of an organic base, the present invention includes, for example, salts of trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the present invention includes, for example, salts of hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As the salt of an organic acid, the present invention includes, for example, salts of formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, lactic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As the basic amino acid salt, the present invention includes, for example, salts of arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

As used herein, the term "reference level" refers to a level of a substance that may be of interest for purposes of comparison. In some embodiments, the reference level can be one particular component dose, which is the average dose level from samples taken from control subjects. In other embodiments, the reference level can be a level in the same subject at a different time, e.g., a time course of administration, such as levels at 2,4, 6, 8, and 10 minutes (min), etc.

As used herein, the terms "treatment" or "treating" or "alleviating" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) a targeted pathological condition or disorder. If the subject is successfully "treated" after receiving a therapeutic agent according to the methods of the present invention, then it is a disorder that the subject exhibits an observable and/or measurable reduction or absence of one or more signs and symptoms of the particular disease or condition.

As used herein, the term "unsubstituted alkyl" refers to an alkyl group that does not contain heteroatoms. Thus, the phrase includes straight chain alkyl groups, such as methyl, ethyl, propyl, butyl, pentylHexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched isomers of straight chain alkyl groups, including, but not limited to, the following groups provided by way of example: -CH (CH)₃)₂，-CH(CH₃)(CH₂CH₃)，-CH(CH₂CH₃)2，-C(CH₃)₃，-C(CH₂CH₃)₃，-CH₂CH(CH₃)₂，-CH₂CH(CH₃)(CH₂CH₃)，-CH₂CH(CH₂CH₃)₂，-CH₂C(CH₃)₃，-CH₂C(CH₂CH₃)₃，-CH(CH₃)CH(CH₃)(CH₂CH₃)，-CH₂CH₂CH(CH₃)₂，-CH₂CH₂CH(CH₃)(CH₂CH₃)，-CH₂CH₂CH(CH₂CH₃)₂，-CH₂CH₂C(CH₃)3，-CH₂CH₂C(CH₂CH₃)₃，-CH(CH₃)CH₂CH(CH₃)₂，-CH(CH₃)CH(CH₃)CH(CH₃)₂，-CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃) And others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and the aforementioned rings substituted with straight and branched alkyl groups as defined above. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl norbornyl, and bicyclo [2.2.2]Octyl and the aforementioned rings substituted with straight and branched chain alkyl groups as defined above. Thus, the phrase unsubstituted alkyl includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon, oxygen, nitrogen and/or sulfur atoms of the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. Furthermore, the utility modelPreferred such unsubstituted alkyl groups have 1 to 10 carbon atoms, and more preferred such groups have 1 to 5 carbon atoms. In some embodiments, unsubstituted alkyl groups include straight and branched alkyl groups having 1 to 3 carbon atoms, including methyl, ethyl, propyl, and-CH (CH)₃)₂。

As used herein, the term "substituted alkyl" refers to an unsubstituted alkyl group as defined above wherein one or more bonds to one or more carbons or one or more hydrogens are replaced with bonds to non-hydrogen and non-carbon atoms, such as, but not limited to, halogen atoms in halides, such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine groups; silicon atoms in groups such as trialkylsilanes, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; and heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to one or more carbon or one or more hydrogen atoms are replaced with a bond to a heteroatom, such as oxygen in carbonyl groups, carboxyl groups, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. In suitable embodiments, substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds to a fluorine atom. Examples of substituted alkyl groups are trifluoromethyl and other trifluoromethyl containing alkyl groups. Other alkyl groups include those in which one or more of the bonds to a carbon or hydrogen atom are replaced with a bond to an oxygen atom, such that the substituted alkyl group includes a hydroxyl group, an alkoxy group, an aryloxy group, or a heterocyclyloxy group. Other alkyl groups also include alkyl groups having amine, alkylamine, dialkylamine, arylamine, (alkyl) (aryl) amine, diarylamine, heterocyclylamine, (alkyl) (heterocyclyl) amine, (aryl) (heterocyclyl) amine, or a diheterocyclylamine group.

As used herein, the term "unsubstituted aryl" refers to an aryl group that does not contain heteroatoms. The term thus includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl, by way of example. While the phrase "unsubstituted aryl" includes groups containing fused rings such as naphthalene, it does not include aryl groups having other groups such as alkyl or halogen groups bonded to one of the ring members, aryl groups such as tolyl are considered substituted aryl groups herein, as described below. Unsubstituted aryl groups may be bonded to one or more carbon, oxygen, nitrogen and/or sulfur atoms.

As used herein, the term "substituted aryl" has the same meaning with respect to unsubstituted aryl as substituted alkyl has with respect to unsubstituted alkyl. However, substituted aryl groups also include aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above, and also include aryl groups in which one or more of the aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein. This includes bonded arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl or alkynyl group to define a fused ring system (e.g., dihydronaphthyl or tetrahydronaphthyl). Thus, the term "substituted aryl" includes, but is not limited to, tolyl and hydroxyphenyl, and the like.

As used herein, the term "unsubstituted alkenyl" refers to straight and branched chain and cyclic groups, such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Non-limiting examples include vinyl groups, -CH ═ c (h) (CH)₃)，-CH＝C(CH₃)₂，-C(CH₃)＝C(H)₂，-C(CH₃)＝C(H)(CH₃)，-C(CH₂CH₃)＝CH₂Cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, and the like.

As used herein, the term "substituted alkenyl" has the same meaning with respect to unsubstituted alkenyl as substituted alkyl has with respect to unsubstituted alkyl. Substituted alkenyl groups include alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bond that is bonded to another carbon, and those alkenyl groups in which one of the non-carbon/non-hydrogen atoms is bonded to a carbon not involved in the carbon double bond.

As used herein, the term "unsubstituted alkynyl" refers to straight and branched chain groups, such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to, -C.ident.C (H), -C.ident.C (CH)₃)，-C≡C(CH₂CH₃)，-C(H₂)C≡C(H)，-C(H)₂≡C(CH₃) and-C (H)₂C ≡ C (CH2CH3), and so on.

As used herein, the term "substituted alkynyl" has the same meaning with respect to unsubstituted alkynyl substitution as substituted alkyl has with respect to unsubstituted alkyl. Substituted alkynyl groups include alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bond that is bonded to another carbon, and those alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a carbon triple bond.

As used herein, the term "unsubstituted aralkyl" refers to an unsubstituted alkyl group as defined above, wherein a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl (-CH)₃) Is an unsubstituted alkyl group. If the hydrogen atom of a methyl group is replaced with a bond to a phenyl group, as if the carbon of the methyl group is bonded to a benzene carbon, then the compound is an unsubstituted aralkyl group, i.e., a benzyl group. Thus, the term includes, but is not limited to, groups such as benzyl groups, biphenyl methyl groups, and1-phenylethyl (-CH (C)₆H₅)(CH₃) Etc.).

As used herein, the term "substituted aralkyl" has the same meaning with respect to the substituted aryl group as substituted aryl group has with respect to unsubstituted aryl group. However, substituted aralkyl groups also include groups in which the carbon or hydrogen bond of the alkyl portion of the group is replaced with a bond to a non-carbon or non-hydrogen atom. Non-limiting examples of substituted aralkyl groups include-CH₂C(＝O)(C₆H₅) and-CH₂(2-methylphenyl), and the like.

As used herein, the term "unsubstituted heterocyclyl" refers to aromatic and non-aromatic cyclic compounds, including monocyclic, bicyclic, and polycyclic compounds, such as, but not limited to, quinuclidinyl, containing 3 or more ring members, one or more of which is a heteroatom such as, but not limited to, N, O, and S. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, e.g., 4H-1,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, etc., tetrazolyl, e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; fused unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms, such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, but not limited to,azolyl radical, isoThe group of azolyl groups,oxadiazolyl groups, e.g. 1,2,4-Oxadiazole, 1,3,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, etc.; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g. benzoAzolyl radical, benzoDiazolyl, benzoAzinyl radicals, e.g. 2H-1, 4-benzoOxazine groups, etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms, such as, but not limited to, thiazolyl, isothiazole, thiadiazolyl, e.g., 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, and the like; saturated 3 to 8-membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as, but not limited to, thiazolidinyl (thiazolidinyl); saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dithiinyl, dihydrodithione, tetrahydrothiophene, tetrahydrothiopyran; saturated fused heterocycles containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazolyl (e.g. benzothiazolyl)2H-1, 4-benzothiazinyl, etc.), dihydrobenzothiazine groups, e.g., 2H-3, 4-dihydrobenzothiazine groups, etc., unsaturated 3 to 8-membered rings containing an oxygen atom, such as, but not limited to, furyl; unsaturated fused heterocycles containing 1 to 2 oxygen atoms, e.g., benzodioxolyl, such as 1, 3-benzodioxolyl, and the like; unsaturated 3-to 8-membered rings containing oxygen atoms and 1 to 2 sulfur atoms, e.g. but not limited to, dihydroOctyl; saturated 3 to 8-membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, such as 1, 4-oxathiane (oxathiane); unsaturated fused rings containing 1 to 2 sulfur atoms, such as benzothienyl groups, benzodithienyl groups; and unsaturated, fused heterocyclic rings containing oxygen atoms and 1 to 2 oxygen atoms, e.g. benzoAnd (4) octyl. Heterocyclyl also includes those groups described above in which one or more S atoms in the ring is double bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1, 1-dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2, 3-triazole, 1,2, 4-triazole, tetrazole, thiophene, thiomorpholine wherein the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine,oxazolidin-2-one, pyrrolidin-2-one,azole, quinuclidine, thiazole, isozaineOxazole, furan, tetrahydrofuran.

As used herein, the term "substituted heterocyclyl" refers to an unsubstituted heterocyclyl group as defined, wherein one or more ring members are bonded to a non-hydrogen atom as described above for substituted alkyl and substituted aryl groups. Examples include, but are not limited to, 2-methylbenzimidazole, 5-chlorobenzothiazolyl, N-alkylpiperazino groups such as 1-methylpiperazino, piperazine-N-oxide, N-alkylpiperazino N-oxide, 2-phenoxythiophene, and 2-chloropyridyl, and the like. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which the bond to a non-hydrogen atom is a bond to a carbon atom that is part of a substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, or unsubstituted heterocyclyl group. Examples include, but are not limited to, 1-benzylpiperidinyl, 3-phenylthiomorpholinyl, 3- (pyrrolidin-1-yl) -pyrrolidinyl, and 4- (piperidin-1-yl) -piperidinyl. Groups such as N-alkyl substituted piperazinyl groups, e.g., N-methylpiperazine, substituted morpholinyl groups, and piperazine-N-oxide groups, e.g., piperazine N-oxide and N-alkylpiperazine N-oxide are examples of some substituted heterocyclyl groups. Groups such as substituted piperazine groups, e.g., N-alkyl substituted piperazine groups, e.g., N-methylpiperazine and the like, substituted morpholine groups, and N-oxide groups are examples of some substituted heterocyclyl groups suitable for the various "R" groups.

As used herein, the term "unsubstituted heterocyclylalkyl" refers to an unsubstituted alkyl group as defined above wherein the hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl (-CH)₃) Is an unsubstituted alkyl group. A compound is an unsubstituted heterocyclyl group if the hydrogen atom of the methyl group is replaced with a bond to the heterocyclyl group, for example if the carbon of the methyl group is bonded to carbon 2 of the pyridine (to one of the carbon atoms of the N of the pyridine) or carbon 3 or 4 of the pyridine.

As used herein, the term "substituted heterocyclylalkyl" has the same meaning with respect to unsubstituted heterocyclylalkyl as substituted aralkyl has with respect to unsubstituted aralkyl. However, substituted heterocyclylalkyl also includes heterocyclylalkyl groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group, such as, but not limited to, a nitrogen atom in the piperidine ring of the piperidinylalkyl group. In addition, substituted heterocyclylalkyl groups also include those groups in which the carbon or hydrogen bonds of the alkyl portion of the group are replaced with bonds linking substituted and unsubstituted aryl or substituted and unsubstituted aralkyl groups.

As used herein, the term "unsubstituted alkylaminoalkyl" refers to an unsubstituted alkyl group, as defined above, in which a carbon or hydrogen bond is replaced with a bond to a nitrogen atom which is bonded to a hydrogen atom and an unsubstituted alkyl group, as defined above. For example, methyl (-CH)₃) Is an unsubstituted alkyl group. If the hydrogen atom of the methyl group is replaced with a bond to a nitrogen atom that is bonded to a hydrogen atom and an ethyl group, the resulting compound is-CH₂-N(H)(CH₂CH₃) It is unsubstituted alkylaminoalkyl.

As used herein, the term "substituted alkylaminoalkyl" refers to unsubstituted alkylaminoalkyl groups as defined above, except that wherein one or more of the bonds connecting carbon or hydrogen atoms in one or both of the alkyl groups are replaced with bonds connecting non-carbon or non-hydrogen atoms as described above for substituted alkyl groups, except that unsubstituted alkylaminoalkyl groups, the bonds connecting nitrogen atoms in all alkylaminoalkyl groups do not themselves define that all alkylaminoalkyl groups are substituted.

As used herein, the term "unsubstituted dialkylaminoalkyl" refers to an unsubstituted alkyl group, as defined above, in which a carbon or hydrogen bond is replaced with a bond to a nitrogen atom that is bonded to two other unsubstituted alkyl groups, as defined above.

As used herein, the term "substituted dialkylaminoalkyl" refers to an unsubstituted dialkylaminoalkyl group, as defined above, in which one or more of the bonds to a carbon or hydrogen atom in one or more of the alkyl groups are replaced with a bond to a non-carbon or non-hydrogen atom, as described with respect to the substituted alkyl group. The bond linking the nitrogen atoms in all dialkylaminoalkyl groups is not itself restricted to all dialkylaminoalkyl groups being substituted.

As used herein, the term "unsubstituted alkoxy" refers to a hydroxyl group (-OH) wherein the bond to the hydrogen atom is replaced with a bond to a carbon atom of an additional unsubstituted alkyl group as defined above. As used herein, the term "substituted alkoxy" refers to a hydroxyl group (-OH) wherein the bond to the hydrogen atom is replaced with a bond to a carbon atom of an otherwise substituted alkyl group as defined above.

As used herein, the term "unsubstituted heterocyclyloxy" refers to a hydroxyl group (-OH) wherein the bond to a hydrogen atom is replaced with a bond to a ring atom of the unsubstituted heterocyclyl group as defined above. As used herein, the term "substituted heterocyclyloxy" refers to a hydroxyl group (-OH) wherein the bond to the hydrogen atom is replaced with a bond to a ring atom of an otherwise substituted heterocyclyl group as defined above. As used herein, the term "unsubstituted heterocyclyloxyalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon bond or a hydrogen bond is replaced with an oxygen bond, which is bonded to the unsubstituted heterocyclyl group.

As used herein, the term "substituted heterocyclyloxyalkyl" refers to a heterocyclyloxyalkyl group as defined above, wherein the bond connecting the carbon or hydrogen groups of the alkyl group of the heterocyclyloxyalkyl group is bonded to a non-carbon and non-hydrogen atom as described above for the unsubstituted alkyl group, or a heterocyclyloxyalkyl group as defined above, wherein the heterocyclyl group of the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined above.

As used herein, the term "unsubstituted heterocyclylalkoxy" refers to an unsubstituted alkyl group as defined above wherein carbon or hydrogen bonds are replaced with bonds to the oxygen atom that is bonded to the parent compound, and wherein other carbon or hydrogen bonds of the unsubstituted alkyl group are bonded to the unsubstituted heterocyclyl group as defined above. As used herein, the term "substituted heterocyclylalkoxy" refers to an unsubstituted heterocyclylalkoxy group, as defined above, wherein the bond of a carbon or hydrogen group of the alkyl group of the heterocyclylalkoxy group is bonded to a non-carbon and non-hydrogen atom, as defined above for a substituted alkyl group, or wherein the heterocyclyl group of the heterocyclylalkoxy group is a substituted heterocyclyl group, as defined above. In addition, substituted heterocyclylalkoxy groups also include those in which the carbon or hydrogen bonds linking the alkyl portions of the groups may be replaced with one or more additional substituted and unsubstituted heterocyclic rings.

As used herein, the term "unsubstituted arylaminoalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced with a bond to a nitrogen atom which is bonded to at least one unsubstituted aryl group as defined above.

As used herein, the term "substituted arylaminoalkyl" refers to an arylaminoalkyl group as defined above, except that the alkyl group of any one of the arylaminoalkyl groups is a substituted alkyl group as defined above or the aryl group of said arylaminoalkyl group is a substituted aryl group, except that the bond linking the nitrogen atoms in all arylaminoalkyl groups does not itself define that all arylaminoalkyl groups are substituted. However, substituted arylaminoalkyl groups do include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with atoms other than carbon and hydrogen.

As used herein, the term "unsubstituted heterocyclylaminoalkyl" refers to an unsubstituted alkyl group, as defined above, in which carbon or hydrogen bonds are replaced with bonds to nitrogen atoms that are bonded to at least one unsubstituted heterocyclyl group, as defined above. As used herein, the term "substituted heterocyclylaminoalkyl" refers to an unsubstituted heterocyclylaminoalkyl group, as defined above, in which the heterocyclyl group is a substituted heterocyclyl group, as defined above, and/or the alkyl group is a substituted alkyl group, as defined above. The bond linking the nitrogen atoms of all heterocyclylaminoalkyl groups does not in itself limit all heterocyclylaminoalkyl groups to being substituted.

As used herein, the term "unsubstituted alkylaminoalkoxy" refers to an unsubstituted alkyl group, as defined above, in which a carbon or hydrogen bond is replaced with a bond to an oxygen atom, which is bonded to the parent compound, and in which the other carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom, which is bonded to a hydrogen atom and to the unsubstituted alkyl group, as defined above.

As used herein, the term "substituted alkylaminoalkoxy" refers to an unsubstituted alkylaminoalkoxy group, as defined above, in which the bond to the carbon or hydrogen atom of the alkyl group is replaced with one or more bonds to a non-carbon and non-hydrogen atom that is bonded to the oxygen atom bonded to the parent compound, as discussed above for substituted alkyl groups, and/or if the hydrogen bonded to the amino group is bonded to a non-carbon and non-hydrogen atom and/or if the alkyl group bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom, as described above for substituted alkyl groups. The presence of amine and alkoxy functionalities in all alkylaminoalkoxy groups does not in itself limit all of these groups to substituted alkylaminoalkoxy groups.

As used herein, the term "unsubstituted dialkylaminoalkoxy" refers to an unsubstituted alkyl group, as defined above, wherein a carbon or hydrogen bond is replaced with a bond that is bonded to an oxygen atom of the parent compound, and wherein another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom that is bonded to two other similar or different unsubstituted alkyl groups, as defined above.

As used herein, the term "substituted dialkylaminoalkoxy" refers to a substituted unsubstituted dialkylaminoalkoxy group, as defined above, wherein the bond to the carbon or hydrogen atom of the alkyl group bonded to the oxygen atom bonded to the parent compound is replaced with one or more bonds to a non-carbon and non-hydrogen atom, as discussed above for substituted alkyl groups, and/or if one or more of the alkyl groups bonded to the nitrogen of the amine are bonded to a non-carbon and non-hydrogen atom, as described above for substituted alkyl groups. The presence of amine and alkoxy functionality in all dialkylaminoalkoxy groups does not in itself limit all such groups to substituted dialkylaminoalkoxy groups.

As used herein, the term "protected" with respect to hydroxyl Groups, amine Groups, and thiol Groups refers to forms of these functional Groups that are protected from undesired reactions by protecting Groups well known to those skilled in the art, such as those described in Protective Groups in Organic Synthesis, Greene, t.w.; wuts, p.g.m., john wiley & Sons, New York, NY, (3 rd edition, 1999) can be used to add or remove the protecting group using the methods described therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of hydroxyl groups with reagents such as, but not limited to, tert-butyldimethylchlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers, such as, for example, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, tert-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, acetate, trichloroacetate, and trifluoroacetate. Non-limiting examples of protected amine groups include amides, such as formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and the like. Non-limiting examples of protected mercapto groups include thioethers such as S-benzyl sulfide and S-4-pyridylmethyl sulfide; substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals, and the like.

Overview

Various compounds have been found to be useful in the treatment of certain diseases, such as, for example, cancer. For example,other experimental drugs include sorafenib and PNU-166196, which are used for the respective treatment of renal cell carcinoma and leukemia although significant progress has been made in the development of pharmaceutical compositions for the treatment of certain cancers, there is a need for new compounds, compositions, methods of treatment, and for the development of pharmaceutical model systems for the prevention and/or treatment of cancer and other diseases, e.g., pulmonary vascular diseases such as Pulmonary Arterial Hypertension (PAH), in particular, platelet-derived growth factor (PDGF) receptor tyrosine kinases are attractive therapeutic targets for PAH.

Migration of PASMCs is inhibited by Imatinib, a PDGFR α inhibitor, Imatinib also reduces RVSP and improves survival in the rat MCT model of PAH in several case reports of refractory PAH patients, a favorable response to Imatinib has been observed, see Ghofrani et al, "Imatinib in pulmonary hypertension patients with acquired responsiveness to administered therapy," Am J resistance clinical Care. Vol. 1171-7(2010) IMPRES test, which examines the effects of Imatinib in patients with severe PAH, showing improvement in the six minute walking distance and in cardiopulmonary hemodynamics.

Furthermore, imatinib was developed using an in vivo murine MCT model system that is an imperfect system for preclinical drug candidate efficacy assessment, at least because it is unreliable with respect to the development of neointimal and/or plexiform lesions that express certain human disease phenotypes, e.g., associated with PAH. Cool et al, "Pathology and elimination of complex elimination in pulmony hypertension and human immunological diagnosis virus infection. "Hum pathol.28: 434-442(1997). Thus, examination of the role of kinase inhibitors in more aggressive models that exhibit human disease phenotypes is essential to more accurately reflect the pathology of human disease and, therefore, the development of next-generation compounds and compositions for effective treatment of human disease.

The inventors employed such a model while further comparing the compounds and methods of treatment of the present invention with imatinib. As described in further detail below, the inventors conducted efficacy studies using the murine Monocrotaline (MCT) plus the whole lung resection (PN) model system (MCT + PN). This model characterizes neointimal and/or plexiform lesions of human diseases, such as PAH. To this end, for example, the pathological features of PAH consist of concentric and plexiform lesions in the anterior capillary pulmonary arteriole. See Cool et al (1997); and Tuder et al, "Plexiform loss in section pulmony hypertension: association with virologic loss" Am J paper 159: 382-383(2001). Concentric lesions result from neointimal cell proliferation that blocks the lumen of the blood vessel. These concentric obstructive neointimal lesions are reported to be composed of myofibroblasts and/or endothelial cells. See, for example, Yi et al, Am J Respir Crit Care Med 162: 1577 to 1586 (2000).

In addition, perivascular infiltrates, including T cells, B cells and macrophages, have been found in PAH of plexin. See, Sakagami, "In vivo, In vitro and ex vivo models to access the lower pulp area and distribution of the affected therapeutics for system delivery. "AdvDrug Deliv Rev 58: 1030 to 60 years (2006). Furthermore, plexiform lesions, characterized by disorganized vascular pathways, are stained with endothelial cell markers, and lesions in lung specimens from such idiopathic and/or primary PAH patients include monoclonal proliferation of endothelial cells. Lee et al, "Monoclonal end termination presentation in primary storage secondary drive hierarchy. "J Clin Invest, 101: 927-934(1998). Thus, this type of PAH is essentially a "cancer" of the endothelial cells of the pulmonary arterioles (see above), at least because acute apoptotic loss of normal endothelial cells at the initial or early stages of the disease may lead to the appearance and clonal proliferation of apoptosis-resistant endothelial cells. Lee et al. (1998). The neoplastic methods associated with PAH, as determined by the MCT + PN model, not only provide kinase inhibitor treatment of PAH, but also enhance the development of new compounds, compositions and methods with better efficacy, potency and broader spectrum of inhibition than kinase inhibitors previously generated using inferior model systems, which may have narrow RTK inhibition selectivity for the treatment of neoplastic diseases. Drug kinase homology modeling ensures that such inhibitors, including, for example, their non-selective and irreversible derivatives, target labile kinase domains for optimal therapeutic efficacy, as further described below.

Synthesis of compounds

In one aspect, the present disclosure provides for the synthesis of compounds of structure I, which are readily synthesized using the methods described in the following section and disclosed in WO2008/058341, which WO2008/058341 is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein. Moreover, the compounds of structure I are typically prepared from starting materials such as, for example, dihaloheterocycles. The first step is nucleophilic aromatic substitution to produce a monoamino monohalogenated intermediate. Nucleophilic aromatic substitution is typically carried out by: the primary or secondary amine is added to the dihaloheterocycle in a solvent such as ethanol, isopropanol, t-butanol, dioxane, THF, DMF, ethoxyethanol, toluene or xylene. The reaction is typically carried out at elevated temperature in the presence of an excess of an amine or non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.

Alternatively, the amino substituent may be introduced by a transition metal catalyzed amination reaction. Typical catalysts for such conversions include Pd (OAc)₂/P(t-Bu)₃，Pd₂(dba)₃BINAP and Pd (OAc)₂The reactions are typically carried out in a solvent such as toluene or dioxane, in the presence of a base such as cesium carbonate or sodium or potassium tert-butoxide, at temperatures ranging from room temperature to reflux see, for example, Hartwig and Angew, chem.int.Ed37, 2046 (1998.) the amines used in the first step of the synthesis of these compounds are commercially available or can be prepared using techniques well known to those skilled in the art moreover, α -alkylbenzylamines can also be prepared by reduction of oximes typical reducing agents include lithium aluminum hydride, hydrogen in the presence of a palladium on charcoal catalyst, zinc in the presence of hydrochloric acid, Lewis acids such as TiCb, ZrCU, NiCl₂And MoO₃α -alkylbenzylamines can also be prepared by reductive amination of the corresponding ketone, using either sodium borohydride in the presence of, or with Amberlyst H15 ion exchange resin and LiCl₂NH₄，[(CH₃)₅C₅RhCl₂]₂) Or other processes, e.g. NH₄OAc，Na(CN)BH₃) α -Alkylbenzylamines can also be prepared from the corresponding α -alkylbenzyl alcohols, such methods include derivatization of the hydroxyl group as a mesylate or tosylate and displacement with a nitrogen nucleophile, such as phthalimide or azide, converting the nitrogen nucleophile to a primary amine using conventional synthetic methods, or, alternatively, displacement of the hydroxyl group with a suitable nitrogen nucleophile under Mitsunobu-like conditions α -alkylbenzyl alcohols can be prepared by reducing the corresponding ketone with a reducing agent such as sodium borohydride in a solvent such as methanol α -alkylbenzyl alcohols can alternatively be prepared by reacting an alkyl metal species (such as a Grignard reagent)Agent) to a benzaldehyde derivative, which addition is usually carried out at room temperature or lower in a solvent such as tetrahydrofuran α -alkylbenzylamine of high optical purity can be prepared from chiral α -alkylbenzyl alcohol using the process outlined above chiral α -alkylbenzyl alcohol can be obtained by the corresponding ketone chiral reduction.

The monoamino monohalogenated intermediate formed from the dihaloheterocycle and amine described above may then be further functionalized. For example, where the amine substituent carries an additional functional group, this functional group may be derivatized or functionalized using methods well known to those skilled in the art. For example, the free primary amino group may be further functionalized as an amide, sulfonamide or urea function, or may be alkylated to produce a secondary or tertiary amine derivative. Preferred methods of forming the amide include coupling the amine with the carboxylic acid using a coupling reagent such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, diisopropylcarbodiimide, or carbonyldiimidazole in a solvent such as dichloromethane, tetrahydrofuran or 1, 4-dioxane. Alternatively, the acid component may be activated by conversion to an acid chloride (using thionyl chloride, oxalyl chloride, bis (trichloromethyl) carbonate or cyanuric chloride), or a mixed anhydride species (using, for example, tert-butyl or isopropyl chloroformates) or an active ester intermediate (such as N-hydroxysuccinimide, pentafluorophenyl or p-nitrophenyl ester) prior to reaction with the amine.

The monoaminomonochloro intermediate may then be reacted with an appropriately functionalized coupling partner in a palladium-mediated cross-coupling reaction to replace the halogen atom with an alternative moiety. Typical coupling partners are organoboronic acids or esters. See, for example, gonpu and Suzuki (Miyaura and Suzuki), Chem rev.952457 (1995); stille, chem., int.ed.engl 25, 508 (1986); kumada et al, org.synth.col.6, 407 (1998); and: negishi, j.organomet.chem.653, 34(2002), which are used for Suzuki coupling, organotin hydride, Stille coupling, grignard reagent, Kumada coupling, organozinc species, and Negishi coupling, respectively. Suzuki coupling is the preferred coupling method and is usually carried out in a solvent such as DME, THF, DMF, ethanol, propanol, tolueneOr 1, 4-dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, cesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate. The reaction may be carried out at elevated temperature and the palladium catalyst used may be selected from Pd (PPh)₃)₄Selecting, adding Pd (OAc)₂，[PdCl₂(dppf)]，Pd₂(dba)₃/P(t-Bu)₃。

The monoamino monochloro intermediate may also be subjected to a second nucleophilic aromatic substitution reaction using similar conditions as outlined above. Those skilled in the art will appreciate that the order of the reactions described in the above syntheses may in some cases be varied and that in some cases certain functional groups may need to be derivatised, i.e. protected, for use in the above reactions to allow the reactions to proceed with reasonable yield and efficiency. The types of protecting functional groups are well known to those skilled in the art. The products formed from the above reaction sequence may be further derivatized using techniques well known to those skilled in the art. The leaving group may be of any suitable known type, as described in March, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4 th edition. Pages 352-7, John Wiley & Sons, NY (1992). In some embodiments, the leaving group is halogen, e.g., chloro.

Kinase enzymes

Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins. These enzymes are generally divided into three classes, those that preferentially phosphorylate serine and/or threonine residues, those that preferentially phosphorylate tyrosine residues, and those that phosphorylate tyrosine and serine/threonine residues. Protein kinases are therefore key elements of signal transduction pathways responsible for transducing extracellular signals, including the action of cytokines on their receptors, to the nucleus, initiating various biological events. Many roles of protein kinases in normal cell physiology include cell cycle control, including proliferation, differentiation, metabolism, apoptosis, cell motility, mitosis, transcription, translation and other signaling processes.

Platelet derived growth factor receptor kinases (PDGFR) are a class of RTKs. The sequence of PDGFR can be found in GenBank under accession numbers NM-002609(mRNA) and NP-002600 (protein) and has been described, at least, in Matsui et al, "Isolation of a novel receiver cDNA experiments the existence of two PDGfreceptives genes" Science 243 (4892): 800-804 (1989); Claesson-Welsh, L. "cDNAcloning and expression of a human platlet-derived growth factor (PDGF) receptor specific for B-chain-associating PDGF molecules" mol.cell.biol.8 (8): 3476 3486 (1988); and Gronwald, et al. Pnas.85 (10): 3435-3439(1988).

In addition, PDGF, a cognate binding ligand for PDGFR, a strong mitogenic factor for cells of mesenchymal origin, such as fibroblasts, smooth muscle cells and glial cells PDGF is a 32kDa protein heterodimer which usually consists of two polypeptide chains, a and B, which are linked by disulfide bonds except for the PDGF AB heterodimer, PDGF is present in two homodimeric forms (AA and BB.) during hemagglutination and platelet adhesion, PDGF is released from the site of damaged blood vessels, which suggests that PDGF may have a role in vascular repair PDGF may stimulate migration of arterial smooth muscle cells from the intima to the intima layers of the arteries, where muscle cells may proliferate.

PDGF expression has been demonstrated in a number of different solid tumors, from glioblastoma to prostate cancer. In these different types of tumors, the biological role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and angiogenesis. Thus, inhibition of PDGFR kinase activity with small molecules can interfere with tumor growth, angiogenesis, diseases with tumor etiology, immunological and inflammatory diseases, hyperproliferative diseases, including cancer and diseases involving neovascularization, kidney and renal diseases, bone remodeling diseases, metabolic diseases, vascular diseases, and pulmonary vascular diseases, such as, for example, PAH. Other diseases mediated by PDGF, and therefore involving its cognate receptors, include, for example, restenosis, coronary restenosis after other invasive procedures including angioplasty, arteriotomy, atherectomy, or plaque removal, and restenosis of the kidney or peripheral artery after the same procedure; vascular proliferation phenomena and fibrosis associated with other forms of acute injury, such as pulmonary fibrosis associated with adult respiratory distress syndrome, renal fibrosis associated with nephritis, coronary stenosis associated with Kawasake's disease and vascular narrowing associated with other arteritis such as Takayasha's disease; prevention of narrowing in vein transplantation; preventing the narrowing due to the acceleration of smooth muscle cell migration and proliferation in transplanted organs, and other fibrotic processes such as scleroderma and myofibrosis and inhibition of tumor cell proliferation.

c-Kit is another receptor tyrosine kinase belonging to the PDGF receptor family, commonly expressed in hematopoietic progenitor cells, mast cells and germ cells. c-kit expression has been implicated in a number of cancers, including mast cell leukemia, germ cell tumors, small cell lung cancer, GIST, Acute Myeloid Leukemia (AML), neuroblastoma, melanoma, ovarian cancer, breast cancer. Smolich et al, Blood, 97(5) 1413-21.

Extracellular signal-regulated protein kinases 1 and 2(ERK1/2) are members of the mitogen-activated protein (MAP) kinase superfamily that can mediate cell proliferation and apoptosis. The Ras-Raf-MEK-ERK signaling cascade for the control of cell proliferation is well studied, but the mechanisms involved in ERK 1/2-mediated cell death are largely unknown. ERK1/2 translocates to the nucleus, but may also remain in the cytoplasm. The cytoplasmic retention of ERK1/2 denies access to transcription factor substrates, which are responsible for mitotic responses. In addition, cytosolic ERK1/2, in addition to inhibiting survival and proliferation signals in the nucleus, effects the catalytic activity of some pro-apoptotic proteins, such as DAP kinase, in the cytoplasm. Further defining the function of cytosolic ERK1/2 and its cytoplasmic substrates to enhance cell death would be crucial to exploiting this pathway to develop effective treatments for cancer and chronic inflammatory diseases.

STAT3 is a member of the STAT protein family, whose typical function is in response to cytokines and growth factors. STAT family members are phosphorylated by receptor-associated kinases and then form homo-or heterodimers that translocate to the nucleus where they act as transcriptional activators. STAT3 is activated by phosphorylation in response to various cytokines and growth factors, including IFNs, EBF, IL5, IL6, HGF, LIF, and BMP 2. This protein mediates the expression of various genes, which in response to cellular stimuli, play a key role in many cellular processes, such as cell growth and apoptosis. Small gtpase Rac1 has been shown to bind to and modulate the activity of this protein, whereas PIAS3 has been shown to inhibit STAT 3.

AKT (also known as PKB) is involved in the regulation of metabolism, cell survival, motility, transcription and cell cycle progression. AKT belongs to the AGC subfamily of the protein kinase family, which includes more than 500 members in humans. The AKT subfamily includes three mammalian isoforms, AKT1, AKT2, and AKT3, which are products of different genes and share conserved structures that include three functional domains: an N-terminal Pleckstrin Homology (PH) domain, a central kinase domain, and a C-terminal regulatory domain containing a Hydrophobic Motif (HM) phosphorylation site [ FxxF (S/T) Y ].

Kinase inhibitors

In one aspect, the present disclosure provides compounds and methods of inhibiting a kinase, e.g., a tyrosine kinase, such as a RTK, in a subject and/or treating a biological condition mediated by a kinase, e.g., a tyrosine kinase, such as a RTK, in a subject the kinase is Cdc2 kinase, AKT, c-Kit, c-ABL, ERK 5/2, STAT3, p60src, VEGFR3, PDGFR α β 3, PDGFR- αα - ββ - αβ -3, Fyn, Lck, Tie-2, GSK-3, Cdk2, Cdk 56, MEK1, epk-2, CHK2, CK1 epsilon, Raf, -CHK1, Rsk2, FMS (IR), KDR, kdha 2, epk 828672, flk 2, pdgf 2, VEGFR-related kinase, e.g., a VEGFR-kinase, VEGFR-related to a kinase, such as a Cdk2, a kinase, a Cdk2, a pharmaceutically acceptable salt of said compound, a Cdk2, a kinase, a Cdk2, a Cdk, a VEGFR-2, a VEGFR-related compound, a kinase, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug.

Previously, various indolyl-substituted compounds have been shown to inhibit one or more kinases, as disclosed in WO 01/29025, WO 01/62251, and WO 01/62252. Likewise, a variety of benzimidazole compounds have recently been disclosed in WO 01/28993. Such compounds are reported to be capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor tyrosine kinases. Certain disclosed compounds contain a quinolone fragment bonded to an indolyl or benzimidazolyl group. The synthesis of 4-hydroxyquinolone and 4-hydroxyquinoline derivatives has also been reported. For example, Ukrainets et al have disclosed the synthesis of 4-hydroxy-2-oxo-1, 2-dihydroquinoline from 3- (benzimidazol-2-yl). Ukrainets et al, Tet.Lett.42, 7747-48(1995) also disclose the synthesis of other 4-hydroxyquinolones and thio analogs such as 1H-2-oxo-3- (2-benzimidazolyl) -4-hydroxyquinoline, anticonvulsant and antithyroid activity. Ukrainets et al, Khimiya Geterotsilicekkikh Soediini, 1, 105-108 (1993). Furthermore, other compounds, such as, for example, 4-amino-5-fluoro-3- [5- (4-methyl)Piperazin-1-yl) -1H-benzimidazol-2-yl]Quinoline-2 (1H) -ones have been described as orally bioavailable benzimidazol quinolinones that show inhibition of receptor tyrosine kinases that drive endothelial and tumor cell proliferation, show inhibitory effects on 9 tyrosine kinases, FGFR1, FGFR3, VEGFR1, VEGFR2, VEGFR3, PDGFR β, c-Kit, p60src, and FLT-3, such as WO-3₂005/047244, respectively. However, pharmaceutically acceptable doses of the compounds do not significantly inhibit the EGFR kinase family or the insulin receptor kinase.

Furthermore, 4- (4-methylpiperazin-1-ylmethyl) -N- [ 4-methyl-3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl ] -benzamide (imatinib), as disclosed in US 2006/0154936, inhibited PDGFR α and β kinases, Abl, DDR and c-KIT as described in US2011/0190313, however, paragraph [0117] of US2011/0190313 indicates that while imatinib appears to be safe and well tolerated over a period of 6 months, the primary efficacy parameter (6MWD) was not improved in patients randomly given imatinib, despite significant improvement in the secondary endpoint, thus, there is a continuing need to inhibit kinases, such as tyrosine kinases, compounds like RTKs, at least because of previous limitations, drug resistant disease phenotypes, and a need for more potent kinases, such as RTK inhibition, as described in further detail below, see US 2008/0268460.

Furthermore, small molecules reported in Frey et al (1998) have been shown to irreversibly inhibit Epidermal Growth Factor Receptor (EGFR) by covalently interacting with the receptor, while alkylating the ATP-binding pocket cysteine residues of the molecule. In fact, Leproult et al, "Cysteine Mapping in formatting connecting deletion nucleic acid Binding Sites: Application to the Design of Selective genetic inhibitors," J.Med.Chem.54, 1347-1355(2011) disclose that one approach to designing irreversible inhibitors is to exploit the nucleophilicity of the Cysteine thiol group present in the target protein via systematic analysis of the Cysteine residues present at the nucleotide Binding site of the kinase. Such an approach may promote irreversible inhibition even when different kinase conformations are considered, thus improving dose and toxicity. See above.

The general term "warhead" is used to refer to an electrophilic trap, which is used to form a covalent bond between the inhibitor and the target protein kinase.

In some embodiments, other electrophiles other than those described by Leproult et al (2011) are used to increase therapeutic efficacy, see Barf et al (2012) and Oballa et al, Bioorg Med Chem Lett 17:998-1002(2007) "A generating usable method for assessing the electrophoresis and reactivity of the second nitride-containing compounds": 998-1002(2007) (describing nitrile-containing electrophiles.) furthermore, Diller et al, J Med Chem 46: 4638-4647(2003) report a homology model for the PDGF β receptor based on VEGFR2 (55% homology).

In contrast to one aspect of the present invention, by using a homology model for RTKs, the inventors previously used molecular docking based on homology structures, e.g., 59% and 63% homology to the PDGF α and PDGF β receptors, respectively, for c-KitThe spatial orientation of the target cysteine residue can be analyzed to calculate the free energy of binding and the estimated K_iThe value is obtained. In some embodiments, the compound with the lowest free energy of binding and the warhead closest to the cysteine residue produces an irreversible, non-selective RTK inhibitor.

Accordingly, the present disclosure provides a compound of structure 1, an enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a tautomer, enantiomer, isomer, or stereoisomer of the compound, or a pharmaceutically acceptable salt of any mixture thereof, that covalently interacts with a Receptor Tyrosine Kinase (RTK), such as, for example, PDGFR or c-Kit, or both in some embodiments, PDGFR is selected from PDGFR- α - β - αα - ββ, and PDGFR- αβ, as evidenced by homology modeling.

Pharmaceutical composition

In one aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of structure 1 and a pharmaceutically acceptable carrier. The compositions of the invention may contain other therapeutic agents, as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of administration desired, such as, for example, excipients, binders, preservatives, stabilizers, flavorants, and the like, according to techniques well known in the art of pharmaceutical formulation, such as those described below.

The pharmaceutical compositions are generally formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, intraperitoneal, or subcutaneous), oral, inhalation, transdermal (topical), intraocular, iontophoretic, and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral formulations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. For the convenience of the patient or treating physician, the administration formulations may be provided in a kit containing all the necessary equipment for a course of treatment.

The compounds of the present disclosure may be administered by any suitable means, e.g., orally, such as in the form of tablets, capsules, granules, or powders; under the tongue; transbuccal; parenteral, such as by subcutaneous, intravenous, intramuscular, (transdermal) intradermal, or intracisternal injection or infusion techniques, for example, as a sterile injectable aqueous or nonaqueous solution or suspension, nasal, such as by inhalation spray or insufflation, topical, such as in the form of a cream or ointment, such as by eye in the form of a solution or suspension, vaginal in the form of a pessary, tampon or cream, or rectal, such as a suppository, in unit dose formulations containing a non-toxic, pharmaceutically acceptable vehicle or diluent. The compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by using a suitable pharmaceutical composition comprising a compound of the invention, or, for extended release, by using a device, such as a subcutaneous implant or osmotic pump.

For administration to the respiratory tract, e.g., inhalation, including intranasal administration, the active compounds may be administered by any of the methods and formulations used in the art for administration to the respiratory tract. Thus, the active compound may be administered in the form of, for example, a solution, a suspension, or as a dry powder. The medicament according to this aspect of the invention may also be administered directly to the airways in the form of an aerosol. For use as an aerosol, the compounds of the invention in solution or suspension may be packaged in a pressurized aerosol container with a suitable propellant, e.g., a hydrocarbon propellant such as propane, butane, or isobutane, together with conventional adjuvants. The substances of the present invention may also be administered in a non-pressurized form, such as in a nebulizer or atomizer.

The propellant-driven inhalation aerosols which can be used according to the invention may also contain other ingredients, such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH regulators. The propellant-driven inhalation aerosols according to the invention which can be used according to the invention can be administered using inhalers known in the art, for example metered dose inhalers. Alternatively, the agent of the present invention may be administered to the respiratory tract in the form of a lung surfactant formulation. The lung surfactant preparation can comprise an exogenous lung surfactant preparation (e.g.,(forest laboratories) and (B) a forest laboratory,(Ross products), and(DEY, California, USA) or synthetic lung surfactant formulations (e.g.,(GlaxoWellcome Co.), and ALEC). These surfactants are administered by airway instillation (i.e., post intubation) or intratracheal administration.

Alternatively, the medicament of the invention may be administered to the respiratory tract in the form of an inhalable powder. Powder formulations may comprise physiologically acceptable excipients, for example monosaccharides (such as glucose or arabinose), disaccharides (such as lactose, sucrose and maltose), oligo-and polysaccharides (such as dextran), polyols (such as sorbitol, mannitol, xylitol), salts (such as sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, a mono-or disaccharide is used, whereas the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of a hydrate.

The excipient in the inhalable powder according to the invention has a maximum average particle size of up to 250 μm, preferably 10 to 150 μm, most preferably 15 to 80 μm. It may sometimes seem desirable to add to the above excipients a finer excipient component having an average particle size of 1 to 9 μm. These finer excipients are also selected from the possible excipients listed above. Finally, for the preparation of the inhalable powders according to the invention, preferably micronized formulations with an average particle size of 0.5 to 10 μm are added to the excipient mixture. Known in the art are processes for the preparation of inhalable powders according to the invention by grinding and micronization and finally by mixing the components together.

In formulations for administration to the respiratory tract, including intranasal formulations, the active compounds are typically formulated to have a small particle size, e.g., about 5 microns or less, by micronization techniques and the like. Sustained release formulations of the active compounds are used in some embodiments. In some embodiments, the active compound is administered by oral inhalation via an inhaler as a free-flowing powder.

Pharmaceutical compositions and methods of the present disclosure further include additional therapeutically active compounds (second agents) that are described herein and/or known in the art, which together with compositions comprising a compound of structure 1 of the present disclosure are generally useful in the treatment of one or more pathological conditions the combination of therapeutic agents act synergistically to effect treatment or prevention of various diseases, disorders, and/or conditions described herein such second agents include, but are not limited to, prostaglandins, endothelin antagonists, cytoplasmic kinase inhibitors, receptor kinase inhibitors, endothelin receptor antagonists, e.g., ambrisentan, bosentan, and sitaxsentan, PDE5(PDE-V) inhibitors, e.g., sildenafil, tadalafil, and vardenafil, calcium channel blockers, e.g., amlodipine, felodipine, varepap, thiodil, and menthol, prostacyclin, loprostinidin, iloprost, nitric oxide, bexadine, heparin, warfarin, valnemaderin, a prodrug, a.

The compounds of the present invention may also be prepared as salts, which are pharmaceutically acceptable, but it is understood that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, at least to some extent, which salts are useful as intermediates in the preparation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of sulfate, phosphate, mesylate, bismesylate, tosylate, lactate, tartrate, malate, bis-acetate, citrate, dihydrochloride, pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, orthophosphoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid; or pharmaceutically acceptable salts of organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic, toluenesulfonic, benzenesulfonic, isethionic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric and orotic acids. Salts of amine groups may also include quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl group, alkenyl group, alkynyl or aralkyl moiety. The salts may be formed by conventional methods, for example by reacting the free base form of the compound with one or more equivalents of a suitable acid in a solvent or medium in which the salt is insoluble, or by reacting the free base form of the compound with one or more equivalents of a suitable acid, for example water, in a solvent which may be removed in vacuo or by freeze-drying, or by exchanging the anion of an existing salt for another anion in a suitable ion exchange resin. In some embodiments, the salt is a sulfate, phosphate, mesylate, bismesylate, tosylate, lactate, tartrate, malate, diacetate, citrate, or dihydrochloride salt.

In some embodiments, a compound of the present disclosure is administered in a therapeutically effective amount. Such administration is such that the compound of structure 1 will elicit a response in a subject that is sought by the clinician, e.g., cell, tissue, body fluid-related. In treating or preventing a condition mediated by, or associated with, kinase inhibition, e.g., RTK inhibition, an appropriate dosage level is administered. In some embodiments, about 0.01 to 500 mg/kg of subject body weight per day is administered in single or multiple doses. Thus, in some embodiments the dosage level is from about 0.1 to about 250mg/kg per day, while in other embodiments from about 0.5 to about 100mg/kg per day is administered to the subject. Suitable dosage levels include, for example, from about 0.01 to 250mg/kg per day, from about 0.05 to 100mg/kg per day, or from about 0.1 to 50mg/kg per day. Within this range, in some embodiments, the dose is about 0.05 to 0.5, 0.5 to 5, or 5 to 50mg/kg per day. For oral administration, compositions are provided in the form of tablets containing 1.0 to 1000 milligrams of active ingredient, including, but not limited to, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The dosage may be selected, for example, for any dosage within any of these ranges for therapeutic effectiveness and/or symptom modulation of the subject dosage being treated. In some embodiments, the compounds of the present disclosure are administered by inhalation from 1 to 20 times daily, from 1 to 15, from 1 to 10 times daily, from 1 to 5 times, from 1 to 4 times, or from 1 to 3 times daily, or once or twice daily, as described in, for example, US 8257741, US8263128, WO 2010/132827, WO 2010/102066, WO 2012/040502, WO 2012/031129, and/or WO 2010/102065. In some embodiments, a compound of the present disclosure is administered 1-5 times daily.

In some embodiments, the unit dose is sufficient to provide one or more of the following burdens: (a) a Cmax of about 1 to 5000ng/mL of the compound in the plasma of the subject when it is administered to the subject_maxOr a C of about 1 to 5000ng/mL of the compound in the blood of the subject_max(ii) a And (b) about 1 to 5000ng/mL of the compound in the plasma of the subject 24 hours after administration to the subject or about 1 to 5000ng/mL of the compound to the subject in the blood of the subject 24 hours after administration to the subject.

In some embodiments, a therapeutically effective amount of a compound of structure 1, a tautomer of the compound, an enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer, or stereoisomer of the compound, or any mixture thereof, is not associated with an adverse side effect. Such adverse side effects include, but are not limited to, decreased lung function, increased or decreased systemic blood pressure, decreased immune function, bone marrow suppression, anemia, hypoxia in the subject as compared to prior to administration to the subject.

Prevention and treatment of diseases

In one aspect, the present disclosure provides a compound of structure 1, a tautomer, enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, a tautomer, enantiomer, isomer, or stereoisomeric pharmaceutically acceptable salt of the compound, or any mixture thereof, for use in the treatment of one or more diseases, wherein structure 1 is described herein.

For example, the disclosure provides methods of inhibiting one or more kinases such as, for example, cell division cycle 2 kinase (Cdc kinase), c-Kit, c-ABL, p60SRC, AKT, VEGFR, PDGFR-0, PDGFR-1, PDGFR-2, FGFR, FLT-3, SRC-associated FYN oncogene kinase genes, FGR, YES (Fyn), lymphocyte-specific protein tyrosine kinase (Lck), tyrosine kinase having Ig and homology domains (of Tie-2), FMS (CSF-IR), KDR, EphA, EphA, FLT, FLT, PTK, RET, SYK, DDRl, EGF, synthase (KiK-3), cell kinase, EphA, EphA, FLT, FLT, FLT, PKK, kinase, tyrosine kinase (VEGF-2), tyrosine kinase-related kinase (VEGF-kinase), and tyrosine kinase-related kinase (protein kinase) such as, kinase domain kinase domain, kinase domain of cell division cycle 2, tyrosine kinase (VEGF-kinase), cell division cycle 2 kinase (VEGF-kinase) kinase, cell kinase (VEGF-kinase) and/cell kinase domain, and particularly, cell kinase related kinase (FLT-kinase, kinase domain, and kinase domain of interest, such as, kinase-kinase, kinase-kinase, kinase-kinase (VEGF-kinase domain-kinase, kinase domain-kinase, kinase-related kinase, and kinase (VEGF-related kinase domain-related kinase (VEGF-related kinase domain-kinase, and kinase domain of cell-kinase (protein kinase, and kinase (protein kinase domain of cell-related kinase, such as, cell-kinase domain-related kinase domain-kinase, cell-related kinase, cell-kinase (protein kinase, cell-related kinase (protein kinase, cell-kinase (protein kinase, cell-related kinase, cell-kinase (protein kinase, cell-related kinase.

The disclosure also provides compounds, compositions and methods for treating biological conditions mediated by or associated with kinases such as tyrosine kinases including Cdc kinase, c-Kit, AKT, c-ABL, ERK/2, STAT, p60src, VEGFR, PDGFR-0, PDGFR-1, PDGFR-2, FLT-3, Fyn, Lck, Tie-2, GSK-3, Cdk, MEK, NEK-2, CHK, CK epsilon, Raf, -CHK, Rsk, FMS (CSF-IR), KDR, EphA, FLT, HCK, PTK, RET, SYK, DDRl, DDR and PAR-1 in particular, the disclosure provides compounds, compositions and methods for treating biological conditions mediated by tyrosine kinases or associated with tyrosine kinases including tyrosine, kinase, Cdk, VEGFR, Cdk, VEGFR, pkr, PDGFR-2, VEGFR, PDGFR-3, PDGFR, pkf, frk, PDGFR, and frk, or RTK, and frk, or a combination thereof.

Diseases or conditions mediated by, or associated with, one or more kinases of the invention include, but are not limited to, PAH, primary PAH, idiopathic PAH, inherited PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with or secondary to one or more of the following: systemic sclerosis, mixed connective tissue disease, cancer, refractory cancer, metastatic cancer, neoplasia, hypoplasia, hyperplasia, dysplasia, metaplasia, abnormal differentiation, connective tissue generation, angiogenic diseases, pulmonary dysfunction, cardiovascular dysfunction, HIV infection, hepatitis, portal hypertension, pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease (valvular disease), lung disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, Chronic Obstructive Pulmonary Disease (COPD), sleep disordered breathing, alveolar hypoventilation disorder, long term exposure to high altitude, dysplasia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension with an unclear multifactorial mechanism, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatis, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage disorders, gaucher's disease, thyroid disease, tumor obstruction, fibrosing mediastinitis, and chronic renal failure dialysis; and diseases such as pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), pulmonary hypertension of the left heart disease, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, Chronic Obstructive Pulmonary Disease (COPD), sleep disordered breathing, conditions of alveolar hypoventilation, long-term exposure to high altitude, dysplasia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension and unclear multifactorial mechanisms, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage disorders, gaucher's disease, thyroid disease, tumor obstruction, fibrosing mediastinitis, immune and inflammatory diseases, hyperproliferative diseases, kidney and kidney diseases, bone remodeling diseases, metabolic diseases, vascular diseases, and dialysis chronic renal failure.

In one aspect, the invention provides a method of treating Pulmonary Arterial Hypertension (PAH) in a subject or a biological condition associated with PAH in a subject by administering to the subject a therapeutically effective amount of a compound of structure 1, a tautomer of the compound, a pharmaceutically acceptable salt of the tautomer of the compound, or a mixture thereof (wherein the compound of structure 1 is described herein). In some embodiments, the disease or disorder mediated by or associated with one or more kinases of the present disclosure is selected from the group consisting of pulmonary hypertension, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, and PAH with a secondary disease.

Pulmonary Arterial Hypertension (PAH) is a life-threatening disease characterized by a significant and sustained increase in pulmonary arterial pressure. This disease leads to Right Ventricular (RV) failure and death. Current treatments for treating chronic pulmonary arterial hypertension provide mainly symptomatic relief, as well as some improvement in prognosis. Although assumed for all therapeutic reasons, there is no evidence of direct antiproliferative effects of most approaches. Furthermore, the use of recently applied agents is hampered by undesirable side effects or inconvenient routes of drug administration. Hypertensive pulmonary pathological changes include endothelial injury, proliferation and hyper-constriction of vascular Smooth Muscle Cells (SMCs), and fibroblast proliferation. Also PAH patient status may be assessed according to the World Health Organization (WHO) Classification (modified after the new york Association Functional Classification), as is known in the art.

In some embodiments, a compound of structure 1 is one that treats or prevents PAH in a patient, particularly after receiving at least one prostanoid, endothelin antagonist, or PDE V inhibitor, for which the previous treatment failed. In other embodiments, the compounds treat or prevent PAH in patients who are more severely affected by disease, particularly patients with stage II to stage IV functional status, or more severe stage III or IV functional status. In further embodiments, the compounds treat or prevent PAH in a patient having a mutation in BMPR 2.

The present invention provides a method of preventing or treating idiopathic or primary pulmonary hypertension, familial hypertension, pulmonary arterial hypertension secondary to, but not limited to, the following, connective tissue diseases, congenital heart defects (shunts), pulmonary fibrosis, portal hypertension, HIV infection, sickle cell diseases, drugs and toxins, e.g., anorexigens, cocaine, chronic hypoxia, chronic pulmonary obstructive diseases, sleep apnea and schistosomiasis, pulmonary arterial hypertension associated with significant venous or capillary involvement (pulmonary venous obstructive diseases, pulmonary capillary angiomatosis), secondary pulmonary hypertension disproportionate to the extent of left ventricular dysfunction, and/or neonatal persistent pulmonary hypertension, especially in subjects who have previously experienced a prior failure in PAH treatment.

In one aspect, the present disclosure provides a compound of structure 1, a tautomer of the compound, an enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, a tautomer, enantiomer, isomer, or stereoisomeric pharmaceutically acceptable salt of the compound, or any mixture thereof, for use in the treatment of one or more diseases associated with hyperproliferation, neoplasia, hypoplasia, hyperplasia, dysplasia, metaplasia, dysplasia, desmoplasia, angiogenesis, inflammation, lung function, and cardiovascular function, wherein the compound of structure 1 is described herein.

Hyperproliferative, immunological and inflammatory, metabolic, vascular diseases are known in the art, and such diseases, as described in U.S. provisional patent No. 61/751217, which is incorporated herein by reference in its entirety, are therapeutic targets for the compounds and agents described herein.

Another aspect of the present disclosure relates to a method of preventing or reducing elevated pulmonary pressure in a subject by administering to the subject a therapeutically effective amount of a compound of structure 1, a tautomer of the compound, a pharmaceutically acceptable salt of the tautomer of the compound, or a mixture thereof, wherein the compound of structure 1 is described herein. See, for example, the summary of the invention. In some embodiments, the compounds of structure 1 treat or prevent a biological state associated with PAH, such as, for example, abnormal: right Ventricular Systolic Pressure (RVSP); pulmonary hypertension; cardiac output; right Ventricular (RV) hypertrophy; and PA hypertrophy.

In some embodiments, the compound of structure 1 reduces pulmonary arterial hypertension (pulmonary pressure) in the subject associated with an increase in one or more of the following, as compared to the subject prior to administration: right Ventricular (RV) function, systolic pressure of Pulmonary Artery (PA) and/or cardiac output. In some embodiments, the reduction in pulmonary pressure (pulmonary arterial hypertension) is associated with one or more of RV hypertrophy, PA hypertrophy, a reduction in RVSP, sustained PA pressure, and stroke risk in the subject, as compared to the subject prior to administration. In some embodiments, the reduction is at least a 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% reduction. In some embodiments, the reduction is a reduction of at least 40%.

In some embodiments, the reduction in pulmonary pressure in the subject is not associated with reduced lung function and/or increased systemic blood pressure compared to the subject prior to administration. Methods of measuring lung function and blood pressure are known in the art. In one aspect, the present disclosure provides a method of treating Pulmonary Arterial Hypertension (PAH) in a subject, comprising: by administering to a subject a compound of structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, a tautomer, enantiomer, isomer or stereoisomer of the compoundOr any mixture thereof, thereby modulating the phosphorylation state ("PS") of one or more downstream targets of platelet-derived growth factor receptor- α or platelet-derived growth factor receptor- β or both, wherein the downstream target is any phosphorylation substrate as a result of activation of PDGFR- α and/or PDGFR- β, wherein the downstream target is selected from AKT, PDGFR, STAT3, ERK1 and ERK2, or any other downstream target of PDGFR- α and/or PDGFR- β, and wherein the compound of structure 1 is described hereinAnd other kinase assays known in the art.

In suitable embodiments, modulation of kinase receptor activity is inhibition of kinase receptor activity PDGFR, i.e., PDGFR- α - β - αα - ββ, and PDGFR- αβ, and/or c-Kit is an example of a RTK that is inhibited in some embodiments of the invention in some embodiments, inhibition is at least 0.001, 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% inhibition in some embodiments, PSR modulation is modulation of one or more of AKT, 3, ERK1, ERK2, PDGFR, i.e., PDGFR- αα - ββ, and PDGFR- αβ in some embodiments, modulation of PS is a decrease in the subject relative to the total phosphorylation of STAT3, 3, in some embodiments, as compared to the previous administration of the kinase receptor activity, at least 0.001, 50, 60, 50, 65, 95% decrease in the subject, 50, 95, or 95% of all other embodiments.

In some embodiments, the modulation of PS is a reduction in monophosphorylated ERK1 in the subject relative to total ERK1, as compared to PS in the subject prior to the administration. In some embodiments, the reduction is a reduction of at least 0.001, 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%. In some embodiments, modulation of PS is a decrease in phosphopdgfr relative to total PDGFR in the subject compared to PS in the subject prior to administration. In some embodiments, the reduction is a reduction of at least 0.001, 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%. In some embodiments, the modulation of PS is a decrease in phosphorylated AKT in the subject relative to total AKT, as compared to PS in the subject prior to administration. In some embodiments, the reduction is a reduction of at least 0.001, 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%.

The present invention provides embodiments including, but not limited to:

1. a method of non-selective kinase receptor inhibition for treating a pulmonary disorder in a subject, comprising: administering to a subject a therapeutically effective amount of a compound of structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer or stereoisomer of the compound, or any mixture thereof, wherein structure 1 has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃-a-C-N-C-group, -a-C-N-C (═ O) -group, -C (═ O) R⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical, substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂-a C ≡ N, -a C ═ N group, -a C-N-C-group, -a C-N-C (═ O) -C-F, -a C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstitutedSubstituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -a-C (═ O) -aryl group, -a-C (═ O) O-alkyl group, -a-C (═ O) O-aryl group, -a-C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; - (alkanes)A group) (aryl) aminoalkyl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted hydroxyalkyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted aryloxyalkyl group, and substituted and unsubstituted heterocyclyloxyalkyl group, -NH (alkyl) group, -NH (aryl) group, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N- (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and-N (aryl) O-aryl group;

R⁸is selected from R¹，R²，R³，R⁴，R⁵，R⁶，R⁷H, absent, -C ═ C, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups (R)⁹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰) A radical, substituted and unsubstituted-C (═ C)O) -heterocyclyl (R)¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹) Radical, substituted and unsubstituted aryl (R)¹⁰) Radical, substituted and unsubstituted aryl (R)¹¹) Radical, substituted and unsubstituted aryl (R)⁹)(R¹⁰) Radical, substituted and unsubstituted aryl (R)⁹)(R¹¹) Radical, substituted and unsubstituted aryl (R)¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹)(R¹⁰)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰)(R¹¹) A group, and substituted/unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰)(R¹¹) A group;

R⁹，R¹⁰and R¹¹May be the same or different and is independently selected from the group consisting of absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²A group, -C ≡ N, -C-N-C, -C-N- (═ O) -group, -C-N-C- (═ O) -C-F, -C-N-C- (═ O) -C ═ C, -C ═ N group, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkanesA phenylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted alkylamino group, a substituted and unsubstituted arylamino group, and a substituted and unsubstituted dialkylamino group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted alkylamino group, a substituted and unsubstituted arylamino group, a substituted and unsubstituted dialkylamino group, a substituted and unsubstituted diarylamino group, a substituted and unsubstituted (alkyl) (aryl) amino group, -C (═ O) H, -a C (═ O) -alkyl group, -a C (═ O) -aryl group, -a C (═ O) O-alkyl group, -a C (═ O) O-aryl group, -a C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted cyano group, substituted and unsubstituted pyrimidinyl group, substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) group, and substituted and unsubstituted cyano-pyrimidinyl group;

R¹²selected from absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-a group, -C ≡ N, -C-N-C, -a group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -a group-C ═ N,-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃An alkoxy group, an aryloxy group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary, and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidyl group, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

Q¹selected from direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-, -C ≡ N, -C-N-C group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, -C (═ O) -C-group, -C (═ O) -C ═ C, -CF ═ C, -C ═ C₃a-C ≡ N, -C-N-C-group, -C-N- (═ O) -group, -C-N-C- (═ O) -C-F, -C-N-C- (═ O) -C ═ C, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, methoxy groups, dimethoxy groups, methoxyphenol groups, dimethoxyphenol groups, dimethoxybenzene, dimethoxyphenyl groups, methoxymethylbenzyl groups, substituted and unsubstituted arylbenzyl groupsAlkyl radical, -NH₂Substituted and unsubstituted heterocyclylalkyl groups, substituted/unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

Q²selected from absent, H, Q¹，Q¹(Q³) -OH, alkoxy groups, aryloxy groups; and

Q³selected from absent, direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-a group, -C ≡ N, -C-N-C, -a group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N-a group, -C (═ O) -C ═ C, -CF ═ C₃a-C ≡ N, -C-N-C-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -OH, an alkoxy group, an aryloxy group, a methoxy group, a dimethoxy group, a methoxyphenol group, a dimethoxyphenol group, a dimethoxybenzene, a dimethoxyphenyl group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, and a substituted and unsubstituted heterocyclyl group.

2. The method according to embodiment 1, wherein R⁸Has the following formula:

and wherein X is independently selected from C, N, O, S and-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-C ≡ N, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, alkoxy groups, aryloxy groups, substituted and unsubstituted amidino groups, substituted and unsubstituted guanidino groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkynyl groups, substituted or unsubstituted alkynyl groups, orSubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups.

3. The method of embodiment 2 wherein R⁸Is selected from the group a.

4. The method of embodiment 1 wherein Q¹Or Q²Is selected from the group B structures, -CH₃，-OH，-O-CH₃-C-N-C (═ O) -C ═ C and-C-N-C (═ O) -CF.

5. The method of embodiment 1 wherein the compound of structure 1 is a compound of structure 2, structure 2a, structure 3, structure 4 or structure 5 as shown in group C structures.

6. The method of any one of embodiments 1-5, wherein the compound of structure 1,2, 2a, 3,4 or 5 is administered orally, intravenously, subcutaneously, transdermally, intraperitoneally, or by inhalation.

7. The method of any one of embodiments 1-6, wherein said kinase receptor is a Receptor Tyrosine Kinase (RTK), and wherein said RTK is a Platelet Derived Growth Factor Receptor (PDGFR).

8. The method of embodiment 7, wherein said PDGFR is platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both.

9. The method of embodiment 7, wherein said PDGFR is a homodimer or heterodimer selected from PDGFR- αα - ββ and PDGFR- αβ, or any combination thereof.

10. The method of any one of embodiments 7-9, wherein inhibition of PDGFR is effective to treat a pulmonary disease, wherein the pulmonary disease is Pulmonary Arterial Hypertension (PAH), PAH associated with plexiform and/or neointimal lesions, PAH associated with pulmonary fibrosis and/or progressive vascular degeneration, abnormal fibroblast and/or myofibroblast proliferation, or a pulmonary vascular disease associated with abnormal endothelial cell proliferation, or any combination thereof.

11. The method of any one of embodiments 7 to 10, wherein said inhibition is a combined inhibition of both PDGFR- α and PDGFR- β.

12. The method of embodiment 11, wherein said inhibiting prevents activation of both PDGFR- α and PDGFR- β by modulating cognate substrate interaction.

13. The method of embodiment 12, wherein said homologous base is selected from PDGFAA, PDGFBB and PDGFAB, or any combination thereof.

14. The method of embodiment 1, wherein said pulmonary disease is selected from Pulmonary Arterial Hypertension (PAH), PAH associated with plexiform and/or neointimal lesions, PAH associated with pulmonary fibrosis and/or progressive vascular degeneration, abnormal fibroblast and/or myofibroblast proliferation, and pulmonary vascular disease associated with abnormal endothelial cell proliferation.

15. The method of embodiment 14, wherein said PAH is selected from the group consisting of primary PAH, idiopathic PAH, inherited PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, PAH associated with toxin-induced PAH, PAH associated with systemic sclerosis, mixed connective tissue disease, HIV, hepatitis, and portal hypertension.

16. The method of any one of embodiments 1-15, wherein the PAH is secondary to pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, neonatal persistent pulmonary hypertension, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, Chronic Obstructive Pulmonary Disease (COPD), sleep disordered breathing, alveolar hypoventilation disorder, long-term exposure to high altitude, dysplasia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension with unclear multi-factorial mechanisms, hematologic disorders, myeloproliferative disorders, splenectomy, systemic disease, sarcoidosis, pulmonary Langerhans cell histocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage disease, gaucher's disease, thyroid disease, tumor obstruction, fibrosing mediastinitis, and chronic renal failure on dialysis.

17. The method of embodiment 1, wherein the pulmonary disorder is associated with an abnormality of: right Ventricular Systolic Pressure (RVSP); pulmonary pressure; cardiac output; right Ventricular (RV) hypertrophy; and/or Pulmonary Artery (PA) hypertrophy.

18. The method of one of embodiments 1-17, wherein the compound of structure 1 has an IC for kinase receptor of less than 300nM₅₀。

19. The method of any one of embodiments 1-18, wherein the kinase receptor is platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both, wherein the lung disease is pulmonary hypertension.

20. The method of any one of embodiments 1-19, wherein said inhibiting occurs through a non-covalent interaction.

21. The method of any one of embodiments 1-19, wherein said inhibiting occurs by covalent interaction.

22. A method of treating Pulmonary Arterial Hypertension (PAH) in a subject, comprising modulating the phosphorylation state of one or more downstream targets of platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both, wherein the downstream target is any phosphorylated substrate as a result of activation of PDGFR- α and/or PDGFR- β, by administering to the subject a compound of structure 1, or a tautomer, enantiomer, isomer, or stereoisomer of the compound, a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer, or stereoisomer, or any mixture thereof, wherein the downstream target is selected from any phosphorylated substrate as a result of AKT, PDGFR, STAT3, ERK1 and ERK2, or any other downstream target of PDGFR- α and/or PDGFR- β, and wherein the compound of structure l has the formula:

wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃-a-C-N-C-group, -a-C-N-C (═ O) -group, -C (═ O) R⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical, substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylamino group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted arylamino group, a substituted and unsubstituted diarylamino group, a substituted and unsubstituted arylamino group, a substituted orAminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂a-C ≡ N, -C ═ N-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -C (═ O) -aryl groups, -C (═ O) O-alkyl groups, -C (═ O) O-aryl groups, -C (═ O) NH-alkyl groups, -C (═ O) O-aryl groups₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl groupO) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; - (alkyl) (aryl) aminoalkyl groups, -C (═ O) -heterocyclyl groups, -C (═ O) -O-heterocyclyl groups, -C (═ O) NH (heterocyclyl) groups, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted hydroxyalkyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted aryloxyalkyl group, and substituted and unsubstituted heterocyclyloxyalkyl group, -NH (alkyl) group, -NH (aryl) group, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N- (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and N (aryl) O-aryl group;

wherein R is⁸Has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-C ≡ N, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, alkoxy groups, aryloxy groups, substituted and unsubstituted amidino groups, substituted and unsubstituted guanidino groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groupsSubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

wherein Q¹Or Q²Is selected from the group B structures, -CH₃，-OH，-O-CH₃-C-N-C (═ O) -C ═ C and-C-N-C (═ O) -C-F.

23. The method of embodiment 22 wherein R⁸Is selected from the group a.

24. The method of embodiment 22, wherein the modulation is a decrease in phosphorylated STAT3 relative to total STAT3, a decrease in diphosphorylated ERK1 relative to total ERK1, a decrease in diphosphorylated ERK2 relative to total ERK2, a decrease in monophosphorylated ERK1 relative to total ERK1, a decrease in phosphorylated PDGFR relative to total PDGFR, or a decrease in phosphorylated AKT relative to total AKT, or any combination thereof, in the subject compared to PSR in the subject prior to the administration.

25. The method of embodiment 24, wherein the compound of structure 1 interacts with AKT at residues Thr308 and/or Ser473, or wherein the compound of structure 1 interacts with one or more of PDGFR- α - β - αα - ββ, and/or PDGFR- αβ amino acids, said PDGFR- α - β - αα - ββ, and/or PDGFR- αβ amino acids selected from LYS627, VAL607, GLU644, MET648, hiaps 816, LEU809, 836, CYS814, ILE834, CYS835, PHE937, LYS634, VAL614, GLU651, MET655, HIS824, LEU817, ASP844, CYS822, ILE842, VAL658, ILE647, HIS816, ARG836, LYS 651, GLU651, ALA 824, MET655, ARG825, CYS 842, VAL658, ILE 84826, ILE 826, ILE657, ILE 826, ILE654, ILE 658, ILE654, ILE 826, ILE654, e 658, ILE654, ILE 826, or any combination thereof.

26. The method of embodiment 22 wherein the compound of structure 1 is a compound of structure 2, structure 2a, structure 3, structure 4 or structure 5 as shown in group C structures.

27. The method of embodiment 22, wherein said inhibiting occurs through a non-covalent interaction.

28. The method of embodiment 22, wherein said inhibiting occurs by covalent interaction.

29. A compound of structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, a tautomer, enantiomer, isomer or stereoisomer of the compound, or a pharmaceutically acceptable salt of the compound, or any mixture thereof, for use in treating one or more diseases associated with hyper-proliferation, neoplasia, hypoplasia, hyperplasia, dysplasia, metaplasia, dysplasia, desmogenesis, angiogenesis, inflammation, immune status, metabolism, lung function, and cardiovascular function by non-selectively inhibiting a Receptor Tyrosine Kinase (RTK) selected from the group consisting of AKT, c-Kit, and PDGFR, wherein structure 1 has the formula

Wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃a-C-N-C-group, a-C-N-A group of formula (I), a group of formula (II), a group of formula (III), a group of⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical, substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂a-C ≡ N, -C ═ N-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groupsSubstituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -C (═ O) -aryl groups, -C (═ O) O-alkyl groups, -C (═ O) O-aryl groups, -C (═ O) NH groups₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; - (alkyl) (aryl) aminoalkyl groups, -C (═ O) -heterocyclyl groups, -C (═ O) -O-heterocyclyl groups, -C (═ O) NH (heterocyclyl) groups, -C (═ O) -N (heterocyclyl)₂A group, -a (co) -N (alkyl) (heterocyclyl) group, -a (co) -N (aryl) (heterocyclyl) group, a substituted and unsubstituted heterocyclylaminoalkyl group, a substituted and unsubstituted hydroxyalkyl group, a substituted and unsubstituted alkoxyalkyl group, a substituted and unsubstituted aryloxyalkyl group, and a substituted and unsubstituted aryloxyalkyl groupHeterocyclyloxyalkyl radicals, -NH (alkyl) radicals, -NH (aryl) radicals, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and-N (aryl) O-aryl group;

wherein R is⁸Has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-C ≡ N, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dioxane An arylamino group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, a substituted and unsubstituted cyano (heterocyclyl) group, and a substituted and unsubstituted cyano-pyrimidinyl group;

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidine group, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

wherein Q¹Or Q²Is selected from the group B structures, -CH₃，-OH，-O-CH₃-C-N-C (═ O) -C ═ C and-C-N-C (═ O) -C-F.

30. The method of embodiment 29 wherein R⁸Is selected from the group a.

31. The compound of embodiment 29 wherein the compound of structure 1 is a compound of structure 2, structure 2a, structure 3, structure 4 or structure 5 as shown in group C structures.

32. The compound of embodiment 29, wherein the compound of structure 1 is administered orally, intravenously, subcutaneously, transdermally, intraperitoneally, or by inhalation.

33. The method of embodiment 29, wherein the disease is selected from the group consisting of cancer, metastatic cancer, HIV, hepatitis, PAH, primary PAH, idiopathic PAH, inherited PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with systemic sclerosis, and mixed connective tissue disease, pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, Pulmonary Vein Occlusive Disease (PVOD), pulmonary capillary angiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, COPD, sleep disordered breathing, alveolar hypoventilation disorders, long term exposure to high altitude, dysplasia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension with an unclear multifactorial mechanism, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomata, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage disorders, gaucher's disease, thyroid disorders, tumor blockages, fibrositis, and chronic renal failure of dialysis and PAH associated with the foregoing.

34. A compound of embodiment 29 wherein the salt is chloride, hydrochloride, sulfate, phosphate, methanesulfonate, bismethanesulfonate, toluenesulfonate, lactate, tartrate, malate, diacetate, citrate, or dihydrochloride.

35. A compound of embodiment 29 wherein said inhibition occurs by non-covalent interactions.

36. A compound of embodiment 29 wherein said inhibition occurs by covalent interaction.

37. The compound of embodiment 29, wherein the compound of structure 1 has an IC for kinase receptor of less than 300nM₅₀。

38. The method of embodiment 1, wherein said treatment results in one or more of: improved exercise capacity, improved functional grade, shortness of breath, reduced hospitalization, reduced need for lung transplantation, reduced need for interatrial septal dissection, and increased lifespan or overall survival.

39. The method of embodiment 38, wherein the improved exercise capacity is increased 6 minute walking distance.

40. The method of embodiment 38, wherein the functional level of improvement is grade iv to grade III, II or I improvement, or grade III to grade II or I improvement, or grade II to grade I improvement.

Examples

The invention is further illustrated by the following examples, which should not be construed as being in any way limiting. The following is a description of these material materials and methods used in all examples, where it is shown that the RTK signaling pathway is activated in human disease conditions, e.g., PAH, and in animal models of disease.

Materials PK10453, (S) -N- (3- (1- ((6- (4-hydroxy-3-methoxyphenyl) pyrazin-2-yl) amino) ethyl) phenyl) -5-methylnicotinamide, i.e., structure 2, synthesized by Organix corporation (Walp, Massachusetts.) human PA smooth muscle cells and Cell culture media were obtained from Cell Applications, Inc. PDGFBB, P-toluenesulfonic acid, ammonium hydroxide and IR780 from Sigma Aldrich corporation (St. Louis. Mo.) Imatinib mesylate was obtained from LC laboratory (Walp, MA.) human fetal lung fibroblasts (HLFS) from App cells, Inc., san Diego.) PDGA, FAB and Glutam were obtained from Mediatech corporation (Marnsas, Fragilia) from Lipfech, Nykuchen island, Massa, Sp.J.Pyth.Pdgman, anti-rat-5-rat-2-rat-2-rat-C, rat-2-rat-2-C, rat-2-rat-2, rat-2-rat-2-rat-2, rat-2-rat-2-rat-2-rat.

In vitro kinase assay Z-lyte kinase assay was performed to determine inhibition of PDGFR α and PDGFR β mediated phosphorylation by PK10453 (Structure 2). Ten-bit titration curve modeling to calculate IC₅₀(Invitrogen Select)。

PASMC proliferation assay. Human pulmonary artery smooth muscle cells (papmcs) were obtained from Cell Applications (san diego, CA) and grown to 50% confluence in a 96-well format. Cells were switched to serum-free medium 24 hours prior to stimulation using PDGFBB 50ng/mL and varying concentrations of PK10453 (Structure 2). After 24 hours of treatment, Cyquant NF cell proliferation assay was performedAnd measuring the fluorescence signal with a CytoFluor plate reader. The data are based on the average of 8 replicates at each concentration.

Intracellular protein blotting (In cell Western) (ICW). To compare PK10453 (Structure 2) and imatinib stimulation of PDGFBB and PDGFAAInhibition of AKT phosphorylation, ICW was performed according to the method of Chen et al, "Acell-based immunological assay for monitoring kinase signaling pathway and drug efficacy" Analytical biochemistry Vol.338: 136-42(2005), modified. HLFs were kept in subculture with no more than 6 passages in DMEM with 5% FBS and 4mM Glutamax at 37 ℃ with 5% CO₂HLFs were plated and grown to 70-80% confluence in 96-well plates, then serum starved for 48 hours cells were treated with the indicated concentrations of drug (PK10453 or imatinib) for 30 minutes, then exposed to 10ng/mL of PDGFAA or BB for 7.5 minutes cells were fixed in 3.7% formaldehyde, washed with 0.1% Triton X-100 and treated with Odyssey blocking buffer for 90 minutes protein incubated overnight at 1: 100 dilution of rabbit mAB to phosphorylate AKT (Ser473 or Thr308) and 1: 100 mouse mAB to total AKT-pan 4040 d.

An animal. Male Sprague Dawley rats (body weight 320-330 g; Taconic) were used for this study. Animals were housed in standard mouse cages, 12 hour light/dark cycle, and provided standard rat food and water ad libitum. Animals were cared and used according to NIH guidelines. All animal protocols were approved by the Bassett Medical Center and Pulmokine IACUC.

Formulation and aerosol delivery. PK10453 (structure 2) was dissolved in 1M toluene sulfonic acid at a concentration of 20 mg/ml. Nebulization was performed with a PARI nebulizer at an air pressure of 12.5 pounds. The aerosol droplets are neutralized with ammonia vapor, which is passed into an aerosol gas stream. The particles were then dried by flowing through an annular ring of silica beads before reaching the exposure chamber. The 6-port exposure chamber is the only nasal exposure system custom designed and built by Powerscope corporation (Minneapolis, MN). The vacuum flow rate is controlled at each port individually by a flow meter. The aerosol particle size was measured at the outlet port of the drying column of an Anderson (Anderson) (Mark II) cascade impactor. The median aerodynamic diameter (MMAD) was 2 μm and the associated Geometric Standard Deviation (GSD) was 1.6. Imatinib mesylate was dissolved in water at 20mg/ml and delivered by a PARI nebulizer, then dried by passing through an annular ring of silica beads prior to inhalation.

And (4) estimating the inhaled dose. Exposure to PK10453 (structure 2) for 4 or 8 minutes (n ═ 6 per group) was placed in amber glass vials through filters of the Powerscope exposure chambers. Twelve milliliters of 1:3 (vol/vol) methanol: acetonitrile was added to each vial containing the filter for about 1 hour with periodic mixing followed by sonication for 60 seconds. Aliquots were then added 10 μ L of unknown filter extract diluted 100-fold to 990 μ L of 1: 3(v/v) methanol: and (3) acetonitrile. The sample was vortex mixed for 30 seconds and then 100 μ L of diluted aliquot was mixed with 100 μ L of 172ng/mL solution at 1: 1 methanol: non-chemically related internal standards in water (PK18855) were combined, vortex mixed, and transferred to autosampler vials for LC-MS/MS analysis. Extract of filter and methanol 100%Company). The aerosol concentration of PK10453 in micrograms/liter of air (structure 2) was calculated from the average aggregate micrograms of PK10453 (structure 2) at 4 and 8 minutes exposure time on the filter and the flow rate through each filter (0.8 liter/minute). Calculation of inhaled dose PK 10453/cm²Average filter paper concentration (average 4 and 8 min exposure), average minute ventilation (0.15 liters/min) as measured by plethysmography, and an estimated sedimentation fraction of 0.1. The 8 minute dose of imatinib is based on a gravimetric analysis.

And (6) imaging. The spatial distribution of PK10453 (structure 2) inhaled in the lung was assessed by fluorescence imaging. Near IR fluorescent tracer, IR-780, was added to the liquid drug in the nebulizer to ensure that the dry aerosol particles contained both drug and IR tracer. After two minutes of exposure, the animals were placed under general anesthesia via tracheal intubation, and the lungs were excised. OCT/PBS via pulmonary artery, lung insufflated with air, and pulmonary infusion frozen in liquid nitrogen gas phase. A series of approximately 2 mm slices of the lung were imaged with a Licor Odyssey imager.

Pharmacokinetic studies. PK10453 (structure 2) was administered to the animals either intravenously or by inhalation, and then the animals were euthanized at times 0, 10, 20, and 60 minutes (each time point n ═ 3). Blood samples were taken by cardiac puncture and lungs were excised. Lungs were homogenized and purified using 1:3, acetonitrile: methanol mixture extraction PK10453 (structure 2). Also, with 1:3, acetonitrile: the methanol mixture extracted the plasma. The drug was analyzed by LC MS/MS (PharmOptima, Portage MI). First order exponential curves were fitted to the data using Excel. AUC was determined using an integrated trapezoidal method.

Rat MCT model efficacy studies-PK 10453 (structure 2) dose response studies in rat MCT model. Male Sprague Dawley rats received MCT60 mg/kg IPMCT and after 3 weeks PK10453 (structure 2) or vehicle control was administered by inhalation. Four groups were studied: vehicle control (4 min exposure), and three treatment groups of PK10453 (structure 2), with exposure times of 2 min (D2), 4 min (D4), or 8 min (D8), three times a day. These regimens were administered for two weeks. The vehicle included atomized 1M toluene sulfonic acid, which was neutralized with ammonia vapor, as described above. The pH of each dose of a solution prepared by dissolving the trapped aerosol particles in water was determined, which was always in the range of 5.5-6.0. At the end of the study, the right ventricular systolic pressure was measured and the heart chambers were dissected and weighed.

Rat MCT model efficacy study-PK 10453 (structure 2) on imatinib in rat MCT model. Male Sprague Dawley rats were given MCT60 mg/kg IP. Three weeks later vehicle (1M toluene sulfonic acid), PK10453 (structure 2, 20mg/ml free base in 1M toluene sulfonic acid), or imatinib mesylate (20 mg/ml in nebulizer solution) was administered to the indicated groups, three times a day for 8 min inhalation exposure, two weeks. RVSP pressure was measured at the end of the study; lungs and heart were fixed in formalin. For RVSP animal measurements, isoflurane sedation was applied, intubation was effected by tracheotomy, and ventilation was applied using a TOPOVENT pressure-regulated ventilator (peak inspiratory pressure 18 cm H2O, PEEP5 cm). After sternotomy, a Scisense high fidelity catheter was inserted through the apex of the right ventricle.

Efficacy study of rat MCT + PN model. Whole lung resection and transplantation of the lung in the pulmonary artery and TRM53P Telemetry monitor were performed in rats (Telemetry study, New Zealand and adiinstruments, Colorado). Two weeks after MCT, PK10453 (structure 2) was administered three times daily for 1 week. Dosing was initiated 2 weeks after MCT rather than 3 weeks because PAH developed more rapidly in this more aggressive model animal and pain developed more rapidly than in animals treated with MCT alone (data not shown). Two groups were exposed for 4 minutes to vehicle control or PK10453 (structure 2). Dynamic animals in room air (estimated atmospheric pressure based on altitude of the animal facility 716 mmhg) were pressure sampled 5 minutes of PA each morning prior to dosing. In scheme 4 (imatinib with vehicle), animals received a DSI PAC40 transmitter followed by 50 mg/kg lilium uniflorum (Lot) SLBB 7802V). Lower doses of MCT were used in this study because attempting to use 60 mg/kg of MCT from this batch resulted in a high proportion of animals requiring early euthanasia due to weight loss and shortness of breath. Two weeks after MCT IP injection, vehicle (mesylate 3 mg/ml) or imatinib mesylate 20mg/ml in nebulizer solution) was administered for 8 min exposure three times a day for 9 days. Telemetry data was obtained 10 minutes daily before each morning dose of the regimen.

PV ring measurements. In a separate group of animals, the MCT + PN model was developed as described above, and then PK10453 (structure 2) was administered to the drug treatment group three times per day for 4 or 8 minutes. Vehicle control groups were exposed for 4 minutes three times a day. Cycles (loops) of Pressure Volume (PV) obtained with the admittance system (Scisense Corp.) 14 days after treatment with isoflurane and 100% FiO₂Rats were anesthetized systemically. In addition, or in the alternative, post-treatment 1RV pressure was obtained in each group for 4 days. In a subset of groups, Pressure Volume (PV) rings were obtained using an admittance system (high fidelity catheter FTE1918B, Scisense corporation) 14 days after treatment. After introduction of general anesthesia and intubation via tracheotomy, the rats were placed on a pressure controlled ventilator (TOPOVENT). General anesthesia included isoflurane and 100% FiO2 concentrations with a peak pressure of 18 cm, PEEP5 cm of water. An RV left thoracotomy was performed with an admittance catheter through the right ventricular outflow tract.

Study of systemic blood pressure. The effect of PK10453 (structure 2) on systemic blood pressure was studied in dynamic MCT-treated rats having a DSI PAC40 transmitter implanted in the descending aorta. Three weeks after 60 mg/kg IP administration of MCT, animals inhaled PK10453 (structure 2) or vehicle 3X/day with a 4 minute exposure for 7 days. Blood pressure was recorded daily morning before dosing.

Plethysmography. Plethysmography is performed using an Ameka dual chamber plethysmograph and IOX software. Measured parameters include respiratory rate, tidal volume, minute ventilation, peak inspiratory and expiratory flow rates, and airway resistance (SRaw). Animals were acclimated for three days prior to the first data acquisition to accommodate plethysmography. Before the first dose of the drug and at the end of the study measurements were taken.

Histological and morphological analyses. At the end of the study, the heart and lungs were removed from the ventilated animals under general anesthesia. Heparinized saline is injected under pressure through the main pulmonary artery. The upper right leaf was immediately knotted and placed in liquid nitrogen for western blot and NanoPro 100 assay analysis. The heart was removed and the RV free wall, ventricular septum and left ventricular free wall were dissected and weighed. Buffered formalin (10%) was injected under pressure through the pulmonary arteries and trachea. Morphological analysis was performed on 8 μ M H & E stained formalin-fixed tissue sections. The media area and luminal area of the pulmonary arterioles were measured with Image J software by a technician blinded to the treatment group. Measurements were made on 20 pulmonary arterioles per slice. The ratio of the lumen area to the total mesomembrane area was determined. This ratio normalizes the change in total pulmonary artery area. In addition, occlusion analysis was performed in the Lily wild plus Total Lung resection study (specific efficacy study 5), according to the methods of this time et al, "invasion of RhoA/Rhokinase signaling in protection against monoclonal-induced pulmonary hypertension in pulmonary surgery by hydrophilic surgery" Am J physiological Lung Cell Mol physiology. 295: l71-8 (2008). In short, the pre-capillary arterioles are assigned a rank of 0, since there is no evidence of intimal lesions, a rank of 1 for less than 50% of the luminal occlusions and a rank of 2 for more than 50% of the occlusions. Masson trichrome staining was performed on lung sections from the MCT + PN model.

NanoPro immunoassay. By usingThe immunoassay system measures the relative difference between phosphorylated pERK1/2 and STAT isoforms (Protein Simple/cell Biosciences, CA). See Fan et al, "Nanofluidic proteinaceous assay for serologic assays in clinical assays," Nat Med 15: 566-571(2009).

Immunohistochemistry using citrate buffer (pH 6.0) or Tris-EDTA buffer (pH 9.0.) immunohistochemistry on CD20(B cell marker), CD3(T cell marker), von Willebrand factor (vWF), Total STAT3, STAT phosphate 3(TyR705), Total PDGFR- α, Total PDGFR- β, and PDGFR- β phosphate competitive peptides are available for PDGFR- α and phosphorylated PDGFR- β, using EXEXE POSE HRP/DAB kitAnd carrying out signal detection.

And (5) carrying out statistical analysis. Data are presented as mean ± SEM unless otherwise indicated. A general linear model (SPSS 14.0) with multiple sets of comparative Bonferroni corrections was used. The significance was set at a level where p was 0.05.

Example 1-PK10453 characterization (Structure 2)

In vitro kinase assay showed IC of PK10453 at ATP Km₅₀IC of imatinib with PDGFR- α of 35nM and PDGFR- β of 10.1 nM. for ATP Km₅₀PDGFR- α was 71nM and PDGFR- β was 607 nM. see FIG. 1. IC of PK10453 stimulating AKT phosphorylated PDGFBB at Ser473₅₀0.13. mu.M, compared to 1.8. mu.M (p) of imatinib<0.01) as shown in figure 2. ICW. PDGFBB stimulates IC of PK10453 phosphorylated at Thr308AKT₅₀Is 0.43. mu.M, in contrast to 3.25. mu.M (p) for imatinib<0.001). IC of PK10453 and imatinib₅₀The concentrations did not differ significantly from PDGFAA stimulated AKT phosphorylation.

The inhaled dose-PK 10453 (structure 2) and imatinib were estimated. The mean concentrations of PK10453 were 62.4 ± 3.3 micrograms/square centimeter of filter paper (4 minute exposure), and 137 ± 7.0 micrograms/square centimeter (8 minute exposure), which produced aerosol concentrations of 91.65 micrograms/liter of air (4 minute exposure) and 100.6 micrograms/liter of air (8 minute exposure). The aerosol concentration of imatinib was 167 micrograms/liter by weight. Assuming a 0.1 deposition score and a rat weight of 300g, the mean inhaled dose (8 min) was approximately 20 micrograms/kg PK10453 and 40 micrograms/kg imatinib, as shown in table 1. The inhaled dose, measured concentration of PK10453 in aerosol (structure 2) and gravimetric analysis of imatinib, measured Minute Ventilation (MV), estimated deposition fraction of 0.1, and rat body weight of 300 grams were estimated from the following calculations.

TABLE 1

Pulmonary distribution and pharmacokinetics of inhaled PK10453 (structure 2). A fluorescence image of a lung section after PK1045 inhalation with IR780 tracer is shown in fig. 3, where the fluorescence intensity is shown to be evenly distributed throughout the lung. The network of dark lines emerges from the connective tissue and therefore does not represent an affected airway by the disease. The spatial distribution of imatinib was similar (data not shown).

For pharmacokinetic studies, PK10453 (structure 2) concentration in the lungs when administered by inhalation was compared to that achieved with IV administration. As described below, Moren "Aerosol in medicine, principles, diagnosis, and therapy," Amsterdam; xx,429(1993) and Phalen et al, "occupation exposure method". Environ Health Persport 56: 23-34(1984)), it is possible to estimate the pharmacokinetic advantage of inhalation over intravenous administration, R_dBy comparing AUC under the time-varying drug concentration curve after respiratory and intravenous administration:

R_d(iv) breath [ [ (AUC lung/AUC plasma)]/[ (AUC Lung/AUC plasma) IV]

Pharmacokinetic data were modeled for the first order exponential curve, as well as AUC calculated from the curve (see table 2). Fig. 4 shows the time course of drug levels in the lungs and plasma following inhalation or intravenous administration of PK10453 (structure 2). The data show a 45-fold advantage over IV administered PK10453 (Rd 44.6).

TABLE 2

Example 2 MCT model efficacy

The RVSP values are shown in FIG. 5A. In the vehicle group (n ═ 6), RVSP was 80.4 ± 2.6 mm hg. For the treatment group, D2(n ═ 6), 51.4 ± 6.5; d4(n ═ 6), 44.4 ± 3.8; and D8(n ═ 5), 37.1 ± 4.5 mm hg (p < 0.001). The right ventricular systolic pressure of the normal control group was 28.5 ± 2.6 mmhg (n ═ 3). In the D4 group, there was a 44% reduction in RVSP, and in the D8 group, there was a 54% reduction in RVSP, compared to the vehicle treated group. There is also a significant reduction in the extent of RV hypertrophy as measured by the ratio (RV + IVS)/LV weight. See fig. 5B. These data are represented by the ratio because the septum is shared by the RV and LV. However, the use of the ratio RV/(IVS + LV) also shows similar results.

In addition, there were 6 animals in the vehicle group, but accurate RV-end systolic pressure was not achieved in 2 animals due to bleeding. RV systolic blood pressure is therefore based on n-4 and 57.9 ± 7.6 mmhg in the vehicle group. In the PK10453 (structure 2) group (n ═ 12), the end-systolic ventricular pressure was 36.3 ± 2.6 mmhg, and in the imatinib group (n ═ 6) was 31.8 ± 1.8 mmhg (p ═ 0.001 vehicle with PK10453, p ═ 0.002 vehicle with imatinib, fig. 5C). The end-systolic volume was greater in the vehicle group (158 ± 12.6 μ L) with PK10453(99.5 ± 10 μ L) and imatinib (81 ± 4.3 μ L) (p ═ 0.05 vehicle with PK10453, p ═ 0.014 vehicle versus imatinib, p ═ NS PK10453 versus imatinib). The following parameters were not significantly different between groups: end-diastolic volume, ejection fraction, cardiac output, stroke work. The luminal to media ratio was improved in the MCT model by PK10453 and imatinib, compared to vehicle (V, n ═ 4): 0.55 ± 0.1; PK10453(D8, n ═ 12): 0.94 ± 0.08 imatinib (I8, n ═ 5): 0.99 ± 0.07; p <0.01D8 and V, p <0.05I8 and V, fig. 5D).

EXAMPLE 3 pharmacodynamic study of rat MCT + PN model

And (4) carrying out telemetry research. Results of telemetry studies in the rat MCT + PN model are illustrated. The systolic blood pressure for PA in the vehicle group was 41.0 ± 11.7 mm hg, while in the PK10453 (structure 2) group, it was 43.1 ± 3.5 mm hg (p ═ NS), 0 days before the start of treatment. Five days after treatment, the systolic blood pressure of PA was 69.4 ± 12.9 mmhg in the vehicle group and significantly lower at 47.3 ± 3.0 mmhg in the PK10453 group (p < 0.01). On day 8 of treatment, the systolic blood pressure of PA in the vehicle group was 83.5 ± 8.5, but significantly lower in the PK10453 group at 47.3 ± 4.9 mmhg (p < 0.001).

In a PK10453 (structure 2) telemetry study alone, PA systolic blood pressure in the vehicle group was 47.4 ± 10.2 mm hg the day before treatment was initiated, while in the PK10453 group was 43.1 ± 3.5 mm hg (p ═ NS). Five days after treatment, the systolic blood pressure of PA was 67.4 ± 11.4 mmhg in the vehicle group and significantly lower at 47.2 ± 3.0 mmhg in the PK10453 group (p ═ 0.03). On treatment day 9, the systolic blood pressure of PA in the vehicle group was 92.8 ± 9.1 mmhg, but was significantly lower in the PK10453 group at 50.5 ± 7 mmhg (p ═ 0.03). For the imatinib telemetry study (study 4), the systolic blood pressure of the PA in the vehicle group was 51.4 ± 8.9 mmhg and 41.5 ± 3.5 mmhg in the imatinib group on day 1. On treatment day 9, the systolic blood pressure of PA in the vehicle group was 80.4 ± 14.2 mm hg, and 75.1 ± 7 mm hg in the imatinib group (p-value ═ NS). See fig. 6.

RV pressure and PV ring measurements in MCT + PN model; PK10453 (structure 2) dose response study. In a separate group of animals, the MCT + PN model was developed as described. RV pressure was obtained 14 days after vehicle exposure, and PK10453 treatment with 4 min (D4) and 8 min exposure (D8), three times a day. In the vehicle group (n ═ 9), the right ventricular systolic pressure was 40.4 ± 2.7 mmhg for the right ventricular contractions of 75.7 ± 7.1 mmhg, in the D4 group (each group 10), and 43 ± 3.0 mmhg for the RV systolic pressure in the D8MCT + PN group (p <0.001D4 vs V, V vs D8; fig. 7A). PV rings were obtained on subsets of animals from each group (vehicle n-3; D4 n-5, D8 n-4).

Example 4-MCT + PNMCT + PN model efficacy

Study of the PV Ring. The right ventricular End Systolic Pressure (ESP) was lower and the right ventricular Ejection Fraction (EF) was higher in the treatment groups of D4 and D8, compared to vehicle control. Cardiac output was increased in group D8 compared to vehicle. See table 3. MCT60 mg/kg IP 7 days later, study animals were left total lung resections. MCT administration after two weeks, PK10453 (structure 2) or vehicle was given by inhalation three times a day for two weeks. At the end of this period cycles of photovoltaic power generation are purchased. With respect to table 3: v is vehicle; PK10453 was inhaled for 4 min D4; PK10453 was inhaled for 8 min D8; each group of n-4; p < 0.001; p is less than or equal to 0.01; p <0.05, and V.

TABLE 3

Effect of RV thickening of PK10453 (structure 2). Treatment with PK10453 resulted in a significant reduction in RV hypertrophy in the rat MCT + PNMCT + PN model. See fig. 7B. In a vehicle group with an (RV + IVS)/LV ratio (n 11) of 0.88 ± 0.05, then PK10453D 4(n 13) of 0.62 ± 0.04 and PK10453D 8(n 7) of 0.68 ± 0.05(p <0.001D4 and V, p 0.012D8 and V).

Pulmonary arteriole histology and morphology were analyzed. The membrane area ratio in luminal area (L/M) was significantly higher than in the PK10453 (structure 2) treated D8 group, D4 or vehicle group: d8(n ═ 5) L/M0.72 ± 0.05, D4(n ═ 6) L/M0.33 ± 0.06, and vehicle control V (n ═ 6): 0.26. + -. 0.04 (p)<0.0001D8 with V or D8 with D4). See fig. 7C. Occlusion analysis was performed on samples from the same animal used for lumen/media ratio measurements. Occlusion analysis showed a significant reduction in grade 2 occlusion lesion PK10453D8 treatment group (V (n ═ 6)₄1.5±7.1％，D4(n＝6)₂8.5±4.2％；D8 11.4±4.1％；p<0.01D8 and V; see fig. 7D fig. 8A for an occlusion H&E staining (secondary), lesions in vehicle treated animals (MCT + PN model), comparison of animals treated from a PK 10453-grade 0 container (D8), see fig. 8 b. an example of a secondary lesion stained phosphopdgfr β is shown in fig. 8C versus a grade 0 lesion treated animals (MCT + PN model) from PK10453(D8) at fig. 8D.

Pulmonary arteriolar hypertrophy and intraluminal cell proliferative disorder Futher as exemplified, but in quantitative analysis, in the figure. 9. The membrane area ratio (L/M) in luminal area was significantly higher than vehicle in the PK10453 treatment group, with higher dose, D8(n ═ 4) L/M1.17 ± 0.07, lower dose, D4 large size/M0.75 ± 0.14, and vehicle control V (n ═ 6): 0.36 + -0.09 (p-values 0.032D4 and V, p-values 0.00014D8 and V, p-values 0.028D8 and D4). Endothelial cell marker, vWF, appears primarily as a signal in the pulmonary arterioles. The tyrosine705 phosphostat 3 antibody is localized to pSTAT3, in the nucleus of endothelial and perivascular cells. See fig. 10A; and fig. 10B (treatment with PK 10453).

Trichromatic and immunohistochemical α -SMC actin and von Willebrand factor endothelial cell markers, vWF, are primarily represented as signals in the pulmonary arterioles, and immunohistochemistry further characterized vascular smooth muscle cells (α SMC actin), endothelial cell markers (vWF), and trichromatic staining + PN in rat MCT pulmonary arterioles, grade 0 and 2 lesions 0 degree lesions are characterized by early intima (intraluminal), Endothelial Cells (ECS) with proliferation preserved in the vector vascular smooth muscle cells, grade 1-2 lesions, partial loss of myofibroblast-like cells (MFS) and endothelial cells with vascular smooth muscle cells in the medial layer by proliferation/mixing of neointima (intraluminal), complete loss of VSM cells in the medial layer by extensive MF/EC intraluminal proliferation with advanced grade 2 lesions, and fibrotic replacement of media see FIG. 11A-I.

Example 5 immunization group PDGF signals

Signals PDGFAA ligand and PDGFR- α are present, but pdgfrb and PDGFR- α, which are not signals qualitatively, are low the phosphorylated PDGFR- β (pdpdgfr- β) intimal and perivascular cells, which have the appearance of a pebble, are stronger than the signal phosphorylated PDGFR- α (PDGFR- α) pre-capillary arterioles the minimal signals detected in the media layer of the pre-capillary arterioles are either pdpdgfr- β or α, see fig. 12A-f, in larger (>50 μ M) vessels, the signal pdpdgfr- α is present in medial VSM cells, in contrast pdpdgfr β medial layer signals are low, see fig. 13A-D.

Example 6-Immunization and immunoblotting

pAKT/AKT of the immune pair is shown in fig. 14 and/STAT 3 of pSTAT3 is shown in fig. 15 there was a significant reduction in the/STAT 3 ratio of pSTAT3 in both D4 and D8 groups compared to vehicle. FIG. 16 shows the effect of ppeRK1/ERK1, phosphorylated ERK1/ERK1, ppeRK2/ERK2 and pERK2/ERK2 on inhalation of PK10453 (structure 2) in lung tissue. Groups D4 and D8 were significantly reduced compared to the vehicle at ppERK1/ERK1 and phosphorylated ERK1/ERK1, respectively.

Example 7-PDGFAA stimulates PDGFR- α, whereas PDGFBB binds to activated PDGFR- β.

Figure 17 shows the efficacy of imatinib, the upper PDGFAA and PDGFBB of PK10453 (structure 2), and PK10571 (structure 2a), at human fetal lung fibroblast stimulated phosphorylation of ERK1 and ERK 2. An increase in total ERK1(ppERK1/ERK1) over diphosphorylated ERK1 stimulated PDGFAA or PDGFBB and significantly reduced 10 μ My concentrations at 1 μm and imatinib, PK10453 and PK 10571. An increase in the ratio of diphosphorylated ERK2 to total ERK2(ppERK2/ERK2) whereas the concentration of 10 μ M in 1 μ M and imatinib, PK10453, and PK10571 in PDGFAA or PDGFBB stimulation (10ng/mL) was significantly reduced. The ratio of diphosphorylated ERK1 to total ERK1(ppERK1/ERK1) and the total ERK2(ppERK2/ERK2) solution of diphosphorylated ERK2 were more effective in reducing PK10453 at 1 μ M and PK10571 compared to imatinib after PDGF BB stimulation. Thus, PK10453 and PK10571 are more potent inhibitors of PDGF BB stimulating erlk 1 compared to ERK2 phosphorylation, imatinib.

In particular, and with reference to fig. 17A-D, stimulation of human fetal lung fibroblasts of PDGFAA and PDGFBB (10ng/mL) as described above increased ppERK1/ERK1 and ppERK2/ERK as compared to serum-free medium only control (SF), imatinib, PK10453 (structure 2), and PK10571 (structure 2a) also equally effective, with decreasing AA of PDGF at 1 μ M stimulating ppERK1 and ppERK2 formation (fig. 17A and C), however, PK10453 and PK10571 were more effective at 1 μ M and 10 μ M at decreasing pdgfb stimulating ppERK1 and ppERK2 (fig. 17B and D) these data indicate that PK10453 and PK10571 can block signal transduction via the PDGF receptor- β more effectively, compared to imatinib receptor-4653 which shows that the difference in mean ± PKs 10453 and 10571 had an effect on PDGF receptor phosphorylation at pgfr-35468 and PDGF receptor phosphorylation at pgfr-354653 and PDGF 4642 which had no effect on PDGF receptor phosphorylation at PDGF-receptor-19.

Example 8-PK10453 (Structure 2), PK10467 (Structure 3), PK10468 (Structure 4), PK10569 (Structure 5) and PK10571 (Structure 2a) with lower IC₅₀Concentrations relative to imatinib were used to inhibit fibroblast-stimulated PDGFBB Akt phosphate.

The data highlight the more potent imatinib-mediated inhibitors of signal transduction of PK10453, PK10467, PK10468, PK10569 and PK10571 as compared to the growth factor β receptor, see figures 18A-D. these data show the importance of achieving effective inhibition of PDGF β receptor signaling in the α receptor signaling in addition to PDGF as a treatment for pulmonary hypertension, pulmonary fibrosis, and related conditions as compared to PK10453, PK10467, PK10468, PK10569, and PK 10571.

Example 9 weight, systemic blood pressure and plethysmography Studies

There was a trend towards slower body weight loss in the treated versus vehicle group. See figure 19. MCT PK10453 (n 3) at 131 ± 10 mmhg in the MCT vehicle group at systolic blood pressure of 111 ± 21 mmhg (7 days of treatment) compared to PK10453 (n 3) in the rat MCT + PNMCT + PN model for 1 day, PK 10453/vehicle tube for 15 days as measured by two-chamber volume profiling in figure 20. The results are shown in table 4 for the mixture of treatment PK10453 with a slower decrease in ventilation per Minute (MV) and a significant improvement in Peak Inspiratory Flow (PIF) and Peak Expiratory Flow (PEF) in the 4 minute exposure group (D4 correlation), vehicle.

TABLE 4

Example 10 discussion and application of embodiments

This PDGF signaling pathway has been found in human Pulmonary Arterial Hypertension (PAH) and is activated in animal models of disease. The hypothesis tested in this study was that a novel, non-selective inhaled PDGF receptor inhibitor, PK10453 (structure 2), reduced pulmonary arterial hypertension both in the rat Monocrotaline (MCT) model and in the rat MCT plus lung (+ PN) model of PAH. PK10453 was delivered by inhalation two weeks with four (D4) and 8(D8) minutes of exposure three times a day, both reducing Right Ventricular Systolic Pressure (RVSP) in rat MCT and rat MCT + PN models: MCT group (n ═ 6) RVSP for vehicle 80.4 ± 2.6 mmhg; MCT group of D4(n ═ 6), 44.4 ± 5.8 mmhg; and D8MCT group (n ═ 5), 37.1 ± 4.5 mm hg (p <0.001 with vehicle); right ventricular systolic pressure at 75.7 ± 7.1 mmhg in vehicle MCT + PN group (n ═ 9); at the D4MCT + PN group (n ═ 10), 40.4 ± 2.7 mm hg, and at the D8MCT + PN group (n ═ 8), 43.0 ± 3.0 mm hg (p < 0.001). Continuous telemetry monitoring of pulmonary artery pressure in the MCT + PN model in rats also indicated that PK10453 prevented the progression of PAH. Imatinib was administered by inhalation with an equally effective MCT model, but no effective MCT + PN model.

Immunohistochemistry showed increased activity of the PDGF β receptor compared to that found in MCT + PN models of intimal and perivascular lesions of the PDGF α receptor, it was shown that imatinib is a selective PDGF α receptor and PK10453 hasWith a lower IC₅₀To inhibit kinase activity of both PDGF α and PDGF β receptors compared to imatinib the proportion of PK10453 phosphorylated AKT (Ser473 of) is reduced to total AKT, phosphorylated STAT3(Y705) to total STAT3, the ratio of diphosphorylated ERK1 to total ERK1 and the ratio of total ERK1 monophosphorylated ERK1 in MCT + PN animals of lung extracts.

Thus, for the first time, it has been shown that a novel, non-selective PDGF receptor inhibitor, PK10453 (Structure 2), when administered by inhalation, reduces the severity of PAH in two animal models of disease, rat MCT, and the rat MCT + PN model, thus, because PK10453 is highly effective against both PDGFR α and PDGFR β receptors and imatinib is a selective PDGFR α receptor, PK10453 has surprisingly superior efficacy, both PK10453 and imatinib are effective models of rat MCT, but only PK10453 reduces pulmonary hypertension by inhalation in the rat MCT + PN model, one of the causal differential effects is likely due to over-activation of the capillary pulmonary artery intimal lesions that pass through the PDGFR β receptor, as compared to the PDGFR α receptor signal in the murine MCT + PN model.

Thus, this data demonstrates that a novel, non-selective, PDGF receptor inhibitor, PK10453 (structure 2), prevents the progression of PAH by inhalation delivery, both rat MCT and rat MCT + PN models. Notably, this is the first study reported PDGF receptor inhibitory effect in the rat MCT + PN model. Continued reduction of PA pressure also found animals treated with PAH and PK10453 (MCT + PN) at the outpatient clinic. Improved vehicle ratios of luminal pulmonary arterioles were demonstrated in these models with a significant reduction in PA and RV systolic pressure. The pressure volume loop showed improved ejection fraction in the right ventricle, higher cardiac output, and a trend towards animals working on the down stroke treated at PK10453 compared to control animals. In the PK10453 lung extract treated animals, there was a significantly reduced ratio of pAKT protein (Ser 473)/AKT, pSTAT 3/STAT 3, ppERK1/ERK1 and phosphorylated ERK1/ERK 1.

Since PAH is a disease, essentially localized in the lung, it is hypothesized that direct administration of the drug through an inhaled target site would provide the advantage of higher local concentrations (greater efficacy) and lower systemic concentrations of the drug (lower side effects) when tested. Pharmacokinetic studies demonstrated a 45-fold advantage of inhalation delivery over intravenous administration of PK10453 (structure 2). PK10453 reduced right ventricular systolic pressure by 50% in rat model MCT, which had no adverse effect on systemic blood pressure. Furthermore, inhalation of PK10453 did not adversely affect lung function over the course of 2 weeks.

MCT in rat model the present inventors inhaled imatinib compared to PK10453 and found that both were equally effective. These results are consistent with previous reports that the PDGF receptor inhibitor imatinib, when delivered systemically, reduces pulmonary arterial hypertension in a rat model MCT. See Schermuly et al, "Experimental pulmonary hypertension PDGF inhibition reversal. "journal of clinical research. 115: 2811-21(2005). However, in the murine MCT + PN model, concurrent inhalation of PK10453 was effective in lowering pulmonary arterial pressure, and inhalation of imatinib did not. The rat MCT + PN model is a more aggressive model of PAH than the MCT-only model and can more accurately reflect the pathology of human disease. White et al, "plexiform lesions and increased tissue factor expression in a rat model of severe pulmonary hypertension. "journal of physiology in morning lung cancer cell and molecular physiology. 293: l583-90 (2007). In IC₅₀Results of in vitro assays inhibiting PDGF- α and- β receptors indicated that PK10453 is more effective than imatinib for both isoforms and that imatinib is only a modest inhibitor of the PDGFR β isoform immunohistochemistry showed that the inner membrane injured rat MCT + PN model had high levels of phosphopdgfr β with low doses of pdpdgfr α these findings explain why both non-selective inhibition of PDGFR β and PDGFR α provided a selective inhibition of PDGFR α, which is a therapeutic advantage.

This data is consistent with panzhinsky et al, cardiovascular resources, "proliferation response specific to adventitial fibroblasts hypoxia-induced activation of pdgf beta receptor JNK1 signaling," 95: 356-65(2012), neonatal calf model of high altitude pulmonary hypertension in this model the extensive proliferation perivascular surrounding of adventitial fibroblasts was demonstrated with activated PDGFR β these lesions are similar to the models observed in the rat MCT + PN model used in this study, these findings are also consistent with literature reports of human PAH, perous et al, "expression and function of platelets derived growth factors for idiopathic PAH," bovine J and respiratory care medicine 178: 81-8(2008), distributions of pulmonary arterial lesions PDGFA, PDGFB, PDGFR α β and PDGFR β in PAH patients PDGFR α expression was found primarily in the tunica media mesenteric hypertrophic arteriole, while pdpffr β and pdpffr β predominate endothelial cells.

Inhibition of imatinib-stimulated PDGFR α phosphorylation by PDGFAA was reported to be 0.1. mu.M, whereas inhibition of PDGFBB-stimulated PDGFR β phosphate 0.38. mu.M, see, e.g., Deininger et al, "development of imatinib as a therapeutic agent for chronic myelogenous leukemia" blood.105: 2640-53 (2005). however, here, ATP was identified, in []Km (apparent), greater than 10-fold selectivity for imatinib to the PDGFR α vs-beta receptor (IC)₅₀PDGFR α 71nM versus 607nM versus PDGFR β most PAH-related cell-based studies interrogate the PDGFR pathway with high doses of imatinib (5-10 μm) and thus exclude differentiating between PDGFR α and β receptor inhibition.

Wu et al, "PDGFR genetic background clear cellular integrated clearing in PDGF-PDGFR signaling pathway of PDGF." public scientific library one.3: e3794(2008), examine PDGFR genetically defined Mouse Embryonic Fibroblast (MEFs) signals.

PDGFBB has found Ser473, which induces phosphorylation of AKT, to be in pulmonary artery smooth muscle cells and fibroblasts, but not pulmonary artery endothelial cells. See, Xiaochuan et al, "upregulation of STIM1/Orai1 by PDGF in human pulmonary artery smooth muscle cells by activating the AKT/mTOR signal increases Ca2+ influx for storage procedures. "am journal of physiology cell physiology. 302: c405-11 (2012). Increased phosphorylation of AKT (Ser 473) was also found in cells and patients with the smooth muscle phenotype of endarteteroectomies in chronic thromboembolic pulmonary hypertension. See Ogawa et al, Am J physiological lung cancer cells and molecular physiology "inhibition of mTOR attenuating pool-manipulated Ca2+ entries from cells of patients' chronic thromboembolic pulmonary hypertension endarterized tissues. "; 297: l666-76 (2009). PDGFBB stimulation increases storage operations calcium entry in these cells via the AKT/mTOR pathway. See above.

In pulmonary artery smooth muscle cells from control and monocrotaline treated rats, however, imatinib (0.1 μ M) reduced fetal bovine serum stimulated Ser473AKT phosphorylation, but had no effect on AKT phosphorylation at Thr 30825. at this concentration, imatinib is likely to act via the PDGF α receptor. Wu et al (2008) found that STI-571 (imatinib) stimulated AKT phosphorylation at 5 μ M blocked PDGFBB (Ser 473) both PDGFR β null and PDGFR α null cell lines.

nM fluidic proteomics immunoassay, in addition, was employed to quantify lung extracts of MCT + PN animals in phosphorylated species of AKT, STAT3 and ERK 1/2. A significant reduction in phosphorylated-AKT (Ser 473), phospho-STAT 3 and ppeRK1/ERK and phosphorylated ERK1/ERK1 in the PK10453 treatment group was found to be the vehicle. Schermuly et al. (2008) A rat model MCT of pERK1/2 pulmonary arterial hypertension was demonstrated to reduce imatinib. Jasmine et al, "short-term administration of subcellular-permeable caveolin 1 peptide prevents monocrotaline-induced pulmonary hypertension, development of right ventricular hypertrophy. Circulating; 114: 912-20(2006), which has been shown to be activated by the MCT model STAT3 in rats, and Masley et al. Hyperproliferative apoptosis resistant endothelial cells in idiopathic PAH "journal of physiology in morning physiology lung cancer cell and molecular physiology; 293: l548-54(2007), human primary PAH of STAT3 was found to be activated. nM fluid proteomic immunizations of the invention were previously used to examine the effect of imatinib on pSTAT3, and pERK1/2 in Chronic Myelogenous Leukemia (CML). See, e.g., et al, "nanofluidic protein assay for the activation sequence analysis of oncoproteins in clinical specimens. "natural medicine". 15: 566-71(2009). This method has the utility of distinguishing between monophosphoric and diphosphorylated isoforms of proteins. For example, CML patients responded with a significant decrease in imatinib, ERK214 monophosphate level. Herein, the ERK1 subtype and both the diphosphorylated form of ERK1 and the monophosphorylated form of ERK1 are mainly concentrated in MCT pneumocectized rat lung tissue. Treatment of PK10453 significantly reduced ppeRK1/ERK and phosphorylated ERK1/ERK 1.

Occlusion analysis was performed according to methods of this work et al, "protection of RhoA/Rho kinase signaling prevents monocrotaline-induced pulmonary hypertension involving pneumococcal communized rats from dehydrogenating. "journal of physiology in morning lung cancer cell and molecular physiology. 295: l71-8 (2008). In the rat MCT + PN model, high dose inhaled PK10453 was used with fewer secondary occlusive lesions. These lesions were then characterized by vascular smooth muscle cells and endothelial cells as immunohistochemical markers, and trichrome staining was performed to differentiate fibrotic diseased muscles. Neointimal proliferative grade 1-2 lesions were determined to contain myofibroblasts and endothelial cells. There is fibrosis to replace container media in advanced grade 2 lesions. The origin of myofibroblasts in these lesions is not completely understood. They may result from infiltration of peripheral vascular fibroblasts or pericytes, from circulating stem cells, resident progenitor cells, or as a result of endothelial-mesenchymal transition. See, Jeger et al, "progenitor cells are reconstituted in pulmonary vessels. "Pulm Protection. 1: 3-16(2011). While these lesions are detected, it is a reasonable suggestion that the type 1 lesion is an earlier stage lesion that can progress to types 2 and 3. In this model, intraluminal endothelial cells proliferate, transition to myofibroblast phenotype (and/or intraluminal infiltration by perivascular/myofibroblast cells) and gradually occlude the vessel lumen.

Data presented herein suggest that pulmonary hypertension plays a significant role in pulmonary vascular remodeling through PDGFR α pathway signaling, whereas PDGFR β pathway is more important in pre-capillary pulmonary artery proliferative intimal lesions, targeting the PDGFR β pathway with PDGFR inhibitors strongly prevents this subtype (more potent than imatinib) from potentially affecting the progression of these lesions.

In summary, inhaled, non-selective PDGF receptor inhibitors, PK10453 (structure 2), are effective in both MCT, and the MCT + PN rat model of PAH treatment of PK10453 with one significantly reduced pulmonary artery pressure, dynamic animals, improved right ventricular function, and reduced right ventricular hypertrophy is associated with histological analysis showing no significant effect of PK10453 on systemic blood pressure (structure 2) and no adverse effect of PK10453 on lung function in pulmonary artery luminal media ratio versus animals treated with PK10453 and reduction in phosphorylation state of AKT (Ser 473), STAT3 and ERK1 compared to imatinib, PK10453 is not a selective PDGFR α receptor, but is highly effective against both PDGFR α and β subtypes because PDGFR β pathways are more highly activated than PAH, non-selective PDGFR inhibitors, e.g., the plexiform fr α receptor of PK10453, thus have efficacy on PAH and related diseases and disease pathways.

Claims (10)

1. A method of non-selective kinase receptor inhibition for treating a pulmonary disorder in a subject, comprising: administering to a subject a therapeutically effective amount of a compound of structure 1, a tautomer, enantiomer, isomer or stereoisomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer, enantiomer, isomer or stereoisomer of the compound, or any mixture thereof, wherein structure 1 has the following formula:

and wherein X is independently selected from C, N, O, S or-CN;

R¹，R²and R³May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃-a-C-N-C-group, -a-C-N-C (═ O) -group, -C (═ O) R⁸A radical, -N-C (═ O) R⁸A radical, -C-N-C (═ O) R⁸Radical, substituted and unsubstituted R⁸Group, by R⁹、R¹⁰And R¹¹One or more substituted and unsubstituted R⁸A group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidinyl group, a substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

R⁴，R⁵，R⁶and R⁷May be the same or different and are independently selected from H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂-a C ≡ N, -a C ═ N group, -a C-N-C-group, -a C-N-C (═ O) -C-F, -a C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aromatic hydrocarbon groups, and aromatic hydrocarbon groupsAn aryloxy group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted alkylamino group, a substituted and unsubstituted arylamino group, a substituted and unsubstituted dialkylamino group, a substituted and unsubstituted diarylamino group, a substituted and unsubstituted (alkyl) (aryl) amino group, -C (═ O) H, -C (═ O) -alkyl group, -C (═ O) -aryl group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclyl aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; - (alkyl) (aryl) aminoalkyl groups, -C (═ O) -heterocyclyl groups, -C (═ O) -O-heterocyclyl groupsO) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted hydroxyalkyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted aryloxyalkyl group, and substituted and unsubstituted heterocyclyloxyalkyl group, -NH (alkyl) group, -NH (aryl) group, -N (alkyl)₂Group, -N (aryl)₂A group, -an N (alkyl) (aryl) group, -an NH (heterocyclyl) group, -an N (heterocyclyl) (alkyl) group, -an N (heterocyclyl) (aryl) group, -an N (heterocyclyl)₂A group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkoxy group, a substituted and unsubstituted aryloxy group, a substituted and unsubstituted heterocyclyl group, -NHOH, -N (alkyl) OH group, -N (aryl) OH group, -N- (alkyl) O-alkyl group, -N (aryl) O-alkyl group, -N (alkyl) O-aryl group, and-N (aryl) O-aryl group;

R⁸is selected from R¹，R²，R³，R⁴，R⁵，R⁶，R⁷H, absent, -C ═ C, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups (R)⁹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)¹⁰)(R¹¹) Group, substituted and unsubstituted heterocyclic radical (R)⁹)(R¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰) The radical(s) is (are),substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)¹⁰)(R¹¹) A radical, substituted and unsubstituted-C (═ O) -heterocyclyl (R)⁹)(R¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹) Radical, substituted and unsubstituted aryl (R)¹⁰) Radical, substituted and unsubstituted aryl (R)¹¹) Radical, substituted and unsubstituted aryl (R)⁹)(R¹⁰) Radical, substituted and unsubstituted aryl (R)⁹)(R¹¹) Radical, substituted and unsubstituted aryl (R)¹⁰)(R¹¹) Radical, substituted and unsubstituted aryl (R)⁹)(R¹⁰)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰) The radical, substituted and unsubstituted-C (═ O) -aryl (R)⁹)(R¹¹) The radical, substituted and unsubstituted-C (═ O) -aryl (R)¹⁰)(R¹¹) A group, and substituted/unsubstituted-C (═ O) -aryl (R)⁹)(R¹⁰)(R¹¹) A group;

R⁹，R¹⁰and R¹¹May be the same or different and is independently selected from the group consisting of absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²A group, -C ≡ N, -C-N-C, -C-N (═ O) -group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstitutedSubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (═ O) H, -C (═ O) -alkyl groups, -C (═ O) -aryl groups, -C (═ O) O-alkyl groups, -C (═ O) O-aryl group, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -aryl radical, -C (═ O) NH₂-a-C (═ O) NH (alkyl) group, -a-C (═ O) NH (aryl) group, -C (═ O) N (alkyl)₂A radical, -C (═ O) -N (aryl)₂A group, -C (═ O) N (alkyl) (aryl) group, -C (═ O) O-alkyl group, -C (═ O) O-aryl group, -C (═ O) -heterocyclyl group, -C (═ O) -O-heterocyclyl group, -C (═ O) NH (heterocyclyl) group, -C (═ O) -N (heterocyclyl)₂A group, -C (═ O) -N (alkyl) (heterocyclyl) group, -C (═ O) -N (aryl) (heterocyclyl) group, substituted and unsubstituted heterocyclylaminoalkyl group, substituted and unsubstituted cyano group, substituted and unsubstituted pyrimidinyl group, substituted and unsubstituted cyano (aryl) group, substituted and unsubstituted cyano (heterocyclyl) group, and substituted and unsubstituted cyano-pyrimidinyl group;

R¹²selected from absent, H, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²A group, -C ≡ N, -C-N-C-, -C-N-C (═ O) -group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, -C (═ O) -C-group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃An alkoxy group, an aryloxy group, a substituted and unsubstituted amidino group, a substituted and unsubstituted guanidino group, a substituted and unsubstituted primary, secondary, and tertiary alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted alkynyl group, a substituted and unsubstituted heterocyclyl group, a substituted and unsubstituted aminoalkyl group, a substituted and unsubstituted alkylaminoalkyl group, a substituted and unsubstituted dialkylaminoalkyl group, a substituted and unsubstituted arylaminoalkyl group, a substituted and unsubstituted diarylaminoalkyl group, a substituted and unsubstituted (alkyl) (aryl) aminoalkyl group, a substituted and unsubstituted heterocyclylalkyl group, a substituted and unsubstituted cyano group, a substituted and unsubstituted pyrimidyl group, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

Q¹selected from direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-, -C ≡ N, -C-N-C group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N group, -C (═ O) -C-group, -C (═ O) -C ═ C, -CF ═ C, -C ═ C₃-a C ≡ N, -a C-N-C-group, -a C-N-C (═ O) -C-F, -a C-N-C (═ O) -C ═ C, -OH, an alkoxy group, an aryloxy group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, a substituted and unsubstituted heterocyclyl group, an alkoxy group, an aryloxy group, a methoxy group, a dimethoxy group, methoxyphenol, a methoxyphenol group, dimethoxyphenol, a dimethoxyphenol group, a dimethoxybenzene, a dimethoxyphenyl group, a methoxymethylbenzyl group, a substituted and unsubstituted aralkyl group, -NH-N-C-group, -a C-N-C (═ O) -group, -a substituted and unsubstituted aryl group, a substituted and unsubstituted heterocyclyl group, an alkoxy group, an aryloxy group, a methoxy₂Substituted and unsubstituted heterocyclylalkyl groups, substituted/unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstitutedSubstituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups;

Q²selected from absent, H, Q¹，Q¹(Q³) -OH, alkoxy groups, aryloxy groups; and

Q³selected from absent, direct bond, H, C, Cl, Br, F, I, -CN, -NO₂，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-a group, -C ≡ N, -C-N-C, -a group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -C ═ N-a group, -C (═ O) -C ═ C, -CF ═ C₃a-C ≡ N, -C-N-C-group, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, -OH, an alkoxy group, an aryloxy group, a methoxy group, a dimethoxy group, a methoxyphenol group, a dimethoxyphenol group, a dimethoxybenzene, a dimethoxyphenyl group, a substituted and unsubstituted alkyl group, a substituted and unsubstituted aryl group, and a substituted and unsubstituted heterocyclyl group.

2. The method according to claim 1, wherein R⁸Has the following formula:

and wherein X is independently selected from C, N, O, S and-CN;

R⁹，R¹⁰and R¹¹May be the same or different and are independently selected from the group consisting of H, C, N, O, S, Cl, Br, F, I, -CN, -NO₂，-OH，-CH₃，-CF₃，-NH₂，-C(＝O)-，-C-N-R¹²-C ≡ N, -C-N-C (═ O) -C-F, -C-N-C (═ O) -C ═ C, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH, alkoxy groups, aryloxy groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, and substituted and unsubstituted dialkylamino groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups; and

R¹²selected from the group consisting of-C (═ O) -group, -C (═ O) -C ═ C-, -S (═ O)₂-a radical, -S (═ O)₂-a C-group, -S (═ O)₂-C ═ C-group, -S (═ O)₂-C＝C-CH₃-OH, alkoxy groups, aryloxy groups, substituted and unsubstituted amidino groups, substituted and unsubstituted guanidino groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted guanidino groups, and substituted or unsubstituted aryl groups, substituted and substituted aryl groups, substituted and unsubstituted heteroarylaminoalkyl groups, substituted and substituted orAnd unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted cyano groups, substituted and unsubstituted pyrimidinyl groups, substituted and unsubstituted cyano (aryl) groups, substituted and unsubstituted cyano (heterocyclyl) groups, and substituted and unsubstituted cyano-pyrimidinyl groups.

3. The method of claim 2, wherein R⁸Is selected from the group a.

4. The method of claim 1, wherein Q¹Or Q²Is selected from the group B structures, -CH₃，-OH，-O-CH₃-C-N-C (═ O) -C ═ C and-C-N-C (═ O) -CF.

5. The method of claim 1, wherein the compound of structure 1 is a compound of structure 2, structure 2a, structure 3, structure 4, or structure 5, as shown in group C structures.

6. The method of any one of claims 1-5, wherein the compound of structure 1,2, 2a, 3,4 or 5 is administered orally, intravenously, subcutaneously, transdermally, intraperitoneally, or by inhalation.

7. The method of any one of claims 1-6, wherein said kinase receptor is a Receptor Tyrosine Kinase (RTK), and wherein said RTK is a Platelet Derived Growth Factor Receptor (PDGFR).

8. The method of claim 7, wherein the PDGFR is platelet-derived growth factor receptor- α (PDGFR- α) or platelet-derived growth factor receptor- β (PDGFR- β) or both.

9. The method of claim 7, wherein the PDGFR is a homodimer or heterodimer selected from PDGFR- αα - ββ and PDGFR- αβ, or any combination thereof.

10. The method of any one of claims 7-9, wherein inhibition of PDGFR is effective to treat a pulmonary disease, wherein the pulmonary disease is Pulmonary Arterial Hypertension (PAH), PAH associated with plexiform and/or neointimal lesions, PAH associated with pulmonary fibrosis and/or progressive vascular degeneration, abnormal fibroblast and/or myofibroblast proliferation, or a pulmonary vascular disease associated with abnormal endothelial cell proliferation, or any combination thereof.